CN101257897A - Methods and related compositions for treating or preventing obesity, insulin resistance disorders, and mitochondrial-associated disorders - Google Patents
Methods and related compositions for treating or preventing obesity, insulin resistance disorders, and mitochondrial-associated disorders Download PDFInfo
- Publication number
- CN101257897A CN101257897A CNA2006800330147A CN200680033014A CN101257897A CN 101257897 A CN101257897 A CN 101257897A CN A2006800330147 A CNA2006800330147 A CN A2006800330147A CN 200680033014 A CN200680033014 A CN 200680033014A CN 101257897 A CN101257897 A CN 101257897A
- Authority
- CN
- China
- Prior art keywords
- activating compounds
- sirtuin activating
- sirtuin
- general formula
- chemical compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Provided herein are methods and compositions for treating or preventing metabolic disorders, such as obesity and diabetes. Methods may comprise modulating the activity or level of a sirtuin, such as SIRTl or Sir2. Exemplary methods comprise contacting a cell with a sirtuin activating compound, such as a flavone, stilbene, flavanone, isoflavone, catechin, chalcone, tannin or anthocyanidin, or an inhibitory compound, such as nicotinamide.
Description
Background technology
Obesity is that a kind of to surpass 25 with Body Mass Index (BMI) be the chronic disease of feature.Congenital and environmental factors is for example taken exercise and dietary habit all can cause this disease.For example, it is relevant that hormone leptin (leptin) has demonstrated its adjusting with fat generation and dietary behavior.Several fat animal models are all obtained by leptin and/or leptin receptor gene sudden change.Except that the individual life style of influence, obesity can cause multiple complications and disease, comprises insulin resistant, type ii diabetes, gallbladder disease, hypertension, cardiovascular disease, hyperlipidemia, sleep apnea, coronary artery disease, knee joint osseous arthritis, gout, infertility, breast carcinoma, carcinoma of endometrium, colon cancer and back pain.
Diabetes are a kind of acute symptoms that caused by significant hyperglycemia or ketoacidosis that show as, or chronic, the disease of Developmental and Metabolic Disorder routinely that are caused by the reduction of hyperglycemia situation that continues or glucose tolerance.Congenital and environmental factors is for example taken exercise and dietary habit all can cause this disease.The cause of disease of diabetes is activity and the sensitivity reduction that insulin produces obstacle, dyssecretosis or excretory insulin.Diabetes mainly are divided into following two classes: insulin-dependent diabetes (being also referred to as type i diabetes) and noninsulindependent diabetes (being also referred to as type ii diabetes).The incidence rate of obese patient's type ii diabetes significantly increases.
Fat treatment pays attention to suppressing experimenter's appetite usually.Although there are many appetite suppressants can use (amfepramone (diethylpropion tenuate), Mazindol, Ao Lisita, phendimetrazine, phentermine, sibutramine), these chemical compounds are can not be to all experimenters all effective or may effect limited.Therefore, need new Therapeutic Method for obesity.
Many Therapeutic Method of diabetes are known, comprise the oral hypoglycemic thing, as the sulfonylurea that increases insulin secretion (for example, tolbutamide, chlorpropamide and glibenclamide), the biguanides that increases glucose absorption and utilization (for example, metformin and buformin) and alpha-glucosidase inhibitor (for example, acarbose and voglibose).In addition, thiazolidinediones is used to improve insulin resistant as troglitazone, rosiglitazone and pioglitazone.Yet the absorption of thiazolidinediones is relevant with weight increase usually.Therefore, still need more effective Therapeutic Method for diabetes.
At present, there is 8% and 15% adult to suffer from diabetes or obesity respectively in the U.S..Along with the individual amount that suffers diabetes, especially type ii diabetes and fat influence increases, need the medicine that is used to prevent and treat these diseases badly.
The invention summary
On the one hand, the sirtuin activator that the invention provides by giving experimenter's high dose treats and/or prevents dysbolismus, as diabetes and fat method.The sirtuin activator can give separately or unite with another kind of blood fat reducing, obesity and/or antidiabetic medicine to give.Unite when giving when sirtuin activator and another kind of therapeutic agent, the dosage that gives of therapeutic agent may be lower than required usually dosage.By using therapeutic agent, might reduce or eliminate the adverse side effect relevant, for example hypertension, heart rate raising etc. with these medicines than low dosage.In some specific embodiments, because the activity of sirtuin activator offsets or avoided relevant side effect with therapeutic agent, so sirtuin activator and anti-diabetic or obesity medicine co-administered can reduce or eliminate side effect.
On the other hand, the invention provides the pharmaceutical composition that contains high dose sirtuin activator of single dosage form.This pharmaceutical composition can be formulated into and can continue to discharge at least about 6 to 48 hours or longer time.The present invention also provides the nutrition medicament that has added the sirtuin activator (neutraceutical), as food or beverage.
On the other hand, the invention provides the method for the treatment of or preventing multiple disease or obstacle by the sirtuin activating compounds that gives experimenter's high dose.Exemplary disease and the obstacle that can treat with the sirtuin activating compounds of high dose for example comprise with old and feeble or stress diseases associated or obstacle, diabetes, obesity, neurodegenerative diseases, the neuropathy that causes with mitochondria dysfunction diseases associated or obstacle, chemotherapy, neuropathy, ocular disease and/or obstacle, cardiovascular disease, blood coagulation disorders, inflammation and/or the flushing etc. relevant with the ischemic incident.As following further describing, this method comprises the sirtuin activating compounds that the experimenter of these needs high dose is arranged.
In some aspects, the sirtuin activating compounds of high dose can give separately or with other chemical compound, comprise that other sirtuin regulates chemical compound or other therapeutic agent and unites and give.
Brief description of drawings
Fig. 1 shows the example of plant polyphenol sirtuin 1 (SIRT1) activator.
Fig. 2 shows the example of stilbene and chalcone derivative SIRT1 activator.
Fig. 3 shows the example of flavone SIRT1 activator.
Fig. 4 shows the example of flavone SIRT1 regulator.
Fig. 5 shows the example of isoflavone, flavanone and anthocyanidin SIRT1 regulator.
Fig. 6 shows the example of catechin (flavan-3-alcohol) SIRT1 regulator.
Fig. 7 shows the example of free radical protectiveness SIRT1 regulator.
Fig. 8 shows the example of SIRT1 regulator.
Fig. 9 shows the example of SIRT1 regulator.
Figure 10 shows the example of resveratrol analogs SIRT1 activator.
Figure 11 shows the more example of resveratrol analogs SIRT1 activator.
Figure 12 shows the more example of resveratrol analogs SIRT1 activator.
Figure 13 shows the example of resveratrol analogs SIRT1 regulator.
Figure 14 shows the more example of resveratrol analogs SIRT1 regulator.
Figure 15 A-G shows the example of sirtuin activator.
Figure 16 shows the example of sirtuin inhibitor.
When Figure 17 A-C gives simultaneously for demonstration Sirt-1 activator resveratrol (400mg/kg/ days) and high fat diet, the curve chart of the obesity of prevention C57BL/6J male mice diet induced.(A) with the mice food ration of kilocalorie/24 hour expression.(B) body weight over time.(C) when the 1st week for the treatment of and the 12nd week, absorb scanning (dexa scanning) analysis according to the dual energy X-ray, to the comparison of body fat content.Numerical value (n=10) is represented with meansigma methods ± standard error of mean (SEM).The result demonstrates significant difference (p value).
When Figure 18 A-C gives simultaneously for demonstration Sirt-1 activator resveratrol (400mg/kg/ days) and high fat diet, increase the curve chart of the energy expenditure of C57BL/6J male mice.(A) 8 male mices were through 13 hours averaged oxygen consumption (V02), and wherein 0 is 7:00 in afternoon constantly.Area is by the histogram graph representation of closing under the averaged curve.(B) respiratory quotient (R.Q.) is VCO2/VO2 (n=8).(C) body temperature of measuring under the room temperature (n=10).Numerical value is represented with meansigma methods ± standard error of mean.The result demonstrates significant difference (p value).
Figure 19 A-C significantly reduces the curve chart of the circadian rhythm spontaneous activity (circadian locomotor activity) of C57BL/6J male mice for showing Sirt-1 activator resveratrol (400mg/ kg/day).(A) be the resting heart rate of high fat diet mice of matched group and resveratrol treatment, and (B) be the blood pressure of the high fat diet mice treated of matched group and resveratrol.(C) the circadian rhythm activity comprises the quantity (number of rears) (curve chart bottom) that active autonomic movement of whole energy (curve chart top) and back leg are stood.The block diagram on next door is represented the circadian rhythm activity of the mensuration of representing with area under curve.Numerical value is represented with meansigma methods ± standard error of mean (n=8).The result demonstrates significant difference (p value).
Figure 20 A-B is the curve chart of the glucose tolerance of the C57BL/6J mice of demonstration Sirt-1 activator resveratrol (400mg/kg/ days) raising high fat diet raising.(A) during the intraperitoneal glucose tolerance test (blood sugar level of 2g glucose/kg) and (B) during the oral glucose tolerance test (blood sugar level of 2g glucose/kg).The block diagram on next door is represented area and body weight under the averaged curve of experimental group.Numerical value is represented with meansigma methods ± standard error of mean (n=5).The result demonstrates significant difference (p value).
Figure 21 shows the result of glucose tolerance test in the mouse peritoneum.
Figure 22 show Sirt-1 activator resveratrol (400mg/kg/ days, R400) with high fat diet (HF) when giving simultaneously, strengthen the adaptability heat production of C57BL/6J male mice.The mouse temperature that curve representative was per hour measured in the cold test at 6 hours and with meansigma methods ± standard error of mean, p＜0.05 expression.
Figure 23 shows the result with the oral glucose tolerance test of 42 days Zucker diabetes obese rat of resveratrol treatment.
Figure 24 shows that Sirt-1 activator resveratrol (400mg/kg/ days) and high fat diet give simultaneously, the obesity of diet induced in the prevention C57BL/6J male mice.Upper left shows that the mice of four diet groups is at the curve chart that surpasses body weight change in the time in nine weeks.Upper right portion shows the curve chart with the food ration of the mice of four diet groups of kilocalorie/24 hour expression.The bottom shows according to the dual energy X-ray and absorbs scanning analysis, to the comparison through the mice body fat content of four diet groups of 9 weeks treatment.Numerical value is represented with meansigma methods ± standard error of mean (n=10).BAT is brown adipose tissue (lower right-most portion); Groin WAT is groin white adipose tissue (bottom left section); And WAT is a white adipose tissue (lower middle portion) behind the peritoneum behind the peritoneum.The result demonstrates significant difference (p value).During illustrating, add 400mg/kg/ days resveratrol (C+R400), high fat diet (HF) or high fat diet and add 400mg/kg/ days resveratrol (HF+R400) letting animals feed with control diet (C), control diet.
Figure 25 shows through control diet (C), high fat diet (HF) or higher fatty acidly adds 400mg/kg/ days resveratrol (HF+R400) diet after 16 weeks, the serum biochemistry analysis result of animal (numerical value is the meansigma methods from 10 animals of each group).
Figure 26 shows through control diet (C), high fat diet (HF) or higher fatty acidly adds 400mg/kg/ days resveratrol (HF+R400) diet after 16 weeks, the h and E dyeing of liver of animal and epididymal adipose section.
Figure 27 shows through control diet (C), high fat diet (HF) or higher fatty acidly adds 400mg/kg/ days resveratrol (HF+R400) diet after 16 weeks that the h and E that brown fat tissue of animal and gastrocnemius are cut into slices dyes.
Figure 28 shows through high fat diet (HF) or higher fatty acidly adds 400mg/kg/ days resveratrol (HF+R400) diet after 16 weeks, the dyeing of the succinate dehydrogenase of brown fat tissue, gastrocnemius and the musculus soleus of animal.
Figure 29 shows through control diet (C), high fat diet (HF) or 400mg/kg/ days resveratrol (HF+R400) diet of higher fatty acid interpolation after 16 weeks, the gastrocnemius of animal (non-oxide fiber non-oxidative fiber) is through 10, the transmission electron microscope figure of 000 and 20,000 times of amplification.Embed figure and show meat fiber dissection sketch map.
Figure 30 shows through control diet (C), high fat diet (HF) or higher fatty acidly adds 400mg/kg/ days resveratrol (HF+R400) diet after 16 weeks that the brown adipose tissue of animal is through the transmission electron microscope figure of 4,000 and 20,000 times of amplifications.
Figure 31 shows the Sirt1 mRNA level measured in animal brown adipose tissue, liver and the muscle after resveratrol (HF+R400) diet of control diet (C), high fat diet (HF) or the higher fatty acid 400mg/kg/ of adding days is handled (numerical value is the meansigma methods from 6 animals of each group).The numerical value that shows is with respect to house-keeping gene 18s, and numerical value afterwards is with respect to full diet (being customized for 1).
Figure 32 shows PEPCK, glucose-6-phosphatase, Foxol in liver, brown adipose tissue and the muscle after control diet (shadow-free), high fat diet (shallow shade) or higher fatty acid resveratrol (dark shade) diet that adds 400mg/kg, the relative gene expression of PGC 1-α and Sirt1.(summations (pool) of following 6 animals of each condition of n=).
Figure 33 display list understands that veratryl alcohol increases the immunoblotting result of the deacetylated effect of PGC1 α.IP is immunoprecipitation; IB is an immunoblotting; HF is high fat diet; And HF+R400 is the resveratrol that high fat diet adds 400mg/kg.
Figure 34 shows that the feces lipid content of mice of the resveratrol (HF+R400) of feed full diet (C), high fat diet (HF) or the higher fatty acid 400mg/kg of adding analyzes.The left side shows total stool weight of each mice.The right shows the excretory cholesterol of animal of different diet groups and the amount of triglyceride.
When Figure 35 gives simultaneously for demonstration Sirt-1 activator resveratrol (400mg/kg/ days) and high fat diet, the curve chart of the obesity of prevention C57BL/6J male mice diet induced.The left side: body weight (among the figure from the top to the bottom is: HF, HF+R400, C and C+R400) over time.The right: the area under curve of the curve chart shown in the left side.
Figure 36 is the sketch map of the treadmill endurance experimental program of the mice of explanation feed full diet (top line) and high fat diet (bottom line).
Figure 37 is the curve chart of the tolerance test result of the mice of demonstration feed full diet or high fat diet.Each bar line in the curve chart represents to utilize each animal of tolerance experimental program test shown in Figure 33.
Figure 38 shows the effect of the resveratrol of euglycemia (5.5mmol/l) hyperinsulinism (18mU/kg/ minute) clamp (hyperinsulinemic euglycemic clamp) technical measurement to insulin sensitivity that utilize.Left-hand component shows after resveratrol (C+R400), high fat diet (HF) or high fat diet that control diet (C), control diet add 400mg/kg add 14 weeks of resveratrol (HF+R400) of 400mg/kg, the glucose infusion rate of each treated animal (GIR).Right-hand component shows the average GIR under the stable state clamp.
Detailed description of the invention
Definition
Following term and phrase that the present invention is used should have following meanings. Unless otherwise defined, all technology used in the present invention are identical with the implication that those of ordinary skills understand usually with scientific terminology.
Unless context separately has clear, singulative " a ", " an " and " the " comprise the implication of plural number.
Term " medicine (agent) " the expression chemical compound that the present invention uses, the mixture of chemical compound, large biological molecule (as nucleic acid, antibody, albumen or its part, for example peptide) or by the extract of the cell or tissue preparation of biomaterial such as bacterium, plant, fungi or animal (especially mammal). The activity of these medicines can make it be suitable for as " therapeutic agent ", and this therapeutic agent is in experimenter's part or biology, physiology or the pharmacological active substance (or many kinds of substance) of whole body onset.
When relating to chemical compound, " naturally occurring form " is meant the chemical compound that exists with the form of for example compositions with a kind of, and the chemical compound in this form can find at nature.For example, because resveratrol can find in red wine, then it is to be present in the red wine with naturally occurring form.If, chemical compound other purification or separate the common molecule that exists of nature and this chemical compound for example from least some, then this chemical compound is not to exist in naturally occurring mode." naturally occurring chemical compound " is meant can be at the chemical compound of nature discovery, promptly without the artificial chemical compound that designs.Naturally occurring chemical compound can be prepared by people or nature.
" Sirtuin regulator " is meant to adjusted (for example, activation or stimulation), regulates (for example, suppressing or compacting) or other change proteic functional characteristic of sirtuin or bioactive chemical compound downwards.The Sirtuin regulator can be used for directly or indirectly regulating sirtuin albumen.In some specific embodiments, the Sirtuin regulator can be sirtuin activator or sirtuin inhibitor.
Term " sirtuin activator " or " sirtuin activating compounds " are meant and improve the sirtuin protein level and/or improve the proteic at least a active chemical compound of sirtuin.In an exemplary specific embodiments, the sirtuin activator can improve the proteic at least a biological activity of sirtuin at least about 10%, 25%, 50%, 75%, 100% or more.The proteic exemplary biological activity of sirtuin comprises deacetylation, for example histone and p53; Life-saving; Increase genome stability; Separating of oxidation protein between blast cell and daughter cell transcribed and controlled to silence.Exemplary sirtuin activating compounds comprises for example having the chemical compound of the general formula that is selected from general formula 1-25,30,32-65 and 69-88.
" high dose of sirtuin activating compounds " is meant that the sirtuin activation is equal to or greater than the amount of sirtuin activator of the sirtuin activation of 18mg/kg resveratrol (for example, in the people).In some specific embodiments, the high dose of sirtuin activating compounds is meant that the sirtuin activation is equal to or greater than the amount of sirtuin activator of the sirtuin activation of 18mg/kg resveratrol, described resveratrol is oral with (i), (ii) discharge 6 to 48 hours, and/or (iii) the mode of the time of equivalent gives with slow releasing pattern.In some specific embodiments, the high dose of sirtuin activating compounds is meant that the sirtuin activation is equal to or greater than at least about 20,25,30,35,40,50,60,75,100, the amount of the sirtuin activator of the sirtuin activation of 150mg/kg or more resveratrol.
" sirtuin activation " is meant the level or the degree of one or more therapeutic effect that the sirtuin activating compounds that gives high dose is obtained.Therapeutic effect comprises, for example (i) contains the diet of the fat of increase and/or calorie content by consumption but do not increase activity, heart rate and/or blood pressure; And/or (ii) improve blood sugar level and prevent or suppress weight increase.This therapeutic effect comprises, the therapeutic effect of for example illustrating in an embodiment.
" sirtuin inhibitor " is meant and reduces the sirtuin protein level and/or reduce the proteic at least a active chemical compound of sirtuin.In an exemplary specific embodiments, the sirtuin inhibitor can reduce the proteic at least a biological activity of sirtuin at least about 10%, 25%, 50%, 75%, 100% or more.The proteic exemplary biological activity of sirtuin comprises deacetylation, for example histone and p53; Life-saving; Increase genome stability; Separating of oxidation protein between blast cell and daughter cell transcribed and controlled to silence.
" Sirtuin albumen " is meant a member in the Sirtuin deacetylase protein family; perhaps preferably be meant Sir2 family, it comprises yeast Sir2 (GenBank registration number No.P53685), nematicide (C.elegans) Sir-2.1 (GenBank registration number No.NP_501912) and people SIRT1 (GenBank registration number No.NM_012238 and NP_036370 (or AF083106)) and SIRT2 (GenBank registration number No.NM_030593 and AF083107) albumen.Other family member comprises that term is called four kinds of other yeast Sir2 sample genes of " HST gene " (with the Sir2 homology), HST1, HST2, HST3 and HST4, and five kinds of other and human homologies' hSIRT3, hSIRT4, hSIRT5, hSIRT6 and hSIRT7 (Brachmann etc., (1995) Genes Dev.9:2888 and Frye etc., (1999) BBRC 260:273).Preferred sirtuin has and SIRT1, be the similarity ratio and the more sirtuin of the similarity of SIRT2 of hSIRT1 and/or Sir2, have in SIRT1 as those and to exist and in SIRT2, not exist, the member who has as SIRT3 to small part N-end sequence.
" SIRT1 albumen " is meant a member in the sir2 family of sirtuin deacetylase.In a specific embodiments, SIRT1 albumen comprises yeast Sir2 (GenBank registration number No.P53685), nematicide (C.elegans) Sir-2.1 (GenBank registration number No.NP_501912), human SIRT1 (GenBank registration number No.NM_012238 and NP_036370 (or AF083106)), human SIRT2 (GenBank registration number No.NM_012237, NM_030593, NP_036369, NP_085096 and AF083107) albumen and equivalent and fragment.In another embodiment, SIRT1 albumen comprises contain polypeptide of sequence that the aminoacid sequence listed is formed or that be made up of them substantially in GenBank registration number Nos.NP_036370, NP_501912, NP_085096, NP_036369 and P53685.SIRT1 albumen comprises the polypeptide that contains following all or part aminoacid sequence: the aminoacid sequence of listing in GenBank registration number Nos.NP_036370, NP_501912, NP_085096, NP_036369 and P53685; That lists in GenBank registration number Nos.NP_036370, NP_501912, NP_085096, NP_036369 and P53685 has 1 to about 2,3,5,7,10,15,20,30,50,75 or the aminoacid sequence replaced of more a plurality of conservative amino acid; At least 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% with GenBank registration number Nos.NP_036370, NP_501912, NP_085096, aminoacid sequence and functional fragment thereof that NP_036369 is identical with P53685.Polypeptide of the present invention also comprises autoploid (homolog) (for example lineal autoploid (orthologs) and collateral line autoploid (paralogs)), variant or the fragment of GenBank registration number Nos.NP_036370, NP_501912, NP_085096, NP_036369 and P53685.
" biologically-active moiety of sirtuin " is meant the proteic part of sirtuin of biologically active such as deacetylated ability.The biologically-active moiety of sirtuin can comprise the core space of sirtuin.For example, by 62 to 293 amino acids of the SIRT1 protein sequence of 237 to 932 nucleotide codings of SIRT1 nucleotide sequence, it has comprised NAD
+In conjunction with territory and substrate in conjunction with the territory.Therefore, this zone is called as core space sometimes.Other biologically-active moiety of SIRT1 is also sometimes referred to as core space, comprises about 261 to 447 amino acids by the SIRT1 protein sequence of 834 to 1394 nucleotide codings of SIRT1 nucleotide sequence; About 242 to 493 amino acids by the SIRT1 protein sequence of 777 to 1532 nucleotide codings of SIRT1 nucleotide sequence; Perhaps by about 254 to 495 amino acids of the SIRT1 protein sequence of 813 to 1538 nucleotide codings of SIRT1 nucleotide sequence.
" the direct activation agent " of sirtuin is meant by combine the molecule of activation sirtuin with sirtuin.Sirtuin " directly inhibitor " is meant the molecule that suppresses sirtuin by combining with sirtuin.
Term " comprises (comprise and comprising) " and is used to indicate the open implication that comprises, and is meant to comprise other element.
Term " comprises " and is used to refer to " including but not limited to "." comprise " and " including but not limited to " is used interchangeably.
Term " homogeneity percentage ratio " is meant the sequence homogeneity between two seed amino acid sequences or the two kinds of nucleotide sequences.Homogeneity can be by relatively determining respectively for a position of comparing each sequence of arranging.When the equivalent site in being compared sequence was occupied by identical base or aminoacid, then molecule had homogeneity in this position; When being equal to the site by identical or similar amino acid residue (for example, spatial property and/or electronic property are similar) when occupying, then can be referred to as in this position be homologous (similar) to molecule.Sign as the percentage ratio of homology, similarity or homogeneity is meant by the function that is compared same or similar amino acid whose quantity on the common position of sequence.Sign as the percentage ratio of homology, similarity or homogeneity is meant by the function that is compared same or similar amino acid whose quantity on the common position of sequence.Spendable various alignment algorithm and/or program comprise FASTA, BLAST or ENTREZ.FASTA and BLAST can be used as GCG sequence analysis bag, and (part Wis.) obtains, and can use with for example default setting for University of Wisconsin, Madison.ENTREZ is by NCBI (National Centerfor Biotechnology Information), National Library of Medicine (National Library ofMedicine), (the National Institutes of Health of NIH, Bethesda MD) obtains.In a specific embodiments, the homogeneity percentage ratio of two sequences can be determined by the GCG program, wherein the weight in space (gap weight) is 1, for example to each aminoacid space (gap) when weighing (weighted) will to be used as each space be two single amino acids or nucleoside mispairing between the sequence.
Other comparison technology is recorded in " Enzymology method ", the 266th volume: be used for the computer approach (1996) of macromole sequence analysis, editor Doolittle, academic press company, Harcourt Brace ﹠amp; Co. company department, Santiago, the California, the U.S. (Methods inEnzymology, vol.266:Computer Methods for Macromolecular SequenceAnalysis (1996), ed.Doolittle, Academic Press, Inc., a division of HarcourtBrace ﹠amp; Co., San Diego, California, USA).Preferably, utilize permission in sequence, to exist the comparison program in space to come aligned sequences.Smith-Waterman is a class allows to exist the space in sequence alignment a algorithm.Referring to Meth.Mol.Biol.70:173-187 (1997).Equally, use the GAP program of Needleman and Wunsch comparison method also to can be used for aligned sequences.Another kind of search strategy is to use the MPSRCH software that moves on the MASPAR computer.MPSRCH uses the Smith-Waterman algorithm on massively parallel computer sequence to be marked.This method has improved the ability that obtains not too relative coupling, and especially can tolerate little space and nucleotide sequence mistake.The aminoacid sequence of nucleic acid coding can be used to search for protein and DNA data base.
Term " polynucleotide " and " nucleic acid " are used interchangeably.They are meant the nucleotide of any length, perhaps deoxyribonucleotide or ribonucleotide, or the polymerized form of its analog.Polynucleotide can have any three dimensional structure, and can bring into play any known or unknown function.Below be the example of the indefiniteness of polynucleotide: isolating RNA, nucleic probe and the primer of the coding of gene or genetic fragment or noncoding region, site, exon, intron, messenger RNA (mRNA), transfer RNA, ribosomal RNA, ribozyme, cDNA, recombination of polynucleotide, side chain polynucleotide, plasmid, carrier, the separated DNA of any sequence, any sequence according to the connection analytic definition.Polynucleotide can comprise the nucleotide of modification, as methylated nucleotide and nucleotide analog.If modification is arranged, then can before or after this polymer assembling, carry out the modification of nucleotide structure.Nucleotide sequence can be interrupted by the non-nucleotide composition.Polynucleotide can further be modified, as by combining with marked member.Term " reorganization " polynucleotide are meant the polynucleotide in genome, cDNA, semi-synthetic or synthetic source, they or do not exist or be connected on the polynucleotide that another non-natural arranges at nature.
" patient ", " experimenter " or " host " are meant people or non-human animal.The non-human animal comprises domestic animal (for example cattle, horse, pig, sheep, goat) and companion animals (for example Canis familiaris L., cat etc.).
When using with aminoacid sequence, term " homology in fact " is meant on sequence same or similar in fact each other, forms the homology of conformation and therefore remain valid level, i.e. one or more biologies (comprising immunologic) activity.This term is not the common evolution (common evolution) of having a mind to infer sequence.
Term " adjusting " is well known in the art and is meant rise (i.e. activation or stimulate), downward modulation (promptly suppressing or compacting) to response, perhaps both in conjunction with or separately.
Term " preventative " or " therapeutic " treatment are well known in the art, and are to point to host's administration.If before the clinical manifestation of harmful situation (as disease or other adverse condition of host animal), give; treatment is preventative so; be that it protects the host to resist the development of harmful situation; otherwise; if give after the performance of harmful situation, treating so is curative (being that this is in order to reduce, to improve or keeping existing harmful situation or its side effect).
Term " mammal " is known in the art, and exemplary mammal comprises: people, primates, cattle, pig, dog, felid and rodent (for example mice and rat).
When relating to chemical compound, term " biological available " is well known in the art and is meant the chemical compound that is given of chemical compound or part amount is absorbed by introducing, and perhaps other is the form of available chemical compound on the physiology to the experimenter or the patient that are given.
Term " medicine " is meant any chemical compound with pharmacological action.For example, native compound and the non-natural compound with pharmacological action contained in this term " medicine ".
Term " pharmaceutically acceptable salt " is well known in the art and is meant nontoxic relatively, the mineral acid or the organic acid addition salt of chemical compound, and the solvate of this salt, eutectic, polymorph etc., comprise the salt that comprises in the compositions of for example the present invention record.
Term " pharmaceutically acceptable carrier " is well known in the art and is meant pharmaceutically acceptable material, compositions or carrier, as liquid or solid filler, diluent, excipient, solvent or encapsulating material.Various carriers must be " can accept ", and are promptly compatible and harmless to the patient with objective composition and composition thereof.Some examples that can be used as the material of pharmaceutically acceptable carrier comprise: (1) sugar, as lactose, dextrose plus saccharose; (2) starch is as corn starch and potato starch; (3) cellulose and derivant thereof are as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) Powdered tragacanth; (5) Fructus Hordei Germinatus; (6) gelatin; (7) Talcum; (8) excipient is as cocoa butter and suppository wax (suppository waxes); (9) oil is as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, safflower oil, Oleum sesami, olive oil, Semen Maydis oil and soybean oil; (10) dihydroxylic alcohols is as propylene glycol; (11) polyhydric alcohol is as glycerol, sorbitol, mannitol and Polyethylene Glycol; (12) ester is as ethyl oleate and ethyl laurate; (13) agar; (14) buffer agent is as magnesium hydroxide and aluminium hydroxide; (15) alginic acid; (16) apirogen water; (17) normal saline; (18) Ringer's mixture (Ringer ' s solution); (19) ethanol; (20) phosphate buffer; And other nontoxic compatible material that uses in (21) pharmaceutical preparation.
Term " whole body administration " (systemic administration, administered systemically), " peripherally administered " (peripheral administration, administered peripherally) are well known in the art and are meant and give objective composition, directly do not enter the central nervous system when therapeutic or other material, but enter patient's whole body and therefore process metabolism and other similar process.
Term " gastrointestinal tract external administration " (parenteral administration, administeredparenterally) is well known in the art and is meant the administering mode that is different from intestinal and topical, normally by injection, and include, without being limited in the intravenous, intramuscular, intra-arterial, sheath, in the capsule, in the socket of the eye, in the heart, Intradermal, intraperitoneal, under trachea, subcutaneous, epidermis, under the intraarticular (intra-articulare), capsule, under the arachnoidea, in the spinal column, breastbone inner injection and infusion.
" transcriptional regulatory sequences " is to run through the technical term that this description is used, be meant DNA sequence, as enabling signal, enhancer and promoter (promoter), they are induced or control with them is to handle transcribing of (operable linked) protein coding sequence that is connected.In preferred specific embodiments, transcribing of a kind of recombination is to be under the control of the promoter sequence (perhaps other transcriptional regulatory sequences) of control recombinant gene expression in the cell type of expressing by expection.Will also be understood that recombination can be under the control of transcriptional regulatory sequences, described transcriptional control joint row are same as or are different from those sequences of transcribing of the natural existence form of controlling gene of the present invention.
" carrier " is that the nucleic acid molecules that will insert is transferred to the self-replication nucleic acid molecules between host cell and/or the host cell.This term comprises main the duplicating of carrier of being responsible for that nucleic acid molecules inserted the carrier of cell and mainly being responsible for nucleic acid replication, and the expression vector of responsible DNA or rna transcription and/or translation.The carrier that also comprises the above-mentioned functions that more than one are provided.
" expression vector " that the present invention uses is defined as when being introduced into appropriate host cell, can be transcribed and translate into the polynucleotide of polypeptide." expression system " typically refers to the host cell that is fit to that comprises the expression vector with the function that produces required expression product.
" mitochondrial function index " is any parameter of the indication mitochondrial function that can be measured by those skilled in the art.In some specific embodiments, the mitochondrial function index is a mitochondrion electron transport chain enzyme, tricarboxylic acid cycle enzyme, mitochondrial matrix composition, mitochondrial membrane composition or the ATP biosynthesis factor.In other specific embodiments, the mitochondrial function index is the mitochondrion quantity of each cell or the mitochondrial mass of each cell.In other specific embodiments, the mitochondrial function index is the ATP biosynthesis factor.In other specific embodiments, the mitochondrial function index is the amount of each mitochondrial ATP, the amount of per unit mass mitochondrial ATP, the amount of per unit a-protein TP or the amount of per unit mitochondrial protein ATP.In other specific embodiments, the mitochondrial function index comprises the generation of free radical.In other specific embodiments, the mitochondrial function index comprises the cell effect that calcium increases in the pair cell.In other specific embodiments, the mitochondrial function index is a cyclophorase, as example as indefiniteness, the activity of citrate synthetase, hexokinase II, cytochrome C oxidase, phosphofructokinase, glyceraldehyde phosphate dehydrogenase, glycogen phosphorylase, creatine kinase, nadh dehydrogenase, glycerol-3-phosphate dehydrogenase, phosphotriose dehydrogenase or malic dehydrogenase.In other specific embodiments, the mitochondrial function index be in each cell of patient mitochondrial DNA relatively or absolute magnitude.
" raising mitochondrial function " or " change mitochondrial function " can be meant that (a) is in fact (for example in significant mode on the statistics, and preferably to promote to improve significantly on the statistics clinical parameter such as prognosis, clinical score or result's mode) glucose responding is reduced, mitochondrial mass reduces and/or at least a glucose responding index of the cell that mitochondrial function damages returns to normal level; Or (b) respectively, in fact (as in significant mode on the statistics, and preferably to promote to improve significantly on the statistics clinical parameter such as prognosis, clinical score or result's mode) cell of mitochondrial function infringement or at least a mitochondrial function index with cell of NM function are returned to normal level, perhaps be increased to the level that is higher than or surpasses normal level.The improvement of mitochondrial function or change and to cause by extramitochondrial structure or movable and mitochondrial structure or active variation, and cause the direct interaction between mitochondrion and mitochondrion alia gene and/or their gene outcome or the intermediate that causes may forming by described interaction between interaction, and consequent structure or changing function, above-mentioned intermediate comprises metabolite, catastate, substrate, precursor, cofactor etc.
" mitochondrial function infringement " can comprise in the cell of some or all biogenetic derivations, any breathing, metabolism or other biochemistry or the active level of biophysics and/or speed reduces wholly or in part, suppresses, reduces, loses or other damage.As the example of indefiniteness, significantly damage electron transfer chain (ETC) activity and may damage relevantly with mitochondrial function, may cause that also reactive oxygen species (ROS) increases or the oxidative phosphorylation deficiency.As a further example, change mitochondrial membrane potential, cell death inducing approach and in cell, form atypia chemistry and biochemistry cross-linking agent (crosslinked species), no matter be that can be used as is the index of mitochondrial function by zymetology or non-zymetology mechanism.The example of these or other indefiniteness of mitochondrial function infringement has more detailed description hereinafter.
" treatment " disease or disease are meant the symptom of curing and improving at least a disease or disease.
Term " cis " is well known in the art, and is meant that two atoms around two keys or group are arranged as the same side that atom or group are in two keys.Cis-configuration is marked as (Z) configuration usually.
Term " trans " is well known in the art, and is meant that two atoms around two keys or group are arranged as the heteropleural that atom or group are in two keys.Anti-configuration is labeled as (E) configuration usually.
" covalent bond " is well known in the art and is meant two interatomic keys that wherein electronics is attracted to the nuclear of two atoms by static, and the net effect of the internuclear cloud density that increases has been offset internuclear repulsion to term.When this key had metal ion, the term covalent bond comprised coordinate bond.
Term " therapeutic agent " be well known in the art and be meant as act on experimenter part or whole body biologically, the physiology is last or the pharmacology on any chemical compound of active substance.This term also refers to be used for the diagnosis of animal or human's apoplexy due to endogenous wind, healing, alleviation, treatment or prevent disease or strengthens required physics or any material of spirit progress and/or state.
Term " therapeutic effect " is well known in the art and is meant animal, mammal particularly, more especially among the mankind by caused part of pharmacological active substance or systemic effect.Phrase " treatment effective dose " is meant and is being suitable for producing the described amount of substance of some ideal part or general action under the rational interests of any treatment/risk ratio.The treatment effective dose of this material will change according to the order of severity of experimenter and the morbid state of being treated, experimenter's body weight and age, morbid state, administering mode etc., and this is that those of ordinary skills are easy to determine.For example, some compositions of the present invention can be suitable for the rational interests of described treatment/risk than under, come administration with the amount that enough metabolic obstacle or diabetes or its complication is produced required effect.
Term " synthetic " is well known in the art and is meant by external chemistry or enzymatic synthesis production.
Term " meso compound " is well known in the art and is meant to have at least two chiral centres but owing to symmetrical plane or point of symmetry are achiral chemical compound.
Term " chirality " is well known in the art and is meant the have mirror partners molecule of not plyability of (partner), and term " achirality " is meant that mirror partners (partner) can eclipsed molecule." prochirality molecule " is meant to have the molecule that is converted into the potentiality of chiral molecule through specific process.
Term " stereoisomer " is well known in the art and is meant to have identical chemical composition but the different chemical compound of the spatial arrangements of atom or group.Particularly, " enantiomer " is meant two kinds of stereoisomers of the nonoverlapping chemical compound of mirror image each other.On the contrary, " diastereomer " is meant and has the stereoisomer that two or more asymmetric centers and its molecule are not mutually mirror image.
And " Stereoselective method " is meant other possible stereoisomer of having precedence over product and the method for particular stereoisomer in the preparation feedback product." enantioselectivity method " is meant the method for one of two kinds of possible enantiomers being partial to the preparation feedback product.
Term " position isomer " is well known in the art and is meant to have identical molecular formula but the different chemical compound of the connected mode of atom.Correspondingly, " regioselectivity method " is meant the method that other position isomer is partial to prepare the ad-hoc location isomer of comparing, and for example, the output of some position isomer that reaction produces significantly increases statistically.
Term " epimer " is well known in the art and is meant to have identical chemical composition and comprise three-dimensional center more than, but has only the different molecule of configuration at one of these three-dimensional centers.
Term " ED
50" be well known in the art.In some specific embodiments, ED
50Be meant the drug dose that produces 50% peak response or effect, perhaps the dosage of generation predetermined response in 50% experimenter or goods (preparation).Term " LD
50" be well known in the art.In some specific embodiments, LD
50Be meant the lethal drug dose of 50% experimenter.Term " therapeutic index " is a term well known in the art, and it is meant and is defined as LD
50/ ED
50The Drug therapy index.
Term " structure activity relationship " or " SAR " be well known in the art and be meant that the molecular structure that changes medicine or other chemical compound changes its biological activity, for example the interactional mode of itself and receptor, enzyme, nucleic acid or other target spots etc.
Term " aliphatic " is well known in the art and is meant straight chain, side chain, cyclic alkane, alkene or alkynes.In some specific embodiments, the aliphatic group of The compounds of this invention be straight or branched and have from 1 to about 20 carbon atoms.
Term " alkyl " is well known in the art, and comprises saturated aliphatic groups, comprises straight chained alkyl, branched alkyl, cycloalkyl (alcyl), the cycloalkyl of alkyl replacement and the alkyl of cycloalkyl substituted.In some specific embodiments, the straight or branched alkyl has about 30 or carbon atom still less on its skeleton (for example straight chain is C
1-C
30, side chain is C
3-C
30), perhaps about 20 or carbon atom still less.Equally, cycloalkyl has on its ring structure from about 3 to about 10 carbon atoms, perhaps has about 5,6 or 7 carbon on ring structure.
Term " aralkyl " is well known in the art and is meant the alkyl that is replaced by aryl (for example aryl or heteroaryl).
Term " thiazolinyl " and " alkynyl " are well known in the art and are meant length and possible replacement is similar to abovementioned alkyl, but contain at least one two keys or triple-linked unsaturated aliphatic group respectively.
Unless carbon number is had explanation in addition, " low alkyl group " be meant as defined above but have 1 to about 10 carbon atoms in its framing structure, perhaps 1 alkyl to about 6 carbon atoms.Equally, " low-grade alkenyl " has similar chain length with " low-grade alkynyl ".
Term " hetero atom " is well known in the art and is meant any atoms of elements except carbon or hydrogen.Exemplary hetero atom comprises boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
Term " aryl " is well known in the art and is meant and can contains 0 to 4 heteroatomic 5-, 6-and 7-unit monocyclic aryl, for example benzene, naphthalene, anthracene, pyrene, pyrroles, furan, thiophene, imidazoles, oxazole, thiazole, triazole, pyrazoles, pyridine, pyrazine, pyridazine and pyrimidine etc.Those contain heteroatomic aryl on ring structure also can be referred to as " fragrant heterocycle " or " heteroaryl ".Aromatic ring can be replaced by above-mentioned substituent group on one or more position, for example halogen, azido (azide), alkyl, aralkyl, thiazolinyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfydryl, imino group, amide groups, phosphonate radical, phosphinic acid root, carbonyl, carboxyl, silicyl, ether, alkylthio group, sulfonyl, sulfoamido, ketone, aldehyde, ester, heterocyclic radical, aryl or heteroaryl moieties ,-CF
3,-CN etc.Term " aryl " also comprises the multi-loop system with 2 or more a plurality of rings, wherein 2 or more a plurality of carbon are two adjacent rings common (this ring is " condensed ring "), wherein at least one ring has armaticity, and for example other ring can be cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl and/or heterocyclic radical.In chemical compound 77-88, " aryl " is used to refer to carbocyclic ring and heterocyclic aryl.
Term " neighbour ", " " and " to " are well known in the art and are meant 1 respectively, 2-, 1,3-and 1,4-disubstituted benzenes.For example, called after 1,2-dimethyl benzene and adjacent dimethyl benzene are synonyms.
Term " heterocyclic radical " or " heterocyclic group " be well known in the art and be meant that 3-arrives about 10 ring structures, and perhaps 3-is to about 7 yuan of rings, and its ring structure comprises 1 to 4 hetero atom.Heterocycle also can be multi-ring.Heterocyclic group comprises for example thiophene, thianthrene, furan, pyrans, isobenzofuran, .alpha.-5:6-benzopyran, xanthene, benzodiphenylene oxide (phenoxanthene), the pyrroles, imidazoles, pyrazoles, isothiazole isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, iso-indoles, indole, indazole, purine, quinolizine, isoquinolin, quinoline, phthalazines, naphthyridines, quinoxaline, quinazoline, cinnolines, pteridine, carbazole, carboline, phenanthridines, acridine, pyrimidine, phenanthroline, azophenlyene, phenarsazine, phenothiazine, furazan phenoxazine, pyrrolidine, oxolane (oxolane), Tetramethylene sulfide oxazole, piperidines, piperazine, morpholine, lactone, lactams such as aza cyclo-butanone and ketopyrrolidine, sultam, sultone etc.Heterocycle can be on one or more position be replaced by above-mentioned substituent group, for example halogen, alkyl, aralkyl, thiazolinyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfydryl, imino group, amide groups, phosphonate radical, phosphinic acid root, carbonyl, carboxyl, silicyl, ether, alkylthio group, sulfonyl, ketone, aldehyde, ester, heterocyclic radical, aryl or heteroaryl moieties ,-CF
3,-CN etc.
Term " multi-ring base " or " multi-ring group " are well known in the art and (for example are meant two or more rings, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl and/or heterocyclic radical), wherein 2 or more a plurality of carbon are that two adjacent rings are common, and for example this ring is " condensed ring ".The ring that links to each other by non-conterminous atom is called " bridged ring ".Polycyclic each ring can be replaced by above-mentioned substituent group, for example halogen, alkyl, aralkyl, thiazolinyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfydryl, imino group, amide groups, phosphonate radical, phosphinic acid root, carbonyl, carboxyl, silicyl, ether, alkylthio group, sulfonyl, ketone, aldehyde, ester, heterocyclic radical, aryl or heteroaryl moieties ,-CF
3,-CN etc.
Term " carbocyclic ring " is well known in the art and is that each atom is the fragrance or the non-aromatic ring of carbon on the finger ring.
Term " nitro " is well known in the art and is meant-NO
2Term " halogen " is well known in the art and be meant-F ,-Cl ,-Br or-I; Term " sulfydryl " is well known in the art and is meant-SH; Term " hydroxyl " is meant-OH; And term " sulfonyl " is well known in the art and is meant-SO
2 -" halogenide " refers to the corresponding anion of halogen, and " pseudohalide " has " definition of the 560th page of proposition of Advanced Inorganic Chemistry (Advanced Inorganic Chemistry) at Cotton and Wilkinson.
Term " amine " and " amino " is well known in the art and is meant not the amine that replaces or replace, for example can be by the part of following general formula representative:
Wherein R50, R51 and R52 represent independently of one another hydrogen, alkyl, thiazolinyl ,-(CH
2)
m-R61 or R50 and R51 and coupled N atom form the heterocycle that has 4 to 8 atoms in the ring structure together.R61 represents aryl, cycloalkyl, cycloalkenyl group, heterocycle or multi-ring; And m be 0 or scope be 1 to 8 integer.In some specific embodiments, have only one can be carbonyl among R50 or the R51, for example R50, R51 and nitrogen do not form acid imide.In other specific embodiments, R50 and R51 (and optional R52) represent independently of one another hydrogen, alkyl, thiazolinyl or-(CH
2)
m-R61.Therefore, term " alkylamine " comprises having the replacement that is connected on the amine or the amido of unsubstituted alkyl as defined above, and promptly at least one is an alkyl among R50 and the R51.
Term " acyl amino " is well known in the art and be meant can be by the part of following general formula representative:
Wherein R50 as above defines, and R54 represent hydrogen, alkyl, thiazolinyl or-(CH
2)
m-R61, wherein m and R61 as above define.
Term " amide groups " known in this field for the amino carbonyl that replaces and comprise can be by the part of following general formula representative:
Wherein R50 and R51 as above define.Some specific embodiments of amide does not comprise the acid imide of potentially unstable.
Term " alkylthio group " is meant to have the alkyl that is connected in the sulfenyl on the alkyl as defined above.In some specific embodiments, " alkylthio group " part be by-S-alkyl ,-the S-thiazolinyl ,-the S-alkynyl and-S-(CH
2)
mOne of-R61 representative, wherein m and R61 as above define.Representational alkylthio group comprises methyl mercapto, ethylmercapto group etc.
Term " carbonyl " is well known in the art and comprise can be by the part of following general formula representative:
Wherein X50 is a key or represents oxygen or sulfur, and R55 and R56 represent hydrogen, alkyl, thiazolinyl ,-(CH
2)
m-R61 or pharmaceutically acceptable salt, R56 represent hydrogen, alkyl, thiazolinyl or-(CH
2)
m-R61, wherein m and R61 as above define.When X50 is oxygen and R55 or R56 when being not hydrogen, this general formula representative " ester ".When X50 is oxygen and R55 when as above defining, this part at this moment is meant carboxyl, particularly when R55 is hydrogen, and this general formula representative " carboxylic acid ".When X50 is an oxygen, and R56 is when being hydrogen, this general formula representative " formic acid esters ".Usually, when the oxygen atom of above-mentioned general formula during by sulfur, this general formula representative " thiocarbonyl ".When X50 is sulfur and R55 or R56 during for hydrogen, this general formula representative " thioesters ".When X50 is sulfur and R55 when being hydrogen, this general formula representative " thiocarboxylic acid ".When X50 is sulfur and R56 when being hydrogen, this general formula representative " thiocarboxylic (thiolformate) ".On the other hand, when X50 is a key, and R55 is not when being not hydrogen, above-mentioned general formula representative " ketone " base.When X50 is a key, and R55 is when being hydrogen, above-mentioned general formula representative " aldehyde " base.
Term " alkoxyl (alkoxyl, alkoxy) " is well known in the art and is meant the alkyl as defined above with the oxygen base that is connected on the alkyl.Representational alkoxyl comprises methoxyl group, ethyoxyl, propoxyl group, tert-butoxy etc." ether " is by two alkyl that oxygen is covalently bound.Therefore, the substituent group that becomes the alkyl of ether is or is similar to alkoxyl, for example can by-O-alkyl ,-the O-thiazolinyl ,-the O-alkynyl ,-O-(CH
2)
mOne of-R61 representative, wherein m and R61 are as mentioned above.
Term " sulphonic acid ester " is well known in the art and be meant can be by the part of following general formula representative:
Wherein R57 is electron pair, hydrogen, alkyl, cycloalkyl or aryl.
Term " sulfuric ester (sulfate) " is well known in the art and comprise can be by the part of following general formula representative:
Wherein R57 such as above-mentioned definition.
Term " sulfoamido " is well known in the art and comprise can be by the part of following general formula representative:
Wherein R50 and R56 such as above-mentioned definition.
Term " sulfamoyl (sulfamoyl) " is well known in the art and be meant can be by the part of following general formula representative:
Wherein R50 and R51 such as above-mentioned definition.
Term " sulfonyl " is well known in the art and be meant can be by the part of following general formula representative:
Wherein R58 is one of following group: hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl.
Term " sulfoxide group (sulfoxido) " is well known in the art and be meant can be by the part of following general formula representative:
Wherein R58 such as above-mentioned definition.
Term " phosphoryl " is well known in the art and usually can be by the following formula representative:
Wherein Q50 represents S or O, and R59 represents hydrogen, low alkyl group or aryl.When being used to replace, alkyl for example, the phosphoryl of phosphoryl alkyl can be by following general formula representatives:
Wherein Q50 and R59 independently of one another as above-mentioned definition, and Q51 represents O, S or N.When Q50 is S, this phosphoryl partly is " thiophosphate ".
Term " phosphoramidite (phosphoramidite) " is well known in the art and can be represented by following general formula:
Wherein Q51, R50, R51 and R59 such as above-mentioned definition.
Term " phosphonamidite " is well known in the art and can be represented by following general formula:
Wherein Q51, R50, R51 and R59 such as above-mentioned definition, and R60 represents low alkyl group or aryl.
Can similarly replace to generate the alkenyl or alkynyl of for example amino thiazolinyl, amino alkynyl, amide groups thiazolinyl, amide groups alkynyl, imino group thiazolinyl, imino group alkynyl, sulfo-thiazolinyl, sulfo-alkynyl, carbonyl-replacement thiazolinyl and alkynyl.
The definition of various statements is in order to be different from the same structure definition elsewhere more than for example alkyl, m, n etc. occur once in any structure.
Term " seleno alkyl " is well known in the art and is meant to have the alkyl that is connected the seleno that replaces on the alkyl.Exemplary " selenide " that can replace on alkyl be selected from-the Se-alkyl ,-the Se-thiazolinyl ,-the Se-alkynyl and-Se-(CH
2)
mOne of among-the R61, m and R61 such as above-mentioned definition.
Term trifyl (triflyl), p-toluenesulfonyl (tosyl), mesyl (mesyl) and nonaflyl are well known in the art and are meant trifyl (trifluoromethanesulfonyl), p-toluenesulfonyl (p-toluenesulfonyl), mesyl (methanesulfonyl) and perfluoro butyl sulfonyl (nonafluorobutanesulfonyl) respectively.Term trifluoromethane sulfonic acid ester (triflate), p-toluenesulfonic esters (tosylate), methanesulfonates (mesylate) and nonaflate are well known in the art and are meant the fluoroform sulfonyl ester (trifluoromethanesulfonate ester) that comprises above-mentioned group respectively, tolysulfonyl ester (p-toluenesulfonate ester), the functional group and the molecule of methylsulfonyl ester (methanesulfonate ester) and perfluoro butyl sulfonyl ester (nonafluorobutanesulfonate ester).
Abbreviation Me, Et, Ph, Tf, Nf, Ts and Ms be represent methylidene, ethyl, phenyl, trifyl, perfluoro butyl sulfonyl, p-toluenesulfonyl and mesyl respectively.The employed more fully abbreviated list publication of organic chemist with this area routine techniques is on the first phase of the every volume of organic chemistry magazine (Journal of Organic Chemistry).This tabulation normally occurs with the form that is entitled as " standard list of abbreviation " (Standard List of Abbreviations).
Some chemical compound that is included in the compositions of the present invention can exist with specific geometry or stereoisomer form.In addition, chemical compound can also have optical activity.The present invention pays close attention to all these chemical compounds, comprises cis and transisomer, R-and S-enantiomer, diastereomer, (D)-isomer, (L)-isomer, its racemic mixture, and other mixture.Other asymmetric carbon atom may reside in substituent group such as the alkyl.All this isomers and composition thereof all comprise in the present invention.
If, for example wish to obtain a kind of specific enantiomeric of chemical compound, can by asymmetric synthesis or by utilizing deriving of chirality adminicle to prepare, wherein separating obtained non-enantiomer mixture be also removed auxiliary group to obtain required pure enantiomer.Perhaps work as molecule and comprise alkaline functional base such as amino, or when acid function base such as carboxyl, form diastereomeric salt with suitable optically active acid or alkali, split the diastereomer of above-mentioned formation then by fractional crystallization well known in the art or chromatographic process, reclaim pure enantiomer afterwards.
Should understand chemical compound disclosed by the invention and be in order to represent this chemical compound itself, and solvate of this chemical compound, cocrystallization, polymorphic (polymorph) etc.
Should understand " replacement " or " using ... replace " comprises condition in secret: this replacement is to meet to be substituted valent that atom and substituent group are allowed, and should replace the stable chemical compound of generation, for example it is by spontaneously changing as rearrangement, cyclisation, elimination or other reaction.
The substituent group that includes all permissions of organic compounds also considered in term " replacement ".In scope widely, the substituent group of permission includes non-annularity and ring-type, side chain and non-side chain, carbocyclic ring and heterocycle, armaticity and the nonaromatic substituent group of organic compounds.Typically substituent group comprises, for example the above-mentioned substituent group of the present invention.For suitable organic compound, admissible substituent group can be one or more and identical or different.Hetero atom such as nitrogen can have hydrogen substituent group and/or any substituent group that satisfies the permission of the valent organic compound of the present invention of hetero atom.Chemical compound is not that the substituent mode that allows by any organic compound intentionally limits.
Chemical element is according to " chemistry and physics handbook ", CAS version, the 67th edition, 1986-87 " (CAS version, Handbook of Chemistry and Physics, 67th Ed., the periodic table of elements that comprises in 1986-87) is definite.
Term " blocking group " is well known in the art and is meant that the provisional substituent group of undesirable chemical conversion does not take place the potential reactive functional group of protection.The example of this protecting group comprises the ester of carboxylic acid, the methyl silicon ether of alcohol and the acetal and the ketal of aldehyde and ketone respectively.The field of blocking group chemistry by Greene and Wuts at " blocking group of organic synthesis " second edition (Protective Groupsin Organic Synthesis (2
NdEd., Wiley:New York, 1991)) in summarize.
Term " hydroxy-protective group " is well known in the art and is meant that those are used for protecting hydroxyl in building-up process the group of undesirable reaction not to take place, and comprises benzyl for example known in the art or other suitable ester or ether
Term " carboxyl-protecting group " is well known in the art and is meant that those are used to protect hydroxy-acid group, as C-end or the acidity or the hydroxyl azepine of aminoacid or peptide
The group of undesirable reaction does not take place in ring (azepine ring) substituent group in building-up process.The example of carboxyl-protecting group comprises, for example benzyl ester, cyclohexyl ester, 4-nitrobenzyl ester, tertiary butyl ester, 4-picolyl ester etc.
Term " amino blocking group " is well known in the art and is meant and can prevents that amino from participating in the reaction of carrying out on some other functional groups, but the group that when needing, can remove from amine.This group is in the Ch.7 of Greene that above quotes and Wuts and " blocking group in the organic chemistry " of Barton (Protective Groups in Organic Chemistry ch.2) (McOmie volume; PlenumPress; New York, 1973) come into question in.The example of suitable group comprises the acyl group protecting group, illustrate, benzyl as formoxyl, dansyl (dansyl), acetyl group, benzoyl, trifluoroacetyl group, succinyl group, methoxyl group succinyl group, benzyl and replacement, as 3,4-dimethoxy-benzyl, neighbour-nitrobenzyl and trityl; Group with general formula-COOR, wherein R comprises as methyl, ethyl, propyl group, isopropyl, 2,2,2-three chloroethyls, 1-methyl isophthalic acid-phenethyl, isobutyl group, tert-butyl, uncle-amyl group, vinyl, pi-allyl, phenyl, benzyl, right-nitrobenzyl, neighbour-nitrobenzyl and 2, the group of 4-dichloro benzyl; The acyl group of acyl group and replacement is as formoxyl, acetyl group, chloracetyl, dichloro-acetyl, tribromo-acetyl base, trifluoroacetyl group, benzoyl and right-anisoyl; And other group, as mesyl, ptoluene-sulfonyl, right-bromobenzenesulfonyl, right-Nitrobenzol ethyl and ptoluene-sulfonyl amino carbonyl.Preferred amino blocking group is benzyl (CH
2C
6H
5), acyl group [C (O) R1] or SiRl
3, wherein R1 is C
1-C
4Alkyl, halogenated methyl or 2-be halogenated-(C
2-C
4Alkoxyl), fragrant urea alkane (urethane) protecting group, for example carbonyl benzyloxy (Cbz); And aliphatic urea alkane (urethane) protecting group, as uncle-butoxy carbonyl (Boc) or 9-fluorenyl (fluorenyl) methoxycarbonyl (FMOC).
The definition of various statements, for example low alkyl group, m, n, p etc. are in order to be different from same structure definition elsewhere more than occurring once in any structure.
Term " electron withdraw group " is well known in the art and is meant the trend of substituent group from contiguous atom attraction valency electron that promptly this substituent group is electronegative to contiguous atom.Quantitatively providing of electron-withdrawing power level by Hammett sigma (σ) constant.This constant of knowing is on the books in many reference materials, for example the 251st to 259 page of (Advanced OrganicChemistry 251-59) (McGraw Hill Book Company:New York, 1977) of " Advanced Organic Chemistry " of March.The Hammett constant value is generally negative value (NH concerning electron-donating group
2σ (P)=-0.66), and be concerning electron withdraw group on the occasion of (σ of nitro (P)=0.78).σ (P) shows para-orientation.Exemplary electron withdraw group comprises nitro, acyl group, formoxyl, sulfonyl, trifluoromethyl, cyano group, chlorine etc.Exemplary electron-donating group comprises amino, methoxyl group etc.
I. be used to improve the illustrative methods and the compositions of proteic activity of sirtuin or protein level
In a specific embodiments, exemplary Sirtuin activating compounds is the chemical compounds described in (2003) Nature 425:191 such as Howitz, for example comprises, resveratrol (3,5,4 '-trihydroxy-trans-stilbene), butein (3,4,2 ', 4 '-the tetrahydroxy chalcone derivative), Rhizoma Euonymus China fir alcohol (piceatannol, 3,5,3 ', 4 '-tetrahydroxy-trans-stilbene), isoliquiritigenin (4,2 ', 4 '-the trihydroxy chalcone derivative), fisetin (3,7,3 ', 4 '-kaempferol), Quercetin (3,5,7,3 ', 4 '-pentahydroxyflavone), deoxyrhapontin (deoxyrhapontin, 3,5-dihydroxy-4 '-methoxyl group stilbene 3-O-β-D-glucoside), trans-stilbene, ponticin (3,3 ', 5-trihydroxy-4 '-methoxyl group stilbene 3-O-β-D-glucoside), cis-stilbene, butein (3,4,2 ', 4 '-the tetrahydroxy chalcone derivative), 3,4,2 ' 4 ' 6 '-the penta hydroxy group chalcone derivative, chalcone derivative, 7,8,3 ', 4 '-kaempferol, 3,6,2 ', 3 '-kaempferol, 4 '-flavonol, 5,4 '-dihydroxyflavone, 5, the 7-dihydroxyflavone, morin (3,5,7,2 ', 4 '-pentahydroxyflavone), flavone, the 5-flavonol, (-)-epicatechin (hydroxy position: 3,5,7,3 ', 4 '), (-)-catechin (hydroxy position: 3,5,7,3 ', 4 '), (-)-nutgall catechin (hydroxy position: 3,5,7,3 ', 4 ', 5 '), (+)-catechin (hydroxy position: 3,5,7,3 ', 4 '), 5,7,3 ', 4 ', 5 '-pentahydroxyflavone, luteolin (5,7,3 ', 4 '-kaempferol), 3,6,3 ', 4 '-kaempferol, 7,3 ', 4 ', 5 '-kaempferol, kaempferol (Kaempferol, 3,5,7,4 '-kaempferol), 6-hydroxyl apigenin (Hydroxyapigenin, 5,6,7,4 '-kaempferol), baicalin (scutellarein), apigenin (5,7,4 '-trihydroxyflavone), 3,6,2 ', 4 '-kaempferol, 7,4 '-dihydroxyflavone, daidzein (daidzein, 7,4 '-dihydroxy isoflavone), genistein (genistein, 5,7,4 '-the trihydroxy flavanone), naringenin (5,7,4 '-the trihydroxy flavanone), 3,5,7,3 ', 4 '-the penta hydroxy group flavanone, flavanone, pelargonidin chloride (3,5,7,4 '-tetrahydroxy chlorination Huang
Salt), Hinokitiol (b-arborvitae element, 2-hydroxyl-4-isopropyl-2,4,6-cycloheptatriene-1-ketone), L-(+)-ergothioneine ((S)-a-carboxyl-2,3-dihydro-N, N, N-trimethyl-2-sulfo--1H-imidazoles-4-second ammonium (ethanaminium) inner salt), the caffeic acid phenyl ester, MCI-186 (3-methyl isophthalic acid-phenyl-2-pyrazolin-5-one), HBED (N, N '-two-(2-hydroxybenzyl) ethylenediamine-N, N '-oxalic acid H2O), ambroxol (trans-4-(2-amino-3,5-dibromo-benzyl amino) (((4-(2 for (-)-2-for cyclohexylamine HCl and U-83836E, 6-two-1-pyrrolidinyl-4-pyrimidine radicals)-and 1-piperazine (piperzainyl)) methyl)-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-.alpha.-5:6-benzopyran-6-alcohol 2HCl).Its analog and derivant also can be used.
Other Sirtuin activating compounds can have following any general formula 1-25,30,32-65 and 69-88.In a specific embodiments, the Sirtuin activating compounds is stilbene shown in the general formula 1 or chalcone compounds:
Wherein, each variable (occurrence) is independently of one another,
R
1, R
2, R
3, R
4, R
5, R '
1, R '
2, R '
3, R '
4And R '
5Represent H, alkyl, aryl, heteroaryl, aralkyl, alkaryl, heteroaryl alkyl, halogenide, NO
2, SR, OR, N (R)
2Or carboxyl;
R represents H, alkyl, aryl, heteroaryl or aralkyl;
M represents O, NR or S;
A-B represents divalent alkyl, thiazolinyl, alkynyl, amide groups, sulfoamido, diazo, ether, alkyl amino, alkyl sulfide (alkylsulfide), azanol or diazanyl; And
N is 0 or 1.
In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 1 and subsidiary definition thereof, and wherein n is 0.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 1 and subsidiary definition thereof, and wherein n is 1.The Sirtuin activating compounds is the chemical compound with general formula 1 and subsidiary definition thereof more specifically in the embodiment at one, and wherein A-B is a vinyl.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 1 and subsidiary definition thereof, and wherein A-B is-CH
2CH (Me) CH (Me) CH
2-.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 1 and subsidiary definition thereof, and wherein M is O.In a more particular embodiment, method comprises the chemical compound with general formula 1 and subsidiary definition thereof, wherein R
1, R
2, R
3, R
4, R
5, R '
1, R '
2, R '
3, R '
4And R '
5Be H.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 1 and subsidiary definition thereof, wherein R
2, R
4And R '
3Be OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 1 and subsidiary definition thereof, wherein R
2, R
4, R '
2And R '
3Be OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 1 and subsidiary definition thereof, wherein R
3, R
5, R '
2And R '
3Be OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 1 and subsidiary definition thereof, wherein R
1, R
3, R
5, R '
2And R '
3Be OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 1 and subsidiary definition thereof, wherein R
2And R '
2Be OH; R
4Be O-β-D-glucoside; And R '
3Be OCH
3In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 1 and subsidiary definition thereof, wherein R
2Be OH; R
4Be O-β-D-glucoside; And R '
3Be OCH
3
In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 1 and subsidiary definition thereof, and wherein n is 0; A-B is a vinyl; And R
1, R
2, R
3, R
4, R
5, R '
1, R '
2, R '
3, R '
4And R '
5Be H (trans stilbene).In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 1 and subsidiary definition thereof, and wherein n is 1; A-B is a vinyl; M is O; And R
1, R
2, R
3, R
4, R
5, R '
1, R '
2, R '
3, R '
4And R '
5Be H (chalcone derivative).In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 1 and subsidiary definition thereof, and wherein n is 0; A-B is a vinyl; R
2, R
4And R '
3Be OH; And R
1, R
3, R
5, R '
1, R '
2, R '
4And R '
5Be H (resveratrol).In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 1 and subsidiary definition thereof, and wherein n is 0; A-B is a vinyl; R
2, R
4, R '
2And R '
3Be OH; And R
1, R
3, R
5, R '
1, R '
4And R '
5Be by H (Rhizoma Euonymus China fir alcohol).In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 1 and subsidiary definition thereof, and wherein n is 1; A-B is a vinyl; M is O; R
3, R
5, R '
2And R '
3Be OH; R
1, R
2, R
4, R '
1, R '
4And R '
5Be H (butein).In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 1 and subsidiary definition thereof, and wherein n is 1; A-B is a vinyl; M is O; R
1, R
3, R
5, R '
2And R '
3Be OH; R
2, R
4, R '
1, R '
4And R '
5For H (3,4,2 ', 4 ', 6 '-the penta hydroxy group chalcone derivative).In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 1 and subsidiary definition thereof, and wherein n is 0; A-B is a vinyl; R
2And R '
2Be OH, R
4Be O-β-D-glucoside, R '
3Be OCH
3R
1, R
3, R
5, R '
1, R '
4And R '
5Be H (ponticin).In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 1 and subsidiary definition thereof, and wherein n is 0; A-B is a vinyl; R
2Be OH, R
4Be O-β-D-glucoside, R '
3Be OCH
3And R
1, R
3, R
5, R '
1, R '
2, R '
4And R '
5Be H (deoxyrhapontin).In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 1 and subsidiary definition thereof, and wherein n is 0; A-B is-CH
2CH (Me) CH (Me) CH
2-; R
2, R
3, R '
2And R '
3Be OH; R
1, R
4, R
5, R '
1, R '
4And R '
5Be H (NDGA).
In another embodiment, the Sirtuin activating compounds is the flavanone compound shown in the general formula 2:
Wherein, each variable is independently of one another,
R
1, R
2, R
3, R
4, R '
1, R '
2, R '
3, R '
4, R '
5And R " represents H, alkyl, aryl, heteroaryl, aralkyl, alkaryl, heteroaryl alkyl, halogenide, NO
2, SR, OR, N (R)
2Or carboxyl;
R represents H, alkyl, aryl, heteroaryl or aralkyl;
M represents H
2, O, NR or S
Z represents CR, O, NR or S
X represents CR or N; And
Y represents CR or N.
In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 2 and subsidiary definition thereof, and wherein X and Y are CH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 2 and subsidiary definition thereof, and wherein M is O.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 2 and subsidiary definition thereof, and wherein M is H
2In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 2 and subsidiary definition thereof, and wherein Z is O.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 2 and subsidiary definition thereof, and wherein R " is H.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 2 and subsidiary definition thereof, and wherein R " is OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 2 and subsidiary definition thereof, and wherein R " is an alkoxy carbonyl group.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 2 and subsidiary definition thereof, wherein R
1For
In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 2 and subsidiary definition thereof, wherein R
1, R
2, R
3, R
4, R '
1, R '
2, R '
3, R '
4, R '
5And R " is H.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound of general formula 2 and subsidiary definition thereof, wherein R
2, R
4And R '
3Be OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 2 and subsidiary definition thereof, wherein R
4, R '
2, R '
3And R " is OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 2 and subsidiary definition thereof, wherein R
2, R
4, R '
2, R '
3And R " is OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 2 and subsidiary definition thereof, wherein R
2, R
4, R '
2, R '
3, R '
4And R " is OH.
In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 2 and subsidiary definition thereof, and wherein X and Y are CH; M is O; Z is O; R " is H; R
1, R
2, R
3, R
4, R '
1, R '
2, R '
3, R '
4, R '
5And R " is H (flavanone).In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 2 and subsidiary definition thereof, and wherein X and Y are CH; M is O; Z is O; R " is H; R
2, R
4And R '
3Be OH; R
1, R
3, R '
1, R '
2, R '
4And R '
5Be H (naringenin).In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 2 and subsidiary definition thereof, and wherein X and Y are CH; M is O; Z is O; R " is OH; R
2, R
4, R '
2And R '
3Be OH; R
1, R
3, R '
1, R '
4And R '
5For H (3,5,7,3 ', 4 '-the penta hydroxy group flavanone).In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 2 and subsidiary definition thereof, and wherein X and Y are CH; M is H
2Z is O; R " is OH; R
2, R
4, R '
2And R '
3Be OH; And R
1, R
3, R '
1, R '
4And R '
5Be H (epicatechin).In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 2 and subsidiary definition thereof, and wherein X and Y are CH; M is H
2Z is O; R " is OH; R
2, R
4, R '
2, R '
3And R '
4Be OH; R
1, R
3, R '
1And R '
5Be H (nutgall catechin).In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 2 and subsidiary definition thereof, and wherein X and Y are CH; M is H
2Z is O; R " is
R
2, R
4, R '
2, R '
3, R '
4And R " is OH; R
1, R
3, R '
1And R '
5Be H (epigallocatechin gallate (EGCG)).
In another embodiment, the Sirtuin activating compounds is the isoflavanone chemical compound shown in the general formula 3:
Wherein, each variable is independently of one another,
R
1, R
2, R
3, R
4, R '
1, R '
2, R '
3, R '
4, R '
5And R "
1Represent H, alkyl, aryl, heteroaryl, aralkyl, alkaryl, heteroaryl alkyl, halogenide, NO
2, SR, OR, N (R)
2Or carboxyl;
R represents H, alkyl, aryl, heteroaryl or aralkyl;
M represents H
2, O, NR or S;
Z represents C (R)
2, O, NR or S;
X represents CR or N; And
Y represents CR or N.
In another embodiment, the Sirtuin activating compounds is the chromocor compound shown in the general formula 4:
Wherein, each variable is independently of one another,
R
1, R
2, R
3, R
4, R '
1, R '
2, R '
3, R '
4And R '
5Represent H, alkyl, aryl, heteroaryl, aralkyl, alkaryl, heteroaryl alkyl, halogenide, NO
2, SR, OR, N (R)
2Or carboxyl;
R represents H, alkyl, aryl, heteroaryl or aralkyl;
M represents H
2, O, NR or S;
Z represents CR, O, NR or S; And
X represents CR " or N, wherein
R " is H, alkyl, aryl, heteroaryl, alkaryl, heteroaryl alkyl, halogenide, NO
2, SR, OR, N (R)
2Or carboxyl.
In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein X is C.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein X is CR.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein Z is O.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein M is O.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 subsidiary definition, and wherein R " is H.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein R " is OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, wherein R
1, R
2, R
3, R
4, R '
1, R '
2, R '
3, R '
4And R '
5Be H.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, wherein R
2, R '
2And R '
3Be OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, wherein R
2, R
4, R '
2, R '
3And R '
4Be OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, wherein R
2, R
4, R '
2And R '
3Be OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, wherein R
3, R '
2And R '
3Be OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, wherein R
2, R
4, R '
2And R '
3Be OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, wherein R
2, R '
2, R '
3And R '
4Be OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, wherein R
2, R
4And R '
3Be OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, wherein R
2, R
3, R
4And R '
3Be OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, wherein R
2, R
4And R '
3Be OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, wherein R
3, R '
1And R '
3Be OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, wherein R
2And R '
3Be OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, wherein R
1, R
2, R '
2And R '
3Be OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, wherein R
3, R '
1And R '
2Be OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, wherein R '
3Be OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, wherein R
4And R '
3Be OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, wherein R
4And R
4Be OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, wherein R
2, R
4, R '
1And R '
3Be OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, wherein R
4Be OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, wherein R
2, R
4, R '
2, R '
3And R '
4Be OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, wherein R
2, R '
2, R '
3And R '
4Be OH.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, wherein R
1, R
2, R
4, R '
2And R '
3Be OH.
In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein X is CH; Z is O; M is O; And R
1, R
2, R
3, R
4, R '
1, R '
2, R '
3, R '
4And R '
5Be H (flavone).In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein X is COH; Z is O; M is O; R
2, R '
2And R '
3Be OH; R
1, R
3, R
4, R '
1, R '
4And R '
5Be H (fisetin).In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein X is CH; Z is O; M is O; R
2, R
4, R '
2, R '
3And R '
4Be OH; R
1, R
3, R '
1And R '
5For H (5,7,3 ', 4 ', 5 '-pentahydroxyflavone).In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein X is CH; Z is O; M is O; R
2, R
4, R '
2And R '
3Be OH; R
1, R
3, R '
1, R '
4And R '
5Be H (luteolin).In a more particular embodiment, Sirtuin reactivity chemical compound is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein X is COH; Z is O; M is O; R
3, R '
2And R '
3Be OH; R
1, R
2, R
4, R '
1, R '
4And R '
5For H (3,6,3 ', 4 '-kaempferol).In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein X is COH; Z is O; M is O; R
2, R
4, R '
2And R '
3Be OH; And R
1, R
3, R '
1, R '
4And R '
5Be H (Quercetin).In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein X is CH; Z is O; M is O; R
2, R '
2, R '
3And R '
4Be OH; R
1, R
3, R
4, R '
1And R '
5Be H.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein X is COH; Z is O; M is O; R
2, R
4And R '
3Be OH; R
1, R
3, R '
1, R '
2, R '
4And R '
5Be H.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein X is CH; Z is O; M is O; R
2, R
3, R
4And R '
3Be OH; And R
1, R '
1, R '
2, R '
4And R '
5Be H.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein X is CH; Z is O; M is O; R
2, R
4And R '
3Be OH; R
1, R
3, R '
1, R '
2, R '
4And R '
5Be H.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein X is COH; Z is O; M is O; R
3, R '
1And R '
3Be OH; R
1, R
2, R
4, R '
2, R '
4And R '
5Be H.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein X is CH; Z is O; M is O; R
2And R '
3Be OH; And R
1, R
3, R
4, R '
1, R '
2, R '
4And R '
5Be H.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein X is COH; Z is O; M is O; R
1, R
2, R '
2And R '
3Be OH; And R
1, R
2, R
4, R '
3, R '
4And R '
5Be H.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein X is COH; Z is O; M is O; R
3, R '
1And R '
2Be OH; And R
1, R
2, R
4, R '
3, R '
4And R '
5Be H.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein X is CH; Z is O; M is O; R '
3Be OH; R
1, R
2, R
3, R
4, R '
1, R '
2, R '
4And R '
5Be H.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein X is CH; Z is O; M is O; R
4And R '
3Be OH; And R
1, R
2, R
3, R '
1, R '
2, R '
4And R '
5Be H.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein X is CH; Z is O; M is O; R
2And R
4Be OH; R
1, R
3, R '
1, R '
2, R '
3, R '
4And R '
5Be H.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein X is COH; Z is O; M is O; R
2, R
4, R '
1And R '
3Be OH; R
1, R
3, R '
2, R '
4And R '
5Be H.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein X is CH; Z is O; M is O; R
4Be OH; R
1, R
2, R
3, R '
1, R '
2, R '
3, R '
4And R '
5Be H.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein X is COH; Z is O; M is O; R
2, R
4, R '
2, R '
3And R '
4Be OH; And R
1, R
3, R '
1And R '
5Be H.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein X is COH; Z is O; M is O; R
2, R '
2, R '
3And R '
4Be OH; And R
1, R
3, R
4, R '
1And R '
5Be H.In a more particular embodiment, the Sirtuin activating compounds is the chemical compound with general formula 4 and subsidiary definition thereof, and wherein X is COH; Z is O; M is O; R
1, R
2, R
4, R '
2And R '
3Be OH; And R
3, R '
1, R '
4And R '
5Be H.
In another embodiment, the Sirtuin activating compounds is the isoflavone compounds shown in the general formula 5:
Wherein, each variable is independently of one another,
R
1, R
2, R
3, R
4, R '
1, R '
2, R '
3, R '
4And R '
5Represent H, alkyl, aryl, heteroaryl, aralkyl, alkaryl, heteroaryl alkyl, halogenide, NO
2, SR, OR, N (R)
2Or carboxyl;
R represents H, alkyl, aryl, heteroaryl or aralkyl;
M represents H
2, O, NR or S;
Z represents C (R)
2, O, NR or S; And
Y represents CR " or N, wherein
R " represents H, alkyl, aryl, heteroaryl, alkaryl, heteroaryl alkyl, halogenide, NO
2, SR, OR, N (R)
2Or carboxyl.
The Sirtuin activating compounds is the chemical compound with general formula 5 and subsidiary definition thereof more specifically in the embodiment at one, and wherein Y is CR ".The Sirtuin activating compounds is the chemical compound with general formula 5 and subsidiary definition thereof more specifically in the embodiment at one, and wherein Y is CH.The Sirtuin activating compounds is the chemical compound with general formula 5 and subsidiary definition thereof more specifically in the embodiment at one, and wherein Z is O.The Sirtuin activating compounds is the chemical compound with general formula 5 and subsidiary definition thereof more specifically in the embodiment at one, and wherein M is O.At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound with general formula 5 and subsidiary definition thereof, wherein R
2And R '
3Be OH.At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound with general formula 5 and subsidiary definition thereof, wherein R
2, R
4And R '
3Be OH.
The Sirtuin activating compounds is the chemical compound with general formula 5 and subsidiary definition thereof more specifically in the embodiment at one, and wherein Y is CH; Z is O; M is O; R
2And R '
3Be OH; R
1, R
3, R
4, R '
1, R '
2, R '
4And R '
5Be H.The Sirtuin activating compounds is the chemical compound with general formula 5 and subsidiary definition thereof more specifically in the embodiment at one, and wherein Y is CH; Z is O; M is O; R
2, R
4And R '
3Be OH; And R
1, R
3, R '
1, R '
2, R '
4And R '
5Be H.
In another embodiment, the Sirtuin activating compounds is the anthocyanidin chemical compound shown in the general formula 6:
Wherein, each variable is independently of one another,
R
3, R
4, R
5, R
6, R
7, R
8, R '
2, R '
3, R '
4, R '
5And R '
6Represent H, alkyl, aryl, heteroaryl, aralkyl, alkaryl, heteroaryl alkyl, halogenide, NO
2, SR, OR, N (R)
2Or carboxyl;
R represents H, alkyl, aryl, heteroaryl or aralkyl; And
A
-Representative is selected from following anion: Cl
-, Br
-Or I
-
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound with general formula 6 and subsidiary definition thereof, wherein A
-Be Cl
-At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound with general formula 6 and subsidiary definition thereof, wherein R
3, R
5, R
7And R '
4Be OH.At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound with general formula 6 and subsidiary definition thereof, wherein R
3, R
5, R
7, R '
3And R '
4Be OH.At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound with general formula 6 and subsidiary definition thereof, wherein R
3, R
5, R
7, R '
3, R '
4And R '
5Be OH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound with general formula 6 and subsidiary definition thereof, wherein A
-Be Cl
-R
3, R
5, R
7And R '
4Be OH; And R
4, R
6, R
8, R '
2, R '
3, R '
5And R '
6Be H.At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound with general formula 6 and subsidiary definition thereof, wherein A
-Be Cl
-R
3, R
5, R
7, R '
3And R '
4Be OH; And R
4, R
6, R
8, R '
2, R '
5And R '
6Be H.At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound with general formula 6 and subsidiary definition thereof, wherein A
-Be Cl
-R
3, R
5, R
7, R '
3, R '
4And R '
5Be OH; And R
4, R
6, R
8, R '
2And R '
6Be H.
At one more specifically in the embodiment, the Sirtuin activating compounds is the stilbene shown in the general formula 7, chalcone derivative or chromocor compound:
Wherein, each variable is independently of one another,
M does not exist or is O;
R
1, R
2, R
3, R
4, R
5, R '
1, R '
2, R '
3, R '
4And R '
5Represent H, alkyl, aryl, heteroaryl, aralkyl, alkaryl, heteroaryl alkyl, halogenide, NO
2, SR, OR, N (R)
2Or carboxyl;
R
aRepresent H or two R
aForm a key;
R represents H, alkyl, aryl, heteroaryl, aralkyl; And
N is 0 or 1.
The Sirtuin activating compounds is the activating compounds of general formula 7 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein n is 0.The Sirtuin activating compounds is the activating compounds of general formula 7 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein n is 1.The Sirtuin reactive compound is the activating compounds of general formula 7 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein M does not exist.The Sirtuin activating compounds is the activating compounds of general formula 7 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein M is O.At one more specifically in the embodiment, the Sirtuin activating compounds is the activating compounds of general formula 7 and subsidiary definition representative thereof, wherein R
aBe H.The Sirtuin activating compounds is the activating compounds of general formula 7 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein M is O and two R
aForm a key.
At one more specifically in the embodiment, the Sirtuin activating compounds is the activating compounds of general formula 7 and subsidiary definition representative thereof, wherein R
5Be H.At one more specifically in the embodiment, the Sirtuin activating compounds is the activating compounds of general formula 7 and subsidiary definition representative thereof, wherein R
5Be OH.At one more specifically in the embodiment, the Sirtuin activating compounds is the activating compounds of general formula 7 and subsidiary definition representative thereof, wherein R
1, R
3And R '
3Be OH.At one more specifically in the embodiment, the Sirtuin activating compounds is the activating compounds of general formula 7 and subsidiary definition representative thereof, wherein R
2, R
4, R '
2And R '
3Be OH.At one more specifically in the embodiment, the Sirtuin activating compounds is the activating compounds of general formula 7 and subsidiary definition representative thereof, wherein R
2, R '
2And R '
3Be OH.At one more specifically in the embodiment, the Sirtuin activating compounds is the activating compounds of general formula 7 and subsidiary definition representative thereof, wherein R
2And R
4Be OH.
The Sirtuin activating compounds is the chemical compound of general formula 7 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein n is 0; M does not exist; R
aBe H; R
5Be H; R
1, R
3And R '
3Be OH; And R
2, R
4, R '
1, R '
2, R '
4And R '
5Be H.The Sirtuin activating compounds is the activating compounds of general formula 7 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein n is 1; M does not exist; R
aBe H; R
5Be H; R
2, R
4, R '
2And R '
3Be OH; And R
1, R
3, R '
1, R '
4And R '
5Be H.The Sirtuin activating compounds is the activating compounds of general formula 7 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein n is 1; M is O; Two R
aForm a key; R
5Be OH; R
2, R '
2And R '
3Be 0H; And R
1, R
3, R
4, R '
1, R '
4And R '
5Be H.
Other Sirtuin activating compounds comprises the chemical compound with the general formula that is selected from following general formula 8-25 and 30.
R
1, R
2=H, aryl, heterocycle, little alkyl R
1, R
2=H, aryl, heterocycle, little alkyl
A, B, C, D=CR
1, N R3=H, little alkyl
n＝0、1、2、3 A、B＝CR
1、N
n＝0、1、2、3
R
1, R
2=H, aryl, heterocycle, little alkyl R
1, R
2=H, aryl, heterocycle, little alkyl
R '
1-R '
5=H, OH R
3=H, little alkyl
A、B、C、D＝CR
1、N R′
1-R′
5＝H、OH
n＝0、1、2、3 A、B＝CR
1、N
n＝0、1、2、3
R
1, R
2=H, alkyl, thiazolinyl R=heterocycle, aryl
n＝0-10
R
1=H, halogen, NO
2, SR (R=H, alkyl, aryl), OR (R=H, alkyl, aryl), NRR ' (R, R '=alkyl, aryl), alkyl, aryl, carboxyl
R
2=H, halogen, NO
2, SR (R=H, alkyl, aryl), OR (R=H, alkyl, aryl), NRR ' (R, R '=alkyl, aryl), alkyl, aryl, carboxyl
R
3=H, halogen, NO
2, SR (R=H, alkyl, aryl), OR (R=H, alkyl, aryl), NRR ' (R, R '=alkyl, aryl), alkyl, aryl, carboxyl
R
4=H, halogen, NO
2, SR (R=H, alkyl, aryl), OR (R=H, alkyl, aryl), NRR ' (R, R '=alkyl, aryl), alkyl, aryl, carboxyl
R
5=H, halogen, NO
2, SR (R=H, alkyl, aryl), OR (R=H, alkyl, aryl), NRR ' (R, R '=alkyl, aryl), alkyl, aryl, carboxyl
R '
1=H, halogen, NO
2, SR (R=H, alkyl, aryl), OR (R=H, alkyl, aryl), NRR ' (R, R '=alkyl, aryl), alkyl, aryl, carboxyl
R '
2=H, halogen, NO
2, SR (R=H, alkyl, aryl), OR (R=H, alkyl, aryl), NRR ' (R, R '=alkyl, aryl), alkyl, aryl, carboxyl
R '
3=H, halogen, NO
2, SR (R=H, alkyl, aryl), OR (R=H, alkyl, aryl), NRR ' (R, R '=alkyl, aryl), alkyl, aryl, carboxyl
R '
4=H, halogen, NO
2, SR (R=H, alkyl, aryl), OR (R=H, alkyl, aryl), NRR ' (R, R '=alkyl, aryl), alkyl, aryl, carboxyl
R '
5=H, halogen, NO
2, SR (R=H, alkyl, aryl), OR (R=H, alkyl, aryl), NRR ' (R, R '=alkyl, aryl), alkyl, aryl, carboxyl
R "
1=H, halogen, NO
2, SR (R=H, alkyl, aryl), OR (R=H, alkyl, aryl), NRR ' (R, R '=alkyl, aryl), alkyl, aryl, carboxyl
A-B=ethylene, acetylene, amide, sulfonamide, diazo, alkyl ether, alkylamine, alkyl sulfide, azanol, hydrazine
X＝CR、N
Y＝CR、N
Z＝O、S、C(R)
2、NR
R=H, alkyl, aryl, aralkyl
Wherein, each variable is independently of one another,
R=H, alkyl, aryl, heterocyclic radical, heteroaryl or aralkyl; And
R '=H, halogen, NO
2, SR, OR, NR
2, alkyl, aryl or carboxyl.
Wherein, each variable is independently of one another,
R=H, alkyl, aryl, heterocyclic radical, heteroaryl or aralkyl.
Wherein, each variable is independently of one another,
R '=H, halogen, NO
2, SR, OR, NR
2, alkyl, aryl, aralkyl or carboxyl;
And
R=H, alkyl, aryl, heterocyclic radical, heteroaryl or aralkyl.
Wherein, each variable is independently of one another,
L represents CR
2, O, NR or S;
R represents H, alkyl, aryl, aralkyl or heteroaryl alkyl; And
R ' represents H, halogen, NO
2, SR, OR, NR
2, alkyl, aryl, aralkyl or carboxyl.
Wherein, each variable is independently of one another,
L represents CR
2, O, NR or S;
W represents CR or N;
R represents H, alkyl, aryl, aralkyl or heteroaryl alkyl;
Ar represents fused aromatic rings or fragrant heterocycle; And
R ' represents H, halogen, NO
2, SR, OR, NR
2, alkyl, aryl, aralkyl or carboxyl.
Wherein, each variable is independently of one another,
L represents CR
2, O, NR or S;
R represents H, alkyl, aryl, aralkyl or heteroaryl alkyl; And
R ' represents H, halogen, NO
2, SR, OR, NR
2, alkyl, aryl, aralkyl or carboxyl.
Wherein, each variable is independently of one another,
L represents CR
2, O, NR or S;
R represents H, alkyl, aryl, aralkyl or heteroaryl alkyl; And
R ' represents H, halogen, NO
2, SR, OR, NR
2, alkyl, aryl, aralkyl or carboxyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the stilbene shown in the general formula 30, chalcone derivative or chromocor compound:
Wherein, each variable is independently of one another,
D is phenyl or cyclohexyl;
R
1, R
2, R
3, R
4, R
5, R '
1, R '
2, R '
3, R '
4And R '
5Represent H, alkyl, aryl, heteroaryl, alkaryl, heteroaryl alkyl, halogenide, NO
2, SR, OR, N (R)
2, carboxyl, azido, ether; Or any two adjacent R or R ' form condensed phenyl ring or cyclohexyl together;
R represents H, alkyl, aryl or aralkyl; And
A-B represents vinyl, ethenylidene or imido grpup;
Condition is A-B when being ethenylidene, and D is a phenyl, and R '
3Be H: work as R
1, R
2, R
4And R
5During for H, R
3Be not OH; And work as R
1, R
3And R
5During for H, R
2And R
4Be not OMe; Work as R
1, R
2, R
4And R
5During for H, R
3Be not OMe.
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein D is a phenyl.
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein A-B is ethenylidene or imido grpup.
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein A-B is an ethenylidene.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof, wherein R
2Be OH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof, wherein R
4Be OH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof, wherein R
2And R
4Be OH.
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein D is a phenyl; And A-B is an ethenylidene.
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein D is a phenyl; A-B is an ethenylidene; R
2And R
4Be OH.
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein A-B is inferior ethylene; D is a phenyl ring; R
2And R
4Be OH; And R '
3Be Cl.
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein A-B is inferior ethylene; D is a phenyl ring; R
2And R
4Be OH; And R '
3Be OH.
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein A-B is inferior ethylene; D is a phenyl ring; R
2And R
4Be OH; And R '
3Be H.
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein A-B is inferior ethylene; D is a phenyl ring; R
2And R
4Be OH; And R '
3Be CH
2CH
3
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein A-B is inferior ethylene; D is a phenyl ring; R
2And R
4Be OH; And R '
3Be F.
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein A-B is inferior ethylene; D is a phenyl ring; R
2And R
4Be OH; And R '
3Be Me.
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein A-B is inferior ethylene; D is a phenyl ring; R
2And R
4Be OH; And R '
3Be azido.
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein A-B is inferior ethylene; D is a phenyl ring; R
2And R
4Be OH; And R '
3Be SMe.
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein A-B is inferior ethylene; D is a phenyl ring; R
2And R
4Be OH; And R '
3Be NO
2
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein A-B is inferior ethylene; D is a phenyl ring; R
2And R
4Be OH; R '
3Be CH (CH
3)
2
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein A-B is inferior ethylene; D is a phenyl ring; R
2And R
4Be OH; And R '
3Be OMe.
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein A-B is inferior ethylene; D is a phenyl ring; R
2And R
4Be OH; R '
2Be OH; R '
3Be OMe.
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein A-B is inferior ethylene; D is a phenyl ring; R
2Be OH; R
4Be carboxyl; And R '
3Be OH.
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein A-B is inferior ethylene; D is a phenyl ring; R
2And R
4Be OH; And R '
3Be carboxyl.
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein A-B is inferior ethylene; D is a phenyl ring; R
2And R
4Be OH; And R '
3And R '
4Form fused benzene rings together.
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein A-B is inferior ethylene; D is a phenyl ring; And R
4Be OH.
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein A-B is inferior ethylene; D is a phenyl ring; R
2And R
4Be OCH
2OCH
3And R '
3Be SMe.
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein A-B is inferior ethylene; D is a phenyl ring; R
2And R
4Be OH; And R '
3Be carboxyl.
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein A-B is inferior ethylene; D is a cyclohexyl ring; And R
2And R
4Be OH.
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein A-B is inferior ethylene; D is a phenyl ring; And R
3And R
4Be OMe.
The Sirtuin activating compounds is the chemical compound of general formula 30 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein A-B is inferior ethylene; D is a phenyl ring; R
2And R
4Be OH; And R '
3Be OH.
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 32:
Wherein, each variable is independently of one another,
R be H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl; And
R
1And R
2For replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl.
The Sirtuin activating compounds is a chemical compound shown in general formula 32 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H.
At one more specifically in the embodiment, the Sirtuin activating compounds is chemical compound, wherein R shown in general formula 32 and the subsidiary definition thereof
1Be the 3-hydroxy phenyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 32 and the subsidiary definition thereof, wherein R
2Be methyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 32 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H and R
1Be the 3-hydroxy phenyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 32 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be the 3-hydroxy phenyl, and R
2Be methyl.
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 33:
Wherein, each variable is independently of one another,
R be H or replacement or unsubstituted alkyl, alkenyl or alkynyl;
R
1And R
2For replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl; And
L is O, S or NR.
The Sirtuin activating compounds is a chemical compound shown in general formula 33 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is an alkynyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 33 and the subsidiary definition thereof, wherein R
1Be 2, the 6-Dichlorobenzene base.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 33 and the subsidiary definition thereof, wherein R
2Be methyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 33 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein L is O.
The Sirtuin activating compounds is the chemical compound shown in general formula 33 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is alkynyl and R
1Be 2, the 6-Dichlorobenzene base.
The Sirtuin activating compounds is the chemical compound shown in general formula 33 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is an alkynyl, R
1Be 2,6-Dichlorobenzene base, and R
2Be methyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 33 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is an alkynyl, R
1Be 2,6-Dichlorobenzene base, R
2Be methyl, and L is O.
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 34:
Wherein, each variable is independently of one another,
R, R
1And R
2For H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl; And
N comprises 0 to 5 integer.
The Sirtuin activating compounds is the chemical compound shown in general formula 34 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is 3,5-two chloro-2-hydroxy phenyls.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 34 and the subsidiary definition thereof, wherein R
1Be H.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 34 and the subsidiary definition thereof, wherein R
2Be H.
The Sirtuin activating compounds is the chemical compound shown in general formula 34 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1.
The Sirtuin activating compounds is the chemical compound shown in general formula 34 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is 3,5-two chloro-2-hydroxy phenyl and R
1Be H.
The Sirtuin activating compounds is the chemical compound shown in general formula 34 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is 3,5-two chloro-2-hydroxy phenyls, R
1Be H and R
2Be H.
The Sirtuin activating compounds is the chemical compound shown in general formula 34 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is 3,5-two chloro-2-hydroxy phenyls, R
1Be H, R
2For H and n are 1.
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 35:
Wherein, each variable is separate,
R be H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
R
1For replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
R
2Be hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro, or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl, heteroaryl alkyl;
L is O, NR or S;
M comprises 0 to 3 integer;
N comprises 0 to 5 integer; And
O comprises 0 to 2 integer.
The Sirtuin activating compounds is the chemical compound shown in general formula 35 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is a phenyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 35 and the subsidiary definition thereof, wherein R
1Be pyridine radicals.
The Sirtuin activating compounds is the chemical compound shown in general formula 35 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein L is S.
The Sirtuin activating compounds is the chemical compound shown in general formula 35 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein m is 0.
The Sirtuin activating compounds is the chemical compound shown in general formula 35 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1.
The Sirtuin activating compounds is the chemical compound shown in general formula 35 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein o is 0.
The Sirtuin activating compounds is the chemical compound shown in general formula 35 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is phenyl and R
1Be pyridine radicals.
The Sirtuin activating compounds is the chemical compound shown in general formula 35 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is a phenyl, R
1Be pyridine radicals, and L is S.
The Sirtuin activating compounds is the chemical compound shown in general formula 35 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is a phenyl, R
1Be pyridine radicals, L is S, and m is 0.
The Sirtuin activating compounds is the chemical compound shown in general formula 35 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is a phenyl, R
1Be pyridine radicals, L is S, and m is 0, and n is 1.
The Sirtuin activating compounds is the chemical compound shown in general formula 35 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is a phenyl, R
1Be pyridine radicals, L is S, and m is 0, and n is 1, and o is 0.
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 36:
Wherein, each variable is independently of one another,
R, R
3And R
4Be H, hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro, or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl, heteroaryl alkyl;
R
1And R
2For H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl, heteroaryl alkyl;
L
1Be O, NR
1, S, C (R)
2Or SO
2And
L
2And L
3Be O, NR
1, S or C (R)
2
The Sirtuin activating compounds is the chemical compound shown in general formula 36 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 36 and the subsidiary definition thereof, wherein R
1Be the 4-chlorphenyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 36 and the subsidiary definition thereof, wherein R
2Be the 4-chlorphenyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 36 and the subsidiary definition thereof, wherein R
3Be H.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 36 and the subsidiary definition thereof, wherein R
4Be H.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 36 and the subsidiary definition thereof, wherein L
1Be SO
2
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 36 and the subsidiary definition thereof, wherein L
2Be NH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 36 and the subsidiary definition thereof, wherein L
3Be O.
The Sirtuin activating compounds is the chemical compound shown in general formula 36 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H and R
1Be the 4-chlorphenyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 36 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be the 4-chlorphenyl, and R
2Be the 4-chlorphenyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 36 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be 4-chlorphenyl, R
2Be the 4-chlorphenyl, and R
3Be H.
The Sirtuin activating compounds is the chemical compound shown in general formula 36 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be 4-chlorphenyl, R
2Be 4-chlorphenyl, R
3Be H, and R
4Be H.
The Sirtuin activating compounds is the chemical compound shown in general formula 36 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be 4-chlorphenyl, R
2Be 4-chlorphenyl, R
3Be H, R
4Be H, and L
1Be SO
2
The Sirtuin activating compounds is the chemical compound shown in general formula 36 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be 4-chlorphenyl, R
2Be 4-chlorphenyl, R
3Be H, R
4Be H, L
1Be SO
2, and L
2Be NH.
The Sirtuin activating compounds is the chemical compound shown in general formula 36 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be 4-chlorphenyl, R
2Be 4-chlorphenyl, R
3Be H, R
4Be H, L
1Be SO
2, L
2Be NH, and L
3Be O.
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 37:
Wherein, each variable is independently of one another,
R is hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro, or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl, heteroaryl alkyl;
R
1For H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl, heteroaryl alkyl;
R
2And R
3For H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl, heteroaryl alkyl;
L is O, NR
1Or S; And
N comprises 0 to 4 integer;
The Sirtuin activating compounds is the chemical compound shown in general formula 37 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is a methyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 37 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 37 and the subsidiary definition thereof, wherein R
1Be the 3-fluorophenyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 37 and the subsidiary definition thereof, wherein R
2Be H.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 37 and the subsidiary definition thereof, wherein R
3Be the 4-chlorphenyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 37 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein L is O.
The Sirtuin activating compounds is the chemical compound shown in general formula 37 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is that methyl and n are 1.
The Sirtuin activating compounds is the chemical compound shown in general formula 37 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is a methyl, and n is 1, and R
1Be the 3-fluorophenyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 37 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is a methyl, and n is 1, R
1Be the 3-fluorophenyl, and R
2Be H.
The Sirtuin activating compounds is the chemical compound shown in general formula 37 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is a methyl, and n is 1, R
1Be 3-fluorophenyl, R
2Be H, and R
3Be the 4-chlorphenyl.
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 38:
Wherein, each variable is independently of one another,
R and R
1For H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl; And
L
1And L
2Be O, NR or S.
The Sirtuin activating compounds is the chemical compound shown in general formula 38 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is the 3-methoxyphenyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 38 and the subsidiary definition thereof, wherein R
1Be the 4-tert-butyl-phenyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 38 and the subsidiary definition thereof, wherein L
1Be NH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 38 and the subsidiary definition thereof, wherein L
2Be O.
The Sirtuin activating compounds is the chemical compound shown in general formula 38 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is 3-methoxyphenyl and R
1Be the 4-tert-butyl-phenyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 38 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is the 3-methoxyphenyl, R
1Be the 4-tert-butyl-phenyl, and L
1Be NH.
The Sirtuin activating compounds is the chemical compound shown in general formula 38 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is the 3-methoxyphenyl; R
1Be 4-tert-butyl-phenyl, L
1Be NH, and L
2Be O.
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 39:
Wherein, each variable is independently of one another,
R be H, hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
R
1For H or replacement or unsubstituted alkyl, aryl, alkaryl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
L
1And L
2Be O, NR or S; And
N comprises 0 to 4 integer.
The Sirtuin activating compounds is the chemical compound shown in general formula 39 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is a methyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 39 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 39 and the subsidiary definition thereof, wherein R
1Be 3,4, the 5-trimethoxyphenyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 39 and the subsidiary definition thereof, wherein L
1Be S.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 39 and the subsidiary definition thereof, wherein L
2Be NH.
The Sirtuin activating compounds is the chemical compound shown in general formula 39 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is that methyl and n are 1.
The Sirtuin activating compounds is the chemical compound shown in general formula 39 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is a methyl, and n is 1, and R
1Be 3,4, the 5-trimethoxyphenyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 39 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is a methyl, and n is 1, R
1Be 3,4,5-trimethoxyphenyl, and L
1Be S.
The Sirtuin activating compounds is the chemical compound shown in general formula 39 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is a methyl, and n is 1, R
1Be 3,4,5-trimethoxyphenyl, L
1Be S, and L
2Be NH.
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 40:
Wherein, each variable is independently of one another,
R, R
1, R
2, R
3For H or replacement or unsubstituted alkyl, aryl, alkaryl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
R
4Be hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro, or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
L
1And L
2Be O, NR or S; And
N comprises 0 to 3 integer.
The Sirtuin activating compounds is the chemical compound shown in general formula 40 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 40 and the subsidiary definition thereof, wherein R
1Be perfluorophenyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 40 and the subsidiary definition thereof, wherein R
2Be H.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 40 and the subsidiary definition thereof, wherein R
3Be H.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 40 and the subsidiary definition thereof, wherein L
1Be O.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 40 and the subsidiary definition thereof, wherein L
2Be O.
The Sirtuin activating compounds is the chemical compound shown in general formula 40 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0.
The Sirtuin activating compounds is the chemical compound shown in general formula 40 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H and R
1Be perfluorophenyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 40 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be perfluorophenyl, and R
2Be H.
The Sirtuin activating compounds is the chemical compound shown in general formula 40 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be perfluorophenyl, R
2Be H, and R
3Be H.
The Sirtuin activating compounds is the chemical compound shown in general formula 40 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be perfluorophenyl, R
2Be H, R
3Be H, and L
1Be O.
The Sirtuin activating compounds is the chemical compound shown in general formula 40 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be perfluorophenyl, R
2Be H, R
3Be H, L
1Be O, and L
2Be O.
Sirtuin activation compound is the chemical compound shown in general formula 40 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be perfluorophenyl, R
2Be H, R
3Be H, L
1Be O, L
2Be O, and n is 0.
In the another one specific embodiments, the Sirtuin activating compounds is the chemical compound shown in the general formula 41:
Wherein, each variable is independently of one another,
R, R
1And R
3For hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
R
2For H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
L
1, L
2And L
3Be O, NR
2Or S; And
M and n comprise 0 to 8 integer.
The Sirtuin activating compounds is the chemical compound shown in general formula 41 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 41 and the subsidiary definition thereof, wherein R
1Be cyano group.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 41 and the subsidiary definition thereof, wherein R
2Be ethyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 41 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein m is 0.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 41 and the subsidiary definition thereof, wherein L
1Be S.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 41 and the subsidiary definition thereof, wherein L
2Be O.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 41 and the subsidiary definition thereof, wherein L
3Be O.
The Sirtuin activating compounds is the chemical compound shown in general formula 41 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0 and R
1Be cyano group.
The Sirtuin activating compounds is the chemical compound shown in general formula 41 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0, R
1Be cyano group, and R
2Be ethyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 41 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0, R
1Be cyano group, R
2Be ethyl, and m is 0.
The Sirtuin activating compounds is the chemical compound shown in general formula 41 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0, R
1Be cyano group, R
2Be ethyl, m is 0, and L
1Be S.
The Sirtuin activating compounds is the chemical compound shown in general formula 41 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0, R
1Be cyano group, R
2Be ethyl, m is 0, L
1Be S, and L
2Be O.
The Sirtuin activating compounds is the chemical compound shown in general formula 41 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0, R
1Be cyano group, R
2Be ethyl, m is 0, L
1Be S, L
2Be O, and L
3Be O.
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 42:
Wherein, each variable is independently of one another,
R and R
2Be H, hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro, or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
R
1And R
3For H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
L
1, L
2, L
3And L
4Be O, NR
1Or S;
M comprises 0 to 6 integer; And
N comprises 0 to 8 integer.
The Sirtuin activating compounds is the chemical compound shown in general formula 42 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 42 and the subsidiary definition thereof, wherein R
1Be methyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 42 and the subsidiary definition thereof, wherein R
2Be CF
3And m is 1.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 42 and the subsidiary definition thereof, wherein R
3Be the 4-aminomethyl phenyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 42 and the subsidiary definition thereof, wherein L
1Be S.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 42 and the subsidiary definition thereof, wherein L
2Be O.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 42 and the subsidiary definition thereof, wherein L
3Be NR
1
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 42 and the subsidiary definition thereof, wherein L
4Be NR
1
The Sirtuin activating compounds is the chemical compound shown in general formula 42 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0 and R
1Be methyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 42 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0, R
1Be methyl, R
2Be CF
3, and m is 1.
The Sirtuin activating compounds is the chemical compound shown in general formula 42 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0, R
1Be methyl, R
2Be CF
3, m is 1; And R
3Be the 4-aminomethyl phenyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 42 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0, R
1Be methyl, R
2Be CF
3, m is 1; R
3Be the 4-aminomethyl phenyl; And L
1Be S.
The Sirtuin activating compounds is the chemical compound shown in general formula 42 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0, R
1Be methyl, R
2Be CF
3, m is 1; R
3Be the 4-aminomethyl phenyl; L
1Be S, and L
2Be O.
The Sirtuin activating compounds is the chemical compound shown in general formula 42 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0, R
1Be methyl, R
2Be CF
3, m is 1; R
3Be the 4-aminomethyl phenyl; L
1Be S, L
2Be O; And L
3Be NR
1
The Sirtuin activating compounds is the chemical compound shown in general formula 42 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0, R
1Be methyl, R
2Be CF
3, m is 1; R
3Be the 4-aminomethyl phenyl; L
1Be S, L
2Be O; L
3Be NR
1, and L
4Be NR
1
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 43:
Wherein, each variable is independently of one another,
R and R
1Be hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro, or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
R
2And R
3For H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl; And
L
1And L
2Be O, NR
2Or S.
The Sirtuin activating compounds is the chemical compound shown in general formula 43 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is a cyano group.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 43 and the subsidiary definition thereof, wherein R
1Be NH
2
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 43 and the subsidiary definition thereof, wherein R
2Be the 4-bromophenyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 43 and the subsidiary definition thereof, wherein R
3Be 3-hydroxyl-4-methoxyphenyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 43 and the subsidiary definition thereof, wherein L
1Be O.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 43 and the subsidiary definition thereof, wherein L
2Be NR
2
The Sirtuin activating compounds is the chemical compound shown in general formula 43 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is cyano group and R
1Be NH
2
The Sirtuin activating compounds is the chemical compound shown in general formula 43 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is a cyano group, R
1Be NH
2, and R
2Be the 4-bromophenyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 43 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is a cyano group, R
1Be NH
2, R
2Be the 4-bromophenyl, and R
3Be 3-hydroxyl-4-methoxyphenyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 43 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is a cyano group, R
1Be NH
2, R
2Be 4-bromophenyl, R
3Be 3-hydroxyl-4-methoxyphenyl, and L
1Be O.
The Sirtuin activating compounds is the chemical compound shown in general formula 43 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is a cyano group, R
1Be NH
2, R
2Be 4-bromophenyl, R
3Be 3-hydroxyl-4-methoxyphenyl, L
1Be O, and L
2Be NR
2
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 44:
Wherein, each variable is independently of one another,
R be H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
R
1Be hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro, or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
L
1, L
2And L
3Be O, NR or S; And
N comprises 0 to 5 integer.
The Sirtuin activating compounds is the chemical compound shown in general formula 44 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is the 3-trifluoromethyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 44 and the subsidiary definition thereof, wherein R
1Be C (O) OCH
3
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 44 and the subsidiary definition thereof, wherein L
1Be NR.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 44 and the subsidiary definition thereof, wherein L
2Be S.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 44 and the subsidiary definition thereof, wherein L
3Be NR.
The Sirtuin activating compounds is the chemical compound shown in general formula 44 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 2.
The Sirtuin activating compounds is the chemical compound shown in general formula 44 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is 3-trifluoromethyl and R
1Be C (O) OCH
3
The Sirtuin activating compounds is the chemical compound shown in general formula 44 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is the 3-trifluoromethyl, R
1Be C (O) OCH
3, and L
1Be NR.
The Sirtuin activating compounds is the chemical compound shown in general formula 44 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is the 3-trifluoromethyl, R
1Be C (O) OCH
3, L
1Be NR, and L
2Be S.
The Sirtuin activating compounds is the chemical compound shown in general formula 44 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is the 3-trifluoromethyl, R
1Be C (O) OCH
3, L
1Be NR, L
2Be S, and L
3Be NR.
The Sirtuin activating compounds is the chemical compound shown in general formula 44 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is the 3-trifluoromethyl, R
1Be C (O) OCH
3, L
1Be NR, L
2Be S, L
3Be NR, and n is 2.
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 45:
Wherein, each variable is independently of one another,
R be hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl.
R
1And R
2For H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
L
1And L
2Be O, NR
1Or S; And
N comprises 0 to 4 integer.
The Sirtuin activating compounds is the chemical compound shown in general formula 45 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 45 and the subsidiary definition thereof, wherein R
1Be 2-oxolane ylmethyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 45 and the subsidiary definition thereof, wherein R
2For-CH
2CH
2C
6H
4SO
2NH
2
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 45 and the subsidiary definition thereof, wherein L
1Be S.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 45 and the subsidiary definition thereof, wherein L
2Be NR
1
The Sirtuin activating compounds is the chemical compound shown in general formula 45 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0 and R
1Be 2-oxolane ylmethyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 45 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0, R
1Be 2-oxolane ylmethyl, and R
2For-CH
2CH
2C
6H
4SO
2NH
2
The Sirtuin activating compounds is the chemical compound shown in general formula 45 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0, R
1Be 2-oxolane ylmethyl, R
2For-CH
2CH
2C
6H
4SO
2NH
2, and L
1Be S.
The Sirtuin activating compounds is the chemical compound shown in general formula 45 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0, R
1Be 2-oxolane ylmethyl, R
2For-CH
2CH
2C
6H
4SO
2NH
2, L
1Be S, and L
2Be NR
1
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 46:
Wherein, each variable is independently of one another,
R, R
1, R
2And R
3Be hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro, or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
L
1And L
2Be O, NR
4Or S;
R
4For H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
N comprises 0 to 4 integer;
M comprises 0 to 3 integer;
O comprises 0 to 4 integer; And
P comprises 0 to 5 integer.
The Sirtuin activating compounds is the chemical compound shown in general formula 46 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0.
The Sirtuin activating compounds is the chemical compound shown in general formula 46 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein m is 1.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 46 and the subsidiary definition thereof, wherein R
1Be Cl.
The Sirtuin activating compounds is the chemical compound shown in general formula 46 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein o is 1.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 46 and the subsidiary definition thereof, wherein R
2Be Cl.
The Sirtuin activating compounds is the chemical compound shown in general formula 46 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein p is 3.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 46 and the subsidiary definition thereof, wherein R
3Be OH or I.
The Sirtuin activating compounds is the chemical compound shown in general formula 46 and the subsidiary definition thereof more specifically in the embodiment at one, wherein n be 0 and m be 1.
The Sirtuin activating compounds is the chemical compound shown in general formula 46 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0, and m is 1, and o is 1.
The Sirtuin activating compounds is the chemical compound shown in general formula 46 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0, and m is 1, and o is 1, and R
1Be Cl.
The Sirtuin activating compounds is the chemical compound shown in general formula 46 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0, and m is 1, and o is 1, R
1Be Cl, and p is 3.
The Sirtuin activating compounds is the chemical compound shown in general formula 46 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0, and m is 1, and o is 1, R
1Be Cl, p is 3, and R
2Be OH or I.
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 47:
Wherein, each variable is independently of one another,
R and R
1For hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
L
1And L
2Be O, NR
4Or S;
R
4For H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl; And
M and n comprise 0 to 4 integer.
The Sirtuin activating compounds is the chemical compound shown in general formula 47 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 2.
The Sirtuin activating compounds is the chemical compound shown in general formula 47 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is the methyl or the tert-butyl group.
The Sirtuin activating compounds is the chemical compound shown in general formula 47 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein m is 2.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 47 and the subsidiary definition thereof, wherein R
1Be the methyl or the tert-butyl group.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 47 and the subsidiary definition thereof, wherein L
1Be O.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 47 and the subsidiary definition thereof, wherein L
2Be O.
The Sirtuin activating compounds is the chemical compound shown in general formula 47 and the subsidiary definition thereof more specifically in the embodiment at one, wherein n be 2 and R be the methyl or the tert-butyl group.
The Sirtuin activating compounds is the chemical compound shown in general formula 47 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 2, and R is the methyl or the tert-butyl group, and m is 2.
The Sirtuin activating compounds is the chemical compound shown in general formula 47 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 2, and R is the methyl or the tert-butyl group, and m is 2, and R
1Be the methyl or the tert-butyl group.
The Sirtuin activating compounds is the chemical compound shown in general formula 47 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 2, and R is the methyl or the tert-butyl group, and m is 2, R
1Be the methyl or the tert-butyl group, and L
1Be O.
The Sirtuin activating compounds is the chemical compound shown in general formula 47 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 2, and R is the methyl or the tert-butyl group, and m is 2, R
1Be the methyl or the tert-butyl group, L
1Be O, and L
2Be O.
In another embodiment, the Sirtuin reactive compound is the chemical compound shown in the general formula 48:
Wherein, each variable is independently of one another,
R, R
1, R
2, R
3, R
4, R
5And R
6For hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
R
7For H or replacement or unsubstituted alkyl, acyl group, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
L
1, L
2And L
3Be O, NR
7Or S; And
N comprises 0 to 4 integer.
The Sirtuin activating compounds is the chemical compound shown in general formula 48 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1.
The Sirtuin activating compounds is the chemical compound shown in general formula 48 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is a methyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 48 and the subsidiary definition thereof, wherein R
1Be C (O) OCH
3
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 48 and the subsidiary definition thereof, wherein R
2Be C (O) OCH
3
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 48 and the subsidiary definition thereof, wherein R
3Be C (O) OCH
3
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 48 and the subsidiary definition thereof, wherein R
4Be C (O) OCH
3
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 48 and the subsidiary definition thereof, wherein R
5Be methyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 48 and the subsidiary definition thereof, wherein R
6Be methyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 48 and the subsidiary definition thereof, wherein R
7Be C (O) CF
3
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 48 and the subsidiary definition thereof, wherein L
1Be S.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 48 and the subsidiary definition thereof, wherein L
2Be S.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 48 and the subsidiary definition thereof, wherein L
3Be S.
The Sirtuin activating compounds is the chemical compound shown in general formula 48 and the subsidiary definition thereof more specifically in the embodiment at one, wherein n be 1 and R be methyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 48 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is a methyl, and R
1Be C (O) OCH
3
The Sirtuin activating compounds is the chemical compound shown in general formula 48 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is a methyl, R
1Be C (O) OCH
3, and R
2Be C (O) OCH
3
The Sirtuin activating compounds is the chemical compound shown in general formula 48 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is a methyl, R
1Be C (O) OCH
3, R
2Be C (O) OCH
3, and R
3Be C (O) OCH
3
The Sirtuin activating compounds is the chemical compound shown in general formula 48 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is a methyl, R
1Be C (O) OCH
3, R
2Be C (O) OCH
3, R
3Be C (O) OCH
3, and R
4Be C (O) OCH3.
The Sirtuin activating compounds is the chemical compound shown in general formula 48 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is a methyl, R
1Be C (O) OCH
3, R
2Be C (O) OCH
3, R
3Be C (O) OCH
3, R
4Be C (O) OCH
3, and R
5Be methyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 48 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is a methyl, R
1Be C (O) OCH
3, R
2Be C (O) OCH
3, R
3Be C (O) OCH
3, R
4Be C (O) OCH
3, R
5Be methyl, and R
6Be methyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 48 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is a methyl, R
1Be C (O) OCH
3, R
2Be C (O) OCH
3, R
3Be C (O) OCH
3, R
4Be C (O) OCH
3, R
5Be methyl, R
6Be methyl, and R
7Be C (O) CF
3
The Sirtuin activating compounds is the chemical compound shown in general formula 48 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is a methyl, R
1Be C (O) OCH
3, R
2Be C (O) OCH
3, R
3Be C (O) OCH
3, R
4Be C (O) OCH
3, R
5 areMethyl, R
6Be methyl, R
7Be C (O) CF
3, and L
1Be S.
The Sirtuin activating compounds is the chemical compound shown in general formula 48 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is a methyl, R
1Be C (O) OCH
3, R
2Be C (O) OCH
3, R
3Be C (O) OCH
3, R
4Be C (O) OCH
3, R
5Be methyl, R
6Be methyl, R
7Be C (O) CF
3, L
1Be S, and L
2Be S.
The Sirtuin activating compounds is the chemical compound shown in general formula 48 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is a methyl, R
1Be C (O) OCH
3, R
2Be C (O) OCH
3, R
3Be C (O) OCH
3, R
4Be C (O) OCH
3, R
5Be methyl, R
6Be methyl, R
7Be C (O) CF
3, L
1Be S, L
2Be S, and L
3Be S.
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 49:
Wherein, each variable is independently of one another,
R, R
1, R
2, R
3, R
4And R
5For hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
L
1, L
2And L
3Be O, NR
6Or S;
R
6For H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl; And
N comprises 0 to 4 integer.
The Sirtuin activating compounds is the chemical compound shown in general formula 49 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1.
The Sirtuin activating compounds is the chemical compound shown in general formula 49 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is a methyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 49 and the subsidiary definition thereof, wherein R
1Be C (O) OCH
3
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 49 and the subsidiary definition thereof, wherein R
2Be C (O) OCH
3
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 49 and the subsidiary definition thereof, wherein R
3Be methyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 49 and the subsidiary definition thereof, wherein R
4Be methyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 49 and the subsidiary definition thereof, wherein R
5Be CH
2CH (CH
3)
2
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 49 and the subsidiary definition thereof, wherein L
1Be S.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 49 and the subsidiary definition thereof, wherein L
2Be S.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 49 and the subsidiary definition thereof, wherein L
3Be S.
The Sirtuin activating compounds is the chemical compound shown in general formula 49 and the subsidiary definition thereof more specifically in the embodiment at one, wherein n be 1 and R be methyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 49 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is a methyl, and R
1Be C (O) OCH
3
The Sirtuin activating compounds is the chemical compound shown in general formula 49 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is a methyl, R
1Be C (O) OCH
3, and R
2Be C (O) OCH
3
The Sirtuin activating compounds is the chemical compound shown in general formula 49 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is a methyl, R
1Be C (O) OCH
3, R
2Be C (O) OCH
3, and R
3Be methyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 49 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is a methyl, R
1Be C (O) OCH
3, R
2Be C (O) OCH
3, R
3Be methyl, and R
4Be methyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 49 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is a methyl, R
1Be C (O) OCH
3, R
2Be C (O) OCH
3, R
3Be methyl, R
4Be methyl, and R
5Be CH
2CH (CH3)
2
The Sirtuin activating compounds is the chemical compound shown in general formula 49 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is a methyl, R
1Be C (O) OCH
3, R
2Be C (O) OCH
3, R
3Be methyl, R
4Be methyl, R
5Be CH
2CH (CH
3)
2, and L
1Be S.
The Sirtuin activating compounds is the chemical compound shown in general formula 49 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is a methyl, R
1Be C (O) OCH
3, R
2Be C (O) OCH
3, R
3Be methyl, R
4Be methyl, R
5Be CH
2CH (CH
3)
2, and L
1Be S.
The Sirtuin activating compounds is the chemical compound shown in general formula 49 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is a methyl, R
1Be C (O) OCH
3, R
2Be C (O) OCH
3, R
3Be methyl, R
4Be methyl, R
5Be CH
2CH (CH
3)
2, L
1Be S, and L
2Be S.
The Sirtuin activating compounds is the chemical compound shown in general formula 49 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is a methyl, R
1Be C (O) OCH
3, R
2Be C (O) OCH
3, R
3Be methyl, R
4Be methyl, R
5Be CH
2CH (CH
3)
2, L
1Be S, and L
2Be S.
The Sirtuin activating compounds is the chemical compound shown in general formula 49 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is a methyl, R
1Be C (O) OCH
3, R
2Be C (O) OCH
3, R
3Be methyl, R
4Be methyl, R
5Be CH
2CH (CH
3)
2, L
1Be S, L
2Be S, and L
3Be S.
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 50:
Wherein, each variable is independently of one another,
R and R
1For hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
R
2For H, hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
L
1And L
2Be O, NR
3Or S;
R
3For H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
N comprises 0 to 5 integer; And
M comprises 0 to 4 integer.
The Sirtuin activating compounds is the chemical compound shown in general formula 50 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1.
The Sirtuin activating compounds is the chemical compound shown in general formula 50 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is CO
2Et.
The Sirtuin activating compounds is the chemical compound shown in general formula 50 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein m is 0.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 50 and the subsidiary definition thereof, wherein R
2Be cyano group.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 50 and the subsidiary definition thereof, wherein L
1Be S.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 50 and the subsidiary definition thereof, wherein L
2Be S.
The Sirtuin activating compounds is the chemical compound shown in general formula 50 and the subsidiary definition thereof more specifically in the embodiment at one, wherein n be 1 and R be CO
2Et.
The Sirtuin activating compounds is the chemical compound shown in general formula 50 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is CO
2Et, and m is 0.
The Sirtuin activating compounds is the chemical compound shown in general formula 50 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is CO
2Et, m are 0, and R
2Be cyano group.
The Sirtuin activating compounds is the chemical compound shown in general formula 50 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is CO
2Et, m are 0, R
2Be cyano group, and L
1Be S.
The Sirtuin activating compounds is the chemical compound shown in general formula 50 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is CO
2Et, m are 0, R
2Be cyano group, L
1Be S, and L
2Be S.
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 51:
Wherein, each variable is independently of one another,
R and R
1For hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
N comprises 0 to 4 integer; And
M comprises 0 to 2 integer.
The Sirtuin activating compounds is the chemical compound shown in general formula 51 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 2.
The Sirtuin activating compounds is the chemical compound shown in general formula 51 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is Cl or trifluoromethyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 51 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein m is 2.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 51 and the subsidiary definition thereof, wherein R
1Be phenyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 51 and the subsidiary definition thereof more specifically in the embodiment at one, wherein n be 2 and R be Cl or trifluoromethyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 51 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 2, and R is Cl or trifluoromethyl, and m is 2.
The Sirtuin activating compounds is the chemical compound shown in general formula 51 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 2, and R is Cl or trifluoromethyl, and m is 2, and R
1Be phenyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 51 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1.
The Sirtuin activating compounds is the chemical compound shown in general formula 51 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is F.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 51 and the subsidiary definition thereof, wherein R
1Be the 4-aminomethyl phenyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 51 and the subsidiary definition thereof more specifically in the embodiment at one, wherein n be 1 and R be F.
The Sirtuin activating compounds is the chemical compound shown in general formula 51 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is F, and m is 2.
The Sirtuin activating compounds is the chemical compound shown in general formula 51 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is F, and m is 2, and R
1Be the 4-aminomethyl phenyl.
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 52:
Wherein, each variable is independently of one another,
R be H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
R
1And R
6For hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
R
2Be alkylidene, alkenylene or alkynylene;
R
3, R
4And R
5For H, hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
L
1, L
2And L
3Be O, NR or S;
N and p comprise 0 to 3 integer;
M and o comprise 0 to 2 integer.
The Sirtuin activating compounds is the chemical compound shown in general formula 52 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is CH
2CH
2OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 52 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 52 and the subsidiary definition thereof, wherein R
1Be I.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 52 and the subsidiary definition thereof, wherein R
2Be alkynylene.
The Sirtuin activating compounds is the chemical compound shown in general formula 52 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein m is 1.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 52 and the subsidiary definition thereof, wherein R
3Be OH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 52 and the subsidiary definition thereof, wherein R
4Be C (O) OEt.
The Sirtuin activating compounds is the chemical compound shown in general formula 52 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein o is 1.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 52 and the subsidiary definition thereof, wherein R
5Be OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 52 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein p is 0.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 52 and the subsidiary definition thereof, wherein L
1Be NH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 52 and the subsidiary definition thereof, wherein L
2Be O.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 52 and the subsidiary definition thereof, wherein L
3Be O.
The Sirtuin activating compounds is the chemical compound shown in general formula 52 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is CH
2CH
2OH and n are 1.
The Sirtuin activating compounds is the chemical compound shown in general formula 52 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is CH
2CH
2OH, n are 1, and R
1Be I.
The Sirtuin activating compounds is the chemical compound shown in general formula 52 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is CH
2CH
2OH, n are 1, R
1Be I, and R
2Be alkynylene.
The Sirtuin activating compounds is the chemical compound shown in general formula 52 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is CH
2CH
2OH, n are 1, R
1Be I, R
2Be alkynylene, and m is 1.
The Sirtuin activating compounds is the chemical compound shown in general formula 52 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is CH
2CH
2OH, n are 1, R
1Be I, R
2Be alkynylene, m is 1, and R
3Be OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 52 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is CH
2CH
2OH, n are 1, R
1Be I, R
2Be alkynylene, m is 1, R
3Be OH, and R
4Be C (O) OEt.
The Sirtuin activating compounds is the chemical compound shown in general formula 52 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is CH
2CH
2OH, n are 1, R
1Be I, R
2Be alkynylene, m is 1, R
3Be OH, R
4Be C (O) OEt, and o is 1.
The Sirtuin activating compounds is the chemical compound shown in general formula 52 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is CH
2CH
2OH, n are 1, R
1Be I, R
2Be alkynylene, m is 1, R
3Be OH, R
4Be C (O) OEt, o is 1, and R
5Be OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 52 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is CH
2CH
2OH, n are 1, R
1Be I, R
2Be alkynylene, m is 1, R
3Be OH, R
4Be C (O) OEt, o is 1, R
5Be OH, and p is 0.
The Sirtuin activating compounds is the chemical compound shown in general formula 52 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is CH
2CH
2OH, n are 1, R
1Be I, R
2Be alkynylene, m is 1, R
3Be OH, R
4Be C (O) OEt, o is 1, R
5Be OH, p is 0, and L
1Be NH.
The Sirtuin activating compounds is the chemical compound shown in general formula 52 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is CH
2CH
2OH, n are 1, R
1Be I, R
2Be alkynylene, m is 1, R
3Be OH, R
4Be C (O) OEt, o is 1, R
5Be OH, p is 0, L
1Be NH, and L
2Be O.
The Sirtuin activating compounds is the chemical compound shown in general formula 52 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is CH
2CH
2OH, n are 1, R
1Be I, R
2Be alkynylene, m is 1, R
3Be OH, R
4Be C (O) OEt, o is 1, R
5Be OH, p is 0, L
1Be NH, L
2Be O, and L
3Be O.
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 53:
Wherein, each variable is independently of one another,
R, R
1, R
2, R
3, R
4And R
5For H, hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
L
1, L
2, L
3And L
4Be O, NR
6Or S;
R
6For H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl; And
N comprises 0 to 5 integer.
The Sirtuin activating compounds is the chemical compound shown in general formula 53 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is the O-tert-butyl group.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 53 and the subsidiary definition thereof, wherein R
1Be the tert-butyl group.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 53 and the subsidiary definition thereof, wherein R
2Be the O-tert-butyl group.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 53 and the subsidiary definition thereof, wherein R
3Be the tert-butyl group.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 53 and the subsidiary definition thereof, wherein R
4Be C (O) OMe.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 53 and the subsidiary definition thereof, wherein R
5Be C (O) OMe.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 53 and the subsidiary definition thereof, wherein L
1Be NH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 53 and the subsidiary definition thereof, wherein L
2Be O.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 53 and the subsidiary definition thereof, wherein L
3Be O.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 53 and the subsidiary definition thereof, wherein L
4Be NH.
The Sirtuin activating compounds is the chemical compound shown in general formula 53 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1.
The Sirtuin activating compounds is the chemical compound shown in general formula 53 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is the O-tert-butyl group and R
1Be the tert-butyl group.
The Sirtuin activating compounds is the chemical compound shown in general formula 53 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is the O-tert-butyl group, R
1Be the tert-butyl group, and R
2Be the O-tert-butyl group.
The Sirtuin activating compounds is the chemical compound shown in general formula 53 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is the O-tert-butyl group, R
1Be the tert-butyl group, R
2Be the O-tert-butyl group, and R
3Be the tert-butyl group.
The Sirtuin activating compounds is the chemical compound shown in general formula 53 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is the O-tert-butyl group, R
1Be the tert-butyl group, R
2Be the O-tert-butyl group, R
3Be the tert-butyl group, and R
4Be C (O) OMe.
The Sirtuin activating compounds is the chemical compound shown in general formula 53 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is the O-tert-butyl group, R
1Be the tert-butyl group, R
2Be the O-tert-butyl group, R
3Be the tert-butyl group, R
4Be C (O) OMe, and R
5Be C (O) OMe.
The Sirtuin activating compounds is the chemical compound shown in general formula 53 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is the O-tert-butyl group, R
1Be the tert-butyl group, R
2Be the O-tert-butyl group, R
3Be the tert-butyl group, R
4Be C (O) OMe, R
5Be C (O) OMe, and L
1Be NH.
The Sirtuin activating compounds is the chemical compound shown in general formula 53 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is the O-tert-butyl group, R
1Be the tert-butyl group, R
2Be the O-tert-butyl group, R
3Be the tert-butyl group, R
4Be C (O) OMe, R
5Be C (O) OMe, L
1Be NH, and L
2Be O.
The Sirtuin activating compounds is the chemical compound shown in general formula 53 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is the O-tert-butyl group, R
1Be the tert-butyl group, R
2Be the O-tert-butyl group, R
3Be the tert-butyl group, R
4Be C (O) OMe, R
5Be C (O) OMe, L
1Be NH, L
2Be O, and L
3Be O.
The Sirtuin activating compounds is the chemical compound shown in general formula 53 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is the O-tert-butyl group, R
1Be the tert-butyl group, R
2Be the O-tert-butyl group, R
3Be the tert-butyl group, R
4Be C (O) OMe, R
5Be C (O) OMe, L
1Be NH, L
2Be O, L
3Be O, and L
4Be NH.
The Sirtuin activating compounds is the chemical compound shown in general formula 53 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is the O-tert-butyl group, R
1Be the tert-butyl group, R
2Be the O-tert-butyl group, R
3Be the tert-butyl group, R
4Be C (O) OMe, R
5Be C (O) OMe, L
1Be NH, L
2Be O, L
3Be O, L
4Be NH, and n is 1.
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 54:
Wherein, each variable is independently of one another,
R and R
1For H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
R
2, R
4And R
5For hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
R
3, R
6And R
7For H, hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
L is O, NR or S;
N and o comprise 0 to 4 integer; And
M comprises 0 to 3 integer.
The Sirtuin activating compounds is the chemical compound shown in general formula 54 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is an ethyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 54 and the subsidiary definition thereof, wherein R
1Be ethyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 54 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein m is 0.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 54 and the subsidiary definition thereof, wherein R
3Be H.
The Sirtuin activating compounds is the chemical compound shown in general formula 54 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein o is 0.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 54 and the subsidiary definition thereof, wherein R
5Be Cl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 54 and the subsidiary definition thereof, wherein R
6Be H.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 54 and the subsidiary definition thereof, wherein R
7Be methyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 54 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein L is NH.
The Sirtuin activating compounds is the chemical compound shown in general formula 54 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1.
The Sirtuin activating compounds is the chemical compound shown in general formula 54 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is ethyl and R
1Be ethyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 54 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is an ethyl, R
1Be ethyl, and m is 0.
The Sirtuin activating compounds is the chemical compound shown in general formula 54 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is an ethyl, R
1Be ethyl, m is 0, and R
3Be H.
The Sirtuin activating compounds is the chemical compound shown in general formula 54 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is an ethyl, R
1Be ethyl, m is 0, R
3Be H, and o is 0.
The Sirtuin activating compounds is the chemical compound shown in general formula 54 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is an ethyl, R
1Be ethyl, m is 0, R
3Be H, o is 0, and R
5Be Cl.
The Sirtuin activating compounds is the chemical compound shown in general formula 54 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is an ethyl, R
1Be ethyl, m is 0, R
3Be H, o is 0, R
5Be Cl, and R
6Be H.
The Sirtuin activating compounds is the chemical compound shown in general formula 54 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is an ethyl, R
1Be ethyl, m is 0, R
3Be H, o is 0, R
5Be Cl, R
6Be H, and R
7Be methyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 54 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is an ethyl, R
1Be ethyl, m is 0, R
3Be H, o is 0, R
5Be Cl, R
6Be H, R
7Be methyl, and L is NH.
The Sirtuin activating compounds is the chemical compound shown in general formula 54 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is an ethyl, R
1Be ethyl, m is 0, R
3Be H, o is 0, R
5Be Cl, R
6Be H, R
7Be methyl, L is NH, and n is 1.
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 55:
Wherein, each variable is independently of one another,
R, R
1, R
4And R
5For H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
R
2And R
3For H, hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl; And
L
1, L
2, L
3And L
4Be O, NR or S.
The Sirtuin activating compounds is the chemical compound shown in general formula 55 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 55 and the subsidiary definition thereof, wherein R
1Be H.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 55 and the subsidiary definition thereof, wherein R
2Be OEt.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 55 and the subsidiary definition thereof, wherein R
3Be methyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 55 and the subsidiary definition thereof, wherein R
4Be H.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 55 and the subsidiary definition thereof, wherein R
5Be H.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 55 and the subsidiary definition thereof, wherein L
1Be S.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 55 and the subsidiary definition thereof, wherein L
2Be NH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 55 and the subsidiary definition thereof, wherein L
3Be NH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 55 and the subsidiary definition thereof, wherein L
4Be S.
The Sirtuin activating compounds is the chemical compound shown in general formula 55 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H and R
1Be H.
The Sirtuin activating compounds is the chemical compound shown in general formula 55 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be H, and R
2Be OEt.
The Sirtuin activating compounds is the chemical compound shown in general formula 55 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be H, R
2Be OEt, and R
3Be methyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 55 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be H, R
2Be OEt, R
3Be methyl, and R
4Be H.
The Sirtuin activating compounds is the chemical compound shown in general formula 55 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be H, R
2Be OEt, R
3Be methyl, R
4Be H, and R
5Be H.
The Sirtuin activating compounds is the chemical compound shown in general formula 55 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be H, R
2Be OEt, R
3Be methyl, R
4Be H, R
5Be H, and L
1Be S.
The Sirtuin activating compounds is the chemical compound shown in general formula 55 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be H, R
2Be OEt, R
3Be methyl, R
4Be H, R
5Be H, L
1Be S, and L
2Be NH.
The Sirtuin activating compounds is the chemical compound shown in general formula 55 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be H, R
2Be OEt, R
3Be methyl, R
4Be H, R
5Be H, L
1Be S, L
2Be NH, and L
3Be NH.
The Sirtuin activating compounds is the chemical compound shown in general formula 55 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be H, R
2Be OEt, R
3Be methyl, R
4Be H, R
5Be H, L
1Be S, L
2Be NH, L
3Be NH, and L
4Be S.
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 56:
Wherein, each variable is independently of one another,
R and R
1For hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
L
1, L
2And L
3Be O, NR
2Or S;
R
2For H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
N comprises 0 to 4 integer; And
M comprises 0 to 5 integer.
The Sirtuin activating compounds is the chemical compound shown in general formula 56 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 0.
The Sirtuin activating compounds is the chemical compound shown in general formula 56 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein m is 0.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 56 and the subsidiary definition thereof, wherein L
1Be NH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 56 and the subsidiary definition thereof, wherein L
2Be S.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 56 and the subsidiary definition thereof, wherein L
3Be S.
The Sirtuin activating compounds is the chemical compound shown in general formula 56 and the subsidiary definition thereof more specifically in the embodiment at one, wherein m be 0 and n be 0.
The Sirtuin activating compounds is the chemical compound shown in general formula 56 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein m is 0, and n is 0, and L
1Be NH.
The Sirtuin activating compounds is the chemical compound shown in general formula 56 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein m is 0, and n is 0, L
1Be NH, and L
2Be S.
The Sirtuin activating compounds is the chemical compound shown in general formula 56 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein m is 0, and n is 0, L
1Be NH, L
2Be S, and L
3Be S.
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 57:
Wherein, each variable is independently of one another,
R, R
1, R
2And R
3For hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
A is alkylidene, alkenylene or alkynylene;
N comprises 0 to 8 integer;
M comprises 0 to 3 integer;
O comprises 0 to 6 integer; And
P comprises 0 to 4 integer.
The Sirtuin activating compounds is the chemical compound shown in general formula 57 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 2.
The Sirtuin activating compounds is the chemical compound shown in general formula 57 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is OH or methyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 57 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein m is 1.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 57 and the subsidiary definition thereof, wherein R
1Be methyl.
Sirtuin activation compound is the chemical compound shown in general formula 57 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein o is 1.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 57 and the subsidiary definition thereof, wherein R
2Be C (O) CH
3
The Sirtuin activating compounds is the chemical compound shown in general formula 57 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein p is 2.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 57 and the subsidiary definition thereof, wherein R
3Be CO
2H.
The Sirtuin activating compounds is the chemical compound shown in general formula 57 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein A is an alkenylene.
The Sirtuin activating compounds is the chemical compound shown in general formula 57 and the subsidiary definition thereof more specifically in the embodiment at one, wherein n be 2 and R be OH or methyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 57 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 2, and R is OH or methyl, and m is 1.
The Sirtuin activating compounds is the chemical compound shown in general formula 57 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 2, and R is OH or methyl, and m is 1, and R
1Be methyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 57 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 2, and R is OH or methyl, and m is 1, R
1Be methyl, and o is 1.
The Sirtuin activating compounds is the chemical compound shown in general formula 57 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 2, and R is OH or methyl, and m is 1, R
1Be methyl, o is 1, and R
2Be C (O) CH
3
The Sirtuin activating compounds is the chemical compound shown in general formula 57 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 2, and R is OH or methyl, and m is 1, R
1Be methyl, o is 1, R
2Be C (O) CH
3, and p is 2.
The Sirtuin activating compounds is the chemical compound shown in general formula 57 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 2, and R is OH or methyl, and m is 1, R
1Be methyl, o is 1, R
2Be C (O) CH
3, p is 2, and R
3Be CO
2H.
The Sirtuin activating compounds is the chemical compound shown in general formula 57 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 2, and R is OH or methyl, and m is 1, R
1Be methyl, o is 1, R
2Be C (O) CH
3, p is 2, R
3Be CO
2H, and A is an alkenylene.
In another embodiment, the Sirtuin reactive compound is the chemical compound shown in the general formula 58:
Wherein, each variable is independently of one another,
R, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8And R
9For hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
L
1, L
2And L
3Be O, NR
10Or S; And
R
10For H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 58 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is OH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 58 and the subsidiary definition thereof, wherein R
1Be CH
2OH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 58 and the subsidiary definition thereof, wherein R
2Be OH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 58 and the subsidiary definition thereof, wherein R
3Be methyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 58 and the subsidiary definition thereof, wherein R
4Be OH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 58 and the subsidiary definition thereof, wherein R
5Be OH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 58 and the subsidiary definition thereof, wherein R
6Be OH.
At one more specifically in the embodiment, Sirtuin activation compound is the chemical compound shown in general formula 58 and the subsidiary definition thereof, wherein R
7Be OH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 58 and the subsidiary definition thereof, wherein R
8Be OH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 58 and the subsidiary definition thereof, wherein R
9Be methyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 58 and the subsidiary definition thereof, wherein L
1Be O.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 58 and the subsidiary definition thereof, wherein L
2Be O.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 58 and the subsidiary definition thereof, wherein L
3Be O.
The Sirtuin activating compounds is the chemical compound shown in general formula 58 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is OH and R
1Be CH
2OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 58 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is OH, R
1Be CH
2OH, and R
2Be OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 58 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is OH, R
1Be CH
2OH, R
2Be OH, and R
3Be methyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 58 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is OH, R
1Be CH
2OH, R
2Be OH, R
3Be methyl, and R
4Be OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 58 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is OH, R
1Be CH
2OH, R
2Be OH, R
3Be methyl, R
4Be OH, and R
5Be OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 58 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is OH, R
1Be CH
2OH, R
2Be OH, R
3Be methyl, R
4Be OH, R
5Be OH, and R
6Be OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 58 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is OH, R
1Be CH
2OH, R
2Be OH, R
3Be methyl, R
4Be OH, R
5Be OH, R
6Be OH, and R
7Be OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 58 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is OH, R
1Be CH
2OH, R
2Be OH, R
3Be methyl, R
4Be OH, R
5Be OH, R
6Be OH, R
7Be OH, and R
8Be OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 58 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is OH, R
1Be CH
2OH, R
2Be OH, R
3Be methyl, R
4Be OH, R
5Be OH, R
6Be OH, R
7Be OH, R
8Be OH, and R
9Be methyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 58 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is OH, R
1Be CH
2OH, R
2Be OH, R
3Be methyl, R
4Be OH, R
5Be OH, R
6Be OH, R
7Be OH, R
8Be OH, R
9Be methyl, and L
1Be O.
The Sirtuin activating compounds is the chemical compound shown in general formula 58 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is OH, R
1Be CH
2OH, R
2Be OH, R
3Be methyl, R
4Be OH, R
5Be OH, R
6Be OH, R
7Be OH, R
8Be OH, R
9Be methyl, L
1Be O, and L
2Be O.
The Sirtuin activating compounds is the chemical compound shown in general formula 58 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is OH, R
1Be CH
2OH, R
2Be OH, R
3Be methyl, R
4Be OH, R
5Be OH, R
6Be OH, R
7Be OH, R
8Be OH, R
9Be methyl, L
1Be O, L
2Be O, and L
3Be O.
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 59:
Wherein, each variable is independently of one another,
R, R
1, R
2And R
3For H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
L is O, NR, S or Se; And
N and m comprise 0 to 5 integer.
The Sirtuin activating compounds is the chemical compound shown in general formula 59 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 59 and the subsidiary definition thereof, wherein R
1Be H.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 59 and the subsidiary definition thereof, wherein R
2Be H.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 59 and the subsidiary definition thereof, wherein R
3Be H.
The Sirtuin activating compounds is the chemical compound shown in general formula 59 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein L is Se.
The Sirtuin activating compounds is the chemical compound shown in general formula 59 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1.
The Sirtuin activating compounds is the chemical compound shown in general formula 59 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein m is 1.
The Sirtuin activating compounds is the chemical compound shown in general formula 59 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H and R
1Be H.
The Sirtuin activating compounds is the chemical compound shown in general formula 59 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be H, and R
2Be H.
The Sirtuin activating compounds is the chemical compound shown in general formula 59 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be H, R
2Be H, and R
3Be H.
The Sirtuin activating compounds is the chemical compound shown in general formula 59 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be H, R
2Be H, R
3Be H, and L is Se.
The Sirtuin activating compounds is the chemical compound shown in general formula 59 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be H, R
2Be H, R
3Be H, L is Se, and n is 1.
The Sirtuin activating compounds is the chemical compound shown in general formula 59 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be H, R
2Be H, R
3Be H, L is Se, and n is 1, and m is 1.
In another embodiment, the Sirtuin reactive compound is the chemical compound shown in the general formula 60:
Wherein, each variable is independently of one another,
R be hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
R
1And R
2For H, hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
L is O, NR
3, S or SO
2
R3 be H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
N comprises 0 to 4 integer; And
M comprises 1 to 5 integer.
The Sirtuin activating compounds is the chemical compound shown in general formula 60 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1.
The Sirtuin activating compounds is the chemical compound shown in general formula 60 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is Cl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 60 and the subsidiary definition thereof, wherein R
1Be NH
2
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 60 and the subsidiary definition thereof, wherein R
2Be CO
2H.
The Sirtuin activating compounds is the chemical compound shown in general formula 60 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein L is SO
2
The Sirtuin activating compounds is the chemical compound shown in general formula 60 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein m is 1.
The Sirtuin activating compounds is the chemical compound shown in general formula 60 and the subsidiary definition thereof more specifically in the embodiment at one, wherein n be 1 and R be Cl.
The Sirtuin activating compounds is the chemical compound shown in general formula 60 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is Cl, and R
1Be NH
2
The Sirtuin activating compounds is the chemical compound shown in general formula 60 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is Cl, R
1Be NH
2, and R
2Be CO
2H.
The Sirtuin activating compounds is the chemical compound shown in general formula 60 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is Cl, R
1Be NH
2, R
2Be CO
2H, and L is SO
2
The Sirtuin activating compounds is the chemical compound shown in general formula 60 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 1, and R is Cl, R
1Be NH
2, R
2Be CO
2H, L are SO
2, and m is 1.
In another embodiment, the Sirtuin reactive compound is the chemical compound shown in the general formula 61:
Wherein, each variable is independently of one another,
R, R
1, R
2And R
3For H, hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
N and m comprise 0 to 5 integer.
The Sirtuin activating compounds is the chemical compound shown in general formula 61 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 2.
The Sirtuin activating compounds is the chemical compound shown in general formula 61 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is 3-hydroxyl and 5-hydroxyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 61 and the subsidiary definition thereof, wherein R
1Be H.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 61 and the subsidiary definition thereof, wherein R
2Be H.
The Sirtuin activating compounds is the chemical compound shown in general formula 61 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein m is 0.
The Sirtuin activating compounds is the chemical compound shown in general formula 61 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein m is 1.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 61 and the subsidiary definition thereof, wherein R
3Be the 4-hydroxyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 61 and the subsidiary definition thereof, wherein R
3Be the 4-methoxyl group.
The Sirtuin activating compounds is the chemical compound shown in general formula 61 and the subsidiary definition thereof more specifically in the embodiment at one, wherein n be 2 and R be 3-hydroxyl and 5-hydroxyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 61 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 2, and R is 3-hydroxyl and 5-hydroxyl, and R
1Be H.
The Sirtuin activating compounds is the chemical compound shown in general formula 61 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 2, and R is 3-hydroxyl and 5-hydroxyl, R
1Be H, and R
2Be H.
The Sirtuin activating compounds is the chemical compound shown in general formula 61 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 2, and R is 3-hydroxyl and 5-hydroxyl, R
1Be H, R
2Be H, and m is 0.
The Sirtuin activating compounds is the chemical compound shown in general formula 61 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 2, and R is 3-hydroxyl and 5-hydroxyl, R
1Be H, R
2Be H, and m is 1.
The Sirtuin activating compounds is the chemical compound shown in general formula 61 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 2, and R is 3-hydroxyl and 5-hydroxyl, R
1Be H, R
2Be H, m is 1, and R
3Be the 4-hydroxyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 61 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein n is 2, and R is 3-hydroxyl and 5-hydroxyl, R
1Be H, R
2Be H, m is 1, and R
3Be the 4-methoxyl group.
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 62:
Wherein, each variable is independently of one another,
R, R
1, R
2, R
3, R
4, R
5And R
6For H, hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
L is O, NR
7Or S; And
R
7For H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 62 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is OH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 62 and the subsidiary definition thereof, wherein R
1Be OH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 62 and the subsidiary definition thereof, wherein R
2Be CH
2OH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 62 and the subsidiary definition thereof, wherein R
3Be OH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 62 and the subsidiary definition thereof, wherein R
4Be OH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 62 and the subsidiary definition thereof, wherein R
5Be OH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 62 and the subsidiary definition thereof, wherein R
6Be CH
2OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 62 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein L is O.
The Sirtuin activating compounds is the chemical compound shown in general formula 62 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is OH and R
1Be OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 62 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is OH, R
1Be OH, and R
2Be CH
2OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 62 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is OH, R
1Be OH, R
2Be CH
2OH, and R
3Be OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 62 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is OH, R
1Be OH, R
2Be CH
2OH, R
3Be OH, and R
4Be OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 62 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is OH, R
1Be OH, R
2Be CH
2OH, R
3Be OH, R
4Be OH, and R
5Be OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 62 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is OH, R
1Be OH, R
2Be CH
2OH, R
3Be OH, R
4Be OH, R
5Be OH, and R
6Be CH
2OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 62 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is OH, R
1Be OH, R
2Be CH
2OH, R
3Be OH, R
4Be OH, R
5Be OH, R
6Be CH
2OH, and L is O.
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 63:
Wherein, each variable is independently of one another,
R, R
1And R
2For H, hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 63 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is CO
2H.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 63 and the subsidiary definition thereof, wherein R
1Be ethyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 63 and the subsidiary definition thereof, wherein R
2Be the N-1-pyrrolidine.
The Sirtuin activating compounds is the chemical compound shown in general formula 63 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is CO
2H and R
1Be ethyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 63 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is CO
2H and R
2Be the N-1-pyrrolidine.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 63 and the subsidiary definition thereof, wherein R
1Be ethyl and R
2Be the N-1-pyrrolidine.
The Sirtuin activating compounds is the chemical compound shown in general formula 63 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is CO
2H, R
1Be ethyl, and R
2Be the N-1-pyrrolidine.
In another embodiment, the Sirtuin reactive compound is the chemical compound shown in the general formula 64:
Wherein, each variable is independently of one another,
R, R
1, R
2, R
3, R
4, R
5, R
6And R
7For H, hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
L
1, L
2And L
3Be CH
2, O, NR
8Or S; And
R
8For H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is Cl.
The Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof, wherein R
1Be OH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof, wherein R
2Be N (Me)
2
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof, wherein R
3Be OH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof, wherein R
4Be C (O) NH
2
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof, wherein R
5Be OH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof, wherein R
6Be OH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof, wherein R
7Be OH.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof, wherein L
1Be CH
2
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof, wherein L
2Be O.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof, wherein L
3Be O.
The Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is Cl and R
1Be OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is Cl, R
1Be OH, and R
2Be N (Me)
2
The Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is Cl, R
1Be OH, R
2Be N (Me)
2, and R
3Be OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is Cl, R
1Be OH, R
2Be N (Me)
2, R
3Be OH, and R
4Be C (O) NH
2
The Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is Cl, R
1Be OH, R
2Be N (Me)
2, R
3Be OH, R
4Be C (O) NH
2, and R
5Be OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is Cl, R
1Be OH, R
2Be N (Me)
2, R
3Be OH, R
4Be C (O) NH
2, R
5Be OH, and R
6Be OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is Cl, R
1Be OH, R
2Be N (Me)
2, R
3Be OH, R
4Be C (O) NH
2, R
5Be OH, R
6Be OH, and R
7Be OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is Cl, R
1Be OH, R
2Be N (Me)
2, R
3Be OH, R
4Be C (O) NH
2, R
5Be OH, R
6Be OH, R
7Be OH, and L
1Be CH
2
The Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is Cl, R
1Be OH, R
2Be N (Me)
2, R
3Be OH, R
4Be C (O) NH
2, R
5Be OH, R
6Be OH, R
7Be OH, L
1Be CH
2, and L
2Be O.
The Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is Cl, R
1Be OH, R
2Be N (Me)
2, R
3Be OH, R
4Be C (O) NH
2, R
5Be OH, R
6Be OH, R
7Be OH, L
1Be CH
2, L
2Be O, and L
3Be O.
The Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H and R
1Be OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be OH, and R
2Be N (Me)
2
The Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be OH, R
2Be N (Me)
2, and R
3Be OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be OH, R
2Be N (Me)
2, R
3Be OH, and R
4Be C (O) NH
2
The Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be OH, R
2Be N (Me)
2, R
3Be OH, R
4Be C (O) NH
2, and R
5Be OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be OH, R
2Be N (Me)
2, R
3Be OH, R
4Be C (O) NH
2, R
5Be OH, and R
6Be OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be OH, R
2Be N (Me)
2, R
3Be OH, R
4Be C (O) NH
2, R
5Be OH, R
6Be OH, and R
7Be OH.
The Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be OH, R
2Be N (Me)
2, R
3Be OH, R
4Be C (O) NH
2, R
5Be OH, R
6Be OH, R
7Be OH, and L
1Be CH
2
The Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be OH, R
2Be N (Me)
2, R
3Be OH, R
4Be C (O) NH
2, R
5Be OH, R
6Be OH, R
7Be OH, L
1Be CH
2, and L
2Be O.
The Sirtuin activating compounds is the chemical compound shown in general formula 64 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is H, R
1Be OH, R
2Be N (Me)
2, R
3Be OH, R
4Be C (O) NH
2, R
5Be OH, R
6Be OH, R
7Be OH, L
1Be CH
2, L
2Be O, and L
3Be O.
In another embodiment, the Sirtuin activating compounds is the chemical compound shown in the general formula 65:
Wherein, independent between each variable,
R be H or replacement or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl;
R
1, R
2And R
3For hydroxyl, amino, cyano group, halogenide, alkoxyl, ether, ester, amide groups, ketone, carboxylic acid, nitro or replace or unsubstituted alkyl, aryl, aralkyl, heterocyclic radical, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl; And
L
1And L
2Be O, NR or S.
The Sirtuin activating compounds is the chemical compound shown in general formula 65 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is a methyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is chemical compound and attached definition, the wherein R shown in general formula 65 and the subsidiary definition thereof
1Be methyl.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 65 and the subsidiary definition thereof, wherein R
2Be CO
2H.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 65 and the subsidiary definition thereof, wherein R
3Be F.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 65 and the subsidiary definition thereof, wherein L
1Be O.
At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound shown in general formula 65 and the subsidiary definition thereof, wherein L
2Be O.
The Sirtuin activating compounds is the chemical compound shown in general formula 65 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is methyl and R
1Be methyl.
The Sirtuin activating compounds is the chemical compound shown in general formula 65 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is a methyl, R
1Be methyl, and R
2Be CO
2H.
The Sirtuin activating compounds is the chemical compound shown in general formula 65 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is a methyl, R
1Be methyl, R
2Be CO
2H, and R
3Be F.
The Sirtuin activating compounds is the chemical compound shown in general formula 65 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is a methyl, R
1Be methyl, R
2Be CO
2H, R
3Be F, and L
1Be O.
The Sirtuin activating compounds is the chemical compound shown in general formula 65 and the subsidiary definition thereof more specifically in the embodiment at one, and wherein R is a methyl, R
1Be methyl, R
2Be CO
2H, R
3Be F, L
1Be O, and L
2Be O.
Exemplary activating compounds is that the ratio of the relative control rate listed in the subordinate list is greater than 1 chemical compound.Preferred compound shown in the general formula 8 is a dipyridamole; Preferred compound shown in the general formula 12 is a Hinokitiol; Preferred compound shown in the general formula 13 is L-(+)-ergothioneine; Preferred compound shown in the general formula 19 is the caffeic acid phenolic ester; Preferred compound shown in the general formula 20 is that the preferred compound shown in MCI-186 and the general formula 21 is HBED (subordinate list 6).Activating compounds also can be the oxidised form of the chemical compound of table 21.
The present invention also comprises the pharmaceutically acceptable salt and the coordination compound of the chemical compound shown in general formula 1-25,30,32-65 and the 69-88.If chemical compound wherein can have one or more chiral centres, unless explanation, the chemical compound that the present invention considers can be the racemic mixture of single stereoisomers or stereoisomer.
In a specific embodiments, the Sirtuin activating compounds is stilbene, chalcone derivative or the chromocor compound of general formula 7 representatives:
Wherein, independent between each variable,
M does not exist or is O;
R
1, R
2, R
3, R
4, R
5, R '
1, R '
2, R '
3, R '
4And R '
5Represent H, alkyl, aryl, heteroaryl, aralkyl, alkaryl, heteroaryl alkyl, halogenide, NO
2, SR, OR, N (R)
2Or carboxyl;
R
aRepresent H or two R
aForm key;
R represents H, alkyl or aryl; And
N is 0 or 1.
The Sirtuin activating compounds is the chemical compound of general formula 7 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein n is 0.The Sirtuin activating compounds is the chemical compound of general formula 7 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein n is 1.The Sirtuin activating compounds is the chemical compound of general formula 7 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein M does not exist.The Sirtuin activating compounds is the chemical compound of general formula 7 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein M is O.At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound of general formula 7 and subsidiary definition representative thereof, wherein R
aBe H.The Sirtuin activating compounds is the chemical compound of general formula 7 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein M is O and two R
aForm key.At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound of general formula 7 and subsidiary definition representative thereof, wherein R
5Be H.At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound of general formula 7 and subsidiary definition representative thereof, wherein R
5Be OH.At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound of general formula 7 and subsidiary definition representative thereof, wherein R
1, R
3And R '
3Be OH.At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound of general formula 7 and subsidiary definition representative thereof, wherein R
2, R
4, R '
2And R '
3Be OH.At one more specifically in the embodiment, the Sirtuin activating compounds is the chemical compound of general formula 7 and subsidiary definition representative thereof, wherein R
2, R '
2And R '
3Be OH.
The Sirtuin activating compounds is the chemical compound of general formula 7 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein n is 0; M does not exist; R
aBe H; R
5Be H; R
1, R
3And R '
3Be OH; And R
2, R
4, R '
1, R '
2, R '
4And R '
5Be H.The Sirtuin activating compounds is the chemical compound of general formula 7 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein n is 1; M does not exist; R
aBe H; R
5Be H; R
2, R
4, R '
2And R '
3Be OH; And R
1, R
3, R '
1, R '
4And R '
5Be H.The Sirtuin activating compounds is the chemical compound of general formula 7 and subsidiary definition representative thereof more specifically in the embodiment at one, and wherein n is 1; M is O; Two R
aForm key; R
5Be OH; R
2, R '
2And R '
3Be OH; And R
1, R
3, R
4, R '
1, R '
4And R '
5Be H.
In another embodiment, exemplary Sirtuin activating compounds is the Pyrazinamide analog, for example, and United States Patent(USP) Nos. 5,985,848; 6,066,722; 6,228,847; 6,492,347; 6,803,455; With U.S. Patent Publication Nos.2001/0019823; 2002/0061898; 2002/0132783; 2003/0149261; 2003/0229033; 2003/0096830; 2004/0053944; The Pyrazinamide analog of record in 2004/0110772 and 2004/0181063, therefore above-mentioned disclosure is all introduced the present invention as a reference.In an exemplary specific embodiments, the Sirtuin activating compounds can be for having the Pyrazinamide analog of following general formula 69-72 arbitrarily.In a specific embodiments, the Sirtuin activating compounds is the Pyrazinamide similar compound shown in the general formula 69:
Wherein A be nitrogen-, oxygen-or aryl, alkyl, ring or the heterocyclic group of sulfur-connection.A described here partly chooses wantonly has the characteristic of leaving group.In the specific embodiments that the present invention includes, A also is powered subdivision and replaces.B and C are hydrogen, or one of B or C be halogen, amino or mercapto, and among B or the C another is hydrogen; And D is primary alconol, hydrogen or oxygen, nitrogen, carbon or sulfur; and it is connected on phosphate ester, phosphoryl, the pyrophosphoryl base; or by di-phosphate ester or carbon-, nitrogen-or the di-phosphate ester bridging of sulfur-replacement receive on single adenosine phosphate, or by di-phosphate ester or carbon-, nitrogen-or the adenosine diphosphate (ADP) of the di-phosphate ester bridge of sulfur-replacement on.
In one embodiment, A is aryl or heterocyclic group that the N-that replaces connects, has the aryl or the heterocyclic group of the O-connection of general formula-O-Y, or has the aryl or the heterocyclic group of the S-connection of general formula-O-Y; B and C are hydrogen, or B or C one of them be halogen, amino or mercaptan, and another B or C are hydrogen; And D is primary alconol or hydrogen.Below list the nonrestrictive preferred example of A, wherein each R is H or power supply subdivision, and Z is an alkyl, aryl, hydroxyl, Z ' are the OZ ' of alkyl or aryl, amino, Z ' is the NHZ ' of alkyl or aryl, or Z ' and Z " are respectively the NHZ ' Z of alkyl or aryl ".
The example of A comprises following i to xiv:
Wherein Y=has the group of leaving group function.
The example of Y includes, but are not limited to following xv to xxvii:
For i to xxvii, wherein X is the oxygen of the mercaptan, amino of halogen, mercaptan or replacement or the amino, oxygen or the replacement that replace, or aryl or alkyl or heterocycle.
In some specific embodiments, A is the nicotinoyl amido (above-mentioned i, wherein Z is H) that replaces, the pyrazolyl of replacement (the vii) above-mentioned or 3-carboxylic acid amides imidazole radicals (above-mentioned x, wherein Z is H) that replaces.In addition, B and C can be hydrogen, or one of B or C be halogen, amino or mercapto, and another B or C are hydrogen; D is primary alconol or hydrogen.
In other specific embodiments, when another B or C were hydrogen, one of B or C can be halogen, amino or mercapto.And; D can be hydrogen or oxygen, nitrogen, carbon or sulfur; it is connected to phosphate ester, phosphoryl, pyrophosphoryl base; or by di-phosphate ester or carbon-, nitrogen-or the di-phosphate ester bridging of sulfur-replacement receive single adenosine phosphate, or by di-phosphate ester or carbon-, nitrogen-or the di-phosphate ester bridging of sulfur-replacement receive adenosine diphosphate (ADP).The analog of single adenosine phosphate or adenosine diphosphate (ADP) also can replace single adenosine phosphate or adenosine diphosphate (ADP) group.
In some specific embodiments, A has two or more power supply subdivisions.
In other specific embodiments, the Sirtuin activating compounds is the Pyrazinamide similar compound shown in following general formula 70,71 or 72.
Wherein Z is an alkyl, aryl, and hydroxyl, wherein Z ' is alkyl or aryl, amino OZ ', wherein Z ' is the NHZ ' of alkyl or aryl, or wherein Z ' and Z " being the NHZ ' Z of alkyl or aryl independently "; E and F are H, CH independently
3, OCH
3, CH
2CH
3, NH
2, OH, NHCOH, NHCOCH
3, N (CH
3)
2, C (CH
3)
2, aryl or C3-C10 alkyl, preferably, if E or F one of them when being H, another E or F are not H;
Wherein G, J or K are CONHZ, and wherein Z is alkyl, aryl, hydroxyl, and wherein Z ' is alkyl or aryl, amino OZ ', and wherein Z ' is the NHZ ' of alkyl or aryl, or wherein Z ' and Z " being the NHZ ' Z of alkyl or aryl independently "; And two of other of G, J and K are CH independently
3, OCH
3, CH
2CH
3, NH
2, OH, NHCOH, NHCOCH
3
Wherein Z is an alkyl, aryl, and hydroxyl, wherein Z ' is alkyl or aryl, amino OZ ', wherein Z ' is the NHZ ' of alkyl or aryl, or wherein Z ' and Z " being the NHZ ' Z of alkyl or aryl independently "; And L is CH
3, OCH
3, CH
2CH
3, NH
2, OH, NHCOH, NHCOCH
3
In an exemplary specific embodiments, chemical compound is the chemical compound shown in the above-mentioned general formula 70, and wherein E and F are H, CH independently
3, OCH
3Or OH, preferably, if when one of E or F are H, another E or F are not H.
In another particular exemplary embodiments, chemical compound be β-1 '-5-methyl-nicotiamide-2 '-deoxyribose, β-D-1 '-5-methyl-nicotiamide-2 '-deoxyribofuranoside, β-1 '-4,5-dimethyl-nicotiamide-2 '-deoxyribose or β-D-1 '-4,5-dimethyl-nicotiamide-2 '-deoxyribofuranoside.
In another embodiment, chemical compound be β-1 '-5-methyl-nicotiamide-2 '-deoxyribose.
Under the restriction that is not subjected to any special mechanism, should believe that the power supply subdivision on A can be stablized chemical compound of the present invention, thereby make the less influence that is subjected to hydrolysis of remaining part of chemical compound.Keep active owing to the antagonism hydrolysis makes chemical compound long period in biosystem, the chemical stability of this improvement has promoted the value of chemical compound.Those skilled in the art it is contemplated that multiple expection brings into play the power supply subdivision of this stabilization function.The non-limitative example of suitable power supply subdivision is methyl, ethyl, O-methyl, amino, NMe
2, hydroxyl, CMe
3, aryl and alkyl.Preferably, the power supply subdivision is methyl, ethyl, O-methyl, amino.In most preferred specific embodiments, the power supply subdivision is a methyl.
Chemical compound shown in the general formula 69-72 uses with the form of free form and salt.Term " pharmaceutically acceptable salt " is meant that application source is from inorganic or organic acid nontoxic salts, as be derived from the salt of following acid: hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, lactic acid, fumaric acid, succinic acid, tartaric acid, gluconic acid, citric acid, pyrovinic acid and p-methyl benzenesulfonic acid.
Chemical compound shown in the general formula 69-72 that the present invention also provides is tautomer, pharmaceutically acceptable salt, ester and the prodrug of inhibitor compound disclosed by the invention.
The bioavailability of chemical compound shown in the general formula 69-72 can improve by the form that is converted into prodrug.These prodrugs are with respect to unconverted chemical compound, and its lipotropy is enhanced, and this can improve membrane permeability.A form that is particularly useful of prodrug is an ester derivant.Its effect depends on the hydrolysis of one or more ubiquitous cell lactonase catalysis ester groups, and its avtive spot or near the activity of release of active compounds.In a kind of prodrug forms, one or more hydroxyls can be by the O-acyl groupization in the chemical compound, thus the derivant of preparation acidylate.
The prodrug forms that also can prepare the 5-phosphate derivative of chemical compound shown in the general formula 69-72.Because the anionic nature of 5-phosphate ester can limit the ability that it passes cell membrane, so this can be particularly useful.This 5-phosphate derivative is convenient to be converted into uncharged two (acyl-oxygen methyl) ester derivant.The effect of this prodrug depends on the hydrolysis of one or more ubiquitous cell lactonase catalysis ester groups, and avtive spot or near the activity of release formaldehyde molecule and chemical compound of the present invention.The object lesson of the effect of the acyl-oxygen methyl ester prodrug forms of these phosphorylation carbohydrate derivates and general preparation method is by record (Kang etc., 1998; Jiang etc., 1998; Li etc., 1997; Kruppa etc., 1997).
In another embodiment, exemplary Sirtuin activating compounds is O-acetyl group-ADP-ribose analog, comprise 2 '-O-acetyl group-ADP-ribose and 3 '-O-acetyl group-ADP-ribose and analog thereof.Exemplary O-acetyl group-ADP-ribose analog is on the books, and for example U.S. Patent Publication 2004/0053944; 2002/0061898 and 2003/0149261, so its disclosure all is introduced into the present invention as a reference.In an exemplary specific embodiments, the Sirtuin activating compounds can be for having the O-acetyl group shown in following any general formula 73-76-ADP-ribose analog.In a specific embodiments, the Sirtuin activating compounds is the O-acetyl group shown in the general formula 73-ADP-ribose similar compound
Wherein:
A is selected from N, CH and CR, and wherein R is selected from halogen, optional alkyl, aralkyl and aryl, OH, the NH that replaces
2, NHR
1, NR
1R
2And SR
3, R wherein
1, R
2And R
3Respectively do for oneself and choose alkyl, aralkyl or the aryl that replaces wantonly;
B is selected from OH, NH
2, NHR
4, H and halogen, wherein R
4Be optional alkyl, aralkyl or the aryl that replaces;
D is selected from OH, NH
2, NHR
5, H, halogen and SCH
3, R wherein
5Be optional alkyl, aralkyl or the aryl that replaces;
X and Y are independently selected from H, OH and halogen, and condition is that another is a hydrogen when one of X and Y are hydroxyl or halogen;
Z is OH, and perhaps when X was hydroxyl, Z was selected from hydrogen, halogen, hydroxyl, SQ and OQ, and wherein Q is optional alkyl, aralkyl or the aryl that replaces; And
W is OH or H, and condition is when W is OH, and A is CR, wherein R such as above-mentioned definition;
Or its tautomer; Or its pharmaceutically acceptable salt; Or its ester; Or its prodrug.
In some specific embodiments, when B is NHR
4And/or D is NHR
5, R so
4And/or R
5Be the C1-C4 alkyl.
In other specific embodiments, when having one or more halogen, they are selected from chlorine and fluorine.
In another embodiment, when Z was SQ or OQ, Q was the C1-C5 alkyl or phenyl.
In an exemplary specific embodiments, D is H, or when D was not H, B was OH.
In another embodiment, B is OH, and D is H, OH or NH
2, X is OH or H, and Y is H, and most preferably Z is OH, H or methyl mercapto, is in particular OH.
In some specific embodiments, W is OH, and Y is H, and X is OH, and A is CR, and wherein R is methyl or halogen, is preferably fluorine.
In other specific embodiments, W is H, and Y is H, and X is that OH and A are CH.
In other specific embodiments, the Sirtuin activating compounds is the O-acetyl group shown in the general formula 74-ADP-ribose similar compound:
Wherein A, X, Y, Z and the R definition of appearance first in the chemical compound shown in above general formula (73); E is selected from CO
2H or corresponding salt, CO
2R, CN, CONH
2, CONHR or CONR
2And G is selected from NH
2, NHCOR, NHCONHR or NHCSNHR; Or its tautomer, or its pharmaceutically acceptable salt, or its ester, or its prodrug.
In some specific embodiments, E is CONH
2And G is NH
2
In other specific embodiments, E is CONH
2, G is NH
2, X is OH or H, is H, most preferably Z is OH, H or methyl mercapto, is in particular OH.
Exemplary Sirtuin activating compounds comprises following compounds:
(1S)-1, the two deoxidation-1-C-(4-hydroxyl pyrroles [3,2-d] pyrimidin-7-yl)-1 of 4-, 4-imino group-D-ribitol
(1S)-and 1-C-(2-amino-4-hydroxy pyrroles [3,2-d] pyrimidin-7-yl)-1, the two deoxidations-1 of 4-, 4-imino group-D-ribitol
(1R)-and 1-C-(4-hydroxyl pyrroles [3,2-d] pyrimidin-7-yl)-1,4-imino group-1,2,4-three deoxidations-D-erythro form-pentitol
(1S)-and 1-C-(4-hydroxyl pyrroles [3,2-d] pyrimidin-7-yl)-1,4-imino group-1,4,5-three deoxy-D-ribose alcohol
(1S)-1, the two deoxidation-1-C-(4-hydroxyl pyrroles [3,2-d] pyrimidin-7-yl)-1 of 4-, 4-imino group-5-methyl mercapto-D-ribitol
(1S)-1, the two deoxidation-1-C-(2,4-dihydroxy-pyrrolidine [3,2-d] pyrimidin-7-yl)-1 of 4-, 4-imino group-D-ribitol
(1R)-and 1-C-(2,4-dihydroxy-pyrrolidine [3,2-d] pyrimidin-7-yl)-1,4-imino group-1,2,4-three deoxidations-D-erythro form-pentitol
(1S)-and 1-C-(2,4-dihydroxy-pyrrolidine [3,2-d] pyrimidin-7-yl)-1,4-imino group-1,4,5-three deoxy-D-ribose alcohol
(1S)-1, the two deoxidation-1-C-(2,4-dihydroxy-pyrrolidine [3,2-d] pyrimidin-7-yl)-1 of 4-, 4-imino group-5-ethylmercapto group-D-ribitol
(1R)-and 1-C-(2-amino-4-hydroxy pyrroles [3,2-d] pyrimidin-7-yl)-1,4-imino group-1,2,4-three deoxidations-D-erythro form-pentitol
(1S)-and 1-C-(2-amino-4-hydroxy pyrroles [3,2-d] pyrimidin-7-yl)-1,4-imino group-1,4,5-three deoxy-D-ribose alcohol
(1S)-and 1-C-(2-amino-4-hydroxy pyrroles [3,2-d] pyrimidin-7-yl)-1, the two deoxidations-1 of 4-, 4-imino group-5-methyl mercapto-D-ribitol
(1S)-1, the two deoxidation-1-C-(7-hydroxypyrazoles [4,3-d] pyrimidin-3-yl)-1 of 4-, 4-imino group-D-ribitol
(1R)-and 1-C-(7-hydroxypyrazoles [4,3-d] pyrimidin-3-yl)-1,4-imino group-1,2,4-three deoxidations-D-erythro form-pentitol
(1S)-and 1-C-(7-hydroxypyrazoles [4,3-d] pyrimidin-3-yl)-1,4-imino group-1,4,5-three deoxy-D-ribose alcohol
(1S)-1, the two deoxidation-1-C-(7-hydroxypyrazoles [4,3-d] pyrimidin-3-yl)-1 of 4-, 4-imino group-5-ethylmercapto group-D-ribitol
(1S)-1, the two deoxidation-1-C-(5,7-dihydroxy pyrazoles [4,3-d] pyrimidin-3-yl)-1 of 4-, 4-imino group-D-ribitol
(1R)-and 1-C-(5,7-dihydroxy pyrazoles [4,3-d] pyrimidin-3-yl)-1,4-imino group-1,2,4-three deoxidations-D-erythro form-pentitol
(1S)-and 1-C-(5,7-dihydroxy pyrazoles [4,3-d] pyrimidin-3-yl)-1,4-imino group-1,4,5-three deoxy-D-ribose alcohol
(1S)-1, the two deoxidation-1-C-(5,7-dihydroxy pyrazoles [4,3-d] pyrimidin-3-yl)-1 of 4-, 4-imino group-5-methyl mercapto-D-ribitol
(1S)-and 1-C-(5-amino-7-hydroxypyrazoles [4,3-d] pyrimidin-3-yl)-1, the two deoxidations-1 of 4-, 4-imino group-D-ribitol
(1R)-and 1-C-(S-amino-7-hydroxypyrazoles [4,3-d] pyrimidin-3-yl)-1,4-imino group-1,2,4-three deoxidations-D-erythro form-pentitol
(1S)-and 1-C-(5-amino-7-hydroxypyrazoles [4,3-d] pyrimidin-3-yl)-1,4-imino group-1,4,5-three deoxy-D-ribose alcohol
(1S)-and 1-C-(5-amino-7-hydroxypyrazoles [4,3-d] pyrimidin-3-yl)-1, the two deoxidations-1 of 4-, 4-imino group-5-methyl mercapto-D-ribitol
(1S)-and 1-C-(3-amino-2-formamido-4-pyrroles)-1, the two deoxidations-1 of 4-, 4-imino group-D-ribitol
(1S)-1, the two deoxidation-1-C-(4-hydroxyl pyrroles [3,2-d] pyrimidin-7-yl)-1 of 4-, 4-imino group-D-ribitol 5-phosphate ester
(1S)-and 1-C-(2-amino-4-hydroxy pyrroles [3,2-d] pyrimidin-7-yl)-1,4-imino group-D-ribitol 5-phosphate ester
(1S)-and 1-C-(3-amino-2-formamido-4-pyrroles)-1, the two deoxidations-1 of 4-, 4-imino group-D-ribitol
In other specific embodiments, the Sirtuin activating compounds is the O-acetyl group shown in general formula 75 and 76-ADP-ribose similar compound, their tautomer and pharmaceutically acceptable salt.
The bioavailability of the chemical compound shown in general formula (73) or the general formula (74) can improve by being converted into prodrug forms.These prodrugs are with respect to the chemical compound shown in general formula (73) or the general formula (74), and its lipotropy improves, like this membrane permeability that can obtain to improve.A form that is particularly useful of prodrug is an ester derivant.Its effect depends on the hydrolysis of one or more ubiquitous these ester groups of cell lactonase catalysis, and avtive spot or near the activity of the chemical compound shown in release general formula (73) and the general formula (74).
In a kind of prodrug forms, the one or more hydroxyls in the chemical compound shown in general formula (73) or the general formula (74) can be by the O-acyl groupization, thus preparation example such as 5-O-butyrate or 2,3-two-O-butyrate derivant.
The prodrug forms that also can prepare the 5-phosphate derivative of the chemical compound shown in general formula (73) or the general formula (74) is because the anionic nature of 5-phosphate ester can limit the ability that it passes cell membrane, so this is particularly useful.This 5-phosphate derivative is convenient to be converted into uncharged two (acyl-oxygen methyl) ester derivant.The effect of this prodrug depends on the hydrolysis of one or more ubiquitous these ester groups of cell lactonase catalysis, and avtive spot or near the activity of chemical compound of release formaldehyde molecule and general formula (73) or general formula (74).
In an exemplary specific embodiments, 2 '-analog of AADPR or 3 '-AADPR is designed to the replacement known by to the ester oxygen atom that attacked by esterase, thereby increases its stability to esterase.2 '-the unstable oxygen atom of esterase among AADPR and 3 '-AADPR can be understood as the ester oxygen that is connected aceticoceptor and ribose, and the ester oxygen between two phosphorus atoms.Known in the art, one of these ester oxygen atoms or both are by CF
2, NH or S replace will produce more stable in fact 2 because the antiesterase effect increases '-AADPR or 3 '-AADPR analog.
Therefore, in some specific embodiments, the present invention relates to show increase cell inner stablity 2 '-O-acetyl group-ADP-ribose or 3 '-O-acetyl group-ADP-ribose analog.Preferred analog comprises by CF
2, NH or S replace the oxygen between acetonyl ester oxygen or two phosphorus atoms.Most preferred substituent group is CF
2The replacement of acetonyl ester oxygen is especially preferred.In other preferred specific embodiments, the oxygen between ester oxygen and two phosphorus atoms is independently by CF
2, NH or S replace.
The present invention also comprises the pharmaceutically acceptable addition salt and the coordination compound of the Sirtuin reactive compound of record herein.If chemical compound wherein can have one or more chiral centres, unless specified otherwise, the chemical compound that the present invention considers can be the racemic mixture of single stereoisomer or stereoisomer.
In a specific embodiments, be used for sirtuin regulator of the present invention by general formula 77 or 78 or its pharmaceutically acceptable salt representative:
Wherein:
R
301And R
302Be independently-H, replacement or unsubstituted alkyl, replacement or unsubstituted thiazolinyl, replacement or unsubstituted alkynyl, replacement or unsubstituted nonaromatic heterocycles group or replacement or unsubstituted aryl, or R
301And R
302Form that replace or unsubstituted nonaromatic heterocycles group together;
R
303, R
304, R
305And R
306Be independently selected from-H, replacement or unsubstituted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted nonaromatic heterocycles group, halogen ,-OR ,-CN ,-CO
2R ,-OCOR ,-OCO
2R ,-C (O) NRR ' ,-OC (O) NRR ' ,-C (O) R ,-COR ,-SR ,-OSO
3H ,-S (O) nR ,-S (O)
nOR ,-S (O)
nNRR ' ,-NRR ' ,-NRC (O) OR ' ,-NO
2With-NRC (O) R ';
R
307, R
308And R
310Be independently selected from-H, replacement or unsubstituted alkyl, replacement or unsubstituted aryl ,-C (O) R ,-C (O) OR ,-C (O) NHR ,-C (S) R ,-C (S) OR and-C (O) SR;
R
309Be selected from-H, replacement or unsubstituted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted nonaromatic heterocycles group, halogen ,-OR ,-CN ,-CO
2R ,-OCOR ,-OCO
2R ,-C (O) NRR ' ,-OC (O) NRR ' ,-C (O) R ,-COR ,-SR ,-OSO
3H ,-S (O)
nR ,-S (O)
nOR ,-S (O)
nNRR ' ,-NRR ' ,-NRC (O) OR ' and-NRC (O) R ';
R
311, R
312, R
313And R
314Be independently selected from-H, replacement or unsubstituted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted nonaromatic heterocycles group, halogen ,-CN ,-CO
2R ,-OCOR ,-OCO
2R ,-C (O) NRR ' ,-OC (O) NRR ' ,-C (O) R ,-COR ,-OSO
3H ,-S (O)
nR ,-S (O)
nOR ,-S (O)
nNRR ' ,-NRR ' ,-NRC (O) OR ' ,-NO
2With-NRC (O) R ';
R and R ' be independently-H, replacement or unsubstituted alkyl, nonaromatic heterocycles group replacement or unsubstituted aryl or replacement or unsubstituted;
X is O or S; And
N is 1 or 2.
One group of suitable compounds that general formula 77 and 78 is contained is by general structure 79 and 80 or the representative of its pharmaceutically acceptable salt:
Wherein:
R
201And R
202Be independently-H, replacement or unsubstituted alkyl, replacement or unsubstituted thiazolinyl, replacement or unsubstituted alkynyl, replacement or unsubstituted nonaromatic heterocycles group or replacement or unsubstituted aryl, or R
201And R
202Form that replace or unsubstituted nonaromatic heterocycles group together;
R
203, R
204, R
205And R
206Be independently selected from-H, replacement or unsubstituted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted nonaromatic heterocycles group, halogen ,-OR ,-CN ,-CO
2R ,-OCOR ,-OCO
2R ,-C (O) NRR ' ,-OC (O) NRR ' ,-C (O) R ,-COR ,-SR ,-OSO
3H ,-S (O)
nR ,-S (O)
nOR ,-S (O)
nNRR ' ,-NRR ' ,-NRC (O) OR ' ,-NO
2With-NRC (O) R ';
R
207, R
208And R
210Be independently selected from-H, replacement or unsubstituted alkyl, replacement or unsubstituted aryl ,-C (O) R ,-C (O) OR ,-C (O) NHR ,-C (S) R ,-C (S) OR and-C (O) SR;
R
209Be selected from-H, replacement or unsubstituted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted nonaromatic heterocycles group, halogen ,-OR ,-CN ,-CO
2R ,-OCOR ,-OCO
2R ,-C (O) NRR ' ,-OC (O) NRR ' ,-C (O) R ,-COR ,-SR ,-OSO
3H ,-S (O)
nR ,-S (O)
nOR ,-S (O)
nNRR ' ,-NRR ' ,-NRC (O) OR ' and-NRC (O) R ';
R
211, R
212, R
213And R
214Be independently selected from-H, replacement or unsubstituted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted nonaromatic heterocycles group, halogen ,-CN ,-CO
2R ,-OCOR ,-OCO
2R ,-C (O) NRR ' ,-OC (O) NRR ' ,-C (O) R ,-COR ,-OSO
3H ,-S (O)
nR ,-S (O)
nOR ,-S (O)
nNRR ' ,-NRR ' ,-NRC (O) OR ' ,-NO
2With-NRC (O) R ';
R and R ' be independently-H, replacement or unsubstituted alkyl, nonaromatic heterocycles group replacement or unsubstituted aryl or replacement or unsubstituted;
X is O or S, is preferably O; And
N is 1 or 2.
In one group of special compound by general formula 79 or 80 representatives, R
207, R
208And R
210In at least one for that replace or unsubstituted alkyl, replacement or unsubstituted aryl ,-C (O) R ,-C (O) OR ,-C (O) NHR ,-C (S) R ,-C (S) OR or-C (O) SR.Typically, R
207, R
208And R
210In at least one be-C (O) R or-C (O) OR.More typically, R
207, R
208And R
210In at least one is-C (O) R.In these chemical compounds, R is preferably replacement or unsubstituted alkyl especially is a unsubstituted alkyl, as methyl or ethyl.
In the special compound of another group by general formula 79 or 80 representatives, R
204Be halogen (for example, fluorine, bromine, chlorine) or hydrogen (comprising deuterium and/or tritium isotope).Suitable compounds comprises wherein R
207, R
208And R
210In at least one for that replace or unsubstituted alkyl, replacement or unsubstituted aryl ,-C (O) R ,-C (O) OR ,-C (O) NHR ,-C (S) R ,-C (S) OR or-C (O) SR and R
204Be halogen or hydrogen.
For the chemical compound of general formula 79 or 80 representatives, R
203-R
206Be typically-H.In addition, R
209And R
211-R
214Be typically-H.The special compound of general formula 79 or 80 representatives is selected from R
203-R
206, R
209And R
211-R
214Be entirely-chemical compound of H.For these chemical compounds, R
204, R
207, R
208And R
210Has aforesaid implication.
Typically, R
201And R
202For-H or replacement or unsubstituted alkyl, more typically, be-H.Has such R
201And R
202In the chemical compound of implication, R
203-R
206, R
209And R
211-R
214Has aforesaid implication typically.
In some method of the present invention, when X is O, R
201-R
214In at least one is not-H.
In some method of the present invention, work as R
201-R
205And R
207-R
214Be-during H, R
206Be not-H or-NH
2
In a specific embodiments, the sirtuin regulator is by general formula 81 or 82 or the representative of its pharmaceutically acceptable salt:
Wherein:
R
1And R
2Be independently-H, replacement or unsubstituted alkyl, replacement or unsubstituted thiazolinyl, replacement or unsubstituted alkynyl, replacement or unsubstituted nonaromatic heterocycles group or replacement or unsubstituted aryl, or R
1And R
2Form that replace or unsubstituted nonaromatic heterocycles group together, if R
1And R
2One of be-H that another is not quilt-C (O) OCH
2CH
3The alkyl that replaces;
R
3, R
4And R
5Be independently selected from-H, replacement or unsubstituted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted nonaromatic heterocycles group, halogen ,-OR ,-CN ,-CO
2R ,-OCOR ,-OCO
2R ,-C (O) NRR ' ,-OC (O) NRR ' ,-C (O) R ,-COR ,-SR ,-OSO
3H ,-S (O)
nR ,-S (O)
nOR ,-S (O)
nNRR ' ,-NRR ' ,-NRC (O) OR ' ,-NO
2With-NRC (O) R ';
R
6Be selected from-H, replacement or unsubstituted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted nonaromatic heterocycles group, halogen ,-OR ,-CN ,-CO
2R ,-OCOR ,-OCO
2R ,-C (O) NRR ' ,-OC (O) NRR ' ,-C (O) R ,-COR ,-SR ,-OSO
3H ,-S (O)
nR ,-S (O)
nOR ,-S (O)
nNRR ' ,-NRC (O) OR ' ,-NO
2With-NRC (O) R ';
R
7, R
8And R
10Be independently selected from-H, replacement or unsubstituted alkyl, replacement or unsubstituted aryl ,-C (O) R ,-C (O) OR ,-C (O) NHR ,-C (S) R ,-C (S) OR and-C (O) SR;
R
9Be selected from-H, replacement or unsubstituted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted nonaromatic heterocycles group, halogen ,-OR ,-CN ,-CO
2R ,-OCOR ,-OCO
2R ,-C (O) NRR ' ,-OC (O) NRR ' ,-C (O) R ,-COR ,-SR ,-OSO
3H ,-S (O)
nR ,-S (O)
nOR ,-S (O)
nNRR ' ,-NRR ' ,-NRC (O) OR ' and-NRC (O) R ';
R
11, R
12, R
13And R
14Be independently selected from-H, replacement or unsubstituted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted nonaromatic heterocycles group, halogen ,-CN ,-CO
2R ,-OCOR ,-OCO
2R ,-C (O) NRR ' ,-OC (O) NRR ' ,-C (O) R ,-COR ,-OSO
3H ,-S (O)
nR ,-S (O)
nOR ,-S (O)
nNRR ' ,-NRR ' ,-NRC (O) OR ' ,-NO
2With-NRC (O) R ';
R and R ' be independently-H, replacement or unsubstituted alkyl, replacement or unsubstituted aryl or that replace or unsubstituted nonaromatic heterocycles group;
X is O or S, is preferably O; And
N is 1 or 2,
If R
1-R
14Be not entirely-H, work as R
10For-C (O) C
6H
5The time, R
1-R
9And R
11-R
14Be not entirely-H.
In some specific embodiments, R
1For-H.
In some specific embodiments, R
7, R
8And R
10Be independently-H ,-C (O) R or-C (O) OR, be typically-H or-C (O) R, as-H or-C (O) CH
3In specific specific embodiments, R
1For-H and R
7, R
8And R
10Be independently-H ,-C (O) R or-C (O) OR.
In some specific embodiments, R
9For-H.In specific specific embodiments, work as R
1For-H and/or R
7, R
8And R
10Be independently-H ,-C (O) R or-during C (O) OR, R
9For-H.
In some specific embodiments, R
2For-H.In specific specific embodiments, work as R
9For-H, R
1For-H and/or R
7, R
8And R
10Be independently-H ,-C (O) R or-during C (O) OR, R
2For-H.Typically, work as R
9For-H, R
1For-H and R
7, R
8And R
10Be independently-H ,-C (O) R or-during C (O) OR, R
2For-H.
In some specific embodiments, R
4For-H` or halogen, as deuterium or fluorine.
In a specific embodiments, the sirtuin regulator is by general formula 83 or 84 or its pharmaceutically acceptable salt representative:
Wherein:
R
101And R
102Be independently-H, replacement or unsubstituted alkyl, replacement or unsubstituted thiazolinyl, replacement or unsubstituted alkynyl, replacement or unsubstituted nonaromatic heterocycles group or replacement or unsubstituted aryl, or R
101And R
102Form that replace or unsubstituted nonaromatic heterocycles group together;
R
103, R
104, R
105And R
106Be independently selected from-H, replacement or unsubstituted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted nonaromatic heterocycles group, halogen ,-OR ,-CN ,-CO
2R ,-OCOR ,-OCO
2R ,-C (O) NRR ' ,-OC (O) NRR ' ,-C (O) R ,-COR ,-SR ,-OSO
3H ,-S (O)
nR ,-S (O)
nOR ,-S (O)
nNRR ' ,-NRR ' ,-NRC (O) OR ' ,-NO
2With-NRC (O) R ';
R
107And R
108Be selected from-H, replacement or unsubstituted alkyl, replacement or unsubstituted aryl ,-C (O) R ,-C (O) OR ,-C (O) NHR ,-C (S) R ,-C (S) OR and-C (O) SR, wherein R
107And R
108In at least one for that replace or unsubstituted alkyl, replacement or unsubstituted aryl ,-C (O) R ,-C (O) OR ,-C (O) NHR ,-C (S) R ,-C (S) OR or-C (O) SR;
R
109Be selected from-H, replacement or unsubstituted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted nonaromatic heterocycles group, halogen ,-OR ,-CN ,-CO
2R ,-OCOR ,-OCO
2R ,-C (O) NRR ' ,-OC (O) NRR ' ,-C (O) R ,-COR ,-SR ,-OSO
3H ,-S (O)
nR ,-S (O)
nOR ,-S (O)
nNRR ' ,-NRR ' ,-NRC (O) OR ' and-NRC (O) R ';
If R
110Be not-C (O) C
6H
5, R then
110Be selected from-H, replacement or unsubstituted alkyl, replacement or unsubstituted aryl ,-C (O) R ,-C (O) OR ,-C (O) NHR ,-C (S) R ,-C (S) OR and-C (O) SR;
R
111, R
112, R
113And R
114Be independently selected from-H, replacement or unsubstituted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted nonaromatic heterocycles group, halogen ,-CN ,-CO
2R ,-OCOR ,-OCO
2R ,-C (O) NRR ' ,-OC (O) NRR ' ,-C (O) R ,-COR ,-OSO
3H ,-S (O)
nR ,-S (O)
nOR ,-S (O)
nNRR '-NRR ' ,-NRC (O) OR ' ,-NO
2With-NRC (O) R ';
R and R ' be independently-H, replacement or unsubstituted alkyl, nonaromatic heterocycles group replacement or unsubstituted aryl or replacement or unsubstituted;
X is O or S; And
N is 1 or 2.
In another embodiment, the sirtuin regulator is by general formula 85 or 86 or the representative of its pharmaceutically acceptable salt:
Wherein:
R
101And R
102Be independently-H, replacement or unsubstituted alkyl, replacement or unsubstituted thiazolinyl, replacement or unsubstituted alkynyl, replacement or unsubstituted nonaromatic heterocycles group or replacement or unsubstituted aryl, or R
101And R
102Form that replace or unsubstituted nonaromatic heterocycles group together;
R
103, R
104, R
105And R
106Be independently selected from-H, replacement or unsubstituted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted nonaromatic heterocycles group, halogen ,-OR ,-CN ,-CO
2R ,-OCOR ,-OCO
2R ,-C (O) NRR ' ,-OC (O) NRR ' ,-C (O) R ,-COR ,-SR ,-OSO
3H ,-S (O)
nR ,-S (O)
nOR ,-S (O)
nNRR ' ,-NRR ' ,-NRC (O) OR ' ,-NO
2With-NRC (O) R ';
R
107And R
108Be selected from-H, replacement or unsubstituted alkyl, replacement or unsubstituted aryl ,-C (O) R ,-C (O) OR ,-C (O) NHR ,-C (S) R ,-C (S) OR and-C (O) SR, wherein R
107And R
108In at least one for that replace or unsubstituted alkyl, replacement or unsubstituted aryl ,-C (O) R ,-C (O) OR ,-C (O) NHR ,-C (S) R ,-C (S) OR or-C (O) SR;
R
109Be selected from-H, replacement or unsubstituted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted nonaromatic heterocycles group, halogen ,-OR ,-CN ,-CO
2R ,-OCOR ,-OCO
2R ,-C (O) NRR ' ,-OC (O) NRR ' ,-C (O) R ,-COR ,-SR ,-OSO
3H ,-S (O)
nR ,-S (O)
nOR ,-S (O)
nNRR ' ,-NRR ' ,-NRC (O) OR ' and-NRC (O) R ';
If R
110Be not-C (O) C
6H
5, R then
110Be selected from-H, replacement or unsubstituted alkyl, replacement or unsubstituted aryl ,-C (O) R ,-C (O) OR ,-C (O) NHR ,-C (S) R ,-C (S) OR and-C (O) SR;
R
111, R
112, R
113And R
114Be independently selected from-H, replacement or unsubstituted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted nonaromatic heterocycles group, halogen ,-CN ,-CO
2R ,-OCOR ,-OCO
2R ,-C (O) NRR ' ,-OC (O) NRR ' ,-C (O) R ,-COR ,-OSO
3H ,-S (O)
nR ,-S (O)
nOR ,-S (O)
nNRR ' ,-NRR ' ,-NRC (O) OR ' ,-NO
2With-NRC (O) R ';
R and R ' be independently-H, replacement or unsubstituted alkyl, nonaromatic heterocycles group replacement or unsubstituted aryl or replacement or unsubstituted;
X is O or S; And
N is 1 or 2.
For the chemical compound of general formula 83-86 representative, typically, R
107And R
108In at least one is-C (O) R, as-C (O) CH
3In specific specific embodiments, R
107, R
108And R
110Be independently-H or-C (O) R (for example-C (O) CH
3).
In some specific embodiments, as work as R
107, R
108And R
110When having above-mentioned implication, R
101And R
102Be-H.
In some specific embodiments, R
109For-H.
In some specific embodiments, R
103-R
106Be-H.
In some specific embodiments, R
111-R
114Be-H.
In specific specific embodiments, R
107, R
108And R
110Have above-mentioned implication and R
101-R
106, R
109And R
111-R
114Be-H.
In some specific embodiments, R
104For-H or halogen, be deuterium or fluorine typically.Remaining implication as previously discussed.
Sirtuin regulator for general formula 87 or 88 representatives:
In some specific embodiments, R
4For-H (for example, deuterium, tritium) or halogen (for example, fluorine, bromine, chlorine).
In specific embodiments of the present invention, R
1-R
6Can be-during H, typically, they are-H.In specific embodiments of the present invention, R
1-R
6In one of be not-during H, typically, remaining implication is-implication of H and non--H for replace or unsubstituted alkyl or halogen (R typically,
1And R
2For replace or unsubstituted alkyl).
In some specific embodiments, R
11-R
14Be-H.Work as R
11-R
14Be-during H, typically, R
1-R
6Has aforesaid implication.
In some specific embodiments, R
9For-H.Work as R
9During for-H, typically, R
11-R
14Be-H and R
1-R
6Has aforesaid implication.
The Sirtuin regulator (as, sirtuin activator and sirtuin inhibitor) specific example in U.S. Patent Publication Nos.2005/0136537 and 2005/0096256, put down in writing the chemical compound shown in Fig. 1-16 for example.
The present invention also comprises the pharmaceutically acceptable addition salt and the coordination compound of Sirtuin regulator described herein.If chemical compound can have one or more chiral centres, unless specified otherwise, the chemical compound that the present invention considers is the racemic mixture of single stereoisomer or stereoisomer.
Chemical compound that the present invention describes and salt thereof also comprise its corresponding hydrate (as, semihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate) and solvate.The solvent that is applicable to preparation solvate and hydrate is selected by the technical staff usually.
Chemical compound and salt thereof can exist with amorphous or crystallization (comprising mixed crystal and polymorphic) form.
Sirtuin regulates chemical compound and also comprises relevant secondary metabolites; as phosphate ester, sulfuric ester, acyl group (for example; acetyl group, fatty acid acyl) and sugar (for example, glucurondate, glucose) derivant (for example hydroxyl), especially sulfuric ester, acyl group and sugar derivatives.In other words, replacement-OH also comprises-OSO
3 -M
+, M wherein
+For suitable cation (is preferably H
+, NH
4+Or alkali metal ion such as Na
+Or K
+) and sugar, as
These groups are usually by hydrolysis or metabolism (for example enzyme) cracking formation-OH.
Contain when the Sirtuin activating compounds under the situation of undersaturated carbon-carbon double bond, be the present invention along (Z) and anti-(E) isomer and consider.Under the situation that chemical compound may exist with tautomeric form, as the ketoenol tautomerization body, as
Each tautomeric form all is considered, and they are contained in the method for the present invention record, by carry out with R ' suitable replacement determine whether with poised state exist or be fixed in a kind of form.Any substituent implication under any situation is independent of under any other situation this substituent group or the implication of other replacement arbitrarily.
The method of the present invention's record also comprises the prodrug of the Sirtuin activating compounds that the present invention describes.Prodrug is considered to discharge in vivo any covalently bound carrier of active parent drug.
The analog of the Sirtuin activating compounds that the present invention describes and the member that derivant also can be used to activate the Sirtuin protein family.For example, derivant or analog can make chemical compound more stable or improve their permeate through cell membranes or engulfed or the ability of pinocytosis.Exemplary derivant comprises glycosylated derivative, and for example United States Patent (USP) 6,361,815 resveratrols of describing.That other Verakanol derivative comprises is suitable-and anti--resveratrol and with the conjugate of sugar, as form glucoside (referring to, for example United States Patent (USP) 6,414,037).Rhizoma Polygoni Cuspidati glucoside (also being referred to as polydatin or resveratrol 3-O-β-D-glucoside) also can use.Can comprise glucose, galactose, maltose, lactose and sucrose with the bonded saccharide of chemical compound.The glycosylation stilbene further is recorded in Regev-Shoshani etc., among the Biochemical J. (publishing in 4/16/03 with BJ20030141).Other derivant that the present invention describes chemical compound is ester, amide and prodrug.The ester of resveratrol for example is described in the United States Patent (USP) 6,572,882.Resveratrol and derivant thereof can be according in this areas, and for example United States Patent (USP) 6,414, and 037; 6,361,815; 6,270,780; 6,572,882; With Brandolini etc., the record among (2002) J.Agric.Food.Chem.50:7407 prepares.The derivant of flavonol for example is recorded in the United States Patent (USP) 4,591,600.Resveratrol and other activating compounds can also be buied from for example Sigma.
In some specific embodiments, if the Sirtuin activating compounds is naturally occurring, it can be separated from natural surroundings before using at least in part.For example, plant polyphenol can separate from plant before being used for the method for the invention, and the part or be purified substantially.Not with the situation of natural relevant other chemical compound under, reactive compound also can be through synthetic preparation.In an illustrative specific embodiments, activated compositions comprises and is less than about 50%, 10%, 1%, 0.1%, 10
-2% or 10
-3% and natural relevant chemical compound, or activating compounds and be less than about 50%, 10%, 1%, 0.1%, 10
-2% or 10
-3%'s is relevant with natural relevant chemical compound.
In some specific embodiments, specific biological function (for example regulating metabolic activity) is regulated by the Sirtuin activating compounds, and condition is that term Sirtuin activating compounds does not comprise one or more specific compounds.For example, in some specific embodiments, the Sirtuin activating compounds can be any chemical compound that can improve sirtuin protein expression and/or activity level, and condition is any other chemical compound that this chemical compound is not quoted especially for resveratrol, flavone, the present invention.In an exemplary specific embodiments, the Sirtuin activating compounds can be the chemical compound shown in any one among general formula 1-25,30,32-65 and the 69-88, and condition is any other chemical compound that this chemical compound is not quoted especially for resveratrol, flavone or the present invention.In an exemplary specific embodiments, the Sirtuin activating compounds does not comprise United States Patent(USP) Nos. 6,410,596 or 6,552,085 any chemical compound of quoting, so its disclosure all is incorporated herein by reference.
In some specific embodiments, effectively activating sirtuin, for example under the active concentration of the deacetylase of SIRT1 (for example in vivo), this target (subject) sirtuin activator, as the SIRT1 activator, do not have the ability of inhibition PI3-kinases, inhibition aldose reductase (aldoreductase) and/or the inhibiting tyrosine protein kinase of any essence.For example, in preferred specific embodiments, the active EC of activation sirtuin deacetylase that the sirtuin activator of selection has
50Than the EC that suppresses one or more aldose reductases and/or tyrosine protein kinase
50At least low 5 times, even more preferably hang down 10 times, 100 times or even 1000 times at least.The method of analyzing PI3-kinase activity, aldose reductase activity and tyrosine kinase activity is known in the art, and the test kit of implementing these analyses can be bought in market.For example, analyze for the PI3-kinases, referring to for example U.S. Patent Publication No.2003/0158212; For the aldose reductase analysis, referring to for example U.S. Patent Publication No.2002/20143017; The tyrosine kinase assay kit can be from for example Promega (Madison, WI; The promega.com of World Wide Web), Invitrogen (Carlsbad, CA; The invitrogen.com of World Wide Web) or Molecular Devices (Sunnyvale, CA; The moleculardevices.com of World Wide Web) goes up purchase.
In some specific embodiments, under the active concentration of deacetylase that effectively activates sirtuin (for example in vivo), target (subject) sirtuin activator does not have the ability of the trans-activation EGFR tyrosine kinase activity of any essence.For example, in preferred specific embodiments, the active EC of activation sirtuin deacetylase that the sirtuin activator of selection has
50EC than trans-activation tyrosine kinase activity
50At least low 5 times, even more preferably hang down 10 times, 100 times or even 1000 times at least.The method of analyzing the trans-activation of tyrosine kinase activity is known in the art, referring to .Cancer Research 60:5310-5317 (2000) such as .Nat.Med.8:289-93 such as for example Pai (2002) and Vacca.
In some specific embodiments, under the active concentration of deacetylase that effectively activates sirtuin (for example in vivo), target (subject) sirtuin activator does not have any ability that causes coronary dilation in fact.For example, in preferred specific embodiments, the active EC of activation sirtuin deacetylase that the sirtuin activator of selection has
50EC than coronary dilation
50At least low 5 times, even more preferably hang down 10 times, 100 times or even 1000 times at least.It is known in the art analyzing vasodilative method, referring to for example U.S. Patent Publication No.2004/0236153.
In some specific embodiments, under the active concentration of deacetylase that effectively activates sirtuin (for example in vivo), target (subject) sirtuin activator does not have the spasmolytic activity of any essence.For example, in preferred specific embodiments, the active EC of activation sirtuin deacetylase that the sirtuin activator of selection has
50EC than spasmolysis
50(as for gastrointestinal tract muscle) low 5 times at least, even more preferably hang down 10 times, 100 times or even 1000 times at least.It is well known in the art analyzing the active method of spasmolytic, referring to for example U.S. Patent Publication No.2004/0248987.
In some specific embodiments, under the active concentration of deacetylase that effectively activates sirtuin (for example in vivo), target (subject) sirtuin activator does not have any ability that suppresses liver cell pigment P450IB1 (CYP) in fact.For example, in preferred specific embodiments, the active EC of activation sirtuin deacetylase that the sirtuin activator of selection has
50Than the EC that suppresses P450IB1
50At least low 5 times, even more preferably hang down 10 times, 100 times or even 1000 times at least.The active method of analysis of cells cytochrome p 450 is known in the art, and the test kit of implementing these analyses can be purchased.Referring to, U.S. Patent Publication Nos.6 for example, 420,131 and 6,335,428 and Promega (Madison, WI; The promega.com of World Wide Web).
In some specific embodiments, under the active concentration of deacetylase that effectively activates sirtuin (for example in vivo), target (subject) sirtuin activator does not have any ability that suppresses nuclear factor κ B (NF-κ B) in fact.For example, in preferred specific embodiments, the active EC of activation sirtuin deacetylase that the sirtuin activator of selection has
50Than the EC that suppresses NF-κ B
50At least low 5 times, even more preferably hang down 10 times, 100 times or even 1000 times at least.The method of analyzing the NF-kB activity is known in the art and the test kit of implementing these analyses can be purchased (for example, from Oxford Biomedical Research (Ann Arbor, MI; The oxfordbiomed.com of World Wide Web)).
In some specific embodiments, under the active concentration of deacetylase that effectively activates sirtuin (for example in vivo), target (subject) sirtuin activator does not have any ability that suppresses I type histone deacetylase (HDACs), II type HDAC or HDACs I and II in fact.For example, in preferred specific embodiments, the active EC of activation sirtuin deacetylase that the sirtuin activator of selection has
50Than the EC that suppresses HDAC I and/or HDAC II
50At least low 5 times, even more preferably hang down 10 times, 100 times or even 1000 times at least.The test kit that to analyze HDAC I and/or the active method of HDAC II be known in the art and implement these analyses can be purchased.Referring to, BioVision for example, Inc. (Mountain View, CA; The biovision.com of World Wide Web) and Thomas Scientific (Swedesboro, NJ; The tomassci.com of World Wide Web).
In some specific embodiments, under the active concentration of deacetylase that effectively activates human SIRT1 (for example in vivo), target (subject) SIRT1 activator does not have the ability of the lineal autoploid of SIRT1 in any activation more rudimentary eukaryotic cell, particularly yeast in fact or the human pathogen.For example, in preferred specific embodiments, the active EC of deacetylase of the human SIRT1 of the activation that the SIRT1 activator of selection has
50EC than activation yeast Sir2 (as Candida, S.cerevisiae, etc.)
50At least low 5 times, even more preferably hang down 10 times, 100 times or even 1000 times at least.
In some specific embodiments, the sirtuin activating compounds can have activation one or more sirtuin albumen homology bodies, for example ability of one or more human SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 or SIRT7.In other specific embodiments, under the active concentration of deacetylase that effectively activates human SIRT1 (for example in vivo), the SIRT1 activator does not have any other sirtuin albumen homology body, for example ability of one or more human SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 or SIRT7 of activating in fact.For example, the active EC of deacetylase of the human SIRT1 of the activation that the SIRT1 activator that can select has
50EC than activation one or more human SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 or SIRT7
50At least low 5 times, even more preferably hang down 10 times, 100 times or even 1000 times at least.
In some specific embodiments, SIRT3 and SIRT4 regulator can be used to regulate lipid mobilization.For example, SIRT3 and/or SIRT4 activator can be used to the induced lipolysis mobilization and can be used for treating for example obesity and insulin resistance disorders.
In some specific embodiments, under the active concentration of deacetylase that effectively activates sirtuin (for example in vivo), target (subject) sirtuin activator does not have any kinases of Profilin in fact, suppresses catalysis or the transcriptional activity of phosphorylation mitogen activated protein (MAP) kinases, inhibition Cycloxygenase such as COX-2; Suppress nitric oxide synthetase (iNOS); Or inhibition is to the ability of the platelet adhesion of type i collagen.For example, in preferred specific embodiments, the active EC of activation sirtuin deacetylase that the sirtuin activator of selection has
50Than the EC that implements these any functions
50At least low 5 times, even more preferably hang down 10 times, 100 times or even 1000 times at least.Analyzing proteins kinase activity, Cycloxygenase activity, nitric oxide synthetase and the active method of platelet adhesion are known in the art and the test kit of implementing these analyses can be purchased.For example, for the protein kinase assay kit, referring to Promega (Madison, WI; The promega.com of World Wide Web), Invitrogen (Carlsbad, CA; The invitrogen.com of World Wide Web); Molecular Devices (Sunnyvale, CA; The moleculardevices.com of World Wide Web) or Assay Designs (Ann Arbor, MI; The assaydesigns.com of World Wide Web); For the Cycloxygenase assay kit, referring to Amersham Biosciences (Piscataway, NJ; The amershambiosciences.com of World Wide Web); For the nitricoxide synthase assay kit, referring to AmershamBiosciences (Piscataway, NJ; The amershambiosciences.com of World Wide Web) and R﹠amp; D Systems (Minneapolis, MN; The rndsystems.com of World Wide Web); For the platelet adhesion assay kit, referring to United States Patent(USP) Nos. 5,321,010; 6,849,290 and 6,774,107.
In some specific embodiments, the chemical compound that the present invention describes, for example sirtuin activator or inhibitor do not have the antioxidant activity that significantly maybe can measure when the analytical method of any standard known in the art is measured.For example, chemical compound can not be removed free radical significantly, as O
2Free radical.Chemical compound may have than another chemical compound about antioxidant activity of low 2,3,5,10,30 or 100 times of resveratrol for example.
In some specific embodiments, the sirtuin activating compounds can be about 10 to the binding affinity of sirtuin
-9M, 10
-10M, 10
-11M, 10
-12M or still less.The sirtuin activating compounds can be by the factor with sirtuin to its substrate or NAD
+Km reduce about 2,3,4,5,10,20,30,50 or 100 at least.The sirtuin activating compounds can be by the V of the factor with sirtuin
MaxAt least increase about 2,3,4,5,10,20,30,50 or 100.Can increase the V of sirtuin
MaxExemplary compounds comprise Pyrazinamide analog for example, the analog of for example chemical compound shown in the general formula 69-72, and/or O-acetyl group-ADP-ribose, for example chemical compound shown in the general formula 73-76.The active EC of the deacetylase of compound activating sirtuin
50Can be lower than about 1nM, be lower than about 10nM, be lower than about 100nM, be lower than about 1 μ M, be lower than about 10 μ M, be lower than about 100 μ M, or from about 1-10nM, from about 10-100nM, from about 0.1-1 μ M, from about 1-10 μ M or from about 10-100 μ M.According to the acellular analysis of describing in an embodiment or based on the mensuration in the analysis of cell, chemical compound can be at least about 5,10,20,30,50 or 100 by the deacetylase activity that the factor activates sirtuin.With respect to resveratrol or other chemical compound of the present invention of same concentrations, the deacetylase to SIRT1 that chemical compound can produce is active induces increase at least 10%, 30%, 50%, 80%, 2 times, 5 times, 10 times, 50 times or 100 times.The EC of compound activating SIRT5
50Can be than the EC of activation SIRT1
50At least high about 10 times, 20 times, 30 times, 50 times.
In an exemplary specific embodiments, method and composition of the present invention can comprise following combined therapy (i) at least a by the factor with sirtuin to its substrate or NAD
+K
mReduction is at least about 2,3,4,5,10,20,30,50 or 100 sirtuin activating compounds, and (ii) at least a by the V of the factor with sirtuin
MaxRaising is at least about 2,3,4,5,10,20,30,50 or 100 sirtuin activating compounds.In a specific embodiments, combined therapy contains following at least two kinds: (i) at least a general formula 1-25,30 and 32-65 shown in the sirtuin activating compounds, sirtuin activating compounds shown in the (ii) at least a general formula 69-76, and the sirtuin activating compounds shown in the (iii) at least a general formula 77-88.
Chemical compound can pass cytoplasma membrane.For example, chemical compound can have the cell permeability at least about 20%, 50%, 75%, 80%, 90% or 95%.
Chemical compound of the present invention also can have following one or more characteristics: this chemical compound pair cell or experimenter in essence is nontoxic; This chemical compound can be organic molecule or 2000amu or littler, 1000amu or littler micromolecule; The half-life of chemical compound under normal atmospheric condition was at least about 30 days, 60 days, 120 days, 6 months or 1 year; The half-life of chemical compound in solution is at least about 30 days, 60 days, 120 days, June or 1 year; In solution, chemical compound reaches about 50%, 2 times, 5 times, 10 times, 30 times, 50 times or 100 times by at least a factor degree more stable than resveratrol; Chemical compound can promote the deacetylation effect of DNA reparative factor Ku70; Chemical compound can promote the deacetylation of RelA/p65; Chemical compound can promote overall conversion ratio and improve the sensitivity of cell to the inductive apoptosis of TNF.
The exemplary treatment of II.sirtuin activating compounds is used
In some specific embodiments, the invention provides the method that treats and/or prevents multiple disease or obstacle by the sirtuin activator that gives high dose to the experimenter.In an exemplary specific embodiments, can give the sirtuin activator that a certain amount of sirtuin activation of experimenter is equal to or greater than the sirtuin activation of 18mg/kg resveratrol.Can give experimenter's one or many (for example every day) with high dose, up to obtaining desired therapeutic effect.For example, disease or obstacle according to treatment give that high dose reaches 1 day every day, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year or more.The sirtuin activator of high dose can give or be divided into multiple dose to give every day with single dose, for example takes every day twice or three times.In an exemplary specific embodiments, the sirtuin activator of high dose can give with slow releasing preparation.Use the exemplary disease or the obstacle of the treatment of high dose sirtuin activator to comprise, for example with aging maybe stress be relevant disease or obstacle, diabetes, obesity, neurodegenerative diseases, disease or obstacle, cardiovascular disease, blood coagulation disorders, inflammation, cancer and/or flushing etc. that mitochondria dysfunction is relevant.This method comprises the sirtuin activating compounds that gives high dose to the experimenter that these needs are arranged.
In some specific embodiments, the sirtuin activating compounds of high dose can take separately or with other chemical compound administered in combination.In a specific embodiments, the mixture of the sirtuin activating compounds of two or more high doses can have this experimenter who needs.In another embodiment, the sirtuin activating compounds of high dose can give with one or more following compounds: resveratrol, butein, fisetin, Rhizoma Euonymus China fir alcohol (piceatannol) or Quercetin.In an exemplary specific embodiments, the sirtuin activating compounds of high dose can give with the nicotinic acid combination.In another embodiment, one or more sirtuin activating compounds of high dose can be used for the treatment of or prevent multiple treatment of diseases agent to give with one or more, described disease comprises, for example, disease or obstacle, cardiovascular disease, blood coagulation, inflammation, flushing, obesity, the aging that cancer, diabetes, neurodegenerative diseases, mitochondria dysfunction are relevant, stress wait.In a plurality of specific embodiments, the combined therapy that contains high dose sirtuin activating compounds is meant that (1) contain the pharmaceutical composition of the combination of the sirtuin activating compounds of one or more high doses and one or more therapeutic agents; And the sirtuin activating compounds of (2) one or more high doses and giving uniting of one or more therapeutic agents, wherein the sirtuin activating compounds is not formulated in the identical compositions with therapeutic agent.When using isolating preparation, the sirtuin activating compounds of high dose can with other therapeutic agent simultaneously, intermittently, intersects, in advance, afterwards or make up and give.
Dysbolismus/diabetes/body weight control
The invention describes the method that is used for the treatment of or prevents experimenter's fat or common weight increase, this method reduces experimenter's the body weight or the increase that loses weight.Method can comprise to the experimenter, if any this experimenter who needs, gives the increase sirtuin activity of high dose or the medicine of protein level, and described sirtuin is SIRT1 or Sir2 for example, and described medicine is the sirtuin activator for example.The experimenter who needs this treatment fat maybe may become fat, and perhaps weight increase is excessive or for example may the excessive experimenter of weight increase by the family history prediction according to expection.Exemplary medicine be of the present invention those.Also can give drug regimen (for example, the combination of high dose sirtuin activator and obesity medicine).This method also comprises the body weight of monitoring the experimenter and/or the activation levels of sirtuin, in fatty tissue.
The present invention has also put down in writing the method that is used for the treatment of or prevents dysbolismus, as other premonitory symptom or its complication of insulin resistant or type ii diabetes.This method can improve the sensitivity of insulin or reduce experimenter's insulin level.This method can comprise the raising sirtuin activity that gives experimenter (if any the experimenter of these needs) high dose or the medicine of sirtuin protein level, described sirtuin such as SIRT1 or Sir2.Needing the experimenter of this treatment can be other premonitory symptom of suffering from insulin resistant or type ii diabetes, or suffers from type ii diabetes, maybe may develop into the experimenter of any of these disease.For example, this experimenter can be for suffering from the experimenter of insulin resistant, for example have high cyclical level of insulin and/or associated conditions, as hyperlipidemia, lipogenesis obstacle (dyslipogenesis), hypercholesterolemia (hypercholesterolemia), impaired glucose tolerance, hyperglycemia, other performance of X syndrome, hypertension, atherosclerosis and lipodystrophy.The invention describes exemplary medicine.
In some specific embodiments,, the sirtuin activating compounds of high dose promotes to lose weight and/or prevent increase thereby can being used to reduce individual gastrointestinal fat absorption amount.In some specific embodiments, sirtuin regulates chemical compound and can give with the drug regimen that another kind suppresses fat absorption, (is also referred to as tetrahydrochysene Li Pusitading (tetrahydrolipstatin), with trade (brand) name XENICAL as orlistat (Orlistat)
TMSell).Orlistat (Orlistat) is effective inhibitor of gastrointestinal lipase, and promptly lipase is responsible for decomposing the fat (gastric lipase, carboxy-lesterase, pancreatic lipase) of picked-up.As the result that lipase suppresses, undigested fat can not be absorbed and through defecate.In some specific embodiments, sirtuin regulates chemical compound can allow to give fat absorption inhibitor than low dosage, still can reach the expection therapeutic effect.This combined therapy can be avoided the undesirable side effect relevant with fat absorption inhibitor.
Also can give drug regimen (for example, the combination of high dose sirtuin activating compounds and antidiabetic medicine).Method also comprises the state of any of these disease of monitoring the experimenter and/or the activation levels of sirtuin, for example in fatty tissue.
Sirtuin activating compounds of the present invention can be taken separately or unite with other chemical compound and take.Other chemical compound can be other sirtuin and/or AMPK activator.Longevinex for example
TM, a kind of Red wine extract, and except that resveratrol, also contain other sirtuin activator, as Quercetin, it is a kind of medicine of especially effectively mobilizing fat.Longevinex
TMCan obtain from World Wide Web longevinex.com.
In an exemplary specific embodiments, the sirtuin activating compounds of high dose can be used as and the combined therapy of blood fat reducing, obesity and/or antidiabetic medicine gives.The example that is suitable for the blood fat reducing, obesity or the antidiabetic medicine that give with the combination of the Sirtuin activator of high dose comprises chromium, fat-binding polymers, saccharide conjugated polymer, lipase inhibitor, heat generating agent, catecholamine reuptake inhibitor and thyroxin.For example, for losing weight, prevention weight increase or treatment or prevention of obesity, one or more high doses sirtuin activator can with as following one or more obesity medicines be used in combination: phenylpropanolamine, ephedrine, pseudoephedrine, Duromine, cholecystokinin A agonist, monoamine reuptake inhibitors (as sibutramine), sympathomimetic drug (sympathomimetic agent), serotonergic medicine (serotonergic agent) (as dexfenfluramine or fenfluramine), dopamine agonist (as bromocriptine), melanocyte-stimulating hormone receptor stimulating agent or analog, the melanocyte-stimulating hormone analog, cannabinoid receptor antagonists, the melanin concentrating hormone antagonists, OB albumen (leptin), the leptin analog, the leptin receptor agonist, Cannibinoid receptor modulators (as ramonibant), galanin antagonist or GI lipase inhibitor or minimizing agent (as orlistat (orlistat)).Other appetite suppressant comprises Magainin agonist, dehydroepiandrosterone or its analog, glucocorticoid receptor agonist and antagonist, orexin receptor antagonists, the conjugated protein antagonist of urocortin, glucagon-like peptide-1 receptor stimulant such as Exendin, anticonvulsant and ciliary neurotrophic factor such as Axokine.
In other specific embodiments, the sirtuin activating compounds of one or more high doses can with as one or more following antidiabetic medicine applied in any combination: aldose reductase inhibitor, glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, Protein-tyrosine-phosphatase IB inhibitor, two peptide protease inhibitors, insulin (comprising the available insulin preparation of oral biology), insulin analog, metformin, acarbose, peroxisome proliferation-activated receptors-γ (PPAR-γ) part, as troglitazone, rosiglitazone (rosaglitazone), pioglitazone or GW-1929, sulfonylureas, glipizide (glipazide), glibenclamide or chlorpropamide, wherein the amount of first kind and second kind chemical compound can produce therapeutic effect.Other antidiabetic medicine comprise alpha-glucosidase inhibitors, glucagon-like-peptide-1 (GLP-1), insulin, PPAR α/γ dual agonists, MAG for how (meglitimide) and α P2 inhibitor.In an exemplary specific embodiments, antidiabetic medicine can be DPP IV (DP-IV or DPP-IV) inhibitor, for example from LAF237 (the NVP DPP728 of Novartis (Novartis); 1-[[[2-[(5-cyanopyridine-2-yl) amino] ethyl] amino] acetyl group]-2-cyano group-(S)-pyrrolidine) or from the MK-04301 of Merck (Merck) (referring to, Hughes etc. for example, Biochemistry 38:11597-603 (1999)).
In other specific embodiments, the sirtuin activating compounds of one or more high doses can with one or more as following blood lipid-lowering medicine applied in any combination: Statins (statins) is as simvastatin (Zocor), pravastatin (Pravachol), lovastatin (Mevacor), fluvastatin (Lescol), cerivastatin (Baycol), Rosuvastatin (Crestcor) and atorvastatin (Lipitor) and nicotinic acid (niacin).
In some specific embodiments, high dose sirtuin activator gives to reduce, alleviates or elimination and obesity and/or the relevant adverse side effect of antidiabetic medicine with blood fat reducing, obesity and/or antidiabetic medicine combination.For example, blood fat reducing, obesity and/or antidiabetic medicine and the combination of high dose sirtuin activator give to obtain useful therapeutic effect, this is because necessary dosage during with respect to the combination of not using with the sirtuin activator, and the blood fat reducing that gives, obesity and/or antidiabetic medicine dosage are lower.For example, high dose sirtuin activator can give with blood fat reducing, obesity and/or the antidiabetic medicine combination of low dosage (for example, reduce or prevent undesirable side effect as improving the amount of heart rate and/or blood pressure).In some specific embodiments, high dose sirtuin activator can give with the thyroxin combination.In other specific embodiments, high dose sirtuin activator can with absorb blocker, combination gives as Alpha-glucosidase inhibitor.In other specific embodiments, the sirtuin activator of high dose can with the metformin combination medicine-feeding.In some specific embodiments, high dose sirtuin activator can give with catecholamine reuptake inhibitor such as sibutramine combination.Put down in writing other example of blood fat reducing, obesity and/or antidiabetic medicine among the present invention.In other specific embodiments, the dosage of blood fat reducing, obesity and/or antidiabetic medicine is compared normal dose and may do not reduced, and gives the side effect that the sirtuin activator reduces, slows down or eliminated blood fat reducing, obesity and/or antidiabetic medicine.
In some specific embodiments, use the sirtuin activating compounds can reduce the dose of blood fat reducing, obesity and/or antidiabetic medicine.Produce under the unwanted side effect situation when the dosage of blood fat reducing, obesity and/or antidiabetic medicine is having among this patient who needs, this is desirable.For example, typically, give the rising that thyroxin causes heart rate and/or blood pressure to the experimenter.In some specific embodiments, method provided by the invention is by giving the combination of thyroxin and high dose sirtuin activator, to give the amount adjustment (for example, reducing) of patient's thyroxin to not producing the amount of the ill effect of heart rate and/or blood pressure aspect.In other specific embodiments, method provided by the invention is adjusted the metformin dose that (for example, reducing) has this experimenter who needs by giving the combination of metformin and high dose sirtuin activator.In other specific embodiments, high dose sirtuin activator is used to reduce the dose of the experimenter's that these needs are arranged sibutramine.
Method of the present invention can comprise every day, perhaps every other day, or gives the experimenter for example high dose sirtuin activating compounds of the form of pill weekly.Give in the specific embodiments of experimenter's high dose sirtuin activating compounds in every day, the sirtuin activating compounds can give once every day.In other specific embodiments, give every day twice or three times.
In some specific embodiments, the sirtuin activating compounds of high dose gives the experimenter by slow releasing preparation, for example with the embedding of sirtuin activator or be encapsulated in the nano-particle release to realize at least 12 hours.Giving in the specific embodiments of sirtuin activating compounds to the experimenter by slow release formulation, the high dose sirtuin activator that is given can continue to discharge, for example at least about 12,15,18,24 or 36 hours or longer time.In other specific embodiments, the high dose sirtuin activator that gives continue to discharge the time of one day or several days.In other specific embodiments, the high dose sirtuin activator that gives continues to discharge the time in a week or several weeks.
In some specific embodiments, the sirtuin activating compounds gives by nourishing healthy product (nutraceutical formulation)." nutrient and healthcare products " are for providing any functional food (comprising beverage) of the additional effect except that its trophic function.In a preferred specific embodiments, by weight, the nutrient and healthcare products that provide contain has an appointment 0.1% to 99%, or 0.1% to 10% sirtuin activator.In preferred specific embodiments, the high dose sirtuin activator that the present invention describes gives by single part food or beverage.In a kind of preferred product (formulation), the sirtuin activation that the sirtuin activator total amount that the single dose form that provides (beverage of 8 ounce fluid ounce portions for example, Ru Shui, add flavor water or fruit juice) contains is reached is equal to or greater than the sirtuin activation of 25mg resveratrol.In other specific embodiments, the sirtuin activation that the sirtuin activator total amount that the single dose form that provides contains is reached be equal to or greater than per 8 ounce fluid ounces contain have an appointment 10,15,20,25,50,60,75,80,100,150, the sirtuin activation when 200mg or more resveratrol.In other preferred specific embodiments, the sirtuin activator total amount that the single dose form that provides (for example serving, as nutrition bar (nutrition bar)) contains reaches the sirtuin activation that the sirtuin activation is equal to or greater than the 100mg resveratrol.In some specific embodiments, every portion of food provides 100 to 500kcal heats.In other specific embodiments, the sirtuin activator total amount that the single dose form that provides contains reaches that the sirtuin activation is equal to or greater than under per 100 to 500kcal heats 25,50,60,75,80,100,150,200, the sirtuin activation of 250mg or more resveratrols.Phrase " sirtuin activator total amount " is meant the total amount that is present in sirtuin activator in the single dose form.
In a plurality of specific embodiments, the nutrient and healthcare products that contain the sirtuin activator can be the food or the beverages of any kind of.For example, nutrient and healthcare products can comprise beverage, as nourishing beverage, food beverage (diet drinks) (Slimfast for example
TM, Boost
TMDeng) and sports drink, herb beer and other fortified beverage. is in addition, nutrient and healthcare products can comprise the food for the mankind or animals consuming, as baking goods, bread for example, pancake (wafars), cooky, cracknel (crackers), pretzel (pretzel), Piza and roll, instant breakfast cereal (ready-to-eat breakfastcereals), hot cereal (hot cereals), wheaten food (pasta products), dessert (snacks) is as fruit cup (snacks), become flavor dessert (snacks), cereal dessert (grain snacks), nutrition bar and microwave popcorn, dairy products such as yoghourt (yogurt), cheese and ice cream, sweet food such as hard candy (hard candy), soft sweets (soft candy) and chocolate, beverage, animal feed, pet food such as dog food and cat food, aquaculture feed such as fish meal and shrimp feed, food with specific use, as baby food, formulated infant milk, hospital food, medical diets, sports food, performancefood or nutrition bar or condensed food, the premixed food or the mixture that are used for family or food and beverage sevice, premix as soup or gravy, the dessert mixture, the dinner mixture, baking mixture such as bread mixture, with the cake mixture, and cure and use flour. In some specific embodiments, this food or beverage do not comprise one or more Fructus Vitis viniferaes, Fructus Mori, blue berry, Fructus Rubi, Semen arachidis hypogaeae, milk, yeast or its extract.The invention provides the slimming alimentation health care composition of experimenter that can be used to promote to have these needs.For example, in some aspects, the invention provides and be used for the treatment of or the alimentation health care composition of prevention of obesity and/or diabetes.
Except that the sirtuin activator, nutrient and healthcare products can also contain multiple other beneficiating ingredient, including, but not limited to essential fatty acid, vitamin and mineral.In for example U.S. Patent No. 5,902,797; U.S. Patent No. 5,834,048; U.S. Patent No. 5,817,350; U.S. Patent No. 5,792,461; U.S. Patent No. 5,707,657 and U.S. Patent No. 5,656,312 in can find the composition of other description nourishing additive agent and the disclosure of production (introducing the present invention separately as a reference).
When taking in solid form, alimentation health care composition of the present invention can also comprise solid carrier such as gelatin or adjuvant.When giving with liquid form, can add the oil in liquid-carrier such as water, oil, animal or plant source, as Oleum Arachidis hypogaeae semen, mineral oil, soybean oil or Oleum sesami, or artificial oil.Alimentation health care composition of the present invention also can contain stabilizing agent, antiseptic, buffer, antioxidant or other additive well known by persons skilled in the art.
In other specific embodiments, food or beverage contain the additive of one or more sirtuin activating compounds.In some specific embodiments, the sirtuin activation that amount reached of the sirtuin activating compounds that additive contains is equal to or greater than the sirtuin activation of 11mg/g resveratrol.In other specific embodiments, the sirtuin activation that the amount of the sirtuin reactive compound that additive contains reaches is equal to or greater than 5,6,7,8,9,10,11,12,13,14,15,20,25, the sirtuin activation of 50mg/g or more resveratrols.
Other method comprises the medicine that gives experimenter's high dose sirtuin activator and improve AMPK activity or protein level, for example is different from the combination of the medicine that activates sirtuin.The AMPK activator comprises AICAR or metformin.Perhaps, can introduce the protein level that increases AMPK in the cell by the nucleic acid of the AMPK that will encode.The nucleotide sequence of the catalytic domain (α 1) of human AMPK has the nucleotide sequence of listing in GenBank registration number No.NM_206907, and coding has the protein of the aminoacid sequence of listing in GenBank registration number No.NP_996790.The nucleotide sequence in the on-catalytic district (β 1) of human AMPK has the nucleotide sequence of listing in GenBank registration number No.NM_006253, and coding has the protein of the aminoacid sequence of listing in GenBank registration number No.NP_006244.The nucleotide sequence in the on-catalytic district (γ 1) of human AMPK has the nucleotide sequence of listing in GenBank registration number No.NM_212461, and coding has the protein of the aminoacid sequence of listing in GenBank registration number No.NP_997626.For increasing the protein level of human AMPK in the cell, the essential nucleic acid of introducing each protein subunit of coding.The nucleic acid of different subunits of encoding can be contained in identical or the nucleic acid molecules that separates in.
Can comprise some nephropathy by other disease that gives the treatment of high dose sirtuin activator, comprise glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis.
In other specific embodiments, the sirtuin activator of high dose can be used for the treatment of benefits from disease or the disease that loses weight, hypertension (high blood pressure) for example, hypertension (hypertension), hypercholesterolemia (high blood cholesterol), dyslipidemia, type 2 diabetes mellitus, insulin resistant, glucose intolerance, hyperinsulinemia, coronary heart disease, angina pectoris, congestive heart failure, apoplexy, cholelithiasis, cholecystitis and cholelithiasis, gout, osteoarthritis, obstructive sleep apnea and breathing problem, the cancer of some types (as, carcinoma of endometrium, breast carcinoma, carcinoma of prostate and colon cancer), pregnancy complications, women's healthy reproduction not good (as, menoxenia, infertile, irregular ovulation), bladder control problem (as the pressure incontinence); The uric acid nephrolithiasis; Mental maladjustment (as depression, eating disorder, body-image disturbance and low self-respect).Stunkard AJ, WaddenTA. (editor) " obesity: theoretical and treatment ", second edition (Obesity:theory and therapy, SecondEdition.) New York:Raven Press, 1993.At last, AIDS patient may develop into lipodystrophy (lipodystrophy) or insulin resistant, and this is corresponding with the combined therapy of AIDS.Therefore, any of these disease can be treated or prevents by the method for minimizing of the present invention or prevention weight increase.
Other can comprise chylomicronemia syndrome (chlomicronemia syndrome), polycystic ovarian syndrome, body temperature reduction, knee joint fat pad syndrome, alcoholic fatty liver and non-alcoholic fatty liver disease by the disease and the disease of method treatment of the present invention.
In another embodiment, can give high dose sirtuin activating compounds to reduce drug-induced weight increase.For example, can give high dose sirtuin activating compounds and can stimulate appetite or cause weight increase, especially carry out therapeutic alliance by the medicine that is different from the weight increase that the factor that keeps water causes.The example that can cause the medicine of weight increase comprises that for example treating diabetes comprises that for example sulfonylurea (as glipizide and glibenclamide), thiazolidinediones (as pioglitazone and rosiglitazone), MAG are for anti-class (meglitinides), Nateglinide (nateglinide), repaglinide (repaglinide), sulfonylureas and insulin; Antidepressants comprise for example tricyclic antidepressant (as amitriptyline and imipramine), irreversible oxidase inhibitor (MAOIs), selectivity serotonin reuptake inhibitors (SSRIs), amfebutamone (bupropion), paroxetine (paroxetine) and mirtazapine (mirtazapine); Steroidal, for example, prednisone; Hormone therapy; Lithium carbonate; Valproic acid; Carbamazepine; Chlorpromazine; The sulfur thianthrene; Beta receptor blockers (as Propranolol); Alpha blocker (as clonidine, prazosin and terazosin); And contraceptive, comprise that oral contraceptive (family planning pill) or other contain contraceptive (Depoprovera, Norplant, Ortho), testosterone or the megestrol of estrogen and/or progesterone.In another particular exemplary embodiments, give the part that high dose Sirtuin activator can be used as the smoking cessation plan and prevent weight increase or reduce the body weight that has increased.
The method of the invention can also be used to the veterinary, as the dysbolismus of treatment house pet (for example obesity of Canis familiaris L., cat etc. or diabetes) or domestic animal (for example fat syndrome of the milch cow of milch cow).
In some specific embodiments, at the experimenter who consumes high fat diet, the speed that high dose sirtuin activator can be used to lose weight, prevent weight increase or reduce weight increase.For example, the invention provides the method and composition of the experimenter's body weight minimizing that promotes the consumption high fat diet, at least 30% of the consumption of experimenter's average every day of calorie is lipid in the described high fat diet.In other specific embodiments, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60% of experimenter's average every day of calorie consumption is lipid.In some specific embodiments, high fat diet comprises at least 10%, 20%, 30%, 40%, 50%, 60% or calorie consumption every day that more comes self-carbon water compound.
Method and composition of the present invention can also be used to alleviate the weight increase for diet and the unmanageable experimenter of exercise.In exemplary specific embodiments, high dose sirtuin activating compounds can promote not reduce a calorie consumption, do not increase motion, or the losing weight of the experimenter of its combination, and reach and enough cause the degree of when the sirtuin activating compounds does not exist, losing weight.
In some specific embodiments, high dose sirtuin activating compounds can be at some specific tissue (for example, liver), rather than whole body.The tissue specificity treatment can be used for the treatment of for example obesity and insulin resistance disorders.
In some specific embodiments, this method is used for prevention fat at the cell with lipogenesis ability (lipogenic capacity), for example assembles in liver, pancreas and the muscle cell.
In some specific embodiments, the invention provides the method that prolongs the pancreas beta cell life-span or prevent this cell death.This method comprises the pancreas beta cell is contacted with the sirtuin activating compounds.In other specific embodiments, this method comprises the sirtuin activating compounds for the treatment of effective dose to the experimenter that these needs are arranged (for example, suffering from type 1 diabetes, type 2 diabetes mellitus, impaired glucose tolerance etc.).Susceptibility (susceptibility) to type 2 diabetes mellitus needs inherited genetic factors and posteriority factor.Its lasting pathogenesis comprises the interaction of carrying out sexual cell insulin resistant and pancreas beta cell decline (failure).The generation of the free-radical generating and the derivative nitric oxide synthetase (iNOS) of the hyperglycemia that is secondary to type 2 diabetes mellitus can cause the pancreas beta cell to destroy, and the generation of the characteristic diagnostic enzyme indicator of type 1 diabetes.In this case, beta cell is not only exhausted by the pathology of the insulin resistant of type 2 diabetes mellitus progress, and may stand the inductive damage of chronic hyperglycemia.Pancreas beta cell apoptosis is to cause the irreversible reason that develops into insulin dependency in the type 2 diabetes mellitus.The chemical compound of the present invention record can be used to suppress or prevent the experimenter's of these needs the development of type 2 diabetes mellitus.For example, in some specific embodiments, target compound of the present invention suppresses or the death of prevention pancreas beta cell.As described below, death of pancreas beta cell or handicapped prevention can realize by improving mitochondria activity and quantity.
In some specific embodiments, the method for treatment dysbolismus provided by the invention comprises sirtuin activating compounds and sirtuin inhibitor administering drug combinations.In an exemplary specific embodiments, this method comprises the adipose cell to the patient is given the sirtuin activating compounds and give the sirtuin inhibitor to the experimenter's that these needs are arranged liver to combine.
Disease and obstacle that mitochondrion is relevant
In some specific embodiments, the method for treatment disease provided by the invention or obstacle will be benefited from the raising of mitochondria activity.This method comprises the sirtuin activating compounds for the treatment of effective dose to the experimenter that these needs are arranged.The mitochondria activity that improves is meant the mitochondria activity that keeps mitochondrial sum (for example, mitochondrial mass) and improve, and improves mitochondria activity (for example, mitochondrion is biological to be taken place by stimulating), perhaps its combination thereby increase mitochondria number.In an exemplary specific embodiments, this method comprises and gives high dose sirtuin activating compounds.In some specific embodiments, the disease of benefiting from the mitochondria activity raising comprises disease relevant with mitochondria dysfunction or obstacle with obstacle.
In some specific embodiments, the disease of mitochondria activity increase is benefited from treatment and the method for obstacle can comprise that the affirmation experimenter suffers from mitochondria dysfunction.The handicapped method of diagnostics lines plastochondria can be included in Cohen and Gold, molecular genetic, pathology and/or the biochemical analysis method of summing up among the Cleveland Clinic Journal of Medicine, 68:625-642 (2001).Be used for the handicapped method of diagnostics lines plastochondria and be the Thor-Byrne-ier test (referring to, for example Cohen and Gold, supra; Collin S. etc., Eur Neurol.36:260-267 (1996)).
Mitochondrion is most important for the eukaryotic survival and the normal function of nearly all type.In fact the mitochondrion in any cell type all has the congenital or posteriori defective that influences their functions.Therefore, the clinical important sign and the symptom that influence the mitochondrial defects of respiratory chain function are different types of, and according to the order of severity of defective mitochondrial distribution in the cell and their defectives, and institute influences the cells physiological needs and changes.Fissional for example organizing do not take place in what have that high-energy needs, and nervous tissue, skeletal muscle and cardiac muscle are especially responsive to mitochondrial respiratory chain dysfunction, but any tract can be influenced.
Disease relevant with mitochondria dysfunction and obstacle comprise that the active defective of mitochondrial respiratory chain wherein helps the disease or the obstacle of the pathophysiology progress of mammiferous described disease or obstacle.This comprises 1) the active congenital hereditary defective of one or more mitochondrial respiratory chain compositions; And 2) the active acquired defect of one or more mitochondrial respiratory chain compositions, wherein these defectives are to be caused by underlying cause: the intracellular Ca2+ of Zeng Jiaing a) the oxidative damage b in the aging course); C) affected cellular exposure is in nitric oxide; D) anoxia or ischemia; E) defective relevant in the transportation of mitochondrion aixs cylinder, or the f) expression of mitochondrion uncoupling protein with microtubule.
Disease or the obstacle of benefiting from the mitochondria activity of raising generally include, and for example wherein the oxidative damage of free radical mediated causes the disease of tissue deterioration, the unfavorable disease of apoptosis and the disease that wherein cell can not apoptosis of carrying out of cell wherein.Exemplary disease or the obstacle of benefiting from the mitochondria activity raising for example comprise, AD (Alzheimer), ADPD (Alzheimer and parkinson disease), AMDF (ataxia, myoclonus and deafness), autoimmune disease, cancer, CIPO (with myopathy and ophthalmoplegic chronic intestinal pseudo obstruction), congenital muscular dystrophy, CPEO (chronic progressive external ophthalmoplegia), DEAF (deafness that maternal inheritance induced deafness or aminoglycoside bring out), DEMCHO (dementia and chorea), diabetes (I type or II type), DIDMOAD (diabetes insipidus, diabetes, optic atrophy, deaf), DMDF (diabetes and deafness), myodystonia, motion does not tolerate, ESOC (epilepsy, apoplexy, optic atrophy and cognitive function decline), FBSN (necrosis of familial bilateral striatum), FICP (lethal baby's cardiomyopathy (Fatal Infantile CardiomyopathyPlus), mitochondrial encephalomyopathy companion hyperlactacidemia and apoplexy sample outbreak (MELAS) relevant cardiomyopathy), GER (gastroesophageal reflux), HD (Huntington Chorea), KSS (Kearns Sayre syndrome), tardy property myopathy, LDYT (Leber ' s hereditary optic neuropathy and myodystonia), the Leigh syndrome, LHON (Leber hereditary optic neuropathy), LIMM (lethal baby's mitochondrial myopathy (Lethal Infantile Mitochondrial Myopathy)), MDM (myopathy and diabetes), MELAS (mitochondrial encephalomyopathy companion's hyperlactacidemia and the outbreak of apoplexy sample), MEPR (myoclonic epilepsy and psychomotor activity regression (Psychomotor Regression)), MERME (the overlapping disease of MERRF (Lafora's disease is accompanied broken red fiber)/MELAS (mitochondrial encephalomyopathy companion's hyperlactacidemia and the outbreak of apoplexy sample)), MERRF (Lafora's disease is accompanied broken red fiber), MHCM (maternal inheritance hypertrophic cardiomyopathy), MICM (maternal inheritance cardiomyopathy), MILS (maternal inheritance Leigh syndrome), mitochondrion cardiomyopathy (Encephalocardiomyopathy), mitochondrial encephalomyopathy, MM (mitochondrial myopathy), MMC (maternal myopathy (Maternal Myopathy) and cardiomyopathy), MNGIE (the neural digestive tract brain of mitochondrion myopathy) (myopathy, ballet's disease, neuropathy, gastrointestinal, encephalopathy), multisystem mitochondrion obstacle (myopathy, encephalopathy, blind, hearing impairment, peripheral neuropathy), NARP (neuromyasthenia, ataxia and retinitis pigmentosa; About this point, another kind of Phenotype is reported as the Leigh disease), PD (parkinson disease), Pearson ' s syndrome, PEM (carrying out encephalopathy (HIE)), PEO (ocular myopathy), PME (progressive myoclonic epilepsy), PMPS (Pearson Marrow-pancreas syndrome), psoriasis, RTT (Rett syndrome), schizophrenia, SIDS (sudden infant death syndrome), SNHL (phonosensitive nerve deafness), multiple familial performance (Varied Familial Presentation, clinical manifestation is for carrying out sexual disorders and lethal cardiomyopathy from the spastic paraplegia to the multisystem, to truncal ataxia, dysarthria, the severe hearing impairment, mental deterioration, blepharoptosis (ptosis), ophthalmoplegia, tip cyclone (distal cyclones) and diabetes), or the Wolfram syndrome.
Other disease or the obstacle of benefiting from the mitochondria activity of raising comprise, for example, Friedreich ' s ataxia and other ataxia, amyotrophic lateral sclerosis (ALS) and other motor neuron disease, degeneration of macula, epilepsy, the Alpers syndrome, multiple mitochondrial DNA deletion syndrome, the mitochondrial DNA wasting syndrome, complex (Complex) I lacks, complex (Complex) II (SDH) lacks, complex (Complex) III lacks, cytochrome c oxidase (COX, complex (Complex) IV) lacks, complex (Complex V) lacks, adenylic acid transporter (ANT) lacks, pyruvic dehydrogenase (PDH) lacks, ethyl malonic acid urine disease with lacticemia, 3-methylpentene two Acidurias with lacticemia, between infection period with the decline intractable epilepsy, between infection period with the decline the Asperger syndrome, between infection period with the decline autism, attention deficit moves obstacle (ADHD) more, between infection period with the decline cerebral palsy, between infection period with the decline reading disorder, maternal inheritance thrombocytopenia and leukemia syndrome, (the mitochondrion ataxia of MARIAHS syndrome, repeated infection, aphasia, Hypouricemia/myelin forms and reduces, epilepsy and two carboxylic Aciduria), the ND6 myodystonia, between infection period with the decline Cyclical vomiting syndrome, 3-hydroxy-iso-butyric acid urine disease with lacticemia, diabetes with lacticemia, the reactive nervous syndrome (URNS, Uridine responsiveneurologic syndrome) of uridnine, dilated cardiomyopathy, splenic lymphoma and renal tubule acidosis/diabetes/ataxia syndrome.
In other specific embodiments, the invention provides the method that is used for the treatment of the experimenter who suffers from the mitochondrion obstacle, described mitochondrion obstacle is to be caused by the reason that is not limited to following reason: brain injury after the wound (Posttraumatic head injury) and cerebral edema, apoplexy (method of the present invention is effective to prevention or prevention reperfusion injury), Louis (Lewy) body dementia, hepatorenal syndrome, acute hepatic failure, NASH (non-alcoholic stellato-hepatitis), the metastasis of cancer/short differentiation (prodifferentiation) treatment, the Primary Congestive DHF, atrial fibrillation (non-valve), the Wolff-Parkinson-White syndrome, the constitutional heart-block, the prevention of reperfusion injury in the acute myocardial infarction, the familial migraine, irritable bowel syndrome, the secondary prevention of non-q wave myocardial infarction, premenstrual tension syndrome, the prevention of renal failure in the hepatorenal syndrome, antiphospholipid antibody syndrome, eclamposia/preeclampsia, the Oopause infertility, ischemic heart desease/angina pectoris and Shy-Drager and non-classified dysautonomia syndrome.
In another embodiment, provide the method that is used for the treatment of the mitochondrion obstacle relevant with pharmacology's side effect that upward medicine is relevant.The drug type relevant with the mitochondrion obstacle comprises reverse transcriptase inhibitors, protease inhibitor, DHOD inhibitor etc.The example of reverse transcriptase inhibitors for example comprises, azidothymidine AZT (AZT), stavudine (D4T), zalcitabine (ddC), didanosine (DDI), fluorine iodine ara-U (FIAU), lamivudine (3TC), Abacavir etc.The example of protease inhibitor for example comprises, ritonavir, indinavir, Saquinavir, viracept see nelfinaivr (Nelfmavir) etc.The example of dihydroorate dehydrogenase (DHOD) inhibitor for example comprises leflunomide, brequinar etc.
Reverse transcriptase inhibitors not only suppresses reverse transcriptase, also suppresses the required polymerase γ of mitochondrial function.Therefore, the activity (for example, using reverse transcriptase inhibitors) that suppresses polymerase γ causes mitochondria dysfunction and/or mitochondrial mass to reduce, and this shows that the patient suffers from high lactic acid disease.This disease may be benefited from the increase of mitochondria number and/or the enhancing of mitochondrial function, for example by giving sirtuin activating compounds.
The common sympton of mitochondrial disease comprises cardiomyopathy, myasthenia and atrophy, hypoevolutism (comprising motion, language, cognition or executive capability), ataxia, epilepsy, renal tubule acidosis, peripheral neuropathy, optic neuropathy, autonomic neuropathy, neurogenic intestinal dysfunction, sensorineural hearing loss, neurogenic bladder dysfunction, dilated cardiomyopathy, migraine, liver failure, lacticemia and diabetes.
In some specific embodiments, the invention provides and be used for the treatment of the disease that mitochondria activity improves or the method for obstacle benefited from, it comprises the combination that gives one or more sirtuin activating compounds and another kind of therapeutic agent to the experimenter that these needs are arranged, and described therapeutic agent for example is effective to treat the medicine of mitochondria dysfunction (as antioxidant, vitamin or respiratory chain cofactor), be effective to reduce the medicine of the symptom relevant (as antuepileptic with disease that relates to mitochondria dysfunction or obstacle, be effective to slow down the medicine of neuropathic pain, the medicine that is used for the treatment of heart dysfunction), cardiovascular drug (as following further specifying), chemotherapeutant (as following further specifying) or anti-nervus retrogression degeneration medicine (as following further specifying).In an exemplary specific embodiments, the invention provides to be used for the treatment of and benefit from the disease that mitochondria activity improves or the method for obstacle, it comprises the combination that gives one or more sirtuin activating compounds and one or more following materials to the experimenter that these needs are arranged: ubiquinone
10, L-carnitine, thiamine, riboflavin, nicotiamide, folic acid, vitamin E, selenium, thioctic acid or prednisone.The present invention also provides the compositions that comprises these combinations.
In exemplary specific embodiments, the invention provides by the sirtuin activating compounds for the treatment of effective dose to the experimenter and treat the disease that mitochondria activity improves or the method for obstacle benefited from.Exemplary disease or obstacle for example comprise, neuromuscular disorder (for example Friedreich ' s ataxia, muscular dystrophy, multiple sclerosis disease etc.), the unstable obstacle of neuron (epilepsy for example, migraine etc.), hypoevolutism, neurological sexual disorders (for example, Alzheimer, parkinson disease, amyotrophic lateral sclerosis etc.), ischemia, renal tubule acidosis, with age related neural degeneration and cognitive function decline, body void after the chemotherapy (chemotherapy fatigue), relevant or inductive menopause of chemotherapy or menstrual cycle of age or ovulate irregular, mitochondrial myopathy, (for example, calcium gathers mitochondrial injury, exitotoxicity, nitric oxide exposes, anoxia etc.) and mitochondrion imbalance.
The genetic flaw of modal hereditary ataxia-Friedreich ' s ataxia (FA) obtains confirming and being called as " frataxin " recently.In FA, through normal development after a while, defective with grow developedly equally, cause paralysis and dead, typically 30 and 40 years old between.Influence the most serious spinal cord, peripheral nervous, cardiac muscle and the pancreas of being organized as.Typically, the patient loses action control and is confined in the wheelchair, suffers from heart failure and diabetes usually.The hereditary basis of FA is included in the multiple GAA trinucleotide in the coding frataxin gene intron.These multiple existence cause gene transcription and expression decreased.Frataxin is relevant with the adjusting of mitochondrion iron content.When the frataxin of cell content was lower than normal value, excessive ferrum accumulated in the mitochondrion, and the accelerating oxidation damage also causes mitochondrion to be degenerated and dysfunction.When the GAA that has moderate quatity in the frataxin gene intron repeats, may not can develop into serious ataxic clinical manifestation type.Yet, suffer from the trinucleotide of finding such moderate-length among the patient of non-insulin-dependent diabetes mellitus at 25%-30% and extend, by contrast, the crowd who does not suffer from diabetes only is about 5%.In some specific embodiments, the sirtuin activating compounds can be used for treating suffering from and lacks with frataxin or the patient of the obstacle that defective is relevant, comprises Friedreich ' s ataxia, myocardial dysfunction, diabetes and as the diabetic complication of peripheral neuropathy.
Muscular dystrophy is meant the degeneration that comprises neural flesh 26S Proteasome Structure and Function, causes a class disease of skeletal muscle atrophy and mitochondria dysfunction usually.With regard to Duchenne muscular dystrophy, a kind of specific proteins, the sudden change or the defective of dystrophin (dystrophin) are relevant with its cause of disease.The mice of dystrophin gene inactivation shows the feature of some muscular dystrophy, and about 50% has the active defective of mitochondrial respiratory chain.In most of the cases, the final common approaches of neural flesh degeneration is the mitochondrial function damage of calcium mediation.In some specific embodiments, the sirtuin activating compounds can be used for reducing the patient who suffers from muscular dystrophy, with fall off rate that reduces muscle function capacity (functionalcapacities) and the functional status that improves muscle.
Multiple sclerosis (MS) is a kind of neuromuscular disease that deteriorates to feature with local inflammation and alba autoimmune.Periodic deterioration or outbreak and upper respiratory tract and other infection are closely related, comprise bacterial infection and viral infection, and this shows that mitochondria dysfunction brought into play effect in MS.By the active reduction of neuron mitochondrial respiratory chain that nitric oxide (being produced by the astrocyte relevant with inflammation and other cell) causes, be considered to promote the molecular mechanism of MS.In some specific embodiments, the sirtuin activating compounds can be used for prophylactically with the disease progression process in the treatment of multiple sclerosis patients.
Epilepsy often appears among the patient who suffers from mitochondrial cytopathies, and it relates to the intensity of attack and the frequency of certain limit, for example, inattentive, nervous, atonia, muscle clonic spasm and status epilepticus, accidental outbreak or outbreak in a day are repeatedly.In some specific embodiments, the sirtuin activating compounds can be used for treating the patient who suffers from the epilepsy that is secondary to mitochondria dysfunction, comprises the frequency and the intensity that reduce epilepsy.
Metabolism to recurrent migraine patient studies show that the defective of mitochondria activity is relevant with this obstacle usually, shows as the impaired and generation excess lactate of oxidative phosphorylation.This defective is not necessarily to be caused by the mitochondrial DNA genetic defect.Migraine patient is extremely sensitive to nitric oxide, and it is a kind of endogenous inhibitor of cytochrome C oxidase.In addition, suffer from the patient of mitochondrial cytopathies, for example, MELAS suffers from the recurrent migraine usually.In some specific embodiments, the sirtuin activating compounds can be used for treating recurrent migraine patient, comprises the treatment to the headache of Ergota compounds and the tolerance of 5-hydroxytryptamine receptor antagonist.
In suffering from the child of mitochondrial disease, often find the sluggishness of neural or neural psychological development.The neural growth that connects and reinvent and require a large amount of biosynthesis activities relates in particular to neuron film and myelinic synthetic, and the two all needs pyrimidine nucleotide as cofactor.Uridylate participated in deactivation and with sugar transport on glycolipid and glycoprotein.Cytidylic acid is transformed by uridine, the membrane phospholipid main component of its object phosphatidylcholine synthetic most important, and these compositions are accepted the choline part from cytidine diphosphocholine.At mitochondria dysfunction (by the mitochondrial DNA defective, or any such posteriority or opportunistic defective of mitochondria dysfunction that resembles excitotoxicity (exicitoxic) or mediated by nitric oxide causes) or other can cause in the synthetic impaired situation of pyrimidine, it is destroyed that cell proliferation and axon elongation are coupled to each other the critical stage of growing with the loop at neuron, causes growth as the neural mental function of language, motion, social activity, executive capability, cognitive skill to delay or stagnate.With the infantile autism is example, the magnetic resonance spectroscopy of brain phosphate cpd measured show that film or film precursor are synthetic on the whole not enough, this is that the uridine 5'-diphosphate sugar (uridine diphospho-sugars) that relates in synthetic by film and the level decline of cytidine acid derivative show.Be that the obstacle of feature comprises the special Cotard of thunder (Rett ' sSyndrome), popularity hypoevolutism (or POD-NOS " non-other indicated popularity hypoevolutism " with the hypoevolutism, be different from specific subclassification as infantile autism), the moving obstacle (ADHD) of infantile autism, inferior this Burger syndrome (Asperger ' s Syndrome), attention disappearance/how, its neuron paths that is considered to carry out function is grown delays or lags behind to cause.In some specific embodiments, the sirtuin activating compounds can be used for treatment, and to suffer from neurodevelopment slow (for example, relate to motion, language, executive capability and cognitive skill), perhaps other neural nerve and neural psychological development and the body development delay of the non-nervous tissue that resembles muscle and endocrine gland or the patient of stagnation.
(PD is two kinds of neurodegenerative diseases relevant with the age the most serious to Alzheimer's disease (AD), and its pathogeny is all relevant with mitochondria dysfunction with parkinson disease.Especially, in the nigrostriatum neuron of not only in parkinson disease, degenerating, and also often find the composite I disappearance in such surrounding tissue of muscle and platelet and the cell resembling of Parkinsonian.In Alzheimer's disease, the activity of mitochondrial respiratory chain often is suppressed, especially composite I V (cytochrome C oxidase).And as the consequence that the age increases, the harmful sequela that influences other molecular lesion of respiratory chain function is further amplified, and the mitochondrial respiratory function is suppressed fully.In AD, PD and associated disorders, except the constitutional mitochondria dysfunction, other factors also causes nerve degeneration.Two kinds of diseases of excitotoxicity (excitotoxic) stimulation and nitric oxide and this are all relevant, the defective of these factor aggravation mitochondrial respiratory chains, and its detrimental effect is extended on the handicapped basis of mitochondrion.Brain damaged part in the Huntington's disease (Huntington ' s Disease) also exists mitochondria dysfunction, and excitotoxicity stimulates and the synergism of mitochondria dysfunction has caused deterioration of neurons.In some specific embodiments, the sirtuin activating compounds can be effective to treat gentle separate comprise AD and PD with age related neural degenerative disorders.
One of genetic defect that amyotrophic lateral sclerosis (ALS or Lou Gehrig disease) patient is main is copper-Cu/Zn SOD (SOD1), a kind of gene mutation of antioxidase or disappearance.Mitochondrion can produce reactive oxygen species, is again the main target spot of reactive oxygen species simultaneously.In mammlian system, it is the most important physiology of free radical source that the interior electronics of mitochondrion can not effectively transmit oxygen supply.The deficiency of antioxidant or antioxidase can cause or aggravate mitochondrion and degenerate.The symptom that the transgenic mice of SOD1 sudden change occurs and pathology are similar to human ALS's.These advancings of disease of these animals show that itself and mitochondrial oxidation destroy, and the hypofunction of motor neuron subsequently is relevant with the outbreak of clinical symptoms.The mitochondrion composite I activity of ALS patient's skeletal muscle is very low.In some specific embodiments, the sirtuin activating compounds can be effective to treat ALS, is used to reverse or delay the progress of clinical symptoms.
Anoxia is by capturing cell and being used for the terminal electron acceptor that composite I V cytochrome C reoxidizes and directly suppress the mitochondrial respiratory chain activity, and excitotoxicity and nitric oxide generate after the anoxia by being secondary to, especially in nervous system, suppress the mitochondrial respiratory chain activity indirectly.In resembling the critical disease of cerebral anoxia, angina pectoris or sicklemia, organize relative anoxia.In these cases, improve the chemical compound of mitochondria activity and can protect affected tissue to avoid the influence of hypoxia illeffects, and alleviate the cell death of the delay of supervention, quicken from hypoxia organizational stress and damage, to restore.In some specific embodiments, the sirtuin activating compounds can be effective to after cerebral ischemia or anoxia-induced apoptosis the cell death that prevention postpones (after cerebral ischemia about 2-5 days, resemble in the zone of Hippocampus or cortex apoptosis takes place).
No matter respiratory chain dysfunction is geneogenous, or by ischemia or resemble that the such cytotoxic agent of cisplatin causes, often observes the acidosis that is caused by renal insufficiency in suffering from the patient of mitochondrial disease.Renal tubule acidosis need give exogenous sodium bicarbonate usually to keep blood and tissue pH.In some specific embodiments, the sirtuin activating compounds can be effective to treat renal tubule acidosis and other renal dysfunction that is caused by the mitochondrial respiratory chain deficiency.
In the usual aging process, mitochondrial respiration-chain function progressively fails.Approximately since 40 years old, the accumulation of human mitochondrial DNA defective presents the index sample rose, and the active nuclear regulatory factor of mitochondrial respiratory descends simultaneously.In mitochondrion replacement process, particularly in the cell behind mitosis, many mitochondrial DNA damages have selection advantage.The mechanism of its supposition is, compares with the mitochondrion with complete functional respiratory chain, and the mitochondrion with impaired respiratory chain is to the oxidative damage of self less (the mitochondrion Repiration is the main source of free radical in the body).Thereby normally functioning mitochondrion is more faster than defective mitochondrion to the accumulation of membrane lipid oxidative damage, is " marked " thus to be used for being degraded by lysosome.Because the half-life of intracellular plastochondria is about 10 days, selection advantage can cause functional mitochondrion to be replaced rapidly by the mitochondrion that Repiration weakens, particularly in the cell of slowly differentiation.In case final result is exactly to reduce the gene of the mitochondrial protein of mitochondrial oxidative damage is undergone mutation, this defective mitochondrion will occupy cell very soon, weakens or eliminate its respiration capability.The accumulation of this cell causes aging or organizes degenerative disease on the level.Lack progressive mosaic phenomenon (mosaic appearance) in the active cell of electron transport in this and the muscle; almost do not have the active cell random dispersion of cytochrome C oxidase (COX) in having the cell of normal activity, and the easier discovery shortage of old experimenter's biopsy COX negative cells is consistent.Old and feeble or when suffering from various mitochondrial disease, in the face of the inevitable progressively decline of mitochondrial respiration-chain function, therefore body is faced with and must (for example keeps irreplaceable postmitotic cells, neuron, skeletal muscle and cardiac muscle), and their function remained on situation on the significant level.The neuron of mitochondria dysfunction can the such stimulation of object excitotoxicity infringement become more responsive gradually.Mitochondrion is depleted and most, and to be accompanied by the degenerative disease (particularly nerve retrograde affection) of old and feeble appearance all relevant.Congenital mitochondrial disease often relates to the early onset nerve retrograde affection, and its fundamental mechanism is similar to the obstacle that the people who has NM from birth occurs in aging.In other specific embodiments, the sirtuin activating compounds can be effective to treat or alleviate cognitive competence and descend or other old and feeble degeneration consequence.
Meet with oxidative stress or resembling in the cell of the such cancer chemotherapeutic agent of cisplatin, because mitochondrial DNA is easier to be impaired and remediation efficiency is low, mitochondrial DNA damage is more wider than the nuclear DNA damage, and the persistent period is longer.Although to injuring sensitivity, in some cases, the sudden change that mitochondrial DNA causes chemical carcinogen has relative resistance to mitochondrial DNA than nuclear DNA.This is because mitochondrion is by destroying their defective genomes rather than attempting to repair the mitochondrial DNA damage that they deal with some type.This causes occurring whole mitochondria dysfunction in the time after the cytotoxic chemotherapy.Clinical use as the chemotherapeutics of cisplatin, mitomycin, cyclophosphamide often is accompanied by debilitating " chemotherapy weakness ", weak for a long time, motion does not tolerate, this can even last till that the patient recovers from the hematology of these medicines and gastrointestinal toxicity after.In some specific embodiments, the sirtuin activating compounds can be effective to treat the side effect of the cancer chemotherapy relevant with mitochondria dysfunction with prevention.
All derive from the mitochondrion that is present in when becoming pregnant in the oocyte owing to pass to the mitochondrion of fetus, so a critical function of ovary keeps the genomic integrity of mitochondrion in the oocyte exactly.Age in approximately menopause can detect mitochondrial DNA deletion, and this is also relevant unusually with menstrual cycle.Although cell can not directly detect and mitochondrial DNA deletion be responded, but can only detect the cytoplasmic second order effect of influence, as breathe impaired, the oxidoreduction situation, pyrimidine is synthetic not enough, these mitochondrial function products participate in as signal that oocyte is selected and the follicle sealing, finally initiation menopause when accuracy that no longer guarantees to keep mitochondrial genome and functional activity.This is similar to the apoptosis in the DNA damaged cells, and wherein when the gene accuracy can't be realized by repair process, cell carried out the active process of cell suicide.The women who suffers from the mitochondrial cytopathies that influences gonad often suffers premature menopause or shows main circulation unusual.The cytotoxicity anticancer chemotherapy often brings out premature menopause, consequently increases to suffer from osteoporotic risk.The amenorrhea that chemotherapy causes is generally caused by primary ovarian failure.As the function of women's age before the menopause of accepting chemotherapy, the incidence rate of the amenorrhea of chemotherapy induction improves, and this explanation mitochondrion is relevant therewith.The inductive ovulation of inhibitor inhibitory hormone of mitochondrial respiratory or protein synthesis suppresses the generation of ovary steroid hormone thereby in addition pituitary gonadotropic hormone is reacted.Typically, the women's federation of suffering from Downs syndrome (Downs syndrome) suffers premature menopause, also can suffer from early onset Alzheimer's disease sample dementia.Can both find SA cytochrome oxidase organizing always of Downs syndrome and late-onset Alzheimer's disease patient.Therefore, suitably support mitochondrial function or remedy mitochondria dysfunction and can be effective to prevent relevant with the age or inductive menopause of chemotherapy and menstrual cycle or ovulate irregular.In some specific embodiments, the sirtuin activating compounds can be effective to treatment and prevention amenorrhea, irregular ovulation, menopause, or the secondary effect of menopause.
In some specific embodiments, sirtuin regulates chemical compound can be effective to treat mitochondrial myopathy.The scope of mitochondrial myopathy from extraocular muscles obstacle slight, slowly development to serious, fatal infantile myopathy and multisystem brain myopathy.Some syndrome is defined, and some is overlapping each other for it.The clear and definite syndrome that influences muscle comprises ocular myopathy, Kearns-Sayre syndrome (with ophthalmoplegia, pigmentary retinopathy, cardiac conduction defective, cerebellar ataxia and phonosensitive nerve deafness), MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, the outbreak of apoplexy sample), MERFF syndrome (myoclonic epilepsy and ragged red fibers), limb girdle type myasthenia (limb-girdle distribution weakness) and infantile myopathy (benign or serious and fatal).The painted muscle biopsy specimen of Gomori ' s trichrome stain agent with improvement has shown because the red fiber of the fluffy galley proof that the excessive gathering of mitochondrion causes.Can detect the biochemistry defective in substrate transhipment and utilization, tricarboxylic acid cycle, oxidative phosphorylation or the respiratory chain.A large amount of mitochondrial DNA point mutations and disappearance are on the books, and are introduced into maternal non-Mendelian genetic model.In the nuclear encoded mitochondrial enzyme, undergo mutation.
In some specific embodiments, the sirtuin activating compounds can be effective to treat the patient that mitochondrion is subjected to toxic damages, and described toxic damages such as calcium accumulate that the toxicity that causes, excitotoxicity, nitric oxide expose, drug-induced toxic damages and anoxia.
The main mechanism of cell injury in excitable tissue, is that excessive calcium enters cell particularly, and this is by the leakage of cell membrane or the result of intracellular Ca2+ treatment mechanism defective.Mitochondrion is the main position that stores calcium, the energy that preferentially utilizes respiratory chain to produce absorbs calcium, rather than it is synthetic to be used for ATP, because calcium is absorbed and enters the ability drop that mitochondrion can cause power conversion, causes the spiral decline (downward spiral) in the mitochondrion depletion.
The central nervous system, excitatory amino acid is the general mechanism of cell death or damage to neuronic overstimulation.When excitatory toxicity stimulated, glutamate receptor particularly was called as the activation of the hypotype of nmda receptor, and the meeting part causes mitochondria dysfunction by the increase of intracellular Ca2+.Opposite, when cellular exposure under the level of excitatory toxicity neurotransmitter harmless or toxin to normal cell, it is responsive that mitochondrial respiratory effect and oxidative phosphorylation deficiency can make cell that excitatory toxicity is stimulated, and causes cell death or damage.
Nitric oxide (about 1 mole) suppresses cytochrome oxidase (composite I V) and therefore suppresses mitochondrial breathing; In addition, being exposed to nitric oxide (NO) for a long time can make the composite I activity irreversibly descend.Therefore, NO physiological or pathophysiology concentration can suppress the intercrescence one-tenth of pyrimidine.Nitric oxide is relevant with multiple neurological sexual disorders, comprises inflammation and central nervous system's autoimmune disease, and with the mediation of excitatory toxicity and anoxia after relevant to neuronic damage.
Oxygen is the terminal electron acceptor of respiratory chain.Hypoxgia can be damaged the activity of electron transport chain, causes pyrimidine synthetic and reduce through the ATP of oxidation phosphoric acid is synthetic.Under actual anoxia condition, if uracil and pyruvate (perhaps similarly being effective to oxidation NADH to optimize the material that glycolysis ATP generates) are provided, the human cell can breed and maintain vigour.
In some specific embodiments, the sirtuin activating compounds can be effective to treatment and unusual diseases associated of mitochondrion or obstacle.
The transcribing of mitochondrial DNA of coding respiratory chain composition needs nuclear factor.In neuron axon, mitochondrion must commute nucleus, to keep the respiratory chain activity.If hypoxia or the medicine that influences microtubule stability as paclitaxel have damaged axonal transport, mitochondrion can be away from nucleus, and forfeiture cytochrome oxidase activity.Thereby, can be effective to promote nucleus-mitochondrial interaction with the treatment of sirtuin activating compounds.
Mitochondrion is the main source of free radical and reactive oxygen species, this is because free radical and reactive oxygen species overflow from mitochondrial respiratory chain, has particularly damaged electronics from metabolic intermediate to the orderly transfer of molecular oxygen the time when the defective of one or more respiratory chain compositions.In order to reduce oxidative damage, cell can compensate by expressing several certified mitochondrion uncoupling protein (UCP).Transcribing of UCP-2 is to oxidative damage, inflammatory cytokine or excessive lipid load, for example reaction made of fatty liver and fat hepatitis.UCP reduces reactive oxygen species by the proton gradient that discharges cross-line plastochondria inner membrance and overflows from mitochondrion, has wasted the energy that metabolism produces effectively, and the oxidative damage that reduces for balance make cell be subject to energy stress influence.
Muscle function
In other specific embodiments, the invention provides the method that strengthens muscle function by the sirtuin activating compounds for the treatment of effective dose.For example, the sirtuin activating compounds can be effective to improve physical endurance and (for example carry out physical exertion, as taking exercise, physical work, the ability of sports etc.), suppress or delay physical fatigue, improve blood oxygen level, increase healthy individual energy, strengthen ability to work and tolerance, alleviate muscle fatigue, reduce stress, to strengthen heart and cardiovascular function, raising sexuality, improve muscle ATP level and/or reduce lactic acid in the blood.In some specific embodiments, this method comprises and gives a certain amount of raising mitochondria activity, increases that mitochondrion is biological, and the sirtuin activating compounds of mitochondrial mass or the sirtuin activating compounds of high dose take place, improve.
Motor capacity is meant when participating in sports activites, the ability that athletic muscle shows.The raising of motor capacity, strength, speed and endurance is the raising by the raising of muscle contraction intensity, shrinkage amplitude, and the shortening of muscle response time is measured between stimulation and the contraction.The athlete is meant the sports of participating in any level, and pursues the individuality that strength, speed and tolerance level improve in its motion, for example, and body builder, bicyclist, long-distance runner and short runner etc.The athlete through screwing up discipline, that is to say possibly, surpasses three days weekly and carries out fierce sports or match.The athlete pursues the fitness enthusiasts improve general health and happiness, raising energy level, and they move about at every turn 1-2 hour weekly three times approximately at plan.The raising of motor capacity is by the ability that overcomes muscle fatigue, keeps the ability and the more effective exercise of prolonged exercise to show.
On the arena of athlete's muscle ability, people's expectation creates the condition that can keep high level match or training for a long time.Yet, skeletal muscle sharply and intensive anaerobic exercise tend to damage motor capacity, cause that strength weakens, sports achievement descends, and muscle fatigue, ache and handicapped outbreak increases.People recognize now, even the power of single exhausts motion, perhaps thus, any acute injury to body, exhausting muscular movement or non-urgent need surgical operation as muscle injury, resistance or power, all is with short-term and the metabolism disorder that all influences for a long time muscle function is a feature.Muscle metabolism/enzymatic activity and gene expression all are affected.For example, occur all in muscular movement widely that the skeletal muscle nitrogen metabolism goes to pot and the source of metabolisable energy exhausts.Carry out deamination after the aminoacid that comprises branched-chain amino acid discharges from muscle, increased blood ammonia and as the selective oxidation of the energy source of muscle, this has aggravated metabolic acidosis.And the catalytic efficiency of muscle contraction motion reduces, and the enzymatic activity of nitrogen and energy metabolism changes.In addition, when protein synthesis rate reduction and non-contractile protein degraded increase, proteinic catabolism has just begun.These metabolic processes also are accompanied by the generation of free radical, and then the muscle injury cell.
Recovering from fatigue in violent and a large amount of exercise processes needs the reverse of metabolism and non-metabolism fatigue factor.Participate in the known facts of human muscle fatigue, as lactic acid, ammonia, hydrion etc., can only provide imperfect and can't gratifyingly explain to also have the participation (Baker etc. of other X factor probably fatigue/recovery process, J.Appl.Physiol.74:2294-2300,1993; Bazzarre etc., J Am.Coll.Nutr.11:505-511,1992; Dohm etc., Fed.Proc.44:348-352,1985; Edwards In:Biochemistry of Exercise, and Proceedings of the Fifth InternationalSymposium on the Biochemistry of Exercise (Kutrgen, Vogel, Poormans, eds.), 1983; Mac Dougall etc., Acta Physiol.Scand.146:403-404,1992; Walser etc., Kidney Int.32:123-128,1987).Several research has also been analyzed nourishing additive agent and Chinese medicine additive to strengthening the effect of muscle function.
In endurance exercise, except that muscle function, in pathophysiological state, free radical and oxidative stress parameter also are affected.Now, a real data show under pathological and physiological condition, oxidative stress promoted muscle consumption and atrophy (at Clarkson, P.M.Antioxidants and physicalperformance.Crit.Rev.Food Sci.Nutr.35:31-41; 1995; Powers, S.K.; Lennon, S.L.Analysis of cellular responses to free radicals:Focuson exerciseand skeletal muscle.Proc.Nutr.Soc.58:1025-1033; Summary is arranged) in 1999.For example, with regard to the muscular disorders that muscle tolerance and function all are compensated, nitric oxide (NO) is relevant with it.In muscular dystrophy, especially in the muscular dystrophy that causes owing to the albumen defective of forming dystrophin-sugar-protein compound (DGC), enzyme and the nitricoxide synthase (NOS) of synthetic NO are connected.Recently about underfed studies show that relevant with the DGC defective, a kind of mechanism of cell injury is to change with cell NOS and the destruction function associated ischemia of normal N O defencive function.When the sympathetic nerve vasoconstriction increase that contraction is brought out, the effect of this protectiveness is to ischemic prevention.Rando (Microsc Res Tech 55 (4): 223-35,2001) points out that oxidative damage occurs in before the pathology variation, and the muscle cell of DGC defective improves the sensitivity that oxidation stimulates.Shown that the excessive lipid peroxidation that free radical causes also is a kind of factor (Russo etc., MedHypotheses.39 (2): 147-51,1992) of suffering from as the myopathy of McArdle (McArdle ' s disease).And, although seldom research has shown and has known that mitochondria dysfunction will consume (muscle wasting) (skeletal muscle minimizing disease) with the age related muscles and radical damage be linked to each other (Navarro, A.; Lopez-Cepero, J.M.; Sanchezdel Pino, M.L.Front.Biosci.6:D26-44; 2001 summary).Other indication comprises that acute skeletal muscle reduces disease, for example amyotrophy and/or with the relevant cachexia of burn, bed is accomplished, limb brake (limb immobilization), or great chest, abdominal part and/or plastic surgery operations.Expection the inventive method also can be effective to the muscle of treatment of pathological conditions.
In some specific embodiments, the invention provides the new dietary composition that comprises the sirtuin regulator, its preparation method, and use said composition to be used to strengthen the method for muscle function.Therefore, the invention provides and have therapeutic composition, the F﹠B that improves the health tolerance and/or suppress the physical fatigue effect, they are the people at the exercise of the general reference of the work that participates in comprising the motion that needs endurance and needs repetition muscle movement.This dietary composition can comprise electrolyte, caffeine, vitamin, carbohydrate etc. in addition.
Old and feeble/stress
In some specific embodiments, the invention provides the method that is used to prolong cell survival or stops apoptosis, it comprises to the experimenter and gives high dose sirtuin activating compounds that the experimenter will benefit from the prolongation or the decrease of apoptotic cells of cell survival.For example, can be with the sirtuin activating compounds processing skin or the epithelial cell of high dose to anti aging effect (for example, wrinkle occurring, forfeiture elasticity etc.).In an exemplary specific embodiments, will contain medicine or the make-up composition and the contact skin of the sirtuin activating compounds of high dose.The exemplary skin problem that can handle according to method of the present invention and skin disorder comprise obstacle or disease relevant with inflammation, sunburn or naturally-aged or that caused by inflammation, sunburn or naturally-aged.For example, said composition can be used for the influence of damage, discoid lupus erythematosus, dermatomyositis, psoriasis, skin carcinoma and naturally-aged that prevention or treatment contact dermatitis (comprising irritant contact dermatitis and allergic dermatitis), atopic dermatitis (claiming allergic eczema again), solar keratosis, dyskeratosis (comprising eczema), bulla epidermis absent-mindedness disease (comprising penfigus), exfoliative dermatitis, seborrheic dermatitis, erythema (comprising erythema multiforme and erythema nodosum), sunlight or other light source cause.In another embodiment, the sirtuin activating compounds of high dose can be used for treating wound and/or burn, promotes its healing, and it for example comprises one, two or three grade of burn and/or thermal burn, chemical burn and electric burn.Further describe as of the present invention, preparation can give to skin or mucosal tissue partly with forms such as ointment, washing liquid, emulsifiable paste, microemulsion, gel, solution, and its dosage can be realized required result effectively.
The topical formulations that comprises one or more high doses sirtuin activating compounds also can be used as prevention, for example chemoprophylactic compositions.When being used for the chemoprophylaxis method, before any disease appears in particular individual, sensitive skin is handled.
The sirtuin activating compounds can be carried to experimenter part or whole body.In a specific embodiments, the sirtuin activating compounds of high dose is to carry to experimenter's tissue or organ part by forms such as injection or topical formulations.
In another kind of specific embodiments, the sirtuin activating compounds of high dose can be used to treat or prevent the disease or the disease of being brought out or being increased the weight of by experimenter's cell ageing; Reduce experimenter's aging rate method, after for example old and feeble the appearance; Prolong experimenter's method of life; The disease that treatment or prevention are relevant with the life-span or the method for disease; The disease that treatment or prevention are relevant with ability of cell proliferation or the method for disease; Treatment or prevention are by cell injury or the dead disease that causes or the method for disease.In some specific embodiments, this method does not play a role by reducing the disease incidence rate that shortens experimenter's life-span.In some specific embodiments, this method does not play a role by the lethal that the disease that reduces as cancer causes.
In another embodiment, can be used to the sirtuin activating compounds that the experimenter gives high dose usually to prolong life-span of its cell and its cell of protection resist stress and/or apoptosis.It is believed that to be similar to make the experimenter accept stimulation with compounds for treating experimenter of the present invention, promptly to body favourable and may prolong the gentleness in its life-span stress.
Can give the sirtuin activating compounds of high dose with pre-anti-aging with relevant consequence or disease, as apoplexy, heart disease, heart failure, arthritis, hypertension and Alzheimer's disease to the experimenter with aging.Other disease that can be treated comprises the eye obstacle, and is for example old and feeble relevant with eyes, as cataract, glaucoma and degeneration of macula.Can also be used for treating disease to the sirtuin activating compounds that the experimenter gives high dose, for example relevant with cell death chronic disease avoids death with the protection cell.Exemplary disease comprises and nerve cell death, neuron dysfunction or muscle cell death or dysfunction diseases associated, as parkinson disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis and muscular dystrophy; AIDS; Hepatitis gravis (fulminant hepatitis); With brain degeneration diseases associated, as Creutzfeld-Jakob disease, retinitis pigmentosa and cerebellar degeneration; Myelodysplasia (myelodysplasis) is as aplastic anemia (aplastic anemia); Ischemia diseases is as myocardial infarction and apoplexy; Hepatopathy is as alcoholic hepatitis, hepatitis B and hepatitis C; Joint disease is as osteoarthritis; Atherosclerosis; Alopecia (alopecia); Ultraviolet is to the infringement of skin; Lichen planus; Atrophoderma; Cataract and transplant rejection.Surgical operation, Drug therapy, Chemical exposure and radiation irradiation also can cause cell death.
Can also be to suffering from acute illness, the experimenter of organ or tissue's damage for example, the experimenter who for example suffers from the experimenter of apoplexy or myocardial infarction or suffer from spinal cord injury gives the sirtuin activating compounds of high dose.The sirtuin activating compounds of high dose can also be used to repair the alcoholic-toxic liver.
Cardiovascular disease
In another embodiment, the invention provides a kind of method that treats and/or prevents cardiovascular disease by the sirtuin activating compounds that gives high dose to experimenter that these needs are arranged.
Can use the sirtuin activating compounds of high dose to treat or the cardiovascular disease of preventing comprises cardiomyopathy or myocarditis, as primary cardiac myopathy, metabolic cardiomyopathy, alcoholic cardiomyopathy, drug-induced cardiomyopathy, ischemic cardiomyopathy and hypertensive cerebral cardiomyopathy.The disease of using Compounds and methods for of the present invention to treat or to prevent also has main blood vessel, for example the atherosclerosis obstacle (macroangiopathy) of large artery trunks, coronary artery, carotid artery, cerebrovascular tremulous pulse, renal artery, hip tremulous pulse, femoral artery He popliteal tremulous pulse.Other angiopathy that can treat or prevent comprises and platelet aggregation, retina arteriole, glomerule arteriole, vasa nervorum, heart arteriole diseases associated, and the disease relevant with the capillary bed of eyes, kidney, heart, maincenter and peripheral nervous system.The sirtuin reactive compound of high dose can also be used to improve the HDL level of individual blood plasma.
Can use other obstacle of the sirtuin activating compounds treatment of high dose to comprise restenosis, for example after the coronary artery interventional therapy, and the obstacle relevant with the low density cholesterol horizontal abnormality with high density.
In a specific embodiments, the part that the sirtuin activating compounds of high dose can be used as with the therapeutic alliance of another kind of cardiovascular drugs is given, described cardiovascular drugs comprises, for example anti-arrhythmic, antihypertensive, calcium channel blocker, heart stopping collecting liquid, cardiac tonic, fibrinolytic agent, hardening solution (sclerosing solution), vasoconstrictor, vasodilation, nitric oxide donors, potassium channel antagonists, sodium channel inhibitor, Statins, diuresis sodium agent (naturiuretic agent).
In a specific embodiments, the part that the sirtuin activating compounds of high dose can be used as with the therapeutic alliance of anti-arrhythmic gives.Usually anti-arrhythmic is divided into four primary categories according to mechanism of action: I type, sodium channel retardance; The II type, the beta-adrenaline retardance; The III type prolongs repolarization; The IV type, calcium channel blocking.I type anti-arrhythmic comprises lignocaine, moracizine, mexiletine, tocainide, procainamide, encainide, flecainide (flecanide), tocainide, phenytoin, Propafenone, quinine fourth, norpace (disopyramide) and flecainide (flecainide).II type anti-arrhythmic comprises Propranolol and esmolol.The III type comprises the medicine that works by the over reach current potential persistent period, as amiodarone, artilide (artilide), bretylium tosylate, the non-ammonium of chlorine (clofilium), isobutilide, sotalol, azimilide, dofetilide, dronedarone (dronedarone), ersentilide, ibutilide, tedisamil and trecetilide (trecetilide).The IV anti-arrhythmic comprises verapamil, diltiazem
(diltaizem), Folium Digitalis Purpureae, adenosine, Nickel dichloride. and magnesium ion.
In another embodiment, the part that can be used as with the therapeutic alliance of another kind of cardiovascular drug of the sirtuin activating compounds of high dose gives.The example of cardiovascular drug comprises vasodilation, for example hydralazine; Angiotensin-convertion enzyme inhibitor, for example captopril (captopril); Anti-anginal drug, for example sorbide nitrate, nitroglycerin and pentaerythritol tetranitrate; Anti-arrhythmic is as quinidine, procainaltide and lignocaine; Cardiac glycoside, for example digoxin and Digitoxin; Calcium antagonist, for example verapamil and nifedipine; Diuretic, as thiazide and related compound, for example bendroflumethiazide, chlorothiazide, chlortalidone, hydrochlorothiazide and other diuretic, for example furosemide and triamterene, and tranquilizer, for example nitrazepam, flurazepam and diazepam.
Other exemplary cardiovascular drugs comprises, cyclooxygenase-2 inhibitors for example, as aspirin or indomethacin, anticoagulant, as clopidogrel, ticlopidine (ticlopidene) or aspirin, fibrinogen antagonist agent or diuretic are as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methyclothiazide (methylchlorthiazide), trichlormethiazide, polythiazide or benzthiazide and acidum ethacrynicum (ethacrynic acid), card Ke Nafen (tricrynafen), chlortalidone, furosemide, musolimine, bumetanide, triamterene, the salt of amiloride and spironolactone and these chemical compounds; Angiotensin converting enzyme inhibitor, as the salt of captopril, zofenopril (zofenopril), fosinopril, enalapril, ceranopril, cilazapril (cilazopril), delapril, pentopril, quinapril, ramipril, lisinopril and these chemical compounds, Angiotensin II antagonist, as losartan, irbesartan or valsartan; Thrombolytics is as tissue-type plasminogen activator (tPA), Recomposed tPA, streptokinase, urokinase, prourokinase and anisoylated plasminogen streptokinase activator complex (APSAC, Eminase, Beecham laboratory); Or animal salivary gland plasminogen activator, calcium ion channel blockor, as verapamil, nifedipine or diltiazem
The thromboxane receptor antagonist, as ifetroban, epoprostenol analogs (prostacyclin mimetics); Or phosphodiesterase inhibitor.If adjust with fixed dosage, the dosage range of the chemical compound of the present invention that uses in the described combination product is same as above, and the other medicines active medicine is in the dosage range of approval.
Other exemplary cardiovascular drugs comprises, vasodilation for example, for example bencyclane, cinnarizine, citicoline, cyclandelate, ciclonicate (cyclonicate), ebumamonine, phenoxezyl, flunarizine, ibudilast, ifenprodil, lomerizine, naphlole, nikamate, nosergoline, nimodipine, papaverine, pentoxifylline (pentifylline), nofedoline, vincamine, vinpocetine, vichizyl, pentoxifylline; Prostacyclin derivatives (as PGE1 and prostacyclin I2), blockade of endothelin receptors medicine (as bosentan), diltiazem
Nicorandil and nitroglycerin.The example of brain-protection drugs comprises free radical scavenger (as Edaravone, vitamin E and vitamin C); glutamate antagonist; the AMPA antagonist; kainic acid (kainate) antagonist; nmda antagonist, gaba agonist, somatomedin, opiate antagonist, phosphatidylcholine precursor, combination of serotonin agonist, Na
+/ Ca
2+Channel inhibitor, K
+Channel opener.The anti-depressant example of cerebral metabolism comprises amantadine, Tai Bili and γ-An Jidingsuan.The example of anticoagulant comprises heparin (as heparin sodium, clarin, dalteparin sodium (dalteparin sodium), reach calciparine (dalteparin calcium), calciparine, Parnaparin Sodium, Reviparin Sodium and Danaparoid sodium), warfarin, Enoxaparin, argatroban, batroxobin and sodium citrate.The example of antiplatelet drug comprises ticlopidine hydrochloride, persantin, cilostazol, 26 alkane pentaene acetoacetic ester, sarpogrelate hydrochloride, Dilazep Hydrochloride, trapidil, NSAID (non-steroidal anti-inflammatory drug) (as aspirin), beraprost sodium (beraprostsodium), iloprost and indobufene.The example of thrombolytic drug comprises that urokinase, tissue-type plasminogen activator are (as alteplase, tisokinase, Nateplase, pamiteplase, Monteplase, reteplase (rateplase) and nasaruplase.The example of antihypertensive drug comprises that angiotensin-convertion enzyme inhibitor is (as captopril, alacepril, lisinopril, imidapril, quinapril, temocapril, delapril, benazepril, cilazapril, trandolapril, enalapril, ceronapril, fosinopril, imadapril, mobertpril, perindopril, ramipril, spirapril and randolapril), the Angiotensin II antagonist is (as losartan, Candesartan, valsartan, Eprosartan, Irb), calcium channel blocker is (as aranidipine, efonidipine, nicardipine, bamidipine, benidipine, Manidipine, cilnidipine, nisoldipine, nitrendipine, nifedipine, nilvadipine, felodipine, amlodipine, diltiazem
Bepridil, clentiazem
Phendilin, gallopamil (galopamil), mibefradil, prenylamine, semotiadil, terodiline, verapamil, cilnidipine, elgodipine, isradipine, lacidipine, lercanidipine, nimodipine, cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, etafenone and perhexiline), receptor, blocking drugs (Propranolol, pindolol, indenolol, carteolol, bunitrolol, atenolol, acebutolol, metoprolol, timolol, nipradilol, penbutolol, nadolol, tilisolol, carvedilol, bisoprolol, betaxolol, celiprolol, bopindolol, bevantolol, labetalol, alprenolol, amosulalol, arotinolol, befunolol, bucumolol, bufetolol, bufuralol (buferalol), bupranolol (buprandolol), butylidine, butofilolol, carazolol, cetamolol, cloranolol, dilevalol, epanolol, levobunolol, mepindolol, metipranolol, moprolol, nadoxolol, nevibolol, oxprenolol, practol, pronetalol, sotalol, sufinalol, talinolol (talindolol), tertatolol (tertalol), toliprolol, xibenolol (xybenolol) and esmolol), the alpha-receptor blocking drugs is (as amosulalol, prazosin, terazosin, doxazosin, bunazosin, urapidil, phentolamine, arotinolol, dapiprazole, fenspiride, indoramine, labetalol, naftopidil, nicergoline, Tamsulosin, tolazoline, trimazosin and Yohimbine), sympathetic inhibitor is (as clonidine, guanfacine, guanabenz, methyldopa and reserpine), hydralazine, todralazine, budralazine and cadralazine.The example of antianginal drug comprises that nitrate esters medicine is (as amyl nitrite, nitroglycerin and isosorbide (isosorbide)), the receptor, blocking drugs is (as Propranolol, pindolol, indenolol, carteolol, bunitrolol, atenolol, acebutolol, metoprolol, timolol, Nip Luo Er, penbutolol, nadolol, tilisolol, carvedilol, bisoprolol, betaxolol, celiprolol, bopindolol, bevantolol, labetalol, alprenolol, amosulalol, arotinolol, befunolol, bucumolol, bufetolol, bufuralol (buferalol), bupranolol (buprandolol), butylidine, butofilolol, carazolol, cetamolol, cloranolol, dilevalol, epanolol, levobunolol, mepindolol, metipranolol, moprolol, nadoxolol, nevibolol, oxprenolol, practol, pronetalol, sotalol, sufinalol, talinolol (talindolol), tertatolol (tertalol), toliprolol, andxybenolol), the calcium channel blocker thing is (as aranidipine, efonidipine, nicardipine, bamidipine, benidipine, Manidipine, cilnidipine, nisoldipine, nitrendipine, nifedipine, nilvadipine, felodipine, amlodipine, diltiazem
Bepridil, clentiazem
Fendiline (phendiline), Gallopamil (galopamil), mibefradil (mibefradil), prenylamine, semotiadil, terodiline, verapamil, cilnidipine, elgodipine, isradipine, lacidipine, lercanidipine, nimodipine, cinnarizine (cinnarizine), flunarizine, lidoflazine, lomerizine, bencyclane, etafenone and perhexiline), trimetazidine, persantin, etafenone, dilazep, trapidil, nicorandil, Enoxaparin and aspirin.The example of diuretic comprises that thiazide diuretic is (as hydrochlorothiazide, methyclothiazide, trichlormethiazide, behyd and penflutizide), loop diuretic is (as furosemide, etacrynic acid, bumetanide, piretanide, azosemide and torasemide), Potassium-sparing diuretic (spironolactone, triamterene and canrenoate potassium (potassium canrenoate)), osmotic diurtc is (as isosorbide (isosorbide), D-mannitol and glycerol), non-thiazide (nonthiazide) diuretic is (as meticrane, tripamide, chlortalidone and mefruside) and acetazolamide.The example of cardiac tonic comprises that digitalis preparation is (as Digitoxin, digoxin, the lanitop, deslanoside, vesnarinone, cedilanid (lanatosideC) and Proscillaridin), the xanthine preparation is (as aminophylline, Oxtriphylline, diprophylline and proxyphylline (proxyphylline)), the catecholamine preparation is (as dopamine, dobutamine and docarpamine), PDE III inhibitor is (as amrinone, olprinone and milrinone), denopamine, ubidecarenone, pimobendan, levosimendan, taurine, vesnarinone, carperitide and colforsin dapropate (colforsin daropate).The example of antiarrhythmic drug comprises ajmaline, pirmenol, procainamide, cibenzoline, disopyramide, quinidine, Aprindine, mexiletine, lignocaine, phenytoin (phenyloin), a Xi Kani, Propafenone, flecainide (flecainide), atenolol, acebutolol, sotalol, Propranolol, metoprolol, pindolol, amiodarone, Nifekalant, diltiazem
Bepridil and verapamil.The example of lipidemia medicine comprises atorvastatin, simvastatin, pravastatin sodium, fluvastatin sodium, clinofibrate, clofibrate, simfibrate, fenofibrate, bezafibrate, colestimide and colestyramine.The example of immunosuppressant comprises azathioprine, mizoribine, cyclosporin, tacrolimus, gusperimus and methotrexate.
Cell death/cancer
Can or may contact the radiation of doses or the experimenter of toxin gives the sirtuin activating compounds of high dose to nearest contact.In a specific embodiments, contact doses radiation or toxin are relevant with work or medical procedure, for example, in nuclear power plant's work, flight aboard, X ray, computed axial tomography (CAT scan) perhaps gives radioactive dyes in the medical imaging; In such specific embodiments, the sirtuin activating compounds that gives high dose is as preventive measure.In another embodiment, radiation or toxin touch unintentionally, for example, and as industrial accident, inhabit natural radiation area, terrorist activity or relate to radioactivity or the consequence of the act of war of toxicant.In this case, preferably after contact, should give the acute radiation syndrome of sirtuin activating compounds to suppress apoptosis and to occur subsequently of high dose as early as possible.
Neuronal disease/obstacle
In some aspects, the sirtuin activating compounds of high dose can be used for the patient that treatment suffers from neurodegenerative diseases and central nervous system (CNS), spinal cord or peripheral nervous system (PNS) wound or mechanical injuries.Typically, neurodegenerative diseases relates to reducing of human brain quality and capacity, and this may be by brain cell atrophy and/or dead causing, and brain quality that causes because of aging than healthy people and capacity reduce more serious.Because the progressively degeneration (for example neurocyte dysfunction and death) of brain specific region, neurodegenerative diseases be development gradually after the long-term operate as normal of brain.Perhaps, neurodegenerative diseases may be acute attack, as the outbreak relevant with wound or toxin.The actual outbreak that brain is degenerated may be prior to clinical manifestation for many years.The example of neurodegenerative diseases includes but not limited to Alzheimer (AD), parkinson disease (PD), Huntington Chorea (HD), amyotrophic lateral sclerosis (ALS; Lou Gehrig ' s disease), the neuropathy of the neuropathy (for example bringing out) of diffusivity lewy body disease, chorea acanthocytosis, primary lateral sclerosis, disease of eye (ocular nerve inflammation), chemotherapy induction, diabetes-induced and Friedreich ' s ataxia by vincristine, paclitaxel, bortezomib.Improve proteic level of sirtuin and/or active sirtuin adjusting chemical compound and can be used for treating these obstacles and other disease cited below.
AD is a kind of take place gradually chronic, incurable and the central nervous system disorder that can't stop, and it causes the loss of memory, dystropy, personality change and ability of thinking to descend.These losses relate to the death of specific type brain cell, and the destruction of connection between them and network enabled (for example neurogliocyte).The childhood development that AD is described to reverse.The symptom that great majority suffer from the people of AD occurred after 60 years old.Symptom the earliest comprises recent memory forfeiture, misjudge and personality change.In the later stage of disease, the patient who suffers from AD may forget how to do simple motion, as washes one's hands.At last, the people who suffers from AD can lose inferential capability fully, relies on other people and looks after daily life.At last, this disease makes the patient very weak and be unable to leave the bed, and follows complication usually.
PD is a kind of take place gradually chronic, incurable, and the central nervous system disorder that can't stop, its cause body action uncontrolled, stiff, tremble and the dyskinesia.These motor system problems are relevant with the death of the brain cell in the zone of brain generation dopamine, and dopamine is a kind of chemical substance that helps to control musculation.The symptom that great majority suffer from the people of PD occurred after 50 years old.The initial symptom of PD is to influence obviously trembling of extremity, especially at hands or lip.The characteristic symptoms of PD subsequently is stiff or motion is slow, foot (shuffling walk), bow-backed posture (stoopedposture) and balanced capacity are impaired in tow on foot.Also has a large amount of secondary symptoms, as the loss of memory, dementia, depression, emotion changes, dysphagia, heterophthongia, sexual dysfunction, bladder and bowel problems.These symptoms can begin to disturb daily life, as hold table fork or read newspaper.At last, suffer from the serious incapacitation of people of PD and be unable to leave the bed.
ALS (motor neuron disease) is a kind of chronic, incurable and central nervous system disorder that can't stop, and it attacks motor neuron, and connects the composition of brain and skeletal muscle among the central nervous system.In ALS, motor neuron worsens and is final dead, although patient's brain keeps normal repertoire and susceptiveness, movement instruction can not arrive muscle.The people that great majority are suffered from ALS is between 40 to 70 years old.Shuai Tui motor neuron is the motor neuron of control arms and legs at first.Patient's dysbasia of suffering from ALS, they may fall thing, fall, slurred speech, cry beyond control or laugh at.Finally, the muscle of limbs is because of beginning atrophy.This muscle weakness can make that the patient is weak and need wheelchair, and it is movable maybe can't to leave bed.
The cause of disease great majority of these sacred diseases or the unknown.Although these diseases are at the similarity that clearly shows height aspect the basic pathogenic process, and prove their overlapping degrees on symptom at large considerably beyond only according to the desired degree of accidentalia, but people think habitually that still they are different diseases.The definition of present disease can not solve eclipsed problem rightly, needs a kind of sorting technique of new neurodegenerative diseases.
HD is the another kind of neurodegenerative diseases that is caused by the procedural degeneration of neuronic heritability of brain specific region.This degeneration causes moving uncontrolled, intelligence forfeiture and affective disorder.HD is a kind of familial disease, is to pass to child's by a dominant mutation of wild type gene by father and mother.The early symptom of some HD is anxious state of mind, depression, irritability, or controls, learns new things, the memory fact and make a decision to have any problem.Along with the development of the state of an illness, be absorbed in intellectual activity and become more and more difficult, and the patient may oneself have a meal and swallow aspect all have any problem.
Tay Sachs disease (Tay-Sachs disease) and sandhoff disease (Sandhoff disease) are owing to lack the glycolipid storage diseases (Gravel etc. that lysosome β-hexosaminidase causes, in TheMetabolic Basis of Inherited Disease, eds.Scriver etc., Mc Graw-Hill, NewYork, pp.2839-2879,1995).In these two kinds of obstacles, the glycolipid substrate of GM2 ganglioside and relevant β-hexosaminidase accumulates in nervous system and causes acute nerve degeneration.Under serious situation, the outbreak of its symptom is from the baby in early days.Then, nervus retrogression process rapidly takes place thereupon, and ill baby shows dyskinesia, epilepsy, visual loss and deafness.Usually take place dead in 2-5 when year.Proved that neurone loss causes (Huang etc., Hum.Mol.Genet.6:1879-1885,1997) by apoptosis mechanism.
As everyone knows, apoptosis plays a role in immune AIDS pathogeny.Yet HIV-I is the inducing neural disease also.(J.Clin.Invest.98:1979-1990 such as Shi, 1996) studied the apoptosis that causes by HIV-1 infection among the central nervous system in external model and the AIDS patient's cerebral tissue, found that HIV-1 infects the brain primary culture and induced extracorporeal neuron and astrocyte apoptosis.There are in 10 the cerebral tissue also to detect neuron and astrocyte apoptosis whole comprising among 5 patients that suffer from the HIV-1 dementia, 54 of suffering among the dull-witted patient among 11 AIDS patients.
The main peripheral neuropathy relevant with HIV has four kinds, promptly esthesioneurosis, acute/chronic inflammatory demyelinating polyradiculoneuropathy (AIDP/CIPD), drug-induced neuropathy with the relevant neuropathy of cytomegalovirus (CMV).
The modal neuropathy type relevant with AIDS is tip symmetry multiple nerve (DSPN).This syndrome is neurodegenerative result, it is characterized in that numbness and sensation of pricking.DSPN seldom causes serious unusual, and the overwhelming majority causes the numbness of foot or tingling and the Achilles jerk blunt.These often are accompanied by more serious immunosuppressant generation and are stable developments.Can only relief of symptoms with tricyclic antidepressant treatment but can not influence basic nerve injury.
A kind of more rare, but the neuropathy of more serious type is acute/chronic inflammatory demyelinating polyradiculoneuropathy (AIDP/CIPD).In AIDP/CIDP, infringement appears in the panniculus that covers neural impulse.This neuropathy and inflammation-related are similar to the muscle that often occurs because of the life-time service azidothymidine AZT and worsen.This is the initial symptom that HIV infects, and this moment, the patient may not can complain pain, but can not test by standard reflection.This class neuropathy may be changed relevantly with serum, and it can automatically go down sometimes in this case.This disease can be used as the sign of HIV infection and shows has in time carried out antiviral therapy.The root of AIDP/CIDP may be an autoimmune.
Drug-induced or toxic neuropathy may be unusual pain.With other medicines, for example vincristine, phenytoin Sodium (a kind of antiepileptic), high dose vitamin, isoniazid are the same with antifol, and antiviral drugs generally causes peripheral neuropathy.In the clinical experiment of antiviral drugs, peripheral neuropathy is through being commonly used for the side reaction of dose limitation, and it does not mean should give more medicine.In addition, the use of this medicine can increase the weight of other nervelet disease.Usually, these drug-induced neuropathys can reverse after drug withdrawal.
CMV can cause several nervous syndromes among the AIDS, comprises encephalitis, myelitis and polyneuropathy.
Neurone loss also is a distinguishing feature of prion disease, the cat spongiform encephalopathy (felinespongiform encephalopathy (FSE)) of the bovine spongiform encephalopathy (bovine spongiform encephalopathy) of described prion disease such as human Ke-Ya Shi disease (Creutzfeldt-Jakob disease), cattle, the scrapie (Scrapie Disease) of sheep and goat and cat.The neurone loss that the sirtuin activating compounds of high dose can be used for effectively treatment or prevents to cause because of above-mentioned these diseases.
In another embodiment, the sirtuin activating compounds of high dose can be used for the treatment of or prevent any disease or the obstacle sick relevant with axon.Tip axon disease is a kind of peripheral neuropathy that is caused by neuronic some metabolism of peripheral nervous system (PNS) or toxic disorder.This is neural modal reaction to be disturbed in metabolism or toxic, thereby may be caused by metabolic disease, as the influence as malnutrition and alcoholism or toxin or medicine of diabetes, renal failure, deletion syndrome (deficiency syndromes).Cause that the sick modal reason of tip axon is diabetes, and modal tip axon disease is a diabetic neuropathy.Usually the tip part of aixs cylinder is at first degenerated, and the cyton of axonal atrophy neurad slowly develops.Depend on the time length and the order of severity of stimulation though prognosis reduces, if remove destructive stimulus, regeneration is possible.Tip axon patient shows symmetric glove and stocking sample sensorimotor obstacle (symmetrical glove-stockingsensori-motor disturbances) usually.At involved area, the function of deep tendon reflex and autonomic nervous system (ANS) is also lost or is weakened.
Diabetic neuropathy is the neurological disorder relevant with diabetes.These diseases are normally caused by the diabetic microvascular lesions that relates to the little blood vessel (vasa nervorum) that nourishes nerve.The commonplace disease relevant with diabetic neuropathy comprises polyneuropathy, autonomic neuropathy and the ventral thoracic nerve disease of oculomotor paralysis, mononeuropathy, mononeuritis multiplex, diabetic muscular dystrophy, pain.The clinical manifestation of diabetic neuropathy comprises that for example, the sensorimotor polyneuropathy is as numbness, sensory deprivation, insensitive and pain at night (nighttime pain); Autonomic neuropathy such as delayed gastric emptying or gastroparesis; And the cranial nerve disease, as moving eye (the 3rd) neuropathy (oculomotor neuropathies) or chest or the spinoneural mononeuropathy of lumbar vertebra.
Peripheral neuropathy is the medical terminology of the nerve injury of expression peripheral nervous system, and it both may be caused by sacred disease, also may be caused by the side effect of general disease.Peripheral neurophaty is having nothing in common with each other aspect the presentation and the cause of disease, and may affect the nerves or neuromuscular junction.The main diseases of peripheral neuropathy is because of comprising epilepsy, undernutrition and HIV (human immunodeficiency virus), and diabetes are most probable causes of disease.Mechanical pressure, tumor, neural internal hemorrhage, the health that keeps same posture to cause for a long time is exposed to extreme condition such as radiation, low temperature or noxious substance also may cause peripheral neurophaty.
In an exemplary specific embodiments, the sirtuin activating compounds of high dose can be used for treatment or prevention multiple sclerosis (MS), the MS and monosymptomatic MS and other demyelination disease that comprise recurrence, chromium inflammatory demyelinating polyneuropathy (CIDP) for example, or with its related symptoms.
MS is a kind of chronic, common nervus centralis disease that disables.Although the cause of disease of this obstacle does not determine that as yet different evidences is concentrated and shown that this disease may be caused by immune dysfunction.This obstacle makes immune cell " attack " myelin, and myelin is to be arranged in the insulating sheath that contain fat of central nervous system (CNS) around neural axon.Destroyed when myelin, the electric pulse in brain and the spinal cord can not transmit apace or normally along the nerve fiber path.This has caused the obstacle of normal conductivity interruption, fatigue and vision, strength, coordination, balance, sensation and bladder and function of intestinal canal between aixs cylinder.
Similarly, MS is a kind of common and neurological disorder of knowing now, it is characterized in that the discontinuous speckle that inflammation causes and may occur in the demyelination at any position of central nervous system.Yet, almost never have any associated peripheral nervous and participate in.Demyelination has caused the insulator that is similar to the encirclement electric wire to break or has torn the situation that is produced.That is, when insulating sheath destroyed, circuit meeting " short circuit ", associated electrical equipment is with intermittent work or do not work fully.This encirclement myelin sheath remained disappearance causes brain and spinal nerves conduction short circuit to occur, thereby produces the MS symptom.People find that further this demyelination is the form appearance with speckle, rather than take place along whole C NS.In addition, this demyelination may be intermittent.Therefore the existing timeliness of diffusion of this speckle is free intersexuality again.
It is believed that its pathogenesis is relevant with the local damage of blood brain barrier, this causes partial immunity and inflammatory reaction, consequently damages myelin and therefore damages neuron.
Clinically, masculinity and femininity all may be suffered from MS, and can occur in any age.Yet, the most normal occurring on one's body the relatively young adult, and often follow single focus, as optic nerve injury, local anesthesia (sensory deprivation) or paraesthesia (part loses sensibility) or muscle weakness.In addition, dizzy, diplopia, local pain, incontinence, arms and legs pain may take place during neck flexion, also have multiple not too common symptom.
The outbreak first of MS usually is temporary transient, and next outbreak may be after several weeks, several months or several years.The relative situation of some individualities may be stable, many years no diseases, and other unfortunate individualities may experience lasting deterioration process, finally paralysis fully.Modal is a series of alleviation and recurrence to occur, and wherein each recurrence all makes the patient than serious before.Recurrence may be brought out by stress event, viral infection or toxin.Wherein, fervescence is promptly had a fever and can be made that sb.'s illness took a turn for the worse, and body temperature reduces, and for example psychrolusia can make that sb.'s illness took a favorable turn.
In another embodiment, the sirtuin activating compounds of high dose can be used for treating nerve injury, comprises the damage, wound (comprising surgical operation) or the environmental damage (for example, neurotoxin, alcoholism etc.) that are caused by disease.
The sirtuin activating compounds of high dose can also be used to prevent, treat and alleviate the symptom of various peripheral nervous system obstacles.PNS is made up of importing into nervus centrifugalis of spinal cord and CNS.Peripheral nervous is handled a series of body function, comprises sensation, motion and self-discipline function.When individuality suffered from peripheral neurophaty, the nerve of peripheral nervous system sustained damage.Nerve injury is caused by multiple reason, as disease, athletic injury, poisoning or malnutrition.These factors can influence nervus centripetalis, also can influence nervus centrifugalis.According to the reason of damage, the myelin of neurocyte aixs cylinder, its protectiveness or both are damaged or destroy.
Many kinds of obstacles contained in term " peripheral neurophaty ", and the nerve-peripheral nervous of its midbrain and spinal cord outside is destroyed.Peripheral neurophaty also can be called as peripheral neuritis, if relate to a lot of nerves, also can use term " polyneuropathy or polyneuritis ".
The ubiquitous obstacle of peripheral neurophaty, and have many causes of disease.Some is common in these causes of disease, and as diabetes, other then is very rare, as acrylamide poisoning and some genetic disorder.Worldwide, the modal cause of disease of peripheral neurophaty is a leprosy.Leprosy is to be caused by the peripheroneural Mycobacterium leprae of attacking infected crowd.
In the U.S., leprosy is very rare, and diabetes are causes of disease of the peripheral neurophaty the most generally known.According to estimates, there are 1,700 ten thousand people of surpassing to suffer from the polyneuropathy relevant at US and European with diabetes.Many neuropathys are idiopathic, do not find the etiological cause of the disease as yet.At the modal heritability peripheral neurophaty of the U.S. is Charcot Marie Tooth (Charcot-Marie-Tooth disease), and about 125,000 people suffer from this disease.
The another kind of peripheral neurophaty of knowing is Guillain Barre syndrome (Guillain-Barr é syndrome), it be by with viral disease, as cytomegalovirus, Epstein-Barr virus and human immunodeficiency virus (HIV), or bacterial infection, comprise that campylobacter jejuni (Campylobacterjejuni) causes with the relevant complication of Lyme disease (Lyme disease).Worldwide sickness rate approximately is annual per 100,000 philtrums, 1.7 examples.The cause of disease of the peripheral neurophaty that other is known comprises chronic alcoholism, varicella zoster virus infection, botulism and poliomyelitis.Peripheral neurophaty may develop as primary symptom, also may be caused by another kind of disease.For example, peripheral neurophaty is a kind of symptom of some disease, as amyloidotic neuropathy, some cancer or heritability neurological disorder.These diseases may influence peripheral nervous system unify central nervous system and other body tissue.
Sirtuin regulates chemical compound can improve proteic level of sirtuin and/or activity, and the diseases in peripheral nerve system that other available sirtuin regulates compounds for treating comprises: arm is from neuropathy (root behind cervical vertebra and the first thoracic vertebra nerve (first thoracic roots), nerve trunk, nerve tract (cords) and arm nerve from peripheral nervous disease partly).Clinical manifestation comprises that regional pain, paraesthesia, myasthenia and upper limb feel to go down.These obstacles may be relevant with wound, comprises maternal infuries (birth injuries), thoracic outlet syndrome, tumor, neuritis, X-ray therapy and other situation.Referring to Adams etc., Principles of Neurology, 6th ed, pp 1351-2).Diabetic neuropathy (peripheral nerve relevant, autonomic nerve, cranial nerve obstacle) with diabetes.These diseases are normally caused by the diabetic microvascular lesions that relates to the little blood vessel (vasa nervorum) that nourishes nerve.May the commonplace disease relevant comprise oculomotor paralysis with diabetic neuropathy; Mononeuropathy; Mononeuritis multiplex; Diabetic muscular dystrophy; The painful polyneuropathy; Idioneurosis; With ventral thoracic nerve disease (referring to Adams etc., Principles of Neurology, 6th ed, p 1325); Mononeuropathy (, or not meeting the disease or the wound of the feature of diffusivity function of peripheral nerves obstacle) with independently single peripheral nervous is relevant.Mononeuritis multiplex is meant the disease that it is characterized by a plurality of independently nerve injury.Mononeuropathy may be caused by multiple reason, comprises ischemia, wound, compressing, conjunctive tissue disease, accumulated damage and other disease.Neuralgia (severe pain that takes place according to the distribution situation of peripheral nervous or cranial nerve or ache).Peripheral nervous system tumor (tumor that originates from the peripheral nervous tissue).It comprises neurofibroma, schwannoma, GCT and pernicious peripheral nervous sheath tumor.Referring to DeVita Jr etc., Cancer:Principles and Practice of Oncology, 5th ed, pp1750-1); Nerve compression syndrome (the mechanical pressure that endogenous cause of ill or exopathogenic factor cause) to nerve or nerve root.These may cause the conduction block of neural impulse, and its reason is for example myelin dysfunction or aixs cylinder disappearance.Neural and nerve sheath damage may be caused by ischemia, inflammation or direct mechanism, neuritis's (generic term of expression periphery or cranial nerve inflammation).Clinical manifestation may comprise pain, paraesthesia, paresis or hyperesthesia, polyneuropathy (a plurality of perineural disease).Kind (for example sensory nerve, nervus motorius or autonomic nerve) according to affected nerve, according to the distribution of nerve injury (for example tip with respect to nearside), according to affected main nerve component (for example demyelination with respect to aixs cylinder), according to etiology, or various forms is classified according to mode of inheritance.
In another embodiment, the sirtuin activating compounds of the high dose neuropathy that can be used for treating or preventing chemotherapy induction.The sirtuin activating compounds of high dose can when giving chemotherapeutics, and/or begin to give to give behind the chemotherapeutics before giving chemotherapeutics.If after beginning to give chemotherapeutics, give the sirtuin activating compounds of high dose, it is desirable to before the inductive neuropathy of chemotherapy takes place, or give the sirtuin activating compounds of high dose when initial symptom occurring.
Chemotherapeutics can the injured nerve system any part.Fortunately, encephalopathy and myelopathy are rarely found.More general and can be side effect when suffering from cancer such as lymphadenomatous patient treatment to peripheroneural damage.Most of neuropathys influence sensory nerve rather than nervus motorius.Therefore, common symptom is sensation of pricking, numbness or balance.As if nerve the longest in the body is the most responsive, therefore it is reported that the situation of Most patients is their hands and foot numbness or twinge.
The most general chemotherapeutic relevant with neuropathy is vinca alkaloids (being derived from the anticarcinogen of a kind of Vinca plant Herba Catharanthi Rosei) and the platiniferous medicine that is called cisplatin.Vinca alkaloids comprises medicine vinblastine, vincristine and vindesine.Manyly be used for the treatment of lymphadenomatous combination chemotherapy, for example CHOP and CVP contain vincristine, the most frequent this problem that causes of known this medicine.In fact, neuropathic just risk has limited the possible dosage that gives of vincristine.
That has carried out studies show that, uses the vincristine treatment will cause the shank of Most patients to lose some reflections and many patient's finger and toe and can experience to a certain degree twinge (paraesthesia).Usually, neuropathy can not show when just having begun in treatment, and normally just occurs through time a few weeks longer.Needn't drug withdrawal when symptom is shown effect for the first time, if but neuropathy development then may drug withdrawal.The patient reports that to their doctor these symptoms are very important, because if drug withdrawal, nerve injury is reversible to a great extent.If symptom is slight, most of doctors can reduce the dosage of vincristine usually or be changed to other vinca medicine such as vinblastine or vindesine.Occasionally, arrange the neural influenced of intestinal and cause stomachache and constipation.
In another embodiment, high dose sirtuin activating compounds can be used for the treatment of or prevent polyglutamic amide disease.Huntington Chorea (HD) and I type vertebra cerebellar ataxia (SCA1) only are two examples of the class hereditary that caused by the dynamic mutation that relates to three disjunctor repetitive sequences expansions.With regard to its common mechanism, these obstacles are called as trinucleotide and repeat disease.Known at least 14 kinds of these class diseases can influence the mankind.Wherein nine comprise SCA1 and Huntington Chorea, have repetitive sequence CAG (referring to following table A).Because the CAG amino acids coding is called glutamine, these nine kinds of trinucleotides repeat disease and are commonly referred to as polyglutamic amide disease.
Although the gene that different polyglutamic amide diseases relates to is also inequality, the quite similar process of obstacle experience that they cause.Every kind of disease is the gradual feature that deteriorates to one group of different neurocyte.Although inconsistent, the cardinal symptom of these diseases is similar, and influences middle age usually.Based on the similarity on the symptom, polyglutamic amide disease is assumed to be through identical celelular mechanism and develops.In recent years, scientist is making substantial progress aspect its mechanism of announcement.
Be higher than certain threshold value, the multiple number of glutamine is many more in the protein, seizure of disease more early and symptom serious more.This shows that unusual long glutamine district has caused the toxicity of their host protein to neurocyte.
In order to verify this hypothesis, scientist has designed and has expressed the proteic genetic engineering mice with long polyglutamic amide district.No matter whether mice expresses the albumen of total length or only be proteic those parts that contain polyglutamic amide district, they all produce the symptom of polyglutamic amide disease.This shows that long polyglutamic amide district itself damages cell, is not must be a part that causes the functional protein of damage.
For example, the symptom that it is believed that SCA1 is not that disappearance by normal ataxin-1 function directly causes but caused by the interaction between ataxin-1 and the another kind of albumen that is called LANP.LANP is essential to mutual information exchange of neurocyte and their survival.When the ataxin-1 albumen of sudden change was built up in neurocyte, it " caught " LANP albumen, disturbs its normal function.Soon, thus the LANP afunction occurring causes that function of nervous system is not normal.
Table A. the summary of polyglutamic amide disease
The normally heavy disease of disease gene name chromosomal inheritance pattern protein is heavy
Claim the multiple length in location multiple length
Spinal cord oblongata AR Xq13-21 and X dyeing androgen 9-36 38-62
Bulk phase connects
The receptor of amyotrophy recessiveness
(Kennedy (AR)
Sick)
Huntington Chorea HD 4p16.3 autosome Huntingdon egg 6-35 36-121
Dominance is white
The red DRPLA 12p13.31 of dentate nucleus autosome atrophin-1 6-35 49-88
Nuclear pallidum dominance
The Louis body withers
Disease (HRS contracts
Syndrome)
Spinocerebellum SCA1 6p23 autosome ataxin-1 6-44 39-82
Dominance is lost in the type mutual aid
Spinocerebellum SCA2 12q24.1 autosome ataxin-2 15-31 36-63
Dominance is lost in the type mutual aid
Spinocerebellum SCA3 14q32.1 autosome ataxin-3 12-40 55-84
Dominance is lost in the type mutual aid
Look into many-Yue Se
Husband's disease)
Spinocerebellum SCA6 19p13 autosome α 1A-voltage 4-18 21-33
Dominance dependency calcium is lost in the type mutual aid
The position
Spinocerebellum SCA7 3p12-13 autosome ataxin-7 4-35 37-306
Dominance is lost in the type mutual aid
Spinocerebellum SCA17 6q27 autosome TATA knot 25-42 45-63
The dominance hop protein is lost in the type mutual aid
Transfer 17 types
Also find many transcription factor in the neuron inclusion body of various disease (neuronal inclusion).Possible these transcription factor and the protein-interacting that contains the polyglutamic amide are caught in the neuron inclusion body then.Can stop transcription factor opening and closing gene according to the needs of cell so conversely.Another observed result is the low acetylation of the histone in the influenced cell.So just form imagination, the known I/II type Antibiotic FR 901228 (HDACI/II) that can increase acetylation of histone may become the new therapy (U.S. Patent application 10/476,627 of polyglutamic amide disease; " treat the method for nervus retrogression, spirit and other obstacle with deacetylase inhibitors ").
In another embodiment, the invention provides the neuropathic method of a kind of treatment or prevention and ischemic injuries or disease association, for example, coronary heart disease (comprising congestive heart failure and myocardial infarction), apoplexy, emphysema, hemorrhagic shock, peripheral blood vessel (upper limb and lower limb) and the damage relevant with transplanting.
In some specific embodiments, the invention provides and a kind ofly treat the blood flow that central nervous system cell prevents to enter cell for adaptation and reduce the damage cause.The seriousness of the damage that can prevent depends on the minimizing degree that enters the cell blood flow and the persistent period of minimizing usually to a great extent.For example, human ectocinereal normal groundwater increment be about 60 to 70mL/100g cerebral tissue/minute.When blood flow reduce to about 8-10mL/100g cerebral tissue/minute the time, central nervous system cell death appears usually, when being in higher slightly level (20-35mL/100g cerebral tissue/minute), but this tissue keeps survival is inoperative.In a specific embodiments, can prevent the death of apoptosis or non-viable non-apoptotic cell.In a more particular embodiment, the damage of ischemia mediation such as cytotoxic edema (cytoxicedema) or central nervous system tissue's hypoxemia can be prevented.In each specific embodiments, central nervous system cell can be cord cell or brain cell.
Comprise on the other hand to the experimenter and give the sirtuin activating compounds of high dose with treatment central nervous system ischemia disease.Many central nervous system's ischemia diseases can be treated by sirtuin activating compounds of the present invention.In a specific embodiments, the ischemia disease is an apoplexy, and it causes the cerebral infarction nervous system injury of any kind, as apoptosis or non-viable non-apoptotic cell death, cytotoxic edema or central nervous system tissue's anoxia.Apoplexy can influence the arbitrary region of brain or cause the cause of disease that apoplexy takes place to cause by known usually arbitrarily.In an alternative of this specific embodiments, apoplexy is the brain stem apoplexy.Generally speaking, the unconscious function that earns a bare living of brain stem apoplexy damage control is as the brain stem of breathing, blood pressure and heart beating.In another alternative of this specific embodiments, apoplexy is little apoplexy.Typically, the cerebellum zone of wind effect control balance and coordination in the cerebellum.In another embodiment, apoplexy is an embolic stroke.Briefly, embolic stroke can influence the arbitrary region of brain and the artery occlusion that usually causes because of vascular occlusion causes.In another embodiment, apoplexy can be hemorrhagic apoplexy.Similar with cerebral infarction, hemorrhagic apoplexy can influence the arbitrary region of brain and normally by with in the brain or hemorrhage on every side (bleeding) be feature angiorrhexis causes.In a more particular embodiment, apoplexy is the thrombosis apoplexy.Usually, the thrombosis apoplexy is to cause by gathering the angiemphraxis that deposit causes.
In another embodiment, ischemic conditions may be caused by the obstacle that occurs in the part beyond the central nervous system in patient's body, still also cause the blood flow minimizing that flows into the central nervous system.These obstacles can include, but are not limited to peripheral blood vessel obstacle, phlebothrombosis, pulmonary infarction, arrhythmia (for example, atrial fibrillation), myocardial infarction, transient ischemic attack, unstable angina pectoris or herrik syndrome.And central nervous system's ischemic conditions may cause because of the experimenter carries out surgical operation.For example, this experimenter may carry out operation on heart, pulmonary surgery, operation on spinal cord, cerebral operations, vascular surgery, abdominal operation or organ transfer operation.Organ transfer operation can comprise heart, lung, pancreas, kidney or liver transplantation.And central nervous system's ischemic conditions may cause because of the wound or the damage of the part outside the central nervous system in patient's body.For example, wound or damage may cause to a certain degree hemorrhage, and it can significantly reduce subject inner blood total amount.Because such total blood volume reduces, the blood flow that flows to the central nervous system reduces thereupon.For example, this wound or damage also can cause forming the vascular occlusion that restriction of blood flow flows into the central nervous system.
Certainly, the sirtuin activating compounds of expection high dose can be used for the treatment of central nervous system's ischemic conditions, and does not consider the cause of disease.In a specific embodiments, ischemic conditions is caused by vascular occlusion.Vascular occlusion can be the obturation of any type, but is generally cerebral thrombosis or thromboembolism.In a more particular embodiment, ischemic conditions may be caused by hemorrhage.Hemorrhage can be the hemorrhage of any type, but is generally cerebral hemorrhage or subarachnoid space (subararachnoidhemorrhage) is hemorrhage.In another embodiment, ischemic conditions can be caused by angiostenosis.Generally speaking, blood vessel is narrow because of vasoconstriction, as during vasospasm or owing to arteriosclerosis takes place.In another embodiment, ischemic conditions is caused by brain or spinal cord injury.
On the other hand, can give high dose sirtuin activating compounds to reduce to suffer from the infraction size at the ischemia center behind central nervous system's ischemic conditions.In addition, the sirtuin activating compounds that also can give high dose is to reduce to suffer from ischemia half blanking bar behind central nervous system's ischemic conditions or the size of intermediate zone effectively.
In a specific embodiments, the combination medicine-feeding scheme can comprise medicine or the chemical compound that is used for the treatment of or prevents neurological sexual disorders or the secondary disease relevant with these diseases.Therefore, the combination medicine-feeding scheme comprises sirtuin activator and one or more anti-nervus retrogression medicines of one or more high doses.For example, the drug regimen that one or more sirtuin activating compounds can one or more effective doses, described medicine is L-DOPA; Dopamine agonist; Adenosine A
2AReceptor antagonist; The COMT inhibitor; The MAO inhibitor; The N-NOS inhibitor; The sodium channel antagonist; Selective N-methyl-D-asparagic acid (NMDA) receptor antagonist; AMPA/ kainic acid receptor antagonist; Calcium-channel antagonists; The GABA-A receptor stimulating agent; Acetylcholinesteraseinhibitors inhibitors; Matrix metallo-proteinase inhibitor; The PARP inhibitor; P38MAP inhibitors of kinases or c-jun-N-amino terminal kinases; TPA; The NDA antagonist; Beta-interferon; Somatomedin; Glutamic acid inhibitor and/or as the part of cell therapy.
Exemplary nmda receptor antagonist comprises: (+)-(1S, 2S)-1-(4-hydroxyl-phenyl)-2-(4-hydroxy-4-phenyl piperidine)-1-propanol, (1S, 2S)-1-(4-hydroxy 3-methoxybenzene base)-2-(4-hydroxy-4-phenyl piperidine base)-1-propanol, (3R, 4S)-and 3-(4-(4-fluorophenyl)-4-hydroxy piperidine-1-base-)-benzodihydropyran-4,7-glycol, (1R
*, 2R
*)-1-(4-hydroxy-3-methyl phenyl)-2-(4-(4-fluoro-phenyl)-4-hydroxy piperidine-1-yl)-propane-1-alcohol-methanesulfonates or its pharmaceutically-acceptable acid addition.
Exemplary dopamine agonist comprises ropinirole (ropininole); The L-dopa decarboxylase inhibitor is as carbidopa or benserazide, bromocriptine, dihydroergo cryptine(DCS, etisulergine, AF-14, alaptide, pergolide, piribedil; The d1 dopamine receptor agonist is as A-68939, A-77636, dihydrexine and SKF-38393; The d2 dopamine receptor agonist is as cabergoline, lisuride, N-0434, naxagolide, PD-118440, pramipexole, quinpirole and ropinirole; Dopamine/receptor, agonist is as DPDMS and dopexamine; Dopamine/5-HT uptake inhibitor/5-HT-1A agonist is as Roxindole; Dopamine/opioid receptor agonist is as NIH-10494; α 2-epinephrine antagonist/dopamine agonist is as terguride; α 2-epinephrine antagonist/dopamine D 2 agonist is as Ergota bases (ergolines) and talipexole; The dopamine uptake inhibitor is as GBR-12909, GBR-13069, GYKI-52895 and NS-2141; The monoamine oxidase-B inhibitor is as selegiline, N-(2-butyl)-N-methyl propargyl amine, N-methyl-N-(2-amyl group) propargyl amine, AGN-1133, ergoline derivatives, lazabemide, LU-53439, MD-280040 and mofegiline; With the COMT inhibitor, as CGP-28014.
Exemplary acetylcholinesteraseinhibitors inhibitors comprises donepezil, 1-(2-methyl isophthalic acid H-benzimidazole-5-yl)-3-[1-(benzyl)-4-piperidyl]-1-acetone; 1-(2-phenyl-1H-benzimidazole-5-yl)-3-[1-(benzyl)-4-piperidyl]-1-acetone; 1-(1-ethyl-2-methyl isophthalic acid H-benzimidazole-5-yl)-3-[1-(benzyl)-4-piperidyl]-1-acetone; 1-(2-methyl-6-benzothiazolyl)-3-[1-(benzyl)-4-piperidyl]-1-acetone; 1-(2-methyl-6-benzothiazolyl)-3-[1-[(2-methyl-4-thiazolyl) methyl]-the 4-piperidyl]-1-acetone; 1-(5-methyl-benzo [b] thiophene-2-yl)-3-[1-(benzyl) 4-piperidyl]-1-acetone; 1-(6-methyl-benzo [b] thiophene-2-yl)-3-[1-(benzyl)-4-piperidyl]-1-acetone; 1-(3,5-dimethyl-benzo [b] thiophene-2-yl)-3-[1-(benzyl)-4-piperidin-1-yl]-1-acetone; 1-(benzo [b] thiophene-2-yl)-3-[1-(benzyl)-4-piperidyl]-1-acetone; 1-(benzofuran-2-yl)-3-[1-(benzyl)-4-piperidyl]-1-acetone; 1-(1-benzenesulfonyl-6-methyl-indole-2-yl)-3-[1-(benzyl)-4-piperidyl]-1-acetone; 1-(6-methyl-indole-2-yl)-3-[1-(benzyl)-4-piperidyl]-1-acetone; 1-(1-benzenesulfonyl-5-amino-indole-2-yl)-3-[1-(benzyl)-4-piperidyl]-1-acetone; 1-(5-amino-indole-2-yl)-3-[1-(benzyl)-4-piperidyl]-1-acetone; And 1-(5-acetylaminohydroxyphenylarsonic acid indole-2-yl)-3-[1-(benzyl)-4-piperidyl]-1-acetone.1-(6-quinolyl)-3-[1-(benzyl)-4-piperidyl]-1-acetone; 1-(5-indyl)-3-[1-(benzyl)-4-piperidyl]-1-acetone; 1-(5-benzothiophene)-3-[1-(benzyl)-4-piperidyl]-1-acetone; 1-(6-quinazolyl)-3-[1-(benzyl)-4-piperidyl]-1-acetone; 1-(6-benzoxazolyl)-3-[1-(benzyl)-4-piperidyl]-1-acetone; 1-(5-benzofuranyl)-3-[1-(benzyl)-4-piperidyl]-1-acetone; 1-(5-methyl-benzimidazolyl-2 radicals-yl)-3-[1-(benzyl)-4-piperidyl]-1-acetone; 1-(6-methyl-benzimidazolyl-2 radicals-yl)-3-[1-(benzyl)-4-piperidyl]-1-acetone; 1-(5-chloro-benzo [b] thiophene-2-yl)-3-[1-(benzyl)-4-piperidin-1-yl]-1-acetone; 1-(5-azaindole-2-yl)-3-[1-(benzyl) 4-piperidyl]-1-acetone; 1-(6-azepine benzo [b] thiophene-2-yl)-3-[1-(benzyl)-4-piperidyl]-1-acetone; 1-(1H-2-oxo-pyrroles [2 ', 3 ', 5,6] benzo [b] thiophene-2-yl)-3-[1-(benzyl)-4-piperidyl]-1-acetone; 1-(6-methyl-benzothiazole-2-yl)-3-[1-(benzyl)-4-piperidyl]-1-acetone; 1-(6-methoxyl group-indole-2-yl)-3-[1-(benzyl)-4-piperidyl]-1-acetone; 1-(6-methoxyl group-benzo [b] thiophene-2-yl)-3-[1-(benzyl)-4-piperidyl]-1-acetone; 1-(6-acetylaminohydroxyphenylarsonic acid benzo [b] thiophene-2-yl)-3-[1-(benzyl)-4-piperidyl]-1-acetone; 1-(5-acetylaminohydroxyphenylarsonic acid benzo [b] thiophene-2-yl)-3-[1-(benzyl-)-4-piperidyl]-1-acetone; 6-hydroxyl-3-[2-[1-(benzyl)-4-piperidin-1-yl] ethyl]-1, the 2-benzoisoxazole; 5-methyl-3-[2-[1-(benzyl)-4-piperidyl-] ethyl]-1, the 2-benzoisoxazole; 6-methoxyl group-3[2-[1-(benzyl)-4-piperidyl] ethyl]-1, the 2-benzoisoxazole; 6-acetamido 3-[2-[1-(benzyl)-4-piperidyl]-ethyl]-1, the 2-benzoisoxazole; 6-amino-3-[2-[1-(benzyl)-4-piperidyl] ethyl]-1, the 2-benzoisoxazole; 6-(4-morpholinyl)-3-[2-[1-(benzyl)-4-piperidin-1-yl] ethyl]-1, the 2-benzoisoxazole; 5,7-dihydro-3-[2-[1-(benzyl)-4-piperidyl] ethyl]-6H-pyrroles [4,5-f]-1,2-benzoisoxazole-6-ketone; 3-[2-[1-(benzyl)-4-piperidyl] ethyl]-1, the 2-benzisothiazole; 3-[2-[1-(benzyl)-4-piperidyl] vinyl]-1, the 2-benzoisoxazole; 6-phenyl amino-3-[2-[1-(benzyl)-4-piperidyl] ethyl]-1, the 2-benzoisoxazole; 6-(2-thiazolyl)-3-[2-[1-(benzyl)-4-piperidyl] ethyl]-1, the 2-benzoisoxazole; 6-(2-oxazolyl)-3-[2-[1-(benzyl)-4-piperidyl] ethyl]-1, the 2-benzoisoxazole; 6-pyrrolidinyl-3-[2-[1-(benzyl)-4-piperidyl] ethyl]-1 ,-2-benzoisoxazole; 5,7-dihydro-5,5-dimethyl-3-[2-[1-(benzyl)-4-piperidyl] ethyl]-6H-pyrroles [4,5-f]-1,2-benzoisoxazole-6-ketone; 6,8-dihydro-3-[2-[1-(benzyl)-4-piperidines] ethyl]-7H-pyrroles [5,4-g]-1,2-benzoisoxazole-7-ketone; 3-[2-[1-(benzyl)-4-piperidyl] ethyl]-5,6 ,-8-three hydrogen-7H-isoxazole [4,5-g]-quinoline-7-ketone; 1-benzyl-4-((5, the full ketone of 6-dimethoxy-1-Yin)-2-yl) methyl piperidine; 1-benzyl-4-((5, the full ketone of 6-dimethoxy-1-Yin)-2-ylidenyl) methyl piperidine, 1-benzyl-4-((the full ketone of 5-methoxyl group-1-Yin)-2-yl) methyl piperidine, 1-benzyl-4-((5, the full ketone of 6-diethoxy-1-Yin)-and the 2-yl) methyl piperidine, 1-benzyl-4-((5, the full ketone of 6-methylene-dioxy-1-Yin)-and the 2-yl) methyl piperidine, 1-(nitrobenzyl)-4-((5, the full ketone of 6-dimethoxy-1-Yin)-and the 2-yl) methyl piperidine, 1-cyclohexyl methyl-4-((5, the full ketone of 6-dimethoxy-1-Yin)-and the 2-yl) methyl piperidine, 1-(luorobenzyl)-4-((5, the full ketone of 6-dimethoxy-1-Yin)-2-yl) methyl piperidine, 1-benzyl-4-((5, the full ketone of 6-dimethoxy-1-Yin)-2-yl) propyl group piperidines and 1-benzyl-4-((the full ketone of 5-isopropoxy-6-methoxyl group-1-Yin)-2-yl) methyl piperidine.
Exemplary calcium-channel antagonists comprises diltiazem
Omega-conotoxin GVIA, methoxyl group verapamil, amlodipine, felodipine, lacidipine and Mi Bei ground that.
Exemplary GABA-A receptor modulators comprises: clomethiazole; IDDB; Gaboxadol (4,5,6,7-tetrahydrochysene isoxazole [5,4-c] pyridine-3-alcohol); Ganaxolone (3 Alpha-hydroxies-3 Beta-methyl-5 α-pregnant (steroid) alkane-20-ketone); Fengabine (2-[(butyl imido)-(2-chlorphenyl) methyl]-the 4-chlorophenol); 2-(4-methoxyphenyl)-2,5,6,7,8,9-six hydrogen-pyrazoles [4,3-c] cinnolines-3-ketone; 7-cyclobutyl-6-(2-methyl-2H-1,2,4-triazole-3-ylmethoxy)-3-phenyl-1,2,4-triazole [4,3-b] pyridazine; (3-fluoro-4-aminomethyl phenyl)-N-(the 1-[(2-aminomethyl phenyl) methyl]-benzimidazolyl-2 radicals-yl } methyl)-N-amyl group Methanamide; And 3-(amino methyl)-5-methylhexanoic acid.
Exemplary potassium channel openers comprises: diazoxide, fluorine pyridine, pinacidil, left-handed Crow card woods, rilmakalim, clo card woods (chromakalim), PCO-400 and SKP-450 (2-[2 " (1 ", 3 " dioxolone)-the 2-methyl]-4-(2 '-oxo-1 '-pyrrolidinyl)-6-nitro-2H-1-.alpha.-5:6-benzopyran).
Exemplary AMPA/ kainic acid receptor antagonist comprises 6-cyano group-7-nitro quinoxaline-2,3-two-ketone (CNQX); 6-nitro-7-sulfamoyl benzo [f] quinoxaline-2,3-diketone (NBQX); 6,7-dinitro quinoxaline-2,3-diketone (DNQX); 1-(4-aminophenyl)-4-methyl-7,8-methylene dioxy-5H-2,3-benzodiazepine
Hydrochlorate; With 2,3-dihydroxy-6-nitro-7-sulfamoyl benzo-[f] quinoxaline.
Exemplary sodium channel antagonist comprises ajmaline, procainamide, flecainide (flecainide) and riluzole.
Exemplary matrix metallo-proteinase inhibitor comprises 4-[4-(4-fluorophenoxy) benzenesulfonyl amino] Pentamethylene oxide .-4-carboxylic acid azanol; 5-methyl-5-(4-(4 '-fluorophenoxy)-phenoxy group)-pyrimidine-2,4, the 6-triketone; 5-normal-butyl-5-(4-(4 '-fluorophenoxy)-phenoxy group)-pyrimidine-2,4,6-triketone and Puli department he.
Poly-ADP ribose polymerase (PARP) is the abundant ribozyme of a kind of content, and it ruptures by single stranded DNA and activates, and by the synthetic poly-ADP ribose of NAD.Under normal circumstances, the activation by the nuclear dna repairase and raising, the base excision that PARP participates in being caused by oxidative stress is repaired.Therefore, PARP plays an important role in necrocytosis and DNA reparation.PARP also participates in the adjusting of the cytokine-expressing of transmitting inflammation.Under the situation of DNA excessive damage (as acute and too much be exposed under the pathology damage), PARP is by excessive activation, cause with the NAD loss be feature based on the energy decline of cell and cause ATP consumption, necrocytosis, tissue injury and organ injury/depletion.PARP is considered to promote neurological that this is by consumption nicotinamide adenine dinucleotide (NAD+), and then reduces adenosine triphosphate (ATP; Cosi and Marien, Ann.N.Y.Acad.Sci, 890:227,1999) cause cell death, this process can be prevented by the PARP inhibitor.Exemplary PARP inhibitor can be at Southan and Szabo, Current MedicinalChemistry, and 10:321 finds in 2003.
The terminal inhibitors of kinases of exemplary p38MAP kinases and c-jun-nitrogen comprises Pyridinylimidazoles, as isomers, SB 203580, SB 202190, SB 220026 and the RWJ 67657 of PD 169316, PD 169316.Other at United States Patent (USP) 6,288, record and introduce the present invention as a reference in 089.
In an exemplary specific embodiments, be used for the treatment of or prevent the combined therapy of MS to comprise one or more high doses sirtuin activating compounds and one or more
(interferon beta-1a),
(natalizumab) or
(the oral fumarate of BG-12/).
In another embodiment, be used for the treatment of or the combined therapy of prevent diabetes neuropathy or associated disease comprises that one or more high doses sirtuin activating compounds and one or more tricyclic antidepressants (TCAs) (comprise, for example, imipramine, amitriptyline, desipramine and nortriptyline), serotonin reuptake inhibitor (SSRIs) (comprises, for example fluoxetine, paroxetine, Sertraline (sertralene) and citalopram) and antuepileptic (AEDs) (for example comprise gabapentin, carbamazepine and topiramate.
In another embodiment, the invention provides the method that a kind of combination of using one or more high doses sirtuin activating compounds and at least a HDAC I/II inhibitor is used for treating or preventing the poly glumine disease.The example of HDAC I/II inhibitor comprises hydroxamic acid, cyclic peptide, Benzoylamide, short-chain fatty acid and depudecin.
The example of hydroxamic acid and hydroxamic acid derivs including, but not limited to, hachimycin A (TSA), Vorinostat (suberoylanilide hydroxamic acid, SAHA), oxamflatin, hot two basic two hydroxamic acid (suberic bishydroxamic acid, SBHA) ,-carboxyl-cinnamic acid two hydroxamic acid (CBHA), valproic acid and pyroxamide.TSA be used as a kind of antifungal antibiotic separate obtain (Tsuji etc. (1976) J.Antibiot (Tokyo) 29:1-6) and be found to be a kind of effective mammal hdac inhibitor (Yoshida etc. (1990) J.Biol.Chem.265:17174-17179).The discovery of anti-TSA cell line has changed the understanding to HDAC, and promptly this enzyme is the important target spot of TSA.Other the hdac inhibitor based on hydroxamic acid, SAHA, SBHA and CBHA are the synthetic compounds that can suppress HDAC in external or body with micromole or lower concentration.Glick etc. (1999) Cancer Res.59:4392-4399.These hdac inhibitors based on hydroxamic acid all have basic architectural feature: polarity hydroxyl oxime is terminal by the hydrophobicity methylene at interval (for example, length is 6 carbon) be connected to another polarity site, this polarity site and terminal hydrophobic part (for example, phenyl ring) link to each other.The chemical compound of having developed with these basic features also belongs to the scope of the hydroxamic acid that can be used as hdac inhibitor.
Cyclic peptide as hdac inhibitor is mainly the ring-type tetrapeptide.The example of cyclic peptide includes, but are not limited to, trapoxin A, apicidin and ester peptide.Trapoxin A contains 2-amino-8-oxo-9, the segmental ring-type tetrapeptide of 10-epoxy-capryl (AOE).Kijima etc. (1993) J.Biol.Chem.268:22429-22435.Apicidin is potent for demonstrating, the wide range protozoacide active and suppress the active fungal metabolite of HDAC under nanomolar concentration.Darkin-Rattray etc. (1996) Proc.Natl.Acad.Sci.USA.93; 13143-13147.The ester peptide is isolating and demonstrated the activity that suppresses HDAC under micro-molar concentration from Chromobacterium violaceum.
The example of Benzoylamide is including, but not limited to MS-27-275.Saito etc., (1990) Proc.Natl.Acad.Sci.USA.96:4592-4597.The example of short-chain fatty acid includes, but are not limited to butanoic acid salt (for example butanoic acid, arginine butyrate and phenylbutyric acid salt (PB)).Newmark etc., (1994) Cancer Lett.78:1-5; With Carducci etc. (1997) Anticancer Res.17:3972-3973.In addition, demonstrated under micro-molar concentration the depudecin that suppresses HDAC (Kwon etc. (1998) Proc.Natl.Acad.Sci.USA.95:3356-3361) also belong to the scope of Antibiotic FR 901228 of the present invention.
Coagulation disorders
In others, high dose sirtuin activating compounds can be used for the treatment of or prevent blood coagulation disorders (or disorder of hemostasis).The term that the present invention is used interchangeably " hemostasis ", " blood coagulation " and " blood coagulation " are meant to control bleeds, and comprises vasoconstriction and the physiologic character that solidifies.Blood coagulation helps mammal to keep sanguimotor integrity in wound, inflammation, disease, birth defect, malfunction or other destruction back.After the beginning blood coagulation, blood coagulation is (referring to for example, Coleman, R.W. etc. (eds.) Hemostasis andThrombosis, Second Edition, (1987)) of being undertaken by the form of the enzyme that activates into them continuously by some plasminogen.These comprise the plasma glycoprotein of factor XI, plasma thromboplastin antecedent I, factor XI, plasma thromboplastin antecedent, factors IX, factor X, factor VII and the proenzyme that thrombinogen is serine protease.Most these thrombins only are being only when the film surface-assembled becomes complex effectively with factor V with albumen cofactor such as Factor IX with physiological ratio.The formation or the lysed blood grumeleuse of blood clotting regulated and located to other blood factor.Activatory C albumen is a kind of special enzyme of deactivation coagulant blood component.Calcium ion participates in the reaction with many compositions.Blood coagulation is followed intrinsic pathway, and wherein all protein ingredients are present in the blood, perhaps extrinsic pathway, and wherein the epicyte protein tissue factor has important function.Blood clotting appears when Fibrinogen is formed fibrin by the thrombin cracking.
Further, the formation of blood clotting not only limits hemorrhage (hemostasis) under the wound situation, and may cause suffering from organ injury and death serious when causing Atheromatosis by important tremulous pulse or venous occlusion.Therefore thrombosis is that when and where in mistake has formed blood clotting.It comprises complicated between a succession of circulation haemproteins (thrombin), hemocyte (especially platelet) and the impaired blood vessel wall and the biochemical reaction that is conditioned.
Therefore, the invention provides and be intended to suppress anticoagulation that blood clotting forms and antithrombotic treatment, the limb injury that causes as myocardial infarction, apoplexy, by peripheral arterial disease or pulmonary infarction with prevention or treatment blood coagulation disorders.
" hemostasis adjust (modulating or modulation) " and " hemostatic is regulated (regulating or regulation) " that can exchange application in the present invention comprises that hemostatic induces (for example stimulating or increase), and hemostatic suppresses (for example, reduce or reduce).
On the one hand, the invention provides that a kind of high dose sirtuin activating compounds reduces or suppress the hemostatic method by giving to the experimenter.Compositions that the present invention describes and method are effective to treatment or pre-preventing thrombosis sexual disorders.The term " thrombosis sexual disorders " that the present invention uses comprises any with too much or unwanted solidifying or styptic activity, or hypercoagulability is the obstacle or the disease of feature.Thrombosis sexual disorders comprises and relates to platelet adhesion and thrombotic disease or obstacle, and can show as thrombosed tendency and raise, and for example thrombosis quantity increases, the thrombosis in early stage thrombosis, thrombosed family tendency and unusual site.The example of thrombosis sexual disorders comprises, but be not limited to thromboembolism, deep venous thrombosis, pulmonary infarction, apoplexy, myocardial infarction, miscarriage, lack relevant thrombophilia with Antithrombin III, the C hypoproteinosis, the S hypoproteinosis, resist activatory C albumen, dysfibrinogenemia, the fibrinolysis obstacle, homocystinuria, gestation, the inflammation obstacle, myelosis sexual disorders, arteriosclerosis, angina pectoris, unstable angina pectoris for example, disseminated inravascular coagulation, thrombotic thrombocytopenic purpura, cancer metastasis, drepanocytosis, glomerulonephritis and drug-induced thrombocytopenia (comprising for example heparin-induced thrombocytopenia).In addition, can give high dose sirtuin activating compounds in case tampon problem or prevent the therapeutic clot dissolution or as in angioplasty or the surgical procedures or afterwards closed again.
In another embodiment, the combination medicine-feeding scheme can comprise medicine or the chemical compound that is used for the treatment of or prevents blood coagulation disorders or the secondary disease relevant with these diseases.Therefore, the combination medicine-feeding scheme can comprise sirtuin activating compounds and one or more anticoagulations or the antithrombotic reagent of one or more high doses.For example, the sirtuin activating compounds of one or more high doses can with the following drug regimen of one or more effective doses: aspirin, heparin and inhibition vitamin K rely on low molecular weight heparin, thrombin inhibitor, platelet GP IIbIIIa acceptor inhibitor, tissue factor (TF) inhibitor, the human von willebrand disease factor inhibitor of oral warfarin, inhibitive factor X and the II of the factor, the inhibitor (especially in coagulation cascade) of the one or more factors of relevant hemostatic.In addition, the sirtuin activating compounds of one or more high doses can make up with the thrombus medicine, as t-PA, streptokinase, reptilase, TNK-t-PA and Sbphylokinase.
Inflammatory diseases
In others, the sirtuin activating compounds of one or more high doses can be used for treating or the disease and the obstacle of prevention and inflammation-related.The sirtuin activating compounds of one or more high doses can be before inflammation outbreak, in or give after the beginning.When preventative use, preferably before any inflammatory reaction or symptom, provide chemical compound.The sirtuin activating compounds that gives high dose can prevent or slacken inflammatory reaction or symptom.
Exemplary inflammatory disease comprises for example multiple sclerosis disease, rheumatic arthritis, psoriatic arthritis, degenerative arthropathy, SpA (spondouloarthropathies), gouty arthritis, systemic lupus erythematosus (sle), juvenile arthritis, rheumatic arthritis, osteoarthritis, osteoporosis, diabetes (for example, insulin-dependent or young hair style diabetes), dysmenorrhea, cystic fibrosis, inflammatory bowel, irritable bowel syndrome, Crohn disease (Crohn ' s disease), mucous colitis, ulcerative colitis, gastritis, esophagitis, pancreatitis, peritonitis, Alzheimer, shock, ankylosing spondylosis, gastritis, conjunctivitis, pancreatitis (pancreatis) (acute or chronic), multiple organ injury's syndrome (for example, supervention is in septicemia or wound), myocardial infarction, arteriosclerosis, apoplexy, reperfusion injury (for example because extracorporeal circulation or kidney dialysis), acute glomerulonephritis, vasculitis, hot injury's (i.e. sunburn), necrotizing enterocolitis, granulocyte blood transfusion related syndromes (granulocyte transfusion associated syndrome) and/or sjogren syndrome (Sjogren ' s syndrome).Exemplary skin inflammatory disease comprises for example eczema, atopic dermatitis, contact dermatitis, urticaria, scleroderma, psoriasis and the dermatosis relevant with the acute inflammation composition.
In another embodiment, the sirtuin activating compounds of one or more high doses can be used for treatment or Polyglucan and breathing disease, comprises asthma, bronchitis, pulmonary fibrosis, allergic rhinitis, oxygen intoxication, emphysema, chronic bronchitis, adult respiratory distress syndrome and any chronic obstructive pulmonary disease (COPD).The sirtuin activating compounds of one or more high doses can be used for treating chronic hepatitis to be infected, and comprises hepatitis B and hepatitis C.
In addition, the sirtuin activating compounds of one or more high doses can be used for treating autoimmune disease and/or the inflammation relevant with autoimmune, as organ-tissues autoimmune disease (for example, Raynaud's syndrome (Raynaud ' s syndrome)), scleroderma, myasthenia gravis, transplant rejection, endotoxin shock, septicemia, psoriasis, eczema, dermatitis, the multiple sclerosis disease, autoimmune thyroiditis, uveitis, systemic lupus erythematosus (sle), Addison's disease, autoimmunity polyadenous body disease (being also known as autoimmune polyglandular syndrome) and GraveShi disease.
In some specific embodiments, the sirtuin activating compounds of one or more high doses can be taken separately or be effective to treat with other or the chemical compound administered in combination of prevention of inflammation.Exemplary anti-inflammatory drug comprises, for example steroidal (for example, hydrocortisone, cortisone, fludrocortisone, prednisone, 6 Alpha-Methyl prednisones, omcilon, betamethasone or dexamethasone) and NSAID (non-steroidal anti-inflammatory drug) (NSAIDS) (for example aspirin, acetaminophen, pain go out fixed, ibuprofen, mefenamic acid, piroxicam, nabumetone, rofecoxib, celecoxib, etodolac or nimesulide).In another embodiment, other therapeutic agent is antibiotic (for example vancomycin, penicillin, amoxicillin, ampicillin, cefotaxime, rocephin, cefixime, rifampinmetronidazole, doxycycline or a streptomycin).In another embodiment, other therapeutic agent is PDE4 inhibitor (for example roflumilast or Luo Lipunan (rolipram)).In another embodiment, other therapeutic agent is hydryllin (for example, cyclizine, hydroxyzine, promethazine or a diphenhydramine).In another embodiment, other therapeutic agent is antimalarial (for example arteannuin, Artemether, artesunate (artsunate), Arechin (Polfa), Mefloquine Hydrochloride, doxycycline hydrochloride, chloroguanide hydrochloride, atovaquone (atovaquone) or a halofantrine).In a specific embodiments, other therapeutic agent is drotrecogin alfa.
Other example of antiinflammatory comprises for example Aceclofenac; Acemetacin; E-acetamidohexanoic acid (e-acetamidocaproic acid); Paracetamol; Vinegar amine Bimbisara; Antifebrin; Acetylsalicylic acid; The S-adenosylmethionine; Alclofenac; Alclometasone; Alfentanil; Algestone; Allylprodine; Alminoprofen; Aloxiprin; Alphaprodine; Two (acetylsalicylic acid) aluminium; Amcinonide; The fragrant acid of ammonia; Aminochlorthenoxazin; 3-amino-4-hydroxybutyric acid; 2-amino-4-picoline; Aminopropylon; Aminopyrine; Amixetrine; Ammonium salicylate; Ampiroxicam; Amtolmetin Guacil; Anileridine; Antipyrine; Antrafenine; Apazone; Beclomethasone; Bendazac; Benoral; Benoxaprofen; Benzpiperylon; Benzydamine; Benzylmorphine; Bermoprofen; Betamethasone; Betamethasone-17-valerate; Bezitramide; α-bisabol; The fragrant acid of bromine; P-acetobromanilide; The 5 bromosalicylic acid ethyl ester; Bromosaligenin; Bucetin; The bucloxic acid; Bucolome; Budesonide; Bufexamac; Bumadizon; Buprenorphine; Butacetin; Butibufen; Butorphanol; Carbamazepine; Carbifene; Carprofen; Carsalam; Methaform; Chloroprednisone; Chlorthenoxazin; Choline Salicylate; Quinophan; Cinmetacin; Ciramadol; Clidanac; Clobetasol; Clocortolone; Clometacin; Clonitazene; Clonixin; Clopirac; Cloprednol; Cloves (clove); Codeine; The methyl bromide codeine; Codeine phosphate; Codeine sulfate; Cortisone; Cortivazol; Cropropamide; Crotetamide; Cyc; Deflazacort; Boldenone; Desomorphine; (11BETA,16ALPHA)-16,17-[methylethylidenebis(oxy); Desoximetasone; Dexamethasone; Dexamethasone-21-isonicotinate; Dexoxadrol (dexoxadrol); Dextromoramide; Dextropropoxyphene; Deoxycortone; Dezocine; Diampromide; Diamorphone; Diclofenac; Diphenylimidazolidin-4-one; Difenpiramide; Diflorasone; Two fluocortolones; Diflunisal; Two pregna-fluoride butyl esters; Dihydrocodeine; Dihydrocodeinone enol ethyl ester (dihydrocodeinone enol acetate); Dihydromorphine; The dihydroxy aluminum acetylsalicylate; Dimenoxadol; Dimepheptanol; Dimethylthiambutene; Amidalgon; Dipipanone; Dipyrocetyl (diprocetyl); Analgin (dipyrone); Ditazole (ditazol); Drogelor; Emorfazone; Enfenamic acid (enfenamic acid); Enoxolone; Epirizole; Eptazocine; Etersalate; Ethenzamide; Ethoheptazine; Etoxazene; Ethylmethylthiambutene (ethylmethylthiambutene); Ethyl morpholine; Etodolac; Etofenamate; Etonitazene; Eugenol; Felbinac; Fenbufen; Fenclozic acid; Fendosal; Fenoprofen; Fentanyl; Fentiazac; Fepradinol; Feprazone (feprazone); Floctafenine; Fluazacort; Flucloronide; Flufenamic acid (flufenamic acid); Dexamethasone; Flunisolide; Flunixin; Flunoxaprofen; Fluocinonide (fluocinolone acetonide); Fluocinonide (fluocinonide); Fluocinonide (fluocinolone acetonide); Fluocortin (fluocortin butyl); Fluocortolone; Fluoresone; Fluorometholone; Fluperolone; The fluorine pyridine; Fluprednidene; Fluprednisolone; Fluproquazone; Fludroxycortide; Flurbiprofen; Fluticasone; Formocortal; The phosphine salicylic acid; Gentianic acid; Glafenine; Glucametacin; Glycol salicylate; Guaiazulene; Halcinonide; Halogen is his rope doubly; Halometasone; Halopredone; Heroin; Hydrocodone; Hydrocortamate; Hydrocortisone; Hydrocortisone acetate; The hydrocortisone succinate; Hydrocortisone hemisuccinic acid ester; Hydrocortisone 21-lysine ester; Hydrocortisone cipionate (hydrocortisone cypionate); Hydromorphone; Bemidone; Ibufenac; Brufen; Ibuproxam; Imidazole salicylate; Indomethacin; Indoprofen; Isofezolac; Isoflupredone; Isoflupredone acetate; Isoladol; Isomethadone; Isonixin; Isoxepac; Isoxicam; Ketobemidone; Ketoprofen; Ketorolac; Lacto benzene (P-) ether (p-lactophenetide); Li Feitaming; Levallorphan; Levorphanol; Left-handed fen Nahsi general (levophenacyl-morphan); Lofentanil; Lonazolac; Lornoxicam; Loxoprofen; Di-lysine-aspirin (lysine acetylsalicylate); Mazipredone; Meclofenamic Acid; Medrysone; Mefenamic acid; Meloxicam; Pethidine; Meprednisone; Meptazinol; Mesalazine; Metazocine; Methadone; Levomepromazine; Methylprednisolone; Methylprednisolone Acetate; Urbason Solubile; Methylprednisolone Suleptanate; Metiazinic acid; Methopholine; Metopon; Mofebutazone; Mofezolac; Mometasone; Morazone; Morphine; Morphine hydrochloride; The morphine sulfuric ester; The morpholine salicylate; Myrophine; Nabumetone; Nalbuphine; Lethidrone; 1-naphthyl salicylate; Naproxen; Narceine; Nefopam; Nicomorphine; Nifenazone; Niflumic acid (niflumic acid); Aulin; 5 '-nitro-2 '-the propoxyl group antifebrin; Norlevorphanol; Normethadone; Normorphine; Norpipanone; Olsalazine; Opium; Oxaceprol; Oxametacin; Olsapozine; Oxycodone; Oxymorphone (oxymorphone); Oxyphenbutazone; Narsco; Paramethasone; Paranyline; Parsalmide; Pentazocine; Perisoxal; Phenacetin; Phenadoxone; Phenazocine; Phenazopyridine hydrochloride; Phenocoll; Phenoperidine; Phenopyrazone; Phenomorphan; Acetylphenyl salicylate; Phenylbutazone; Phenyl salicytate; Fenyramidol; Piketoprofen; Piminodine; Pipebuzone; Piperylone; Pirazolac; Pirinitramide; Piroxicam; Pirprofen; Pranoprofen; Prednicarbate; Prednisolone; Prednisone; Prednival; Prednylidene; Proglumetacin; Proheptazine; Trimeperidine; Propacetamol; Properidine; Propiram; Dextropropoxyphene; Propyphenazone; Proquazone; Protizinic acid; Proxazole; Ramifenazone; Remifentanil; Rimazolium Metilsulfate; Salacetamide; Salicin (salicin); Salicylamide; Salicylamide O-acetic Acid; Salicylic acid; Salicylsulfuric acid (salicylsulfuric acid); Salsalate; Salverine; Simetride; Sufentanil; Salazosulfadimidine; Sulindac; Superoxide dismutase; Suprofen; Suxibuzone; Talniflumate; Tenidap; Tenoxicam; Terofenamate; Tet; Thiazolinobutazone; Tiaprofenic Acid; Tiaramide; Tilidine; Tinoridine; Tixocortol; Tolfenamic Acid; Tolmentin Sodium; C16H25NO2; Fluoxyprednisolone (triamcinolone); Triamcinolone acetonide (triamcinolone acetonide); Tropesin; Viminol; Xenbucine; Ximoprofen; Zaltoprofen and Zuo Mei acid.
In an exemplary specific embodiments, the sirtuin activating compounds of one or more high doses can be used for the treatment of or prevention of inflammation with cox 2 inhibitor optionally.Exemplary selective COX-2-inhibitor 2 comprises; SC 59046 for example; Parecoxib; celecoxib; penta ground former times cloth; rofecoxib; according to his former times cloth; chlorine cloth of U.S. former times; 2-(3; the 5-difluorophenyl)-3-[4-(methyl sulphonyl) phenyl]-2-cyclopentenes-1-ketone; (S)-6; 8-two chloro-2-(trifluoromethyl)-2H-1-.alpha.-5:6-benzopyran-3-formic acid; 2-(3, the 4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methyl sulphonyl) phenyl]-3-(2H)-2H-Pyridazin-3-one; 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide; 1-benzyl-4-[(4-oxo-piperidine-1-yl } sulfonyl] piperidines-4-t-butyl formate; 4-[5-(phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide; its salt and prodrug.
Flushing
On the other hand, the sirtuin activating compounds of one or more high doses can be used to reduce as the flushing of the symptom of obstacle and/or the sickness rate or the order of severity of hectic fever.For example, this method comprises separately or is used in combination the sirtuin activating compounds of one or more high doses with other medicines, is used to reduce the sickness rate or the order of severity of cancer patient's flushing and/or hectic fever.In other specific embodiments, this method provides the sirtuin activating compounds of one or more high doses to be used to reduce menopause and postmenopausal women's flushing and/or the sickness rate of hectic fever or the purposes of the order of severity.
On the other hand, the sirtuin activating compounds of one or more high doses can be used to reduce the sickness rate of flushing and/or hectic fever or the treatment of the order of severity, and described flushing and/or hectic fever are the side effect of another kind of Drug therapy, for example drug-induced flushing.In some specific embodiments, be used for the treatment of and/or the method for the inductive flushing of prophylactic agent comprises the preparation that comprises the sirtuin activating compounds of at least a chemical compound that brings out flushing and at least a high dose to the patient that these needs are arranged.In other specific embodiments, the method that is used for the treatment of drug-induced flushing comprises the sirtuin activating compounds that gives one or more chemical compounds of inducing flushing and one or more high doses respectively, and for example wherein sirtuin regulates chemical compound and induces the medicine of flushing not to be formulated in the same compositions.When using the preparation that separates, sirtuin regulates chemical compound and can (1) give when inducing the medicine of flushing, (2) with induce the medicine of flushing to give off and on, (3) give with respect to the medicine intersection of inducing flushing, (4) before inducing the medicine of flushing, give, (5) after inducing the medicine of flushing, give, and (6) its various combinations.The exemplary medicine of inducing flushing for example comprises, niacin, faloxifene, antidepressants, psychosis, chemotherapeutic, calcium channel blocker and antibiotic.
In a specific embodiments, the sirtuin activating compounds of one or more high doses can be used to reduce the flushing side effect of blood vessel dilating or blood lipid-lowering medicine (comprising anti-cholesterol drug and lipotropic drug).In an exemplary specific embodiments, the sirtuin activating compounds of one or more high doses can be used for reducing the flushing relevant with giving niacin.
Nicotinic acid, 3-pyridine carboxylic acid or niacin (niacin) are a kind of with for example trade name
With Time Release
The blood lipid-lowering medicine of selling.Nicotinic acid used in treatment dyslipidemia such as hyperlipemia, hypercholesterolemia and arteriosclerosis a lot of years.Just know that for a long time this chemical compound has T-CHOL, low density lipoprotein, LDL or " LDL cholesterol ", triglyceride and the apolipoprotein a (Lp (a)) that reduces in the human body, and increases required high density lipoprotein or the " beneficial effect of HDL cholesterol.
Typical dosage range is to restrain about 3 grams every day about 1.According to the dosage form of selecting, nicotinic acid gives 2 to 4 times common every day after meal.At present, nicotinic acid has two kinds of commercially available dosage forms.A kind of dosage form is give 3 or 4 times the release immediately or the tablet of rapid release every day.Discharge (" IR ") niacin preparation immediately and after taking in, discharge nearly all nicotinic acid usually in about 30 to 60 minutes.Another kind of dosage form is the slow release form that is suitable for administration every day 2 to 4 times.Compare with the IR preparation, slow release (" SR ") niacin preparation is designed to discharge a large amount of medicines and enters blood flow with absorption in particular time interval, make it to keep in 12 or 24 hours after long-term as absorption the treatment level of nicotinic acid.
Term used herein " nicotinic acid " thereby be meant comprises that nicotinic acid or internal metabolism become nicotinic acid to produce the chemical compound that is different from nicotinic acid itself of identical with nicotinic acid in essence effect.The exemplary compounds that produces with the nicotinic acid similar action comprises, for example Roniacol Tartrate (Roche) ester, d-sorbitol six nicotinates (d-glucitolhexanicotinate), aluminum nicotinate, niceritrol (niceritrol) and d, l-Tocopheryl Nicotinate.Each this compounds is referred to as " nicotinic acid " in the present invention.
In another embodiment, the invention provides a kind of method that is used for the treatment of and/or prevents hyperlipidemia and the side effect of minimizing flushing.This method comprises the step for the treatment of the sirtuin activating compounds of the nicotinic acid of effective dose and one or more high doses to the experimenter that these needs are arranged.In an exemplary specific embodiments, nicotinic acid and/or sirtuin regulate chemical compound and can give at night.
In another representational specific embodiments, this method comprises that the sirtuin activating compounds that uses one or more high doses is to reduce the flushing side effect of raloxifene.Raloxifene is similar to estrogen in the effect at some position of health, but is not hormone.It helps women's prevention of osteoporosis disease of entering menopause.Osteoporosis causes skeleton to be tapered, to become fragile and is more prone to fracture.Raloxifene (Evista) slows down the bone loss that occur menopause, reduces the danger of the spinal fracture that causes because of osteoporosis.A kind of common adverse effect of raloxifene is hectic fever (diaphoresis and a flushing).This can make because of menopause the women through producing hectic fever uncomfortable.
In another representational specific embodiments, this method comprises that the sirtuin activating compounds that uses one or more high doses is to reduce the flushing side effect of antidepressants or psychosis.For example, the sirtuin activating compounds of one or more high doses is united use (separately give or give) with serotonin reuptake inhibitor, 5HT2 receptor antagonist, anticonvulsant, NRI, α-adrenoreceptor antagonist, NK-3 antagonist, nk 1 receptor antagonist, PDE4 inhibitor, neuropeptide Y 5 receptor antagonists, D4 receptor antagonist, 5HT1A receptor antagonist, 5HT 1D receptor antagonist, CRP antagonist, oxidase inhibitor or sedative hypnotic.
In some specific embodiments, the sirtuin activating compounds of one or more high doses can be used as the part of treatment to reduce flushing with serotonin reuptake inhibitor (SRI).In some preferred specific embodiments, this SRI is selective serotonin reuptake inhibitor (SSRI), as fluoxetinoid (fluoxetine, Norfluoxetine) or nefazodonoid (nefazodone, hydroxyl nefazodone (hydroxynefazodone), oxonefazodone).Other exemplary SSRT comprises duloxetine, venlafaxine, midalcipran, citalopram, fluvoxamine, paroxetine and Sertraline.The sirtuin activating compounds of one or more high doses can also be used as the part of treatment with the sedative hypnotic, and described sedative hypnotic is as being selected from benzodiazepine
Class is (as alprazolam, chlorine nitrogen
Clonazepam, dipotassium chlorine nitrogen
Clobazam, diazepam, halazepam, lorazepam, oxazepam and prazepam), zolpidem and barbiturates.In other specific embodiments, the sirtuin activating compounds of one or more high doses can with the 5-HT1A acceptor portion agonist as the treatment part, described 5-HT1A acceptor portion agonist is as being selected from buspirone, flesinoxan, gepirone (gepirone) and ipsapirone.The sirtuin activating compounds of one or more high doses can also with as be selected from three cyclic tertiary amines and three the ring secondary amine NRI as the treatment part.Three exemplary cyclic tertiary amines comprise amitriptyline, clomipramine, doxepin, imipramine and trimeprimine.Three exemplary ring secondary amine comprise amoxapine, desipramine, maprotiline, nortriptyline and protriptyline.In some specific embodiments, the sirtuin activating compounds of one or more high doses can be with the part that is used as treatment as the oxidase inhibitor that is selected from isocarboxazid, phenelzine, tranylcypromine, Selegiline and moclobemide.
In another representational specific embodiments, the sirtuin activating compounds of one or more high doses can be used for reducing the flushing side effect of chemotherapeutics such as cyclophosphamide, tamoxifen.
In another embodiment, the sirtuin reactive compound of one or more high doses can be used for reducing the flushing side effect of calcium channel blocker such as amlodipine (amlodipine).
In another embodiment, the sirtuin activating compounds of one or more high doses can be used for reducing antibiotic flushing side effect.For example, the sirtuin activating compounds of one or more high doses can be used in combination with levofloxacin.Levofloxacin is used for the treatment of by the microbial nasal sinuses of susceptible (sinuses), skin, lung, ear, air flue, skeleton and the infection of joint.Levofloxacin also often is used for the treatment of urinary system infection, comprises the infection and the prostatitis that other antibiosis are have resistance.Levofloxacin can effectively be treated by the microbial infectious diarrhea of escherichia coli, campylobacter jejuni and dysentery.Levofloxacin can also be used for the treatment of various obstetric infections, comprises mastitis.
The eye obstacle
One aspect of the present invention is the method that is used for suppressing, reducing or treat impaired vision (vision impairment) by the sirtuin activating compounds that gives one or more high doses of patient.
Aspect some, impaired vision is caused by optic nerve or central nervous system injury of the present invention.In specific specific embodiments, optic nerve injury is to be caused by the high intraocular pressure that causes as glaucoma.In other specific specific embodiments, optic nerve injury is by causing with the neural swelling of infecting or react relevant as the immunity in the optic neuritis (for example autoimmune) usually.
What glaucoma was described is and defect of visual field, cup-shaped (cupping) the optic disc one group obstacle relevant with optic nerve injury.These are commonly called glaucomatous optic neuropathy.Most of glaucomas usually but always not relevant with the intraocular pressure risk.Exemplary glaucoma form comprises glaucoma and penetrating keratoplasty, acute angle-closure, the chronic angle-closure, chronic open-angle, angle recession, aphakia (Aphakic) and artificial intraocular lenses, drug-induced, hyphema, intraocular tumour (Intraocular Tumors), the teenager type, cortex of lens residual (Lens-Particle), low pressure (Low Tension), pernicious, new vessels, phakolysis, Phacomorphic, pigment, plateau iris (Plateau Iris), constitutional congenital (Primary Congenital), primary open-angle, false stripping off property, Secondary cases congenital (Secondary Congenital), Adult Suspect, one-sided, uveitis (Uveitic), high intraocular pressure, ocular hypotension, peripapillary scleral ectasia art in glaucomato-cyclitic syndrome (Posner-SchlossmanSyndrome) and high intraocular pressure and the primary open angle glaucoma (ScleralExpansion Procedure).
Intraocular pressure can also be because of various surgical operations, absorb art (being cataract operation) and increase as the implantation of intraocular lens's structure as ultrasonic emulsification cataract.In addition, special operation on vertebra or the long-time prostrate any operation of patient all can cause intraocular pressure to raise.
Optic neuritis (ON) is the inflammation of optic nerve and causes the acute visual forfeiture.It is very relevant with multiple sclerosis disease (MS), because originally the MS patient of 15-25% suffers from ON, and the ON patient of 50-75% is suffered from MS by diagnosis.ON also with infect (for example viral infection, meningitis, syphilis), inflammation (for example from vaccine), infiltration is relevant with ischemia.
Cause that inattentive another disease through damage is anterior ischemic optic neuropathy AION (AION).Two such AION are arranged.Tremulous pulse inflammatory AION is because giant cell arteritis (vasculitis) causes and cause acute visual to be lost.Non-tremulous pulse inflammatory AION comprises the case of ischemic optic neuropathies all except the case that causes owing to giant cell arteritis.Although as if comprise inflammation and ischemia mechanism both, the pathophysiology of AION is still unclear.
To other damage of optic nerve usually with demyelination, inflammation, ischemia, toxin or relevant to optic nerve trauma.The exemplary disease of optic nerve injury comprises that demyelination optic neuropathy (optic neuritis, retrobulbar neuritis), vagina nervi optici meningioma, adult's optic neuritis, child's optic neuritis, anterior ischemic optic neuropathy AION, posterior ischemic optic neuropathy PION, repressive optic neuropathy, papilloedema, pseudopapilledema and toxic/nutritional optic neuropathy become.
Though other is directly not relevant with optic nerve injury, the neuropathic conditions relevant with visual loss comprises amblyopia, bell's palsy, chronic progressive external ophthalmoplegia, multiple sclerosis disease, pseudotumor cerebri and trigeminal neuralgia.
Aspect some, vision impairment is caused by retina injury of the present invention.In specific specific embodiments, retina injury is to be caused by disturbed (for example arteriosclerosis, the vasculitis) of blood flow stream to eyes.In specific specific embodiments, retina injury is to destroy (for example, exudative or non-exudative degeneration of macula) by macula lutea to cause.
Exemplary retinal diseases comprises the exudative degeneration of macula relevant with the age, the non-exudative degeneration of macula relevant with the age, artificial electronics retina (Retinal Electronic Prosthesis) is transplanted relevant degeneration of macula of age with RPE, acute many kitchen ranges property squamous pigment epithelium pathological changes, acute retinal necrosis, the Best disease, the branch retinal obstruction of artery, the branch retinal vein obstruction, cancer is correlated with and relevant autoimmunity retinopathy, central retinal artery occlusion, the central vein of retina thromboembolism, central serous chorioretinopathy, the Eales disease, the macula lutea skin covering of the surface, the degeneration of grid sample, large aneurysm, diabetic macular edema, Irvine-Gass macular edema (Irvine-GassMacular Edema), macular hole, SRNM, diffuse unilateral subacute neuroretinitis, unartificial crystalline lens cystoid macular edema (Nonpseudophakic CystoidMacular Edema), intend ocular histoplasmosis syndrome (Presumed OcularHistoplasmosis Syndrome), exudative detachment of retina, the postoperative detachment of retina, hypertrophy detachment of retina (Proliferative Retinal Detachment), rhegmatogenous detachment of retina, traction detachment of retina, retinitis pigmentosa, the CMV retinitis, retinoblastoma, retinopathy of prematurity, shot shape retinopathy (Birdshot Retinopathy), background diabetic retinopathy, proliferative diabetic retinopathy, hemoglobinopathy retinopathy (Hemoglobinopathies Retinopathy), the Purtscher retinopathy, the Valsalva retinopathy, teenager type retinoschisis, the veteran form retinoschisis, Terson syndrome and white point syndrome.
Other exemplary disease comprises eye bacterial infection (for example, conjunctivitis, keratitis, pulmonary tuberculosis, syphilis, gonorrhea), viral infection (for example eye herpes simplex virus, varicella zoster virus, cytomegaloviral retinitis, HIV (human immunodeficiency virus) (HIV)) and is secondary to HIV or the carrying out property outer retina necrosis (progressive outer retinal necrosis) of the relevant ocular disease relevant with other immunodeficiency of other HIV-.In addition, ocular disease comprises fungal infection (for example, candidiasis choroiditis (Candida choroiditis), histoplasmosis), protozoal infections (for example toxoplasmosis) and other is as ocular toxocariasis and sarcoidosis.
One aspect of the present invention is at the experience chemotherapeutics (for example to be used for, the neuropoison thing, improve the medicine such as the steroidal of intraocular pressure) among the experimenter of treatment, suppress, reduce or treat VI method by the sirtuin activating compounds that gives one or more high doses to the experimenter who has this treatment to need.
The present invention is used for carrying out the operation that surgical operation comprises that operated eye or other carry out with prone position such as the experimenter of operation on spinal cord, suppresses, reduces or treat VI method by the sirtuin activating compounds that gives one or more high doses to the experimenter who has this treatment to need.Operated eye comprises cataract, red film otomy and crystalline lens replacement.
The present invention treats by the sirtuin activating compounds that gives one or more high doses to the experimenter who has this treatment to need, comprise inhibition and prophylactic treatment, the ocular disease relevant with the age comprises cataract, xerophthalmia, retina injury etc.
Some biochemical variation of cataractous formation and eye lens, as the level reduction of antioxidants ascorbic acid and glutathion, lipid, aminoacid and protein oxidation increase, and sodium and calcium increase, and aminoacid runs off and the crystalline lens metabolism reduces relevant.The crystalline lens that lacks blood vessel is suspended in the extracellular fluid of eyes previous section.It is lenticular transparent to need nutrient such as ascorbic acid, glutathion, vitamin E, selenium, bioflavonoids and carotenoid to keep.The hydrogen peroxide that low-level selenium causes bringing out free radical increases, and it is neutral by selenium dependency antioxidase glutathion peroxidase institute.Crystalline lens protectiveness glutathion peroxidase also depends on amino acid methionine, cysteine, glycine and glutamic acid.
Cataract also may because of do not have ability suitably metabolism contain lactose, the galactose that exists in a kind of milk product of the disaccharide of forming by monosaccharide galactose and glucose and causing.If find early and correct through metabolism, cataract can be prevented, be postponed, be slowed down and even may be reversed.
The reaction that the other factors of retina injury causes owing to the free radical in glaucoma, diabetic retinopathy and age-related macular degeneration (AMD).Eyes are parts of central nervous system and have limited regeneration capacity.Retina is made up of numerous neurocytes that comprise the polyunsaturated fatty acid (PFA) of high concentration and experience oxidation.Free radical is to enter in the mitochondrion of eyes and the retinal rod and the cone by ultraviolet to produce, and their produce light is converted to the necessary energy of visual stimulus.Free radical is by hydroxyl or the peroxide-based peroxidization that causes PFA, described hydroxyl or peroxide-based successively to other free radical transmission.Free radical causes the temporary or permanent damage of retinal tissue.
Glaucoma is considered to a kind of intraocular pressure (IOP) that causes usually and increases, and cause the obstacle of retinal nerve fiber permanent damage, yet sixth does not develop into the IOP that increases in all glaucoma cases.Nowadays have recognized that this obstacle is the disease that a kind of vascular perfusion reduces and the neurotoxicity factor increases.Research has recently shown that it is the reason of retinal ganglial cells death that the level of glutamate, Glu, nitric oxide and peroxynitrite salt in the eye improves.Neuroprotective may become the hope of glaucoma nursing.For example, nitric oxide synthase inhibitors hinders by nitric oxide and peroxide and generates peroxynitrite salt.In nearest research, with aminoguanidine, the retinal ganglial cells loss reduces in the nitric oxide synthase inhibitors animal of handling.Infer that the nitric oxide in the eye causes cytotoxicity and cause neurotoxicity in the central nervous system in many tissues.
Occur diabetic retinopathy when blood vessel develops into microvascular abnormality, described microvascular abnormality mainly comprises microaneurysm and inter-retinal hemorrhage.Oxidative metabolism directly relates to the pathogeny of diabetic retinopathy, and free radical has increased the generation that causes the enhanced somatomedin of proliferation activity.The nitric oxide that vascular endothelial cell produces may cause that also smooth muscle cell is lax and cause the expansion of blood vessel section.After tremulous pulse basement membrane thickened, endothelium propagation and pericyte (pericytes) loss, ischemia and anoxia appear in retina.This oxygenation is insufficient to cause capillary tube obturation (capillaryobliteration) or not to have perfusion, small artery-venule shunting (arteriolar-venular shunts), slow blood flow and erythrocyte that to discharge the ability of oxygen impaired.Radical damage also can cause occurring the lipid peroxidation of retinal tissue.
The effect of macula lutea is the maincenter vision that forms our acumen, and it is made up of photaesthesia cell (cone cell), and basic retinal pigment epithelium (RPE) and choroid nourish and help to remove waste material.RPE nourishes the exterior tip (cones shed outer tips) of cone cell and digestion encirclement cone cell as the substrate of heliosensitivity pigment with vitamin A.RPE is exposed under the high-caliber UV radiation, and secretion suppresses the factor of angiogenesis.Choroid comprises the intensive vasoganglion that nutrition is provided and removes waste material.
In AMD, the tip (shed cone tip) that surrounds cone cell can not be absorbed by RPE, and wherein this cell expands after assembling too many indigested raw material and be dead.Indigested waste material forms gathering under RPE, be referred to as drusen (drusen).Phototoxicity (Photoxic) damage also causes the gathering of lipofuscin in the RPE cell.The drusen gathering of intracellular lipofuscin and Bruch film has disturbed oxygen and nutrient transport to retinal tissue, and finally causes RPE and photoreceptor dysfunction.In exudative AMD, blood vessel is grown from choriocapillary by the defective of Bruch film, and can grow under RPE, separates and seepage liquid or hemorrhage from choroid.
Macular pigment is to prevent one of amphiblestroid protection factor of sun damage; it derives from nutraceutical carotenoid by gathering; form as phylloxanthin, carotenoid is the fatty flavochrome as the transport vehicle of other important nutrient and zeaxanthin).Antioxidant such as vitamin C and E, beta-carotene and phylloxanthin and zinc, selenium and copper are all found in healthy macula lutea.Except nutrition was provided, these antioxidants had protective effect to the radical damage that causes degeneration of macula.
Another aspect of the present invention be by the sirtuin activating compounds that gives one or more high doses to the experimenter who has this treatment to need prevent or treat in response to swash, chemical damage or radiation-induced injury to eyes.Radiation or electromagnetism can comprise by CRT ' s to the injury of eyes or be exposed to daylight and UV-induced damage.
In a specific embodiments, a kind of composition of medicine scheme can comprise medicine or the chemical compound that is used for the treatment of or prevents eye obstacle or the Secondary cases disease relevant with these diseases.Therefore, the composition of medicine scheme can comprise that the sirtuin activating compounds of one or more high doses and one or more are used for the treatment of the therapeutic agent of eye obstacle.For example, the sirtuin activating compounds of one or more high doses can with combinations such as the medicine of the medicine of the medicine of the reduction intraocular pressure of one or more effective doses, the medicine for the treatment of glaucomatous medicine, treatment optic neuritis, treatment CMV retinopathy, treatment multiple sclerosis disease and/or antibiotic.
In a specific embodiments, the sirtuin reactive compound of one or more high doses can be united with the therapy that reduces intraocular pressure and given.One group of therapy comprises that blocking-up water generates.For example, local beta-adrenaline antagonist (timolol and betaxolol) reduces the generation of water.Local timolol causes IOP to descend in 30 minutes, 1-2 hour peaking.A kind of reasonable plan be 0.5%, 2 dosage of timolol (Timoptic) be per 30 minutes 1.The carbonic anhydrase inhibitors acetazolamide also reduce water generation and should with local beta-agonists administering drug combinations.The initial dosage that gives is 500mg, per afterwards 6 hours 250mg.This medicine can be oral, intramuscular or intravenous give.In addition, α 2-agonist (for example An Puleding) works by the generation that reduces water.These effects are adjections of topical administration beta-Blocking agent.They have been approved for the acute pressure in control anterior chamber's laser surgery (anterior chamber laser procedures) back and have raise, and can be effective to treat the acute angle closure glaucoma but be in the news.Reasonable plan be 2 dosage be per 30 minutes 1.
The second group of therapy that reduces intraocular pressure comprises reduction vitreous body (vitreous) volume.High osmotic agent can be used for treating acute attack.These medicines are extracted water out eyeball by making blood keep hyperosmosis.Often use to be dosage be the 50% cold oral glycerite of 1mL/kg (mix make it better to eat with Fructus Citri Limoniae juice).Glycerol is converted into glucose in liver; If blood glucose is too high after taking glycerol may need other insulin for the people who suffers from diabetes.Oral isosorbide is the inert alcohol of metabolism, and it also can be used as the patient that penetrating agent is used to suffer from the acute angle closure glaucoma.Common dosage is oral 100g (45% solution of 220cc).This inert alcohol not should with sorbide nitrate, a kind of heart medication based on nitrate that is used for angina pectoris and congestive heart failure is obscured mutually.Giving mannitol with the dosage intravenous of 1.0-1.5mg/kg also is effectively, and the patient who suffers from nausea and vomiting is easy to tolerance.These high osmotic agents care should be used in any patient with congestive heart failure medical history uses.
The 3rd group of therapy comprises that promotion water flows out from eye.Miotic is from angle of iris tractive iris, and can help to alleviate the obstruction of trabecular reticulum by the periphery iris.2% (blue eyes)-4% (brown eyes) pilocarpine can give every 15 minutes in first 1-2 hour.More frequent give or more high dose may cause the general cholinergic crisis.NSAIDS is used to reduce inflammation sometimes.
The exemplary treatment medicine that is used to reduce intraocular pressure comprises
P (Allergan) (brimonidine tartrate eye drops),
(Alcon) (Bu Linzuo amine (brinzolamide) eye use suspensoid),
(Allergan) (the Levobunolol Hydrochorid eye drop, USP),
(Vistakon) (timolol eye drop),
(Alcon) (hydrochloric acid betaxolol), BRIMONIDINE TARTRATE (Bausch ﹠amp; Lomb), CARTEOLOLHYDROCHLORIDE (Bausch ﹠amp; Lomb),
(Merck) (hydrochloric acid stops up amide-Timolol maleate eye drops),
(Allergan) (bimatoprost eye drop),
(Bausch﹠amp; Lomb) (metipranolol eye drop), TIMOLOL GFS (Falcon) (timolol maleate gel for eye use form solution),
(Merck) (Timolol maleate eye drops),
(Alcon) (travoprost eye drop),
(Merck) (hydrochloric acid stops up the amide eye drop) and
(Pharmacia﹠amp; Upjohn) (latanoprost eye drop).
In a specific embodiments, the sirtuin activating compounds of one or more high doses can give with being used for the treatment of and/or preventing glaucomatous therapy to unite.The example of glaucoma medicine is
Tablets (Merck) (daranide).
In a specific embodiments, the sirtuin activating compounds of one or more high doses can give with being used for the treatment of and/or preventing the therapy of optic neuritis to unite.The example that is used for the medicine of optic neuritis comprises
Phosphate Injection (Merck) (dexamethasone sodium phosphate),
(Pharmacia ﹠amp; Upjohn) (acetic acid methyl meticortelone),
Tablets (Merck) (hydrocortisone),
(Biomarin) (prednisolone phosphate sodium oral liquid) and
(Celltech) (prednisolone phosphate sodium, USP).
In a specific embodiments, the sirtuin activating compounds of one or more high doses can give with being used for the treatment of and/or preventing the therapy of CMV retinopathy to unite.The treatment of CMV retinopathy comprises
(ganciclovir capsule) and
(RocheLaboratories) (valganciclovir hydrochloride tablet).
In a specific embodiments, the sirtuin activating compounds of one or more high doses can give with being used for the treatment of and/or preventing the therapy of multiple sclerosis disease to unite.The example of this medicine comprises
(Procter﹠amp; Gamble Pharmaceuticals) (dantamacrin),
(Serono) (mitoxantrone),
(Biogen Idec) (interferon beta-Ia),
(Berlex) (interferon beta-lb),
(TevaNeuroscience) (the acetic acid lattice draw for thunder (glatiramer acetate) injection) and
(Pfizer) (interferon beta-Ia).
In addition, macrolide and/or the Mycophenolic Acid with various active can give jointly with the sirtuin activating compounds of one or more high doses.Macrolide antibiotic comprises tacrolimus, ciclosporin, sirolimus, everolimus, ascosin, erythromycin, azithromycin, clarithromycin, clindamycin, lincomycin, dirithromycin, josamycin, spiramycin, diacetyl midecamycin, tylosin, Roxithromycin, ABT-773, Telithromycin, kitasamycin and lincosamide.
III. exemplary test
In some aspects, the invention provides the screening technique that is used to identify the chemical compound (medicine) that is used for the treatment of or prevents dysbolismus.The candidate chemical compound of being identified by this screening technique can give the experimenter, if any this experimenter who needs.The experimenter who has this treatment to need suffers from, once suffers from obesity or diabetes, perhaps according to expection, for example suffers from the experimenter of these obstacles probably according to family history.Exemplary medicine is a medicine of the present invention.
Chemical compound is to the sirtuin activity, as the effect of SIRT1 can according to for example Howitz etc. above or following description determine.For example, sirtuin albumen can for example contact with chemical compound in the solution or in the cell external.In a specific embodiments, sirtuin albumen and the chemical compound in the solution contact and measure the activity of sirtuin, for example make protein, the ability partially deacetylated as histone, p53 or one.Usually, when its at least a biological activity, for example deacetylated activity when chemical compound exists when not existing when higher or lower respectively, the combined thing activation of sirtuin or suppress.Activation or inhibition can be represented by a factor in about at least 10%, 30%, 50%, 100% (i.e. one of two factors), 3,10,30 or 100.
Sirtuin is activated or is suppressed can be by for example using deacetylated target spot; as histone, p53 albumen or its a part of cell or cell extract that contacts sirtuin or comprise sirtuin, and the acetylation level of definite deacetylated target spot is determined.The acetylation level of the target spot of hatching with sirtuin to be measured shows that with respect to the acetylation higher level of contrast sirtuin sirtuin to be measured is activated.On the contrary, the acetylation level of the target spot of hatching with sirtuin to be measured shows that with respect to the acetylation level of contrast sirtuin is lower sirtuin to be measured is suppressed.Contrast sirtuin can be the sirtuin through the reorganization preparation that never contacts the sirtuin activation or suppress chemical compound.
The present invention also provides definite experimenter maybe will develop into weight increase, obesity, insulin resistant, diabetes or because of the test method of the probability of its premonitory symptom that causes or disease.This test can comprise the sirtuin that determines the experimenter, as active or (for example mRNA, mRNA precursor or albumen) level of expression of SIRT1 or AMPK.Low-level sirtuin activity or expression are indicating that probably the experimenter or has probably developed into weight increase, obesity, insulin resistant, glycosuria or its premonitory symptom or its secondary disease among the experimenter.Perhaps, the sirtuin of higher level is active or express and indicating probably that the experimenter or has probably developed into and lose weight and be protected and do not develop into the disease relevant with too high body weight among the experimenter, as insulin resistant and diabetes.Other test comprises activity or the expression of determining sirtuin and AMPK.
The present invention also provides the method for identifying the chemical compound of regulating weight increase and/or treatment or prevention insulin resistant (or sensitivity) or diabetes.A kind of method can comprise the activity of evaluation adjusting sirtuin or the medicine of protein level, and tests medicine to be measured and whether regulate weight increase and/or can be used to treatment or prevention insulin resistant or diabetes.The first step of this method can comprise with medicine to be measured contact sirtuin, and determines medicine to be measured to sirtuin, for example active effect of SIRT1 according to the description of for example above-mentioned Howitz etc.The first step of this method can also comprise the cell that comprises sirtuin with medicine contact to be measured, and definite medicine to be measured is to the effect of sirtuin activity or expression.The expression of sirtuin can be determined by mRNA, mRNA precursor or the protein level of measuring sirtuin.Other step can be included in and be used for obesity, testing drug in the animal model of insulin resistant and/or diabetes.These animal models are known in the art.Screening technique can also comprise the toxicity of definite medicine or the step of untoward reaction.
Other screening technique comprises identifies the medicine of regulating AMPK activity or protein level.To activation AMPK but do not have the toxicity of known AMPK activator such as metformin/phenformin or the chemical compound of untoward reaction has demand.
In other specific embodiments, the invention provides and be used for determining and/or the monitoring experimenter regulates the picked-up of chemical compound to sirtuin method.This method can be effective to monitor the course of disease in giving sirtuin modulators for treatment process.This test also is used to identify the individuality that gives the sirtuin regulator.For example, this test can be used for identifying and has taken the sirtuin regulator to strengthen the individuality of its motor capacity and/or endurance, as Scholar Athlete, professional athlete, olympian etc.This method can comprise the amount that detects sirtuin regulator in individual blood and/or the urine or its metabolite.Exemplary Resveratrol Metabolins comprises, for example resveratrol glucuronide and resveratrol sulfuric ester, as resveratrol list glucuronide, dihydro resveratrol Monosulfate, the resveratrol Monosulfate, the dihydro resveratrol, trans-resveratrol-the 3-O-glucuronide, cis-resveratrol-3-O-glucuronide, cis-resveratrol-3-O-glucoside, trans-resveratrol-4 '-sulfuric ester, trans-resveratrol-3, the 5-di-sulfate, trans-resveratrol-3,4 '-di-sulfate, trans-resveratrol-3,4 ', 5-three sulfuric esters and trans-resveratrol-3-O-β-D-glucuronide and resveratrol aglycon and free trans-resveratrol.This method can comprise obtains biological sample from individuality, as urine, blood, saliva, tissue, feces, hair, skin etc., and the type of analytic sample to identify that sirtuin regulates the existing of chemical compound or its metabolite, sirtuin regulates chemical compound or its metabolite amount and/or sirtuin regulate chemical compound or its metabolite.Regulate the evaluation of chemical compound or its metabolite from the sirtuin in the biological sample, quantitatively with qualitative can the realization by the whole bag of tricks well known by persons skilled in the art, for example, immunoassay, chromatography, mass spectrography (MS), comprise liquid chromatograph (LC)-MS/MS, LC-ESI-MS/MS (electron spray ionisation, ESI), high performance liquid chromatography-diode array detector (HPLC-DAD) or online ultraviolet light photo photodiode array detection and Mass Spectrometer Method (LC-DAD-MS and LC-UV-MS-MS) are (referring to for example Wang etc., J.Chromatrogr B analyt TechnolBiomed Life Sci 829:97-106 (2005); Urpi-sarda etc., Anal Chem 77:3149-55 (2005); Wenzel etc., Mol Nutr Food Res 49:472-81 (2005); Wenzel etc., MolNutr Food Res 49:482-94 (2005); Wang etc., J Pharm Sci 93:2448-57 (2004); Meng etc., J Agric Food Chem 52:935-42 (2004); With Yu etc., Pharm Res 19:1907-14 (2002)).In some specific embodiments, extraction from biological sample before this method can be included in and analyze, purification or partial purification sirtuin regulator or its metabolite.In other specific embodiments, may need the standard substance of result and one or more known sirtui regulators or its metabolite are made comparisons.
In other specific embodiments, the invention provides and be used for identifying and be effective to regulate animal or human's class experimenter's the cell mitochondrial mass and/or the medicine of mitochondrial function, regulate the method (for example test is as screening test or high flux screening) of chemical compound as sirtuin.In some specific embodiments, the ability that the candidate medicine increases mitochondrial mass and/or improves mitochondrial function is screened.In an exemplary specific embodiments, method of the present invention can be used for identifying the medicine that increases mitochondrial mass in the cell and/or improve mitochondrial function, for example sirtuin activating compounds.
In a specific embodiments, be used to identify that the method for the medicine of regulating mitochondrial mass and/or function comprises that the sample that will contain mitochondrial cell contacts with the candidate medicine, and the level of definite at least a mitochondrial function index, the level of described index when not having this medicine wherein, the level that drug candidate has changed the mitochondrial function index shows that it is the medicine that changes mitochondrial function.
In another embodiment, be used to identify that the method for the medicine of regulating mitochondrial mass and/or function comprises that the intercrescence of evaluation mitochondrion becomes regulator.This method can be included in is enough to induce mitochondrion to give birth to synthetic condition and in the time, contact with stimulation with comprising mitochondrial cell; And the reformed level of detection candidate signaling molecule, wherein with respect to not with the level that stimulates the candidate signaling molecule in the contacted cell, having changed with the level of inducing mitochondrion to give birth to the candidate signaling molecule in the contacted cell of synthetic stimulation shows that this candidate signal molecule is that mitochondrion is given birth to synthetic regulator.At one more specifically in the embodiment, this stimulation is to be selected from cold stress, electricity irritation or adrenergic stimulation.In some other specific embodiments, the mitochondrion intercrescence becomes by measuring the mitochondrial function index to detect the amount that described mitochondrial function index is oxygen consumption, mitochondrial DNA, mitochondrial mass or the ATP biosynthesis factor.In some other specific embodiments, the activity of this candidate signal molecular regulation PGC gene or NRF gene.In some other specific embodiments, the candidate signaling molecule is regulated by PGC gene or NRF gene.In some other specific embodiments, the candidate signaling molecule level that changes is nucleic acid level, polypeptide level and protein phosphorylation level.
In some specific embodiments, the mitochondrial function index can be a mitochondrion electron transport chain enzyme.This method can comprise in the catalytic activity, working sample of detected electrons transfer chain enzyme in each mitochondrial enzymatic activity, the working sample amount of the proteinic enzyme of per unit in the amount of each mitochondrial enzyme in the amount of the proteinic enzymatic activity of per unit, detected electrons transfer chain enzyme, the working sample and/or the working sample.In some specific embodiments, mitochondrion electron transport chain enzyme comprises the subunit of at least a mitochondrion complex I, mitochondrion complex II, mitochondrion complex III, mitochondrion complex IV and/or mitochondrion complex V.Mitochondrion complex IV subunit can be COX1, COX2 or COX4, and mitochondrion complex V subunit can be ATP synthetase subunit unit 8 or ATP synthetase subunit unit 6.
In other specific embodiments, the mitochondrial function index can be mitochondrial matrix composition, mitochondrial membrane composition and/or mitochondrial inner membrane composition.The mitochondrial membrane composition can be adenylic acid transporter (ANT), voltage dependence anion channel (VDAC), malate aspartate shuttle approach, calcium uniport body, UCP-1, UCP-2, UCP-3 (Boss etc. for example, 2000 Diabetes49:143; Klingenberg 1999 J.Bioenergetics Biomembranes 31:419), hexokinase, periphery benzodiazepine
The Bcl-2 gene family of film creatine kinase, cyclophilin D (cyclophilin D), coded polypeptide, tricarboxylic ester carrier (tricarboxylate carrier) or dicarboxylic ester carrier (dicarboxylate carrier) between receptor, mitochondrion.
In some specific embodiments, the mitochondrial function index is the tricarboxylic acid cycle enzyme.This method can comprise in the catalytic activity of measuring the tricarboxylic acid cycle enzyme, the working sample in each mitochondrial enzymatic activity, the working sample in the proteinic enzymatic activity of per unit, the amount of measuring the tricarboxylic acid cycle enzyme, the working sample the proteinic enzyme amount of per unit in each mitochondrial enzyme amount and/or the working sample.The tricarboxylic acid cycle enzyme can be citrate synthetase, aconitase, Isocitrate dehydrogenase, ketoglurate dehydrogenase, succinic thiokinase, succinate dehydrogenase, fumarase or malic dehydrogenase.
In other specific embodiments, the mitochondrial function index can be the mitochondrial mass in each cell in the sample.Mitochondrial mass can be utilized mitochondrion selective reagent (as the nonyl acridine orange) or measure by the morphometric Analysis method.In some specific embodiments, the mitochondrial function index can be a mitochondrial quantity in each cell of sample, and it can utilize mitochondrion selective reagent such as fluorometric reagent to measure.
In other specific embodiments, the mitochondrial function index can be the amount of mitochondrial DNA (" mtDNA ") in each cell of sample.In each cell the amount of mitochondrial DNA can with absolute (for example amount of mtDNA in each cell) or relatively the term of (for example, examining the ratio of the mtDNA of DNA relatively) measure and/or represent.In some specific embodiments, mitochondrial DNA is by contact the biological sample that comprise mitochondrial DNA in condition and the time of primer and mitochondrial DNA hybridization with oligonucleotide primer being enough to allow, and described oligonucleotide primer has and be present in the complementary nucleotide sequence of the sequence in the mitochondrial DNA; And the hybridization of detection primer and mitochondrial DNA, and mitochondrial DNA is quantitatively measured.In some specific embodiments, the technology that the detection step comprises can be polymerase chain reaction, oligonucleotide primer elongation test, ligase chain reaction or restrictive fragment length polymerphism analysis.In some specific embodiments, mitochondrial DNA is by being enough to allow the condition of primer and mitochondrial DNA hybridization and in the time with oligonucleotide primer, contact comprises the sample of mitochondrial DNA of amplification, described oligonucleotide primer have with the mitochondrial DNA that is present in amplification in the complementary nucleotide sequence of sequence; And the hybridization of detection primer and mitochondrial DNA, and mitochondrial DNA is quantitatively measured.In some specific embodiments, the technology that the detection step comprises can be polymerase chain reaction, oligonucleotide primer elongation test, ligase chain reaction or restrictive fragment length polymerphism analysis.In some specific embodiments, the technology of the amplification mitochondrial DNA of use can be polymerase chain reaction, transcription amplification system or self-sustained sequence replication.In some specific embodiments, mitochondrial DNA is by being enough to allow the condition of primer and mitochondrial DNA hybridization and in the time with oligonucleotide primer, contact comprises the biological sample of mitochondrial DNA, and described oligonucleotide primer has and the complementary nucleotide sequence of sequence that is present in the mitochondrial DNA; And detect the hybridization of primer and mitochondrial DNA and extend preparing product, and mitochondrial DNA is quantitatively measured.In some specific embodiments, the contrast step comprise by with oligonucleotide primer in the condition that is enough to allow primer and mitochondrial DNA be hybridized with in the time, contact comprises the sample of the mitochondrial DNA of amplification, described oligonucleotide primer has and the complementary nucleotide sequence of sequence that is present in the mitochondrial DNA of amplification, and detect the hybridization of primer and mitochondrial DNA and extend preparing product, and mitochondrial DNA is quantitatively come the slotted line mitochondrial DNA.In some specific embodiments, the technology of employed amplification mitochondrial DNA can be polymerase chain reaction (PCR), comprise quantitatively and competitive PCR (Ahmed etc., BioTechniques 26:290-300,1999), transcription amplification system or self-sustained sequence replication.In some specific embodiments, the amount of mitochondrial DNA utilizes the oligonucleotide primer elongation test to measure in the sample.In other specific embodiments, the amount of mitochondrial DNA be by be attached to the labelled compound of measuring (for example bromination second pyridine) on the double-strandednucleic acid in the presence of, utilize the Palladous chloride. gradient to separate the DNA (referring to for example in sample from nuclear, Welter etc., Mol.Biol.Rep.13:17-120,1988) compare, and corresponding to the relative and/or absolute signal of mitochondrion and nuclear DNA and to measure.
In other specific embodiments, the mitochondrial function index is the ATP amount of each cell in the sample.This method can comprise each mitochondrial ATP amount in the measuring samples, the proteinic ATP amount of per unit in the measuring samples, the ATP of per unit mitochondrial mass amount in the measuring samples, the ATP amount in the per unit mitochondrial protein of measuring samples.In some specific embodiments, the mitochondrial function index is the synthesis rate or the ATP biosynthesis factor of ATP in the sample.This method can comprise the catalytic activity of measuring the ATP biosynthesis factor, each mitochondrial ATP biosynthesis factor active in the working sample, the ATP biosynthesis factor active of the per unit mitochondrial mass of working sample, the proteinic ATP biosynthesis of the per unit of working sample factor active, measure the quantity of the ATP biosynthesis factor, the proteinic ATP biosynthesis of the per unit factor quantity of the mitochondrial ATP biosynthesis of each of working sample factor quantity and/or working sample.
In other specific embodiments, the mitochondrial function index can be following one or more: free-radical generating, reactive oxygen species (reactive oxygen species), proteinic nitrosylation, proteinic carbonyl modification, the DNA oxidation, the mtDNA oxidation, protein oxidation, the protein carbonyl group modification, proteinic malonaldehyde adduct (adducts), saccharifying oxidation (glycoxidation product) product, lipid peroxidation product, 8 '-OH-guanosine adduct, BARS, the cell effect that calcium increases in the pair cell and/or to the cell effect of at least a antiapoptotic factors.In some specific embodiments, the mitochondrial function index is an oxygen consumption, and it can determine (for example, Wu etc., 1999 Cell 98:115 according to any multiple known method; .1999 J.Biol.Chem.274:17534 such as Li).
Functional mitochondrion comprises by the mitochondrial gene coding that is arranged in mitochondrial DNA (mtDNA) with by the gene outcome that is not positioned at the genomic mitochondrion alia gene of ringed line plastochondria (for example karyogene) coding.16.5kb the enzyme of mtDNA coding 22 tRNA, two kinds of ribosomal RNAs (rRNA) and 13 kinds of electron transport chains (ETC), described electron transport chain is meticulous many complexs mitochondrion assembly (assembly), for example breathes oxidative phosphorylation and occurs in here.Most mitochondrial 26S Proteasome Structure and Function protein are by extramitochondrial, and may be nuclear, coded by said gene in most cases.Therefore, mitochondrion and mitochondrion alia gene can pass through gene outcome and downstream intermediate thereof, comprise that metabolite, catabolite, substrate, precursor, cofactor etc. interact directly or indirectly.Because the combination of mtDNA defective, the outer DNA defective of mitochondrion, mitochondrion or mitochondrion alia gene product defective, downstream intermediate defective or these and other factor can cause the change of mitochondrial function, the for example active infringement of electron transport, oxidative phosphorylation defective or free radical generate and increase.
In some specific embodiments, a kind of enzyme provided by the invention is the mitochondrial function index.This enzyme can be a cyclophorase, and it can also be ETC enzyme or tricarboxylic acid cycle enzyme.This enzyme can also be the ATP biosynthesis factor, it can comprise as ETC enzyme provided by the invention and/or tricarboxylic acid cycle enzyme or other enzyme or with produce the relevant cell component of ATP." non-enzyme " is meant the mitochondrial function index (that is, it is not the cyclophorase provided by the invention or the ATP biosynthesis factor) that is not enzyme.In some other specific embodiments, enzyme is the corporate target (co-indicator) of mitochondrial function.Following enzyme may not be a mitochondrial function index of the present invention, but may be mitochondrial function corporate target provided by the invention: citrate synthetase (EC 4.1.3.7), hexokinase II (EC 2.7.1.1), cytochrome C oxidase (EC 1.9.3.1), phosphofructokinase (EC 2.7.1.11), glyceraldehyde phosphate dehydrogenase (EC 1.2.1.12), glycogen phosphorylase (EC 2.4.1.1), creatine kinase (EC 2.7.3.2), nadh dehydrogenase (EC 1.6.5.3), glyceraldehyde-3 phosphate dehydrogenase (EC 1.1.1.8), phosphotriose dehydrogenase (EC 1.2.1.12), and malic dehydrogenase (EC 1.1.1.37).
In other specific embodiments, the mitochondrial function indicator is calcium increases in the generation, pair cell of generation, mitochondrial mass or mitochondrion quantity, the free radical of any ATP biosynthesis factor, ATP cell effect and/or to the cell effect of antiapoptotic factors.In some specific embodiments, mitochondrial DNA content may not be the indicator of mitochondrial function, but may be the common forecast agent (predictor) of mitochondrial function provided by the invention or the common indicator of mitochondrial function.
I. enzyme mitochondrial function index
In some specific embodiments, be used for identifying that the method for the medicine of regulating mitochondrial mass and/or function comprises detection and/or definitely or relatively measure at least a mitochondrial function index of biological testing sample that wherein the mitochondrial function index is an enzyme.This kind of enzyme provided by the invention can be a cyclophorase or as the ATP biosynthesis factor of enzyme, for example ETC enzyme or tricarboxylic acid cycle enzyme.
" enzyme amount ", " enzymatic activity " or " expression of enzymes level " that relates at the relevant context that is used for identifying the method for the medicine of regulating mitochondrial mass and/or function is meant the amount, activity or the expression that comprise relevant any cyclophorase or amount, activity or the expression of the ATP biosynthesis factor; They can also comprise separately, for example amount, activity or the expression of the amount of ETC enzyme, activity or expression or tricarboxylic acid cycle enzyme.In the most preferred specific embodiments of the present invention, enzyme is albumen or the polypeptide with the natural of enzymatic activity or reorganization provided by the invention.As the example of indefiniteness, this kind of enzyme can be enzyme, holoenzyme, multienzyme complex, enzyme subunit, enzyme fragment, derivant or analog or or the like, comprise truncate, that handle or cracked enzyme.
The cyclophorase that can be used as the mitochondrial function index provided by the invention is meant the mitochondrial molecule composition with enzymatic activity and/or function, and it can influence the catalytic activity of enzyme as enzyme co-factor.Mitochondrion used in the present invention is made up of " mitochondrial molecule composition ", and it can be protein, polypeptide, peptide, aminoacid or derivatives thereof; Lipid, fatty acid or or the like, or derivatives thereof; Carbohydrate, sugar or or the like or derivatives thereof, nucleic acid, nucleotide (nucleotide), nucleoside (nucleoside), purine, pyrimidine or correlation molecule, or derivatives thereof, or or the like; Or the covalently or non-covalently compound combination of any of these composition or any other stable biomolecule or mitochondrial interim composition.
Can be used as the cyclophorase of mitochondrial function index provided by the invention or mitochondrial function corporate target, or the ATP biosynthesis factor that can be used as mitochondrial function index provided by the invention can comprise the ETC enzyme, it is meant any mitochondrial molecule composition, and it is the cyclophorase composition of mitochondrion electron transport chain (ETC) complex relevant with mitochondrial inner membrane and mitochondrial matrix.The ETC enzyme can comprise any many ETC subunit polypeptide by mitochondrion and nuclear gene encoding.The ubiquinone reductase), complex II (succinate dehydrogenase), complex III (ubiquinone: the cytochrome C oxidoreductase), complex IV (cytochrome C oxidase) and complex V (mitochondrial ATP synzyme) ETC is described to comprise complex I (NADH: usually, wherein each complex comprises that multiple polypeptides and cofactor are (for summary, referring to for example Walker etc., 1995Meths.Enzymol.260:14; Emster etc., 1981 J.Cell Biol.91:227s-255s, and the list of references of quoting).
Can be used as the cyclophorase of mitochondrial function index provided by the invention, the ATP biosynthesis factor that perhaps can be used as mitochondrial function index provided by the invention can also comprise the tricarboxylic acid cycle enzyme, it comprises that the mitochondrial molecule composition regulating the series of biologic chemical/biological be also known as tricarboxylic acid cycle or tricarboxylic acid cycle and can react is (referring to for example, Lehninger, Biochemistry, 1975 WorthPublishers, New York; Voet and Voet, Biochemistry, 1990 John Wiley ﹠amp; Sons, New York; Mathews and van Holde, Biochemistry, 1990 Benjamin Cummings, Menlo Park, Calif.).The tricarboxylic acid cycle enzyme comprises the subunit and the cofactor of citrate synthase, aconitase, Isocitrate dehydrogenase, ketoglurate dehydrogenase complex, succinic thiokinase, succinate dehydrogenase, fumarase and malic dehydrogenase.The tricarboxylic acid cycle enzyme also comprises the enzyme and the cofactor of getting in touch with the reacting phase of tricarboxylic acid cycle on the function, for example nicotinamide adenine dinucleotide, coenzyme A, diphosphothiamine, thioctamide, guanosine diphosphate (GDP), flavin adenine dinucleotide (FAD) and nucloside-diphosphate kinase.
Method of the present invention also partly relates to the dependency of type 2 diabetes mellitus and mitochondrial function index, and described mitochondrial function index can be the ATP amount of the ATP biosynthesis factor, variation or the ATP output that changes.For example, to reduce may be the mitochondrial function index that therefrom can determine to suffer from the danger of type 2 diabetes mellitus to the mitochondrial ATP biosynthesis.
" the ATP biosynthesis factor " is meant that ATP in the raising mitochondrion of any natural generation produces the cell component of efficient.Such cell component can be protein, polypeptide, peptide, aminoacid, or derivatives thereof, lipid, fatty acid or or the like, or derivatives thereof; Carbohydrate, sugar or or the like or derivatives thereof, nucleic acid, nucleotide (nucleotide), nucleoside (nucleoside), purine, pyrimidine or correlation molecule, or derivatives thereof, or or the like.No matter whether this ATP biosynthesis factor is the product of karyogene or dna extranuclear gene (for example mitochondrial gene), the ATP biosynthesis factor comprise at least ETC and tricarboxylic acid cycle composition (referring to for example, Lehninger, Biochemistry, 1975Worth Publishers, New York; Voet and Voet, Biochemistry, 1990 John Wiley ﹠amp; Sons, New York; Mathews and van Holde, Biochemistry, 1990 BenjaminCummings, Menlo Park, Calif.) and the synthetic protein of any participation ATP, enzyme or other cell component.Participate in ATP synthetic can comprise but need not be limited to: the transmembrane input of any reaction, ATP or enzyme co-factor that catalysis is synthetic relevant with ATP and/or output, the encode gene transcription of cyclophorase and/or the translation of this genetic transcription.
Determine that whether cell component is that the compositions and the method for the ATP biosynthesis factor is known in the art, and comprise method (comprising the ATP generating rate of determining in the sample) and ATP self quantitative methods of determining ATP and generating.The contribution that ATP biosynthesis factor pair ATP generates for example can utilize to be determined to the isolating ATP biosynthesis factor of cell or cell-free system adding.The ATP biosynthesis factor can be directly or is regulated indirectly and influence one in the biosynthesis pathway that ATP generates and go on foot or multistep.For example, the ATP biosynthesis factor can be the enzyme that catalysis causes the particular chemical reaction of ATP generation.In another example, the ATP biosynthesis factor can be to improve the cofactor of the efficient of this kind of enzyme.In another example, the ATP biosynthesis factor can be the exogenous genetic factor that is introduced into cell or cell-free system that directly or indirectly influences the ATP biosynthesis pathway.Those of ordinary skills can be easy to comparison when the ATP of the candidate biosynthesis factor exists and do not exist, the ATP that the ATP biosynthesis pathway produces.The conventional determining that ATP generates can utilize any known method that is used for the ATP detection by quantitative to finish, and for example is not limited to by enumerating explanation: by the method differential extraction from sample that randomly comprises chromatographic isolation; Spectrophotometry; From the ATP precursor molecule of the detectable labelling of contacted appropriate format, for example
32The ATP of the labelling that reclaims in the sample of P is also quantitative; To synthetic with ATP or the relevant enzymatic activity of degrading is quantitative; Or other technology known in the art.Therefore, in some specific embodiments of the present invention, the generation of ATP in the amount of the ATP in the biological sample or the biological sample (comprising the ATP generating rate) can be the mitochondrial function index.In a specific embodiments, for example, the fluorescence of luciferase that can be by measuring the oxidation of catalysis D-fluorescein comes ATP is carried out quantitatively, and this is a kind of ATP dependency method.
" enzymatic activity " is meant any function that realizes by at the certain enzyme or the class of enzymes of one or more specific cell functions.For example, " ATP biosynthesis factor catalytic activity " is meant any function that the ATP biosynthesis factor that generates by the ATP of helping provided by the invention is realized.Usually, enzymatic activity shows as by specific enzyme, and for example the enzyme as the ATP biosynthesis factor promotes chemical reaction, wherein at least a zymolyte or reactant by covalent modification to form product.For example, enzymatic activity can cause substrate or reactant to be modified because of the formation or the fracture of covalent chemical bond, but the present invention need not to be subjected to this restriction.The whole bag of tricks of measuring enzymatic activity is known and depend on tested given activity for those of ordinary skills.
For many enzymes, comprise cyclophorase provided by the invention or as the enzyme of the ATP biosynthesis factor, the quantitative criterion of enzymatic activity is set up well.These standards comprise for example can be by iu (IU), enzyme turnover rate, catalytic rate constant (K
Cat), Michaelis-Menten constant (K
m), given activity, be used to measure the defined activity of known in the art any other Enzymology method of at least a enzymatic activity level.Cyclophorase, for example the given activity of the ATP biosynthesis factor can with time per unit and optional further be that the detectable unit that is converted into the substrate of product represents in the per unit sample quality (for example per unit protein or per unit mitochondrial mass).
In some specific embodiments, enzymatic activity can be detectable with per unit total protein time per unit in the sample is the unit of the substrate of product by enzymatic conversion, in the sample per unit mitochondrial mass time per unit detectable be the unit of the substrate of product by enzymatic conversion, perhaps in the sample per unit mitochondrial protein quality time per unit detectable be that the unit of the substrate of product represents by enzymatic conversion.The product of enzymatic activity can be by depending on specific product amount and the proper method of physicochemical property detect.Therefore, can be not restricted to other proper method that actinometry method, colorimetry, spectrophotography, fluorimetry, immunoassay or mass spectrometric analysis method or those of ordinary skills understand easily and detect by for example illustrating.
In some specific embodiments, the detection of the product of enzymatic activity can directly be finished, and in some other specific embodiments, the detection of product can be by to substrate or reactant is introduced detectable indicating section or labelling is finished, for example marker enzyme, dyestuff, radionuclide, luminophore, fluorophor or biotin etc.After the reaction of enzyme analysis catalytic activity, the amount of the described labelling that exists in unreacted substrate and/or the product is to utilize to be applicable to that the method for specific detected indicating section or labelling determines.For the radioactivity group, radioactive nucleus decay monitoring, scinticounting, get close to that scintillation analysis (SPA) or autoradiography method normally be suitable for.For immunizing dose, the antibody that can prepare suitable labelling comprise for example have radionuclide, the antibody of fluorophor, affinity labeling, biotin or biotin simulated series (biotin mimetic sequences) or be prepared into antibody-enzyme conjugates antibody (referring to, Weir for example, D.M., Handbook ofExperimental Immunology, 1986, Blackwell Scientific, Boston; Scouten, W.H., Methods in Enzymology 135:30-65,1987; Harlow and Lane, Antibodies:ALaboratory Manual, Cold Spring Harbor Laboratory, 1988; Haugland, 1996Handbook of Fluorescent Probes and Research Chemicals-Sixth Ed., Molecular Probes, Eugene, Oreg.; Scopes, R.K., Protein Purification:Principles and Practice, 1987, Springer-Verlag, New York; Hermanson, G.T. etc., Immobilized Affinity Ligand Techniques, 1992, Academic Press, Inc., NewYork; Luo etc., 1998J.Biotechnol.65:225 and the list of references of quoting thereof).Spectrographic technique can be used for detecting dyeing (comprising, for example the colorimetric analysis product of enzyme reaction), luminophore and fluorophor.Biotin can utilize the Avidin or the Streptavidin that are coupled on the different indication groups (normally radioactivity or fluorophor or enzyme) to detect.Enzyme indication group usually can be by adding substrate (usually through one section special time), detects by spectrographic method, spectrophotography or to other analytical method of product then.The technology that utilization is known, standard substance and standard additive can be used for the enzymatic activity level in definite sample.
As mentioned above, the enzymatic activity of the ATP biosynthesis factor can also comprise other functional activity that causes ATP to generate, and not only relates to the activity of the covalency variation of substrate or reactant.For example illustrate and not as restriction, can be the transmembrane transport molecule as the ATP biosynthesis factor of enzyme, it promotes that by enzymatic activity metabolite moves between cell compartment.This metabolite can be ATP or relate to synthetic other cell component of ATP, as gene outcome and downstream intermediate thereof, comprise metabolite, catabolite, substrate, precursor, cofactor etc.As the example of another indefiniteness, no matter its enzymatic activity relates on the synthetic cell component of ATP to promote the synthetic mode of ATP to be attached to as the ATP biosynthesis factor of enzyme is instantaneous.This combination can for example be passed to cell component the conformation that another kind relates to the synthetic enzyme of ATP and/or changes cell component in the synthetic mode of promotion ATP.In addition, example hereto, the change of this conformation may be signal transduction path, allosteric activated channel, transcriptional activation approach or or the like a part, wherein the interaction between cell component causes ATP to generate.
Therefore, the ATP biosynthesis factor can comprise for example mitochondrial membrane albumen.The mitochondrial membrane albumen that is fit to comprises such as adenylic acid transporter (ANT; Fiore etc. for example, 1998 Biochimie80:137; Klingenberg 1985 Ann.New York Acad.Sci.456:279), (VDAC also is referred to as porin to voltage dependence anion channel; Manella for example, 1997J.BioenergeticsBiomembr.29:525), malate aspartate shuttle, mitochondrial calcium uniporter (for example, Litsky etc., 1997 Biochem.36:7071), uncoupling protein (UCP-1 ,-2 ,-3; Referring to for example, Jezek etc., 1998 Int.J.Biochem.Cell Biol.30:1163), hexokinase, periphery benzene phenodiazine
Film creatine kinase between receptor, mitochondrion, the Bcl-2 gene family of cyclophilin D, coded polypeptide, tricarboxylic ester carrier (tricarboxylate carrier) (for example, Iocobazzi etc., 1996 Biochim.Biophys.Acta 1284:9; Bisaccia etc., 1990 Biochim.Biophys.Acta 1019:250) and dicarboxylic ester carrier (dicarboxylate carrier) (for example, Fiermonte etc., 1998 J.Biol.Chem.273:24754; Indiveri etc., 1993 Biochim.Biophys.Acta 1143:310; For the comprehensive review of mitochondrial membrane transporter referring to for example, Zonatti etc., 1994J.BioenergeticsBiomembr.26:543 and the list of references of quoting thereof) the mitochondrion composition.
In the method that the present invention uses about evaluation mitochondrial mass and/or function regulator, the enzyme amount is meant the enzyme amount that comprises cyclophorase or the enzyme as the ATP biosynthesis factor provided by the invention, the perhaps another kind of ATP biosynthesis factor that exists, be selected, and do not consider the amount of the physical presence of the enzyme of enzymatic activity or the ATP biosynthesis factor as the mitochondrial function index.Physicochemical property according to the certain enzyme or the ATP biosynthesis factor changes the method for optimizing of determining the enzyme amount.In the most preferred specific embodiments of the present invention, the definite of enzyme amount can use the conventional method that those skilled in the art are easy to be familiar with in the protein chemistry, for example illustrate and be not limited to the method for following more write up, the level of coming quantitative assay protein or polypeptide.
Therefore, the definite of enzyme amount can adopt any proper method known in the art, it is used for the specific cells component quantifying as the enzyme provided by the invention or the ATP biosynthesis factor, and in preferred specific embodiments, described specific cells composition is protein or polypeptide.According to the kind and the physicochemical property of the enzyme or the ATP biosynthesis factor, the definite of enzyme amount can be undertaken by any other method of photodensitometry, mass spectrography, spectrophotography, fluorimetry, immunoassay, chromatography, electrochemistry or detection by quantitative specific cells composition.The method of determining the enzyme amount also comprises the said method of the product that is effective to detect enzymatic activity, comprises the method for direct measurement enzyme amount and measures the method for detectable labelling or indicating section.In some preferred specific embodiments, the enzyme amount is determined by the isolating enzyme of immunoassay or the ATP biosynthesis factor.In some preferred specific embodiments of the present invention, these and other immunity and the immunochemical technique that are used for quantitative assay biomolecule such as enzyme or the ATP biosynthesis factor can utilize the known various analysis of those of ordinary skills, include but not limited to that enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), fluorescent immune method, immunoprecipitation, equilibrium dialysis, immunodiffusion and other technology implement.(referring to for example, Harlow and Lane, Antibodies:A Laboratory Manual, Cold SpringHarbor Laboratory, 1988; Weir, D.M., Handbook of ExperimentalImmunology, 1986, Blackwell Scientific, Boston.).For example, this analysis can be implemented with the form of Western trace (blot), wherein from comprising of biological sample proteinic goods through gel electrophoresis, be transferred to suitable film and make it and have specific antibody response to enzyme or as the ATP biosynthesis factor of albumen or polypeptide.Utilize well known in the art and above-described suitable detectable to detect the existence of antibody on the film afterwards.
In some specific embodiments, comprise that for example the index of the mitochondrial function of enzyme provided by the invention (or corporate target) can exist with isolating form, for example from primal environment (for example, if the natural surroundings during natural the existence), separate.For example, the polypeptide of the natural generation that exists in the living animal is not isolating, is isolating but separate the phase homopolypeptide obtain in some or all the coexistence raw material from natural system.This peptide species can be the part of compositions, and because this compositions is not the part of its natural surroundings, it is isolating that polypeptide remains.
Purposes at the method according to this invention, affine technology is effectively in separation enzyme that context is mentioned or ATP biosynthesis factor protein or polypeptide, and affine technology can comprise utilizes the specificity combination that relates to the enzyme or the ATP biosynthesis factor to realize isolating any method.For example, because enzyme or ATP biosynthesis factor protein or polypeptide can comprise covalently bound oligose fragment, as under permission sugar and the bonded condition of agglutinin, the affine technology that enzyme (or ATP biosynthesis factor) is attached on the suitable immobilized agglutinin is a kind of effective especially affine technology.
Other effective affine technology comprises and is used for separating and/or (for example detects specific protein or polypeptide antigen, the enzyme or the ATP biosynthesis factor) immunological technique, this technology depends on the antigenic determinant that is present on the factor and the specificity combination between the antigenic antibody combining site.Antibody or other affinity reagent are " specific " with antigenic the combination, and the Ka that wherein this combination relates to is more than or equal to about 10
4M
-1, be preferably more than or equal about 10
5M
-1, more preferably more than or equal to about 10
6M
-1, and more preferably more than or equal to about 10
7M
-1Can utilize routine techniques at an easy rate in conjunction with the partner or the affinity of antibody, Scatchard etc. for example, the method described in the Ann.New YorkAcad.Sci.51:660 (1949) is determined.
Immunological technique includes but not limited to immunoaffinity chromatography, immunoprecipitation, solid-phase immunity absorption or other immune affine method.For these and other effective affine technology, referring to for example, Scopes, R.K., Protein Purification:Principles and Practice, 1987, Springer-Verlag, New York; Weir, D.M., Handbook of ExperimentalImmunology, 1986, Blackwell Scientific, Boston; And Hermanson, G.T. etc., Immobilized Affinity Ligand Techniques, 1992, Academic Press, Inc., California; It all incorporates the present invention into as a reference, and as the correlation technique of separating and characterize complex, comprises the particulars of affine technology.
As mentioned above, the mitochondrial function index can be protein or polypeptide, for example enzyme or the ATP biosynthesis factor.Protein or polypeptide can be the polypeptide of unmodified or can be polypeptide through post translational modification; for example by glycosylation, phosphorylation, fatty acidylate comprise the glycosylation phosphatidylinositols fix (anchor) modify or or the like, the hydrolysis of phosphide enzymatic lysis such as phosphatidylinositols-specificity phosphide enzyme c mediation or or the like, modify behind the protein translation of protease cracking, dephosphorylation effect or any other type, as relate to the formation of covalent chemical bond or the modification of fracture.
Ii is as mitochondrial mass, mitochondrion volume or the mitochondrion quantity of mitochondrial function index
In some specific embodiments, the authentication method of regulating the medicine of mitochondrial mass and/or function comprises at least a mitochondrial function index that detects and/or measure in the biological test sample, and wherein this mitochondrial function index is absolute or relative mitochondrial mass, mitochondrion volume or mitochondrion quantity.
The quantitative approach of mitochondrial mass, volume and/or mitochondrion quantity is known in the art, and can comprise for example quantitative dyeing of representational biological sample.Typically, mitochondrial quantitative dyeing can be used organelle selective probe or dyestuff, include but not limited to the mitochondrion selective reagent, as be attached to the fluorescent dye (for example nonyl acridine orange, MitoTrackers) of mitochondrial molecule composition or accumulate in the mitochondrion potential measurement dyestuff (referring to for example as the function of mitochondrial inner membrane electrochemical potentials, Haugland, 1996 Handbook of Fluorescent Probes and ResearchChemicals, Sixth Ed., Molecular Probes, Eugene Oreg.) carries out.As another example, mitochondrial mass, volume and/or quantity can be by morphological analysis quantitative (for example, Cruz-Orive etc., 1990 Am.J.Physiol.258:L148; Schwerzmann etc., 1986 J.CellBiol.102:97).These or mitochondrial mass, volume and/or quantitative any other method of mitochondrion quantity that is used for sample known in the art all are in the scope of consideration of the present invention.For example, this quantitative determination process that is used to calculate mitochondrion density is considered, but does not have a mind to as restriction.In some specific embodiments, the mitochondrion albumen quality is to use the method known to measure in the sample.For example, those of ordinary skills can be easy to use the cell separation technology of having set up to prepare isolating mitochondrion component from biological sample, thereby use any multiple proteins quantitative approach well known in the art to determine protein content.
Iii. the mitochondrial function index that comprises mitochondrial DNA content
In other specific embodiments, the method of identifying the regulator of mitochondrial mass and/or function comprises detection and/or measures at least a mitochondrial function index in the biological test sample that wherein this mitochondrial function index is the absolute or relative amount of mitochondrial DNA.Quantitatively can finishing of mitochondrial DNA (mtDNA) content by any multiple known technology that is effective to this purpose, include but not limited to oligonucleotide probe hybridization or use polymerase chain reaction (PCR) with the specific oligonucleotide primer of mtdna sequence (referring to for example Miller etc., 1996 J.Neurochem.67:1897; Fahy etc., 1997 Nucl.Ac.Res.25:3102; U.S. Patent application No.09/098,079; Lee etc., 1998 Diabetes Res.Clin.Practice 42:161; Lee etc., 1997Diabetes 46 (suppl.1): 175A).A kind of special effective method is the primer extension test of Fahy etc. (Nucl.AcidsRes.25:3102,1997) and Ghosh etc. open (Am.J.Hum.Genet.58:325,1996).The method that suitable hybridization conditions can find or use those of ordinary skills to know in the list of references of quoting, make variation (referring to for example according to the oligonucleotide probe of specific nucleic acid target spot and selection, Ausubel etc., Current Protocols in MolecularBiology, Greene Publishing, 1987; Sambrook etc., Molecular Cloning:ALaboratory Manual, Cold Spring Harbor Press, 1989).
Come the example of other effective technology of the amount of the specific nucleic acid target sequence (for example mtDNA) that exists in the working sample to comprise based on the specific hybrid of primer and target sequence: the specific amplification of target nucleic acid sequence and amplified production quantitatively, include but not limited to polymerase chain reaction (PCR, Gibbs etc., Nucl.Ac.Res.17:2437,1989), the transcription amplification system (for example, Kwoh etc., 1989 Proc.Nat.Acad.Sci.86:1173), strand displacement amplification (for example, Walker etc., Nucl.Ac.Res.20:1691,1992; Walker etc., Proc.Nat.Acad.Sci.89:392,1992) and (3SR of self-sustained sequence replication system, referring to for example, Ghosh etc., in Molecular Methods for Virus Detection, 1995 Academic Press, New York, pp.287-314; Guatelli etc., Proc.Nat.Acad.Sci.87:1874,1990), its list of references of quoting is all introduced the present invention as a reference.Other effective amplification technique comprises for example ligase chain reaction (for example, Barany, Proc.Nat.Acad.Sci.88:189,1991), the test of Q-β replicative enzyme (Cahill etc., Clin.Chem.37:1482,1991; Lizardi etc., Biotechnol.6:1197,1988; Fox etc., J.Clin.Lab.Analysis 3:378,1989) and cycling probe technology (for example, Cloney etc., CHn.Chem.40:656,1994), and the known method that other are fit to of those skilled in the art.
The sequence length of primer extension test product or any known method that is used for the characterisation of nucleic acids sequence size that molecular weight can utilize those skilled in the art to be familiar with are measured.In a specific embodiments, primer extension product characterizes by gel electrophoresis.In another embodiment, primer extension product characterizes by mass spectrum (MS), and it can also comprise analysis of substance assistant laser desorpted ionized/flight time (MALDI-TOF) or other MS method well known by persons skilled in the art.Referring to for example, United States Patent(USP) Nos. 5,622,824,5,605,798 and 5,547,835.In another embodiment, primer extension product characterizes by liquid phase or gas chromatogram, and it can also comprise high performance liquid chromatography (HPLC), gas chromatography-mass spectrum (GC-MS) or other chromatographic process of knowing.
Iv. the cell effect that increases as calcium in the pair cell of mitochondrial function index
Because relevant with detection and/or slotted line plastochondria functional parameter, some aspect of the present invention relates to the dynamic equilibrium of monitor intracellular Ca2+ and/or to disturbing the cell effect of this dynamic equilibrium, comprises the calcium adjusting of physiological and Pathophysiology.Cell effect to the intracellular Ca2+ that increases is in extensive range, and is the same as the scope of method that is used to detect this reaction and reagent.Many specific cell reactions are known for those of ordinary skills; The particular cell types that exists in the biological sample of selection is depended in these reactions.Example as indefiniteness, the cell effect of the intracellular Ca2+ that increases is comprised that exocytosis, glycogen metabolism and the cell proliferation of the secretion of specific secretory product, specific preformed composition increase (referring to for example, Clapham, 1995 Cell 80:259; Cooper, The Cell-AMolecular Approach, 1997 ASM Press, Washington, D.C.; Alberts, B., Bray, D., etc., Molecular Biology of the Cell, 1995 Garland Publishing, New York).
As concise and to the point background, the normal variation of calcium is regulated relevant (Dykens, 1998 in Mitochondria ﹠amp with homergy in the mitochondrion; Free Radicals in NeurodegenerativeDiseases, Beal, Howell and Bodis-Wollner, Eds., Wiley-Liss, New York, pp.29-55; Radi etc., 1998 in Mitochondria ﹠amp; Free Radicals in NeurodegenerativeDiseases, Beal, Howell and Bodis-Wollner, Eds., Wiley-Liss, New York, pp.57-89; Gunter and Pfeiffer, 1991, Am.J.Physio.27:C755; Gunter etc., 1994, Am.J.Physiol.267:313).For example, the level fluctuation of mitochondrion free calcium may be to utilize the reason that increases and regulate oxidative metabolism at ATP, this is that allosteric by enzyme is regulated (by Crompton etc., 1993 Basic Res.Cardiol.88:513-523 summarize) and phosphoglycerol shuttles back and forth, and (Gunter etc. 1994J.Bioenerg.Biomembr.26:471) realize.
The NM function comprises by holding back excessive calcium in (sequestration) mitochondrial matrix regulates the level of free calcium in the Cell sap.According to cell type, calcium concentration is generally 50-100nM in the Cell sap.In normally functioning cell, when calcium level reaches 200-300nM, mitochondrion begins to assemble, and the performance balance goes into and pass through the effusive function of calcium of sodium dependency and sodium dependent/non-dependent calcium carrier by the calcium current of the calcium uniport body in the mitochondrial inner membrane.In some instances, no matter whether calcium regulatory function obstacle is the reason or the result of mitochondrial function, and the destruction of this intracellular Ca2+ dynamic equilibrium is the feature with mitochondrial function diseases associated (as type 2 diabetes mellitus).
Therefore, as mentioned above, the mitochondrial calcium level that increases can be assembled because of free calcium in the Cell sap begins to raise.This mitochondrial calcium concentration that increases reduces in conjunction with ATP or has with mitochondrion pathology
Other disease can cause the mitochondrial inner membrane current potential destruction (referring to, Gunter etc., 1998 Biochim.Biophys.Acta 1366:5; Rottenberg and Marbach, 1990, Biochim.Biophys.Acta1016:87).Outer (Cell sap) calcium level of mitochondrion can be used as the individual risk factor of suffering from type 2 diabetes mellitus than the level height that exists in the mitochondrion in the biological sample.With regard to type 2 diabetes mellitus, mitochondrion or Cell sap calcium level can be from above-mentioned range changings, and its scope can be for example approximately 1nM more be typically about 10nM to about 100mM to about 500mM, and be typically about 20nM to about 1mM, wherein " approximately " represent+/-10%.The polycalcium index is arranged in known this area, include but not limited to, for example fura-2 (McCormack etc., 1989 Biochim.Biophys.Acta 973:420); Mag-fura-2; BTC (U.S. Patent No. 5,501,980); Fluo-3, fluo-4 and fluo-5N (U.S. Patent No. 5,049,673); Rhod-2; Benzothiaza-1; And benzothiaza-2 (all these can be from Molecular Probes, Eugene, Oreg buys).According to the method for the present invention that is used to identify the type 2 diabetes mellitus risk, these of monitoring intracellular Ca2+ or any other method will be considered.
In order to monitor the mitochondrial function index of conduct to the cell effect of the intracellular Ca2+ of increase, inducing increases Cytoplasm and mitochondrial calcium, the chemical compound that comprises Calcium ionophore concentration is well known to those of ordinary skill in the art, the method of measuring calcium in intracellular Ca2+ and the mitochondrion also is so (referring to for example, Gunter and Gunter, 1994 J.Bioenerg.Biomembr.26:471; Gunter etc., 1998Biochim.Biophys.Acta 1366:5; McCormack etc., 1989 Biochim.Biophys.Acta 973:420; Orrenius and Nicotera, 1994 J.Neural.Transm.Suppl.43:1; Leist and Nicotera, 1998 Rev.Physiol.Biochem.Pharmacol.132:79; And Haugland, 1996 Handbook of Fluorescent Probes and Research Chemicals, Sixth Ed., Molecular Probes, Eugene, Oreg.).Therefore, according to disclosed content at once and the method known, those skilled in the art can easily select to be used for the suitable ionophore (or the another kind of chemical compound that causes Cytoplasm and/or mitochondrial calcium ion concentration to raise) of this aspect and detect in the cell and/or the proper method of calcium in the mitochondrion.
As if calcium ionic current gone into mitochondrion and depended primarily on, and may depend on fully at mitochondrial inner membrane and stride membrane electrochemical nagative potential (DY) by what electron transport was set up, and when lacking DY in addition the calcium concentration gradient that applies 8 times of amounts all can't produce this inflow (Kapus etc., 1991 FEBS Lett.282:61).Therefore, when transmembrane potential exhausted, as uncoupling agents occurring as 2, during right-three fluoro-methoxybenzene hydrazones (FCCP) of 2, 4-dinitrophenol and carbonyl cyanide, mitochondrion can discharge calcium.Therefore, according to some specific embodiments of the present invention, the destruction of DY may be reinforced because of Cell sap free calcium inflow line plastochondria, as comprising situation about occurring under the experimenter's who suffers from 2 type DM the physiological situation that cell met with at some.Can realize by several different methods provided by the invention this destructive detection.
Typically, mitochondrial membrane potential can be determined according to the method that those skilled in the art are familiar with easily, include but not limited to detect and/or measure detectable chemical compound, as fluorescence indicator, light probe and/or susceptiveness pH and ion-selective electrode (referring to for example, Ernster etc., 1981 J.CellBiol.91:227s and the list of references of quoting thereof; Also referring to Haugland, 1996 Handbook ofFluorescent Probes and Research Chemicals, Sixth Ed., Molecular Probes, Eugene, Oreg., pp.266-274 and 589-594).For example, by way of example the explanation but not as the restriction, fluorescent probe 2-, 4-dimethylamino styryl-N-picoline salt (DASPMI) and tetramethyl rhodamine ester (tetramethylrhodamine esters) (for example, tetramethyl rhodamine methyl ester TMRM; Tetramethyl rhodamine ethyl ester (TMRE) or related compound (referring to, Haugland for example, 1996, the same) can in mitochondrion, assemble the back by quantitative, this be a kind of depend on mitochondrial membrane potential and with the proportional method of mitochondrial membrane potential (referring to for example, Murphy etc., 1998 inMitochondria ﹠amp; Free Radicals in Neurodegenerative Diseases, Beal, Howell and Bodis-Wollner, Eds., Wiley-Liss, New York, pp.159-186 and the list of references of quoting thereof; And the Molecular ProbesOn-line Handbook of Fluorescent Probes and Research Chemicals on the probes.com/handbook/toc.html of World Wide Web).But other spendable fluorescence detection compound includes but not limited to rhodamine 123, the own ester of rhodamine B, DiOC
6(3), JC-1[5,5 ', 6,6 '-tetrachloro-1,1 ', 3,3 '-tetraethylbenzene imidazoles carbocyanine iodide are (referring to Cossarizza etc., 1993 Biochem.Biophys.Res.Comm.197:40; Reers etc., 1995Meth.Enzymol.260:406), rhod-2 is (referring to U.S. Patent No. 5,049,673; All aforesaid compounds can be from Molecular Probes, Eugene, Oreg buys) and rhodamine 800 (Lambda Physik, GmbH, Gottingen, Germany; Referring to Sakanoue etc., 1997J.Biochem.121:29).The method that is used to monitor mitochondrial membrane potential is also at U.S. Patent application No.09/161, and is open in 172.
Mitochondrial membrane potential can also pass through non-fluorescent method, for example by using TTP (tetraphenyl phosphine ion) and TTP-sensitive electrode (Kamo etc., 1979J.Membrane Biol.49:105; Porter and Brand 1995Am.J.Physiol.269:RI213) measure.But those skilled in the art can select suitable detection compound or other suitable method to be used to measure DYm.Explanation is and unrestricted by way of example, and TMRM is better than TMRE a little, because after flowing out from mitochondrion, the residual signal that TMRE produces in endoplasmic reticulum (endoplasmic reticulicum) and Cytoplasm is more more a little than TMRM.
As another nonrestrictive example, transmembrane potential can utilize substrate volume and/or pyridine nucleoside oxidimetry in conjunction with spectrophotography or fluorescent quantitation, the permeability of detectable charged solute is calculated in addition or selectivity calculates by the mitochondrion of indirect measurement.The substrate exchange diffusion of the dependent cross-line plastochondria of transmembrane potential inner membrance can also provide the indirect measurement of transmembrane potential.(referring to for example, Quinn, 1976, The Molecular Biology of Cell Membranes, University ParkPress, Baltimore, Md., pp.200-217 and the list of references of quoting thereof).
As mentioned above, because of causing calcium, the intracellular Ca2+ increase also can characterize type 2 diabetes mellitus in mitochondrial unusual accumulative high susceptibility.According to the present invention, this mitochondrion sensitivity can provide the mitochondrial function index.In addition, the reagent of being correlated with on the multiple physiology comprises that hydrogen peroxide and free radical can play destruction (Novgorodov etc., the 1991 Biochem.Biophys.Acta 1058:242s of synergism to induce DY with calcium; Takeyama etc., 1993 Biochem.J.294:719; Guidox etc., 1993Arch.Biochem.Biophys.306:139).
V. the mitochondrial function index that comprises the reaction of pair cell apoptotic stimulus
In another embodiment, identify that the method for mitochondrial mass and/or function regulator can comprise detection and/or slotted line plastochondria functional parameter, wherein mitochondrial function comprises apoptosis or apoptosis.In extensive range to the various known reactions that cause apoptotic stimulus is the same as the scope of method that is used to detect this reaction and reagent.
In the chain of events of the apoptosis that causes the various kinds of cell type, it is very crucial that mitochondria dysfunction is considered to.(Kroemer etc., FASEB J 9:1277-87,1995).Mitochondrion physiology can be in (Zamzami etc., J.Exp.Med.182:367-77,1995 in the initial stage incident of apoptosis; Zamzami etc., J.Exp.Med.181:1661-72,1995), and the raising of reactive oxygen species (ROS) level that is caused by this mitochondrial function may cause apoptosis cascade reaction (Ausserer etc., MolCell Biol 14:5032-42,1994).In some cell type, the reduction of mitochondrial membrane potential (DYm) is to take place before following the nuclear dna degradation of apoptosis.In cell free system, be rich in mitochondrion but not nuclear component can induce nuclear apoptosis (Newmeyer etc., Cell 70:353-64,1994).The confusion that causes the cellular metabolism state to change as improving the mitochondrial respiratory activity of ROS in the cell may betide in the type 2 diabetes mellitus, and may further induce pathogenic incident by apoptosis mechanism.
It is condensing that the mitochondrion of oxidative stress can discharge the energy induced chromosome, the preformed soluble factor (Marchetti etc., Cancer Res.56:2033-38,1996) of the incident before promptly a kind of apoptosis.In addition; the member of anti-apoptotic genes expression product B cl-2 family is the (Monaghan etc. that are arranged in mitochondrial outer membrane; J.Histochem.Cytochem.40:1819-25; 1992); and these albumen seem protecting film and avoid oxidative stress (Korsmeyer etc.; Biochim.Biophys.Act.1271:63,1995).As if the location of Bcl-2 on this film be very essential (Nguyen etc., J.Biol.Chem.269:16521-24,1994) to regulating apoptosis.Therefore, the physiological change of mitochondrion may be the important regulator of apoptosis.
Therefore, impaired can to show as the apoptosis-induced threshold value of one or more antiapoptotic factors lower for mitochondrial function.A lot of antiapoptotic factors are those skilled in the art's known (referring to for example, Green etc., 1998 Science 281:1309 and the list of references of quoting thereof), can comprise illustrating but unrestrictedly being: tumor necrosis factor-alpha (TNF-a); The Fas part; Glutamic acid; N-methyl-D-aspartate (NMDA); Interleukin-3 (IL-3); Antibiotic TAN 420F (Mancinit etc., 1997 J.Cell.Biol.138:449-469); N,N'-dimethyl-.gamma..gamma.'-dipyridylium (Costantini etc., 1995 Toxicology 99:1-2); Ethylene glycol; Kinases inhibitor, for example, star spore rhzomorph (staurosporine), calphostin C, CAPE, chlorination chelerythrine, genistein; 1-(5-isoquinolinesulfonylcompounds)-2-methyl piperazine; KN-93; N-[2-((right-bromo-cinnamyl) amino) ethyl]-5-5-isoquinolin sulfanilamide; D-erythro form nerve sheath saddle 01 derivatives; Ultraviolet radiation; Ionophore, for example ionomycin and valinomycins; Map kinase derivant, for example anisomycin, N-arachidonic acid ethylaminoethanol; The cell cycle blocker, for example aphidicolin (aphidicolin), Colchiceinamidum, 5-fluorouracil, homoharringtonine; Acetylcholinesteraseinhibitors inhibitors, for example berberine; Anti-estrogens, for example tamoxifen; Prooxidant, for example tert-butyl peroxide, hydrogen peroxide; Free radical, for example nitric oxide; Inorganic metal ion, for example cadmium; DNA synthetic inhibitor, for example actinomycin D; DNA intercalator, for example amycin, Bleomycin Sulphate, hydroxyurea, methotrexate, ametycin, camptothecine, daunorubicin; Protein synthesis inhibitor, for example cycloheximide, puromycin, rapamycin; Influence the medicine of tubulin formation or stability, for example vinblastine, vincristine, colchicine, 4-hydroxy phenyl dimension methylamine (4-hydroxyphenylretinamide), paclitaxel (paclitaxel); Bad albumen, Bid albumen and Bax albumen (referring to, Jurgenmeier etc. for example, 1998 Proc.Nat.Acad.Sci.USA95:4997-5002 and the list of references of quoting thereof); Calcium and inorganic phosphate (Kroemer etc., 1998Ann.Rev.Physiol 60:619).
In a specific embodiments, wherein the mitochondrial function index is the reaction of cell to antiapoptotic factors, can just carry out can characterizing the detection of the variation of apoptotic state about morphology, permeability and other in apoptotic cells under a cloud in the biological sample.For example, illustrate but be not limited to, the apoptosis of the cell of many types can change morphologic outward appearance, as: plasma membrane bubbles, cell shape changes, the matrix adhesive capacity is lost and other those of ordinary skills for example can be easy to detected metamorphosis by optical microscope.As another example, at the apoptotic cells chromosome fracture and decomposition can appear just, and these phenomenons are by microscope and/or by using the DNA specificity of fluorescent dye or the specific dyestuff of chromatin of comprising known in the art to observe clearly.These cells also can show the variation of plasma membrane permeability, and this can be by adopting vital stain (for example propidium iodide, trypan blue) or detecting lactic acid dehydrogenase and detect to the extracellular environment seepage.For those skilled in the art, these and other by morphological criteria, permeability of cell membrane change and associated change to detect apoptotic method be conspicuous.
In another embodiment, wherein the mitochondrial function index is the reaction of cell to antiapoptotic factors, can analyze to outer field transposition effect from the internal layer of plasma membrane the cell membrane phospholipid acyl serine (PS) in the cell of biological sample, this transposition effect can detect (Martin etc. with outer field combination of cell membrane by for example measuring Phosphatidylserine specific proteins annexin, J.Exp.Med.182:1545,1995; Fadok etc., J.Immunol.148:2207,1992.).In another embodiment, to the cell/biochemical reaction of antiapoptotic factors be by analysis be called as that any member's the activity inducement of specific protease of the apoptosis activated protein enzyme family of Caspase determines (referring to, for example, Green etc., 1998 Science 281:1309).Those of ordinary skills should be easy to be familiar with the active assay method of Caspase, for example by measuring the splitting action to the protein substrate of specific recognition of Caspase mediation.These substrates can comprise, for example poly--(adenosine diphosphate (ADP)-ribose) polymerase (PARP) and other by the cracked naturally occurring or synthetic polypeptide of Caspase known in the art and protein (referring to, for example, Ellerby etc., 1997 J.Neurosci.17:6165).Synthetic peptide substrates (Kluck etc., 1997 Science 275:1132 have been defined; Nicholson etc., 1995 Nature 376:37).The example of other indefiniteness of substrate comprises nucleoprotein, as U1-70kDa and DNA-PKcs (Rosen and Casciola-Rosen, 1997 J.Cell.Biochem.64:50; Cohen, 1997 Biochem.J.326:1).
As mentioned above, mitochondrial inner membrane can show the selectivity of height and to the adjusting of the permeability of many micromolecule solutes, but macromole (less than about 10kDa) can not pass through.(referring to, for example, Quinn, 1976 The Molecular Biology of Cell Membranes, University Park Press, Baltimore, Md.).Yet in carrying out apoptotic cells, the destruction of mitochondrial membrane potential may be accompanied by the raising of permeability, makes macromole pass through mitochondrial membrane through diffusion.Therefore, in another specific embodiments of the inventive method, wherein the mitochondrial function index is the reaction of cell to antiapoptotic factors, detect mitochondrial protein, for example the cytochrome C of revealing from the mitochondrion of apoptotic cell can provide foundation for the reaction to antiapoptotic factors, and this is easy to determine.(Liu etc., Cell86:147,1996).The method that the detection of this pair cell pigment C can adopt spectrophotography, immunochemical method and other mensuration specific protein of having set up to exist.
For example, can adopt panimmunity method pair cell pigment C to follow the trail of from the release that is subjected in apoptotic stimulus (for example, ionomycin, a kind of Calcium ionophore of the knowing) stimulated cells.Because can distinguish both according to the molecular weight of the uniqueness of apo-cytochrome C and complete-cytochrome C, so substance assistant laser desorpted/ionization flight time (MALDI-TOF) mass spectrum combines with affinity capture and is very suitable for carrying out this analysis.For example, (Ciphergen, Palo Alto Calif.) can be used for detecting cytochrome c and discharge from the mitochondrion of the cell of antiapoptotic factors processing in surface-enhanced laser parsing/ionizing (SELDI) system.In this method, the cytochrome c specific antibody is fixed on and is used for catching the d/d cytochrome c that exists in the soluble cell extract on the solid support.Bag is adopted pulse laser to excite captive albumen is got off from the solid support surface desorbing by captive albumen in the substrate of energy absorption molecule (EAM) then.Proteic molecular weight can be determined by its flight time of flying to the mass spectrometric detector of SELDI.
Those of ordinary skills are easy to recognize can also have other to be suitable for the quantitative technology of apoptosis, these be used to measure with cell to the reaction of short apoptotic stimulus as the technology of mitochondrial function index also within the scope of method provided by the present invention.
Vi. with the generation of free radical as the mitochondrial function index
In some specific embodiments, be used for identifying that the method for the regulator of mitochondrial mass and/or function comprises the generation of detection of biological sample as the free radical of mitochondrial function index.Although mitochondrion be free radical in the biosystem main source (referring to, Murphy etc. for example, 1998 inMitochondria and Free Radicals in Neurodegenerative Diseases, Beal, Howell and Bodis-Wollner, Eds., Wiley-Liss, New York, pp.159-186 and the list of references of quoting thereof), method of the present invention should not be restricted yet, and no matter is to derive from special subcellular location, and the generation of free radical still can be used as the index of mitochondrial function.For example, this area has known most the interior biochemical route of the cell that causes free radical to form, they are to generate metabolite by the enzymatic reaction by the oxidase, superoxide dismutase or the nitric oxide synthetase that connect as flavin, as hydrogen peroxide, nitric oxide or superoxide radical, the method that detects these free radicals also be known in the art (referring to, Kelver for example, 1993 Crit.Rev.Toxicol.23:21; Halliwell B. and J.M.C.Gutteridge, Free Radicals in Biology and Medicine, 1989 ClarendonPress, Oxford, UK; Davies, K.J.A. and F.Ursini, The Oxygen Paradox, CleupUniv.Press, Padova, IT).Mitochondrial function goes wrong as any step in the electron transport chain, all may cause the generation of highly active free radical.As mentioned above, the free radical that produces owing to mitochondrial function comprises reactive oxygen species (ROS), for example, and superoxides, peroxynitrite and hydroxyl radical free radical, and other may the toxigenous potential active substance of pair cell.Therefore, in some specific embodiments, the mitochondrial function index can be the detectable free radical material that is present in the biological sample.In some specific embodiments, detectable free radical is ROS.
The detection method that can effectively be used as the free radical of mitochondrial function index is known in the art, and depends on concrete free radical.Usually, the level of free-radical generating can be measured according to the method that those skilled in the art are familiar with easily in the biological sample, includes but not limited to detect and/or measure: the glycosylation oxidation product that comprises pentose element (pentosidine), carboxymethyl-lysine and pyrrolin; The lipid oxidation products that comprises Biformyl, malonaldehyde and 4-hydroxyl nonenyl aldehyde; Thiobarbituricacid active substance (TBARS; Referring to, Steinbrecher etc. for example, 1984 Proc.Nat.Acad.Sci.USA81:3883; Wolff, 1993 Br.Med.Bull.49:642) and/or according to other chemical detection method measure, as (for example, Ghiselli etc., 1998 Meths.Mol.Biol.108:89 of catching of Salicylate to hydroxyl radical free radical; Halliwell etc., 1997 Free Radic.Res.27:239) or the formation of specificity adduct (referring to for example Mecocci etc., 1993 Ann.Neurol.34:609; Giulivi etc., 1994 Meths.Enzymol.233:363), comprise generation, the protein nitrosylation of malonaldehyde, the DNA Oxidation that comprises the mitochondrial DNA oxidation, 8-hydroxyl guanosine adduct (Beckman etc. for example, 1999 Mutat.Res.424:51), protein oxidation, protein carbonylation are modified (Baynes etc. for example, 1991 Diabetes 40:405; Baynes etc., 1999 Diabetes 48:1); Electron spin resonance (ESR) probe; Cyclic voltammetry; Fluorescence or chemiluminescent indicator (also referring to, Greenwald for example, R.A. (ed.), Handbook of Methods for Oxygen Radical Research, 1985 CRCPress, Boca Raton, Fla.; Acworth and Bailey, (eds.), Handbook of OxidativeMetabolism, 1995 ESA, Inc., Chelmsford, Mass.; Yla-Herttuala etc., 1989J.Clin.Invest.84:1086; Velazques etc., 1991 Diabetic Medicine 8:752; Belch etc., 1995 Int.Angiol.14:385; Sato etc., 1979 Biochem.Med.21:104; Traverso etc., 1998 Diabetologia 41:265; Haugland, 1996 Handbook of Fluorescent Probesand Research Chemicals-Sixth Ed., Molecular Probes, Eugene, Oreg., pp.483-502, and the list of references of quoting).For example, illustrate but be not limited to, fluorescent probe dichloro-dihydro fluorescein diacetate and carboxylic acid derivates carboxyl dichloro-dihydro fluorescein diacetate thereof (referring to, Haugland for example, 1996, the same) oxidation product in cell, assemble the back quantitatively, this process depends on the existence of reactive oxygen species, and with the reactive oxygen species that exists proportional (also referring to, Molecular Probes On-line Handbook of Fluorescent Probes and ResearchChemicals for example, World Wide Web: probes.com/handbook/toc.html).Other detectable fluorescent chemicals that can be used for free radical generation detection of the present invention includes but not limited to: dihydro rhodamine and dihydro rhodamine derivant, cis-octadecane tetraenoic acid, the known suitable chemical compound of resorufin derivant, lucigenin and other those skilled in the art.
Therefore, also as mentioned above, the damage of free radical mediated may make one or more inactivations in the countless protein of electron transport chain, may disclose the chemiosmotic mechanism that mitochondrion is responsible for oxidative phosphorylation and ATP generation like this.As the mitochondrial function functional parameter of the ATP biosynthesis factor, comprise that mensuration ATP is created on the present invention more detailed elaboration is arranged.Free radical mediated to the destruction of a mitochondrial function integrity example of the number of mechanisms relevant just with mitochondrial function, described mitochondrial function may cause the electrochemical potentials kept by mitochondrial inner membrane destroyed.
In another embodiment, the invention provides the method that treatment may be benefited from the individuality of mitochondrial mass increase and/or increased functionality.This method can comprise the patient who at first determines to suffer from mitochondria dysfunction.The above-mentioned method that is used to identify the medicine of regulating mitochondrial mass and/or function also is used for affirmation can benefit from that mitochondrial mass increases and/or the individuality of increased activity.For example, said method can be used to measure from the mitochondrial mass and/or the function of the biological sample of body one by one, and compare with the standard predetermined value of another individuality (individuality that for example, has NM quality and/or function), control population or mitochondrial mass and/or function.
IV. pharmaceutical preparation and give mode
Can adopt one or more physiologically acceptable carrier or excipient according to pharmaceutical composition used in the present invention, prepare with any conventional method.Therefore, sirtuin activation and suppress on chemical compound and their physiology acceptable salt and solvate and can be mixed with by following approach and give: for example injection (for example subcutaneous injection, intramuscular injection, lumbar injection), suck or be blown into that (through port or nose), oral, buccal, gastrointestinal tract are outer, Sublingual or rectum give.In a kind of specific embodiments, chemical compound is a topical, i.e. target cell position, adipose cell place for example.
Chemical compound can be mixed with the needs that are suitable for multiple administered dose, comprises that whole body gives to give with part or zone.Technology and prescription usually can be at Remmington ' s Pharmaceutical Sciences, Meade Publishing Co., and Easton finds among the PA.Give for whole body, be preferably injection, comprise intramuscular injection, intravenous injection, lumbar injection, subcutaneous injection.With regard to injection, chemical compound can be mixed with liquid solution, is preferably buffer such as the Hank ' s solution or the Ringer ' s solution of physical compatibility.In addition, chemical compound also can be mixed with solid form, and dissolving or suspension more at once before use.In lyophilized form is also included within.
With regard to orally give, pharmaceutical composition can adopt for example tablet, lozenge (lozanges) or capsular form, use pharmaceutically acceptable excipient, as binding agent (for example, pregelatinized corn starch, polyvidon, hydroxypropyl emthylcellulose); Filler (for example, lactose, microcrystalline Cellulose or calcium hydrogen phosphate); Lubricant (for example, magnesium stearate, Pulvis Talci or silicon dioxide); Disintegrating agent (for example, potato starch or Explotab); Or wetting agent (for example, sodium lauryl sulphate) prepares by conventional method.Tablet can adopt methods known in the art to carry out coating.The liquid preparation that is used for orally give can adopt, the form of solution, syrup or suspension for example, perhaps they can be used as dry products and occur, before using with water or other carrier that is fit to preparation.These liquid preparations can be used pharmaceutically acceptable additive, for example suspending agent (for example, sorbitol syrups, cellulose derivative or hydrogenation edible fat); Emulsifying agent (for example, lecithin or arabic gum); Nonaqueous carrier (for example, ationd oil, grease, ethanol or fractionated vegetable oil); And antiseptic (for example, methyl or propyl group-right-hydroxybenzoate or sorbic acid) prepares with conventional method.If desired, preparation can also comprise buffer salt, flavoring agent, coloring agent and sweeting agent.The preparation that is used for orally give can also suitably be mixed with reactive compound is controllably discharged.
Polyphenols such as resveratrol can oxidations and lose the activity that stimulates sirtuin, when especially existing with liquid or semi-solid form.For anti-oxidation and keep the activity that the chemical compound that contains polyphenol stimulates sirtuin, can be stored in this chemical compound in the nitrogen or be sealed in a class capsule and/or every anoxybiotic foil packing (Capsugel for example
TM) in.
With regard to suction gives, adopt suitable propellant, for example dichlorodifluoromethane, Arcton 11, dichlorotetra-fluoroethane, carbon dioxide or other suitable gas, chemical compound can be exported from pressurized package or nebulizer easily with the form that aerosol spray is sent.With regard to pressurised aerosol, dosage unit can carry a certain amount of valve to determine by providing.When using inhaler or insufflator, the medicated bag of capsule and for example gelatin can be formulated into inclusion compound and the substrate powder that is fit to such as the mixture of powders of lactose or starch.
Chemical compound can be formulated into by injection, for example injects or lasting infusion carries out parenteral route and gives.Injection preparation can be made the form of the unit dose that adds antiseptic, for example in ampoule or in the container of multiple dose.Compositions can adopt as suspension, solution or be the form of the emulsion of carrier with oil or water, also can comprise the regulator as suspending agent, stabilizing agent and/or dispersant.Perhaps, active component can adopt powder type, uses suitable carriers before use, for example pyrogen-free sterilized water preparation.
Chemical compound can also be mixed with rectal compositions, as suppository or for example contain the enema,retention of conventional suppository bases such as cocoa butter or other glyceride.
Except that above-mentioned preparation, chemical compound can also be formulated into and store preparation (depot preparation).This durative action preparation can adopt the implantation (for example, subcutaneous or intramuscular) or the mode of intramuscular injection to give.Therefore, for example, chemical compound can come together to prepare with suitable polymeric or hydrophobic material (for example as the emulsion in the acceptable oil) or ion exchange resin, or makes the microsolubility derivant, for example makes slightly soluble salt.Controlled release form also comprises patch.
In some specific embodiments, pharmaceutical composition can adopt medical treatment device known in the art to give.For example, pharmaceutical composition of the present invention can adopt a kind of hypodermic injection unit of needleless to give, as United States Patent(USP) Nos. 5,399, and 163,5,383,851,5,312,335,5,064,413,4,941,880,4,790,824 or 4,596,556 disclosed devices.The example that is effective to implant of knowing of the present invention and module comprises: U.S. Patent No. 4,487, the 603 disclosed implantable little charge pumps that are used for distributing with controlled rate medicine; U.S. Patent No. 4., 486, the 194 disclosed therapy equipments that are used for transdermal administration; U.S. Patent No. 4,447, the 233 disclosed drug infusion pumps of carrying medicine with accurate infusion rates; U.S. Patent No. 4,447,224 disclosed persistence are carried the implantable device for casting of unsteady flow of medicine; U.S. Patent No. 4,439,196 disclosed penetrating pharmaceutical induction systems with multicell interval; And U.S. Patent No. 4,475,196 disclosed penetrating pharmaceutical induction systems.Certainly, also known many other such implants, induction system and module.
In some specific embodiments, chemical compound of the present invention can be mixed with and be used for carrying (Begley, Pharmacology ﹠amp to central nervous system (CNS); Therapeutics 104:29-45 summarizes in (2004)).The conventional method that is used to conduct drugs to the central nervous system comprises: neurosurgery method (for example, the intracerebral injection or ventricles of the brain perfusion); For the endogenous of inquiring into blood brain barrier transports the molecule manipulation (for example structure comprises the transportation peptide that has the affinity of surface epithelial cell molecule, and itself can't see through the chimeric protein of the medicine of blood brain barrier (BBB)) that path carries out medicine; Be used to improve the fat-soluble pharmacological method (for example water soluble drug being coupled to lipid or cholesterol carrier) of medicine; Utilize height to ooze the integrity (causing) of destruction (hyperosmotic disruption) momentary breakdown blood brain barrier by the bioactive substance that injects mannitol solution to carotid artery or use as angiotensin peptides.
A kind of possible method that continues release dynamics that reaches is with the reactive compound embedding or is encapsulated in the nano-particle.Nano-particle can give with powder, the mixture of powders that adds excipient or the form of suspension.The soliquid of nano-particle can be at an easy rate intubate by minor diameter give.
Nano-particle is that diameter is to the granule up to about 1000nm from about 5nm.Hereinafter used term " nano-particle " is meant the granule that reactive compound is scattered in the polymeric matrix and form, be referred to as " Nano microsphere " again, but also be meant the nano-particle of forming by the nuclear that contains reactive compound, described reactive compound is aggregated the thing film and surrounds, and is referred to as " nano-microcapsule " again.In some specific embodiments, the diameter of preferred nano-particle is that about 50nm arrives about 500nm, and especially approximately 100nm is to 200nm.
Nano-particle can or use ready-formed polymer to prepare by dispersive monomer in-situ polymerization.Because the polymer of in-situ preparing often is not biodegradable and/or contains supervirulent by-product, therefore preferably by ready-formed polymer manufacture nano-particle.Nano-particle by ready-formed polymer manufacture can prepare by different technology, for example emulsifying evaporation, solvent exchange, saltout, mechanical lapping, microprecipitation and emulsifying diffusion.
Based on said method, nano-particle can be by polytype polymer.With regard to the application of the inventive method, nano-particle is preferably prepared by biocompatible polymer.Term " biocompatible " is meant that introducing behind the biotic environment material does not have biotic environment and have a strong impact on.Especially preferably still biodegradable by those polymer that biocompatible polymer obtains.Term " biodegradable " be meant introduce behind the biotic environment material by enzymolysis or chemical degradation the micromolecule for being eliminated subsequently.Example is served as reasons as the polyesters of the hydroxy carboxylic acid formation of polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), the copolymer of lactic acid and glycolic (PLGA), the copolymer of lactic acid and caprolactone, poly-epsilon-caprolactone, poly butyric and poe, polyurethane, poly-anhydride, polyacetals, poly-dihydropyran, polybutylcyanoacrylate, natural polymer comprises dextran and cellulosic polysaccharide, collagen and albumin as alginate and other.
Suitable surface modifier is preferably selected from known organic and inorganic drug excipient.This excipient comprises various polymer, low-molecular weight oligo thing, natural product and surfactant.Preferred surface modifier comprises nonionic and ionic surfactant.The representational example of surface modifier comprises gelatin, casein, lecithin (phospholipid), arabic gum, cholesterol, the tragakanta, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, 18 hexadecanol, cetomacrogol emulsifying wax, sorbitan ester, polyoxyethylene alkyl ether, polyglycol ether for example, as cetomacrogol 1000 (cetomacrogol 1000), castor oil derivatives, the polyoxyethylene sorbitan fatty acid ester, for example commercially available Tweens, Polyethylene Glycol, Myrj 45, silica sol, phosphate, sodium lauryl sulphate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, methylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, noncrystalline cellulose, aluminium-magnesium silicate, triethanolamine, polyvinyl alcohol and polyvidon (PVP).Most of these surface modifiers all are the known drug excipient, and are being had a detailed description in the handbook of pharmaceutical excipients (Handbook of Pharmaceutical Excipients) of combined publication in 1986 by American Pharmaceutical Association (AmericanPharmaceutical Association) and Britain pharmaceutical society (The Pharmaceutical Society ofGreat Britain), Britain medicine publishing house (Pharmaceutical Press).
The write up of relevant preparation of nanoparticles can be in U.S. Patent No. 6,264, finds in 922, and its content is introduced the present invention as a reference.
Liposome is the delivery system that another kind is easy to inject.Therefore, in the method for the invention, reactive compound also can give with the form of liposome induction system.Liposome is well known to those skilled in the art.Liposome can be prepared by multiple phospholipid, as the stearmide of cholesterol, phosphatidylcholine.The liposome that can be used for the inventive method comprises all types of liposomees, includes but not limited to little unilamellar vesicle, big unilamellar vesicle and multilamellar vesicle.
Liposome can be used for multiple therapeutic purposes, arrives target cell especially for carrying medicine.The advantage of liposomal pharmaceutical preparation has been to provide the potentiality of improving drug delivery capability, and it for example comprises that controlled delivery of pharmaceutical agents discharges.Liposome arrives target area, target cell or target site usually needs longer circulation time.Especially in the time of near target area, target cell or target site are not giving the position, this is very important.For example, when liposome is a whole body when giving, the most handy hydroaropic substance bag is by liposome, for example bag by as the hydrophilic polymer chain of Polyethylene Glycol with the blood circulation time of prolongation liposome.The liposome of this finishing is commonly called the liposome of " long circulation " or " spatial stability ".
A kind of finishing to liposome is for connecting Polyethylene Glycol (PEG) chain, and it has the molecular weight from about 1000 dalton (Da) to about 5000 dalton (Da) as characteristics, and molar percentage be about 5% lipid composition liposome (referring to, for example, Stealth Liposomes, CRC Press, Lasic, D. and Martin, F., eds., Boca Raton, FIa., (1995) and the list of references quoted thereof).Compare with the liposome of non-surface modification, the pharmacokinetics nature and characteristic that this liposome shows is that liver and spleen are the dose dependency by mononuclear phagocyte system (MPS) to the picked-up of liposome and descend, and the blood circulation time significant prolongation, but not the liposome of surface modification then can be removed from blood and be built up at liver and spleen soon.
In some specific embodiments, complex is shielded to improve its circulating half-life or to improve nucleic acid to degraded, for example resistance of the degraded of nuclease.
Term " (shielding) of shielding " that the present invention uses and cognate " (shielded) of conductively-closed " thereof are meant that " masked segment " in vivo or external minimizing complex of the present invention and SC or be present in the ability of the non-specific interaction of other material in the serum.Masked segment can by one or more mechanism reduce complex and these materials interaction or with the combining of these materials, comprise for example non-specific space or non-specific electron interaction.This interactional example comprises non-specific electrostatic interaction, charge interaction, Van der Waals force, sterically hindered etc.For the part that works as masked segment, it can minimizing and the interaction of SC or other material, and it is clear and definite that contact or bonded mechanism are not necessarily wanted.People can be by determining that can complex combine with the serum material and bonded degree determines that can a part as masked segment.
It should be noted that " masked segment " can be multi-functional.For example, masked segment can also be as for example targeting factor.With respect to the mechanism of masked segment shielding complex, masked segment also can be called as multi-functional.Do not wish to be subjected to the mechanism or the theoretical limitation that have proposed, the example of this multi-functional masked segment is the endosome film rupture synthetic polymer (pH sensitive endosomalmembrane-disruptive synthetic polymers) of pH sensitivity, as PPAA or PEAA.Some poly-alkyl acrylic has demonstrated and can destroy the endosome film and the cell membrane of outer surface is kept perfectly (Stayton etc. (2000) J.Controll.Release 65:203-220; Murthy etc. (1999) J.Controll.Release61:137-143; WO 99/34831), thus improve the cell biological availability and bring into play the function of the targeting factor.Yet the complex that the PPAA minimizing is introduced into combines with SC, thereby performance is as the function of masked segment.
The another kind of sirtuin regulator of producing, as the preparation of resveratrol and derivant thereof, especially the method for solution is to utilize cyclodextrin.Cyclodextrin be meant α-, β-or gamma-cyclodextrin.Pitha etc. are in U.S. Patent No. 4,727, cyclodextrin are had a detailed description in 064, and it introduces the present invention as a reference.Cyclodextrin is the cyclic oligomeric body of glucose; The medicine that these chemical compounds and any its molecule are fit to enter the lipotropy cavity of cyclodextrin molecular forms clathrate.
Cyclodextrin in the compositions of the present invention can be α-, β-or gamma-cyclodextrin.Alpha-cyclodextrin comprises six glucopyranose units; Beta-schardinger dextrin-comprises seven glucopyranose units; Gamma-cyclodextrin comprises eight glucopyranose units.It is generally acknowledged that these molecules form truncated cone shape, α-, β-, gamma-cyclodextrin has the 4.7-5.3 dust respectively, the core opening of 6.0-6.5 dust and 7.5-8.3 dust.Compositions of the present invention can comprise two or more α-, β-or the mixture of gamma-cyclodextrin.Yet, typically, compositions of the present invention only comprise α-, β-or gamma-cyclodextrin in a kind of.
Most preferred cyclodextrin is amorphous cyclodextrin compound in the compositions of the present invention.Amorphous cyclodextrin is meant the noncrystalline mixture of cyclodextrin, wherein mixture be by α-, β-or gamma-cyclodextrin make.Usually, amorphous cyclodextrin is to be made through non-selective alkylated reaction by the cyclodextrin of required kind.The alkylating reagent that is fit to that is used for this purpose includes but not limited to: expoxy propane, (+)-2,3-Epoxy-1-propanol, iodoacetarnide, chloracetate and 2-lignocaine ethyl chloride.React to produce and contain multiple mixture of ingredients, thereby stop cyclodextrin crystallizationization.According to the kind and the alkylating agent of used initial cyclodextrin, can make various alkylation cyclodextrin, they naturally have difference.The amorphous cyclodextrin that is applicable to compositions of the present invention is hydroxypropyl, ethoxy, glucosyl group, malt-base and maltotriose radical derivative, Carboxylamide methyl-beta-schardinger dextrin-, carboxymethyl-beta-cyclodextrin, HP-and the diethyl amino group-beta-cyclodextrin of beta-schardinger dextrin-.
Marier etc., a dissolving resveratrol example when cyclodextrin exists is provided among the J.Pharmacol.Exp.Therap.302:369-373 (2002), its content is introduced the present invention as a reference, wherein with the resveratrol solution of 0.9% the saline preparation 6mg/mL that contains 20% HP-.
As mentioned above, the compositions of material of the present invention comprises the amorphous cyclodextrin of preferred replacement and the aqueous compositions of one or more sirtuin regulators.Effect to chemical compound changes the relative consumption of sirtuin regulator and cyclodextrin according to the relative quantity of various sirtuin regulators and cyclodextrin.Usually, the ratio as the weight of the weight of the chemical compound of sirtuin regulator and cyclodextrin is in 1: 1 to 1: 100 scope.The scope that is selected from the weight ratio of the chemical compound of sirtuin regulator and cyclodextrin is 1: 5 to 1: 50, and preferred scope is 1: 10 to 1: 20, it is believed that described ratio can be most effective to improve the cyclic utilization rate of sirtuin regulator.
Importantly, adopt parenteral route to give if comprise the aqueous solution of sirtuin regulator and cyclodextrin, especially by intravenous route, basic apyrogeneity pollutant in the cyclodextrin.Various forms of cyclodextrin, as amorphous cyclodextrin, can be from comprising Sigma-Aldrich, Inc. (buy for St.Louis, Mo. by a plurality of distributors USA).The production method of HP-is open in the U.S. Patent No. 4,727,064 of Pitha etc., and it introduces the present invention as a reference.
Can find in US2005/0026849 as other record of solubilising application of compound about cyclodextrin, its content is introduced the present invention as a reference.
Disintegrate or dissolved dosage form can be effective to the fast Absorption of pharmaceutically active substance rapidly, and especially oral cavity and Sublingual absorb.For swallowing classical solid dosage forms, as capsule sheet and inconvenient old age of tablet and pediatric patient, rapidly-soluble dosage form is favourable.In addition, but rapidly-soluble dosage form has been avoided the shortcoming relevant with for example chewable dosage forms, wherein plays a significant role in the degree of the retention time of active substance in disease population to the foreign bodies in the larynx sense (grittiness) of the amount of determining odor mask and the sustainable active medicine of patient.
For overcoming these problems, manufacturer has developed multiple rapidly-soluble solid orally ingestible.These preparations can be from comprising Cima Labs, Fuisz Technologies Ltd., Prographarm, R.P.Scherer, Yamanouchi-Shaklee and McNeil-PPC, and the manufacturer of Inc is buied.All these manufacturers sell dissimilar quick dissolved solid oral formulations.Referring to, for example patent of CimaLabs and publication, as U.S. Patent No. 5,607,697,5,503,846,5,223,264,5,401,513,5,219,574 and 5,178,878, WO 98/46215, WO 98/14179; The patent of FuiszTechnologies (being the part of BioVail now), as U.S. Patent No. 5,871,781,5,869,098,5,866,163,5,851,553,5,622,719,5,567,439 and 5,587,172; The U.S. Patent No. 5,464,632 of Prographarm; The patent of R.P.Scherer, as U.S. Patent No. 4,642,903,5,188,825,5,631,023 and 5,827,541; The patent of Yamanouchi-Shaklee, as U.S. Patent No. 5,576,014 and 5,446,464; The patent of Janssen, as U.S. Patent No. 5,807,576,5,635,210,5,595,761,5,587,180 and 5,776,491; EurandAmerica, the United States Patent(USP) Nos. 5,639,475 and 5,709,886 of Inc; The United States Patent(USP) Nos. 5,807,578 and 5,807,577 of L.A.B.PharmaceuticalResearch; The patent of Schering Corporation, as United States Patent(USP) Nos. 5,112,616 and 5,073,374; The U.S. Patent No. 4,616,047 of Laboratoire L.LaFon; Takeda Chemicals Inc., the U.S. Patent No. 5,501,861 of Ltd.; The U.S. Patent No. 6,316,029 of Elan.
In the example of preparation fast dissolving tablet agent, adopt the granule that is used for the fast dissolving tablet agent and the mixed with excipients of the preparation of spray drying method or preloading method, and utilize the conventional machine of producing tablet to be pressed into tablet.These granules can with variety carrier, comprise that low-density, high-mouldability saccharide, poor-compactibility saccharide, polyhydric alcohol combination are combined, directly be pressed into the dissolution that shows improvement and the tablet of disintegrative then.
Typically, tablet of the present invention has about 2 hardness to about 6 Strong-Cobb units (scu).The tablet of hardness in this scope be disintegrate or dissolving fast when chewing.In addition, tablet disintegrate fast in water.When not stirring, the tablet of typical 1.1 to 1.5 grams can disintegrate in average 1-3 minute.Fast like this disintegrate has promoted the conveying of active substance.
The granule that is used to prepare tablet can be the mixture of low-density alkali salt or carbohydrate for example.For example, the alkaline-earth metal salt mixture comprises the combination of calcium carbonate and magnesium hydroxide.Similarly, the fast dissolving tablet agent can prepared in accordance with the method for the present invention, and described method comprises uses A) spray-dired ultralight calcium carbonate/maltodextrin, B) magnesium hydroxide; And C) the eutectic polyhydric alcohol that comprises sorbitol instant, xylitol, mannitol makes up.These materials are very easy to dissolving through making up to prepare, and promote the quickly disintegrated low-density tablet of active component.In addition, the granule of compacting can be used in combination in same tablet with spray-dired granule in advance.
For rapidly-soluble tablet, effective sirtuin regulator can be the form as solid, microgranule, granule, crystal, oil or solution among the present invention.Being used for sirtuin regulator of the present invention can be spray-dired product or the adsorbate that has been pressed into the harder particle form that can reduce flavour of a drug in advance.Being used for medicinal active ingredient of the present invention can be with the carrier spray drying that prevents that active component from separating out easily when tablet is chewed.
Except being introduced directly into tablet of the present invention, medicine itself can be before making preparation be handled by the pre-stamped technology that is used to improve density.
Be used for the medicine material that pre-stamped technology of the present invention can be used for carrying indissoluble, so that improve the release of this medicine material with respect to conventional dosage forms.This can realize adopting lower dosage level to carry the biological available medicine of equivalent, thereby realizes the at present commercially available medicine and the lower toxic level of new chemical entities.The medicine material of indissoluble can adopt the form as the nano-particle of nano-scale particle.
The granule of making except active component with by low-density alkaline-earth metal salt and/or water soluble carbohydrates, the fast dissolving tablet agent can be adopted conventional carrier or excipient and the pharmaceutical technology known is prepared.Conventional carrier or excipient include but not limited to: diluent, binding agent, adhesive (being cellulose derivative and acrylic acid derivative), lubricant (being magnesium stearate or calcium stearate, vegetable oil, Polyethylene Glycol, Pulvis Talci, sodium laurylsulfate, polyoxyethylene monostearate), disintegrating agent, coloring agent, flavoring agent, antiseptic, sweeting agent and as the various raw materials of buffer, adsorbent.
Other record about the agent of preparation fast dissolving tablet sees for example U.S. Patent No. 5,939,091, and its content is introduced the present invention as a reference.
Pharmaceutical composition (comprising cosmetic formulations) can comprise percentage by weight from about 0.00001 to 100%, as from 0.001 to 10%, and perhaps one or more of from 0.1% to 5% chemical compound of the present invention.
In a specific embodiments, chemical compound of the present invention is added into and contains the topical carrier that is suitable for topical usually and comprise in the local administration preparation of any such material known in the art.Can select topical carrier that the compositions of desired form is provided, for example ointment, lotion, emulsifiable paste, microemulsion, gel, oil, solution or or the like, topical carrier can or derive from synthetic material by natural existence and form.Preferred carrier has no adverse effects to the active component in the topical formulations or other composition.The example that is used for suitable topical carrier of the present invention comprises water, pure and mild other nonpoisonous organic solvent, glycerol, mineral oil, silicone, vaseline, lanoline, fatty acid, vegetable oil, p-Hydroxybenzoate, wax class or the like.
Preparation can be colourless, tasteless ointment, lotion, emulsifiable paste, microemulsion and gel.
It is in the ointment that is generally semi-solid preparation of substrate with vaseline or other petroleum derivative normally that chemical compound can join.Just as is known to the person skilled in the art, employed special ointment base will provide optimal drug to carry, and other Ideal Characteristics, for example property of softening or the like preferably also are provided.The same with other carrier (carriers) or carrier (vehicles), ointment base should be inert, stable, non-irritating and nonsensitized.As described in the Remington ' s that quotes as the front face branch, ointment base can be divided into following four classes: greasing base, emulsifiable base, emulsion bases and water-soluble base.Greasing base comprises, for example the semi-solid Hydrocarbon in the fat of vegetable oil, animal origin, oil source.But the emulsifying ointment base, the absorbability ointment base that is otherwise known as contains seldom or moisture-free and comprising, for example sulphuric acid hydroxy stearic acid glyceride, anhydrous lanolin, hydrophilic vaseline.The Emulsion ointment base is Water-In-Oil (W/O) or oil-in-water (O/W) Emulsion, and comprises for example hexadecanol, glyceryl monostearate, lanoline and stearic acid.Exemplary water-soluble ointment agent substrate is prepared by different molecular weight polyethylene glycol (PEGs).In addition, more information can be with reference to the Remington ' s that above mentioned.
Chemical compound can join in the lotion, it typically is the preparation that is administered to skin surface without friction, and normally liquid or semi-solid preparation, is present in water or the alcohols substrate comprising the solid particle of active component.The normally solid suspension of lotion, and can comprise the liquid oiliness Emulsion of oil-in-water type.Because to use more fluid composition easier, lotion becomes preferred preparation when handling big body surface area.Usually need carry out broken subtly to the insoluble matter in the lotion.Usually contain suspending agent in the lotion obtaining dispersibility preferably, and be effective to the active component location and keep it and the chemical compound of contact skin, for example methylcellulose, sodium carboxymethyl cellulose or or the like.Be used for comprising and the blended propylene glycol of hydrophilic vaseline with the exemplary lotion that the inventive method is used, for example can be from Beiersdorf, (Norwalk Conn.) buys Inc., and trade mark is Aquaphor
RTM
Chemical compound can join normally heavy-gravity liquid or semi-solid Emulsion, is oil-in-water type or is in the emulsifiable paste of water-in-oil type.Emulsifiable paste matrix can be washed, and comprises oil phase, emulsifying agent and water.Oil phase is formed by vaseline with as the aliphatic alcohol of hexadecanol or octadecanol usually.Although not necessarily, the volume of water can surpass oil phase usually, and contains wetting agent usually.Described in Remington ' s, the emulsifying agent in the ointment is nonionic, anionic, cationic or amphoteric surfactant normally as previously mentioned.
Chemical compound can join normally by two kinds of immiscible liquid, in microemulsion stable, isotropic transparent dispersion on the thermodynamics of oil and water composition, its interfacial film by surfactant molecule is stablized (Encyclopedia of Pharmaceutical Technology (New York:Marcel Dekker, 1992), volume 9).For the preparation of microemulsion, surfactant (emulsifying agent), cosurfactant (co-emulsifier), oil phase, water all are necessary.Suitable surfactant comprises any surfactant that is effective to prepare Emulsion, for example is generally used for preparing the emulsifying agent of emulsifiable paste.Cosurfactant (or " co-emulsifier ") normally is selected from polyglycereol derivant, glycerol derivatives and aliphatic alcohol.Although dispensable, the combination of preferred solvent/co-emulsifier is selected from usually: glyceryl monostearate and Myrj 45, Polyethylene Glycol and Palmic acid glycol stearate, sad and tricaprin, oleoyl polyethyleneglycol glyceride.Water comprises that not only water also comprises usually: buffer, glucose, propylene glycol, Polyethylene Glycol; preferred low molecular poly (for example PEG300 and PEG400) and/or glycerol etc.; and oil phase generally comprises, for example the monoesters of the mixture of fatty acid ester, modified vegetable oil, silicone oil, single, double and triglyceride, PEG and dibasic acid esters (for example oleoyl polyethyleneglycol glyceride) etc.
Chemical compound can join in the gel preparation that is generally the semi-solid systems that comprises suspension of being made by little inorganic particulate (two-phase system) or the big organic molecule (single-phase gels) that is dispersed in liquid-carrier fully.The preparation single-phase gels can for example be passed through active component, liquid-carrier and suitable gellant, combine as tragakanta (2-5%), sodium alginate (2-10%), gelatin (2-15%), methylcellulose (3-5%), sodium carboxymethyl cellulose (2-5%), carbomer (0.3-5%) or polyvinyl alcohol (10-20%), and stir until generating characteristic semi-solid product.Other suitable gellant comprises methyl hydroxylated cellulose, polyoxyethylene-polyoxypropylene, hydroxyethyl-cellulose and gelatin.Though gel adopts aqueous liquid-carrier usually, alcohols and oils also can be used as liquid-carrier.
Various additive well known by persons skilled in the art also can be included in the preparation, for example in the topical formulations.The example of additive includes but not limited to, solubilizing agent, dermal osmosis accelerator, opacifier, antiseptic (for example antioxidant), gellant, buffer agent, surfactant (especially nonionic and amphoteric surfactant), emulsifying agent, softening agent, thickening agent, stabilizing agent, wetting agent, coloring agent, aromatic etc.Comprise solubilizing agent and/or dermal osmosis accelerator, and emulsifying agent, softening agent and antiseptic are particularly preferred.Best topical formulations comprises approximately: 2 weight % to 60 weight % are preferably solubilizing agent and/or the dermal osmosis accelerator of 2 weight % to 50 weight %; 2 weight % to 50 weight % are preferably the emulsifying agent of 2 weight % to 20 weight %; The softening agent of 2 weight % to 20 weight %; And the antiseptic of 0.01 weight % to 0.2 weight %, the remainder of preparation is by forming for active substance and carrier (for example water).
The effect of dermal osmosis accelerator is to promote to see through the demonstration treatment level of active substance in the not damaged skin zone of proper area.Suitable promoter is known in the art and comprises, low-grade alkane alcohol for example is as methanol, ethanol and 2-propanol; The alkyl methyl sulfoxide is as dimethyl sulfoxide (DMSO), decyl methyl sulfoxide (C
10MSO) and tetradecyl methyl sulfoxide; Ketopyrrolidine is as 2-Pyrrolidone, N-N-methyl-2-2-pyrrolidone N-and N-(ethoxy) ketopyrrolidine; Carbamide; N, the N-diethyl--toluamide; C
2-C
6The alkane glycol; Various solvents are as dimethyl formamide (DMF), N,N-dimethylacetamide (DMA), tetrahydrofurfuryl alcohol; And 1-substituted nitrogen heterocyclic cycloheptane-2-ketone, particularly 1-just-dodecyl-azepan-2-ketone (Laurel nitrogen
Ketone, from Whitby ResearchIncorporated, Richmond, Va. buys, and trade mark is Azone
RTM).
The example of solubilizing agent includes but not limited to following: the hydrophilic ethers, (ethyoxyl ethylene glycol is with Transcutol as diethylene glycol monoethyl ether
RTMSell) and the diethylene glycol monoethyl ether oleate (with Softcutol
RTMSell); The polyethylene castor oil derivative is as polyoxy 35 Oleum Ricini, polyoxy 40 hydrogenated castor wet goods; Polyethylene Glycol, especially low molecular poly, as PEG 300, PEG 400, and polyethyleneglycol derivative, as PEG-8 caprylic/capric glyceride (with Labrasol
RTMSell); The alkyl methyl sulfoxide is as DMSO; Ketopyrrolidine is as 2-Pyrrolidone and N-N-methyl-2-2-pyrrolidone N-; And DMA.Many solubilizing agents also can be used as absorption enhancer.Single solubilizing agent can be added in the preparation, perhaps the mixture of solubilizing agent can be added wherein.
Suitable emulsifying agent and co-emulsifier include but not limited to those emulsifying agents and the co-emulsifier mentioned in the description of relevant microemulsion.Softening agent comprises, for example propylene glycol, glycerol, isopropyl myristate, polypropylene glycol-2 (PPG-2) myristyl ether propionic ester etc.
Other active substance also can be included in the preparation, for example antiinflammatory, analgesic, antimicrobial, antifungal, antibiotic, vitamin, antioxidant and the sunscreen that exists in sun-screening agent usually, it includes but not limited to: anthranilic acid, benzophenone (especially benzophenone-3), carbomer derivant, cinnamate (for example octyl methoxycinnamate), DBM class (for example butyl methoxyl group DBM), para-amino benzoic acid (PABA) and derivant thereof, salicylate (for example ethylhexyl salicylate).
In some topical formulations, the scope of the amount that active component exists is about 0.25 weight % to 75 weight % of preparation, preferred range is about 0.25 weight % to 30 weight % of preparation, preferred scope is about 0.5 weight % to 15 weight % of preparation, and most preferred scope is about 1.0 weight % to 10 weight % of preparation.
The local skin treatment compositions can adopt suitable containers to pack to adapt to the application target of its viscosity and consumer.For example, lotion or emulsifiable paste can be packed with the aerosol device of bottle or ball-type spreader or propellant actuated or the container that is equipped with the pump that is fit to finger manipulation.When said composition is emulsifiable paste, can easily it be stored in the bottle or squeeze receptacle that can not be out of shape, as pipe or jar with cover.Compositions is also contained in the capsule, as U.S. Patent No. 5,063, described in 507.Therefore, the present invention also provides the hermetic container of the cosmetics acceptable composition that comprises the present invention's definition.
In another selectable specific embodiments, the pharmaceutical preparation that provides is used for oral or parenteral administration, wherein preparation can comprise the above-mentioned microemulsion that comprises activating compounds, and can comprise selectable pharmaceutically acceptablely, be particularly suitable for carrier (carriers), carrier (vehicles), additive of oral or parenteral administration etc.Perhaps, the microemulsion that contains activating compounds can modifiedly fully as mentioned above and not carry out oral or parenteral route gives.
After sirtuin activator or inhibitor give, can measure certain factor of experimenter, as measuring the activity of sirtuin.In an exemplary specific embodiments, after giving experimenter's activation or suppressing chemical compound, from the experimenter, obtain cell, as obtaining, in biopsy, determine activity or the sirtuin expression of sirtuin by biopsy.Perhaps, can follow the tracks of the detection of biological label, as the blood plasma biomarker.Cell can be any cell of experimenter, if but activating compounds is a topical administration, then preferred cell is to be positioned to give the position near cell.For example, cell can be an adipose cell.
V. exemplary test kit
The present invention also provides test kit, and for example test kit is used in treatment, comprises treatment or prevention dysbolismus, as obesity or diabetes, or the test kit of its secondary disease.Test kit can comprise the preparation of the sirtuin activator of one or more high doses, the sirtuin activator as described herein, and optional medicine and the contacted device of cell of being used for.Device comprises that syringe, support and other are used for the device that chemical compound is introduced the experimenter or is applied to experimenter's skin.
In addition, test kit can also comprise and be used to measure for example parts of the above-mentioned factor, and the described factor is as the proteic activity of sirtuin in the tissue sample for example.
Other test kit comprises that being used for diagnosis suffers from or develop into dysbolismus, as the test kit of the probability of obesity or diabetes or its secondary disease.Test kit can comprise the reagent that is used to measure sirtuin activity and/or expression.
The present invention also provides the test kit that is used to screen analysis.Exemplary test kit comprises one or more reagent that is used to screen analysis, for example sirtuin or its biological activity protein part, or cell or comprise their cell extract.Any test kit can also comprise operation instruction.
Description of the present invention is further set forth by following examples, and it should not be construed as the restriction of any way.The content of the list of references of all references (comprising the GenBank registration number that the patent of list of references, publication, disclosed patent application and the application quote in the whole text) is all introduced the present invention as a reference clearly.
Except as otherwise noted, all adopt cytobiology in the art technology, cell culture, molecular biology, genetically modified organism, microbiology, recombinant DNA, immunologic routine techniques in the operation of the inventive method.These technology have detailed explanation in the literature.Referring to, Sambrook for example, Fritsch and Maniatis (Cold Spring Harbor Laboratory Press:1989) editor's Molecular Cloning A Laboratory Manual, 2
NdEd.; DNA Cloning, Volumes Iand II (D.N.Glover compiles, 1985); Oligonucleotide Synthesis (M.J.Gait compiles, 1984); US Patent No such as Mullis: 4,683,195; Nucleic Acid Hybridization (B.D.Hames ﹠amp; S.J.Higgins compiles .1984); Transcription And Translation (B.D.Hames﹠amp; S.J.Higgins compiles .1984); Culture Of Animal Cells (R.I.Freshney, Alan R.Liss, Inc., 1987); Immobilized Cells And Enzymes (IRL Press, 1986); B.Perbal, A Practical Guide To Molecular Cloning (1984); Paper, and Methods InEnzymology (Academic Press, Inc., N.Y.); Gene Transfer Vectors ForMammalian Cells (J.H.Miller and M.P.Calos compile, and 1987, Cold Spring HarborLaboratory); Methods In Enzymology, Vols.154 and 155 (volume such as Wu); Immunochemical Methods In Cell And Molecular Biology (Mayer and Walker compile, Academic Press, London, 1987); Handbook Of Experimental Immunology, Volumes I-IV (D.M.Weir and C C.Blackwell compile, 1986); Manipulating theMouse Embryo, (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986).
Embodiment
The present invention has been done general description now, will be more readily understood the present invention with reference to the following examples, the purpose that the present invention comprises embodiment only is to illustrate some aspect of the present invention and the specific embodiment, is not to limit the present invention intentionally by any way.
Embodiment 1: the metabolic activity of sirtuin activator in diet induced obesity (DIO) mouse model
In order to determine whether the SIRT-1 activator prevents the development of fat and relevant insulin resistant, and the male C57BL6J mice of accepting high fat diet in 16 weeks for a long time gives resveratrol (sneaking into by food).Mice is carried out large-scale phenotype and the adjusting approach of analysis of molecules to determine influenced by the Sirt-1 activation.Referring to, the result shown in Figure 17-21 for example.
The result shows, mice is to having good tolerability as the food additive resveratrol, and do not cause anorexia.In this studies for a long period of time, 50 male C57BL6J mices (age was 5 weeks) have been carried out the analysis in 18 weeks by a definite date.10 animals are one group, are divided into following 5 groups:
1: normal diet
2: normal diet+resveratrol (200mg/kg/ days)
3: high fat diet
4: high fat diet+resveratrol (200mg/kg/ days)
5: high fat diet+resveratrol (400mg/kg/ days)
In whole research, per two weeks are monitored body weight and food intake dose.
In the 1st week, adopt double energy X-ray to absorb scanning method (dexascan) the health composition of all groups is analyzed.
In the 2nd week, serum glucose, triglyceride, cholesterol, HDL-C, low-density lipoprotein cholesterol and insulin level are measured in all group fasting after 12 hours, then with mice with shown in diet dispose (the 0th day).
In the 10th week, by allowing all animals received abdominal cavity glucose tolerance tests (IPGTT) determine glucose tolerance.Carry out before this experiment animal fasting 12 hours.
Measure the energy energy consumption at night of 1,3,5 group (normal diet, high fat diet, high fat diet 400mg) by indirect calorimetry.
In the 12nd week, once more the body weight of all groups is formed and adopted double energy X-ray absorption scanning method (dexascan) to analyze.
In the 13rd week, the circadian rhythm activity in 3,4,5 groups (high fat diets feed mices) 30 hours is studied.
In the 14th week, 3,4 and 5 groups blood pressures and heart rate are measured.
In the 15th week, measure the rectal temperature of all animals under the 10:00 room temperature in the morning.
In the 16th week, the part (n=5) of 3,4,5 treated animals is carried out oral glucose tolerance test (OGTT), another part animal (n=5) is carried out abdominal cavity insulin sensitivity test (IPIST) to analyze the toleration of glucose.In these experiments, also to collect the hemanalysis insulin level.Before these experiments, animal fasting 12 hours.
Collect the feces in 24 hours of all groups, measure the content of feces lipid.
In the 17th week, at the point in mornings 7 that begins corresponding to periodicity of illumination, measure the serum resveratrol level of a part of mice (n=5), (point in the mornings 10) measures another part mice (n=5) after three hours.In addition, measure the level of lipoprotein in the blood of the level of thyroxin T3 in the blood of 7 collections in morning and 10 collections in the morning.
In the 18th week, all animals are carried out cold experiment, promptly be exposed to 4 ℃ and measure animal heat down.
After three days, put to death animal.
During execution, collect blood and analysis: blood plasma lipide (T-CHOL (TC), triglyceride (TG), HDL-C (HDL-C), free fatty (FFAs)); Liver function (alanine aminotransferase (ALAT), aspartate transaminase (ASAT), alkali phosphatase, gamma glutamyl transpeptidase (γ-GT)); And selected group plasma glucose and insulin lipoprotein situation (size exclusion chromatography size-exclusion chomatography).
Collection liver, small intestinal, fatty tissue (white adipose is organized WAT and brown adipose tissue BAT), pancreas, heart and muscle is also weighed.Can adopt Histological method's (HE dyeing, succinate dehydrogenase dyeing, oil red O stain and morphocytology) of standard to analyze the lipid content of these tissues; By the mitochondrion in electronic microscope photos brown adipose tissue (BAT) and the muscle.Isolation of RNA is used to adopt that quantitative RT-PCR carries out to selected expression of gene research, and selected gene relates to the metabolism and the energy balance.Also can carry out the microarray experiment to selected tissue.In addition, can extract protein, as the variation of the acetylation (for example PGC-1 α) of destination protein with research protein level and post translational modification.Method
Animal feeding and processing.Standard according to European Union formulates in the zoo of control temperature (20-22 ℃) and humidity, had 12 hours: under the daily cycle of 12 hours (at 7:00) and the condition of specific-pathogen free, mice group is raised (5 animals/cage).Animal can freely drink water and take food.
Drinking water.Chemical composition to tap water is carried out periodic analysis, does not have Institut d ' Hydrologie, ULP, potential toxicant among the Strasbourg with proof.Adopt hydrogen chloride and perchloric acid that drinking water is handled, make its pH value maintain 5 to 5.5, cl concn is 5 to 6ppm.
Diet.The rodent normal diet of standard obtains from UAR, and high fat diet obtains from ResearchDiet.Feed mice with normal diet (protein 16%, fat 3%, fiber 5%, ash 5%) or high fat diet (protein 26.2%, carbohydrate 26.3%, fat 34.9%).Resveratrol is mixed with Powdered normal diet or Powdered high fat diet, make pelletizing again.Matched group is accepted the pelletizing that company provides.Because high fat diet is heavy-gravity, need not add water it is mixed with resveratrol.Again prepare than difficulty for normal diet, in powder, add low amounts of water and prepare pelletizing again and carry out air drying then.The food for preparing new lot weekly.
Blood sampling.From the eye retro-orbital sinus or from tail vein blood.
Anesthesia.Absorb the scanning experiment for double energy X-ray, the mixture that gives ketamine (200mg/kg)/Xylasine (10mg/kg) by lumbar injection is anaesthetized animal.
Biochemistry
Adopt commercial reagents (Olympus) on Olympus AU-400 automated laboratory work station, to experimentize.
The analysis of lipid and lipoprotein.Serum triglycerides, T-CHOL, HDL-C are to adopt enzymatic analysis to measure.(RocheDiagnostics, Mannheim Germany) measure the serum high-density LP content of cholesterol after the coprecipitation will to contain the lipoprotein of apo B and phosphotungstic acid/magnesium.The mensuration of free fatty acid levels is to utilize the test kit of Wako and carry out according to the explanation of producer.
The research of metabolism and endocrine aspect.Employing Medisense Precis electrode (AbbotLaboratories, Medisense products, Bedford, USA), by Precision Q.I.D analyser (Medisense system) analyzing blood concentration of glucose.By the numerical value of Precision Q.I.D analyser and more verified this method of classical glucose measurements is effective.Precision Q.I.D method is selected owing to need a spot of blood, therefore can be used to as taking multiple measurements in the abdominal cavity glucose tolerance test.(Crystal Chem, Chicago are to adopt the ELISA method to measure according to the explanation of manufacturer IL) to plasma insulin.The blood plasma level of T3 is to adopt the radioactive immunoassay (RIA) of standard to measure according to the scheme that manufacturer provides.
Metabolic test
The lipoprotein situation.By the situation of fast protein liquid chromatogram acquisition lipoprotein, wherein with the lipoprotein of three kinds of primary categories, very low density lipoprotein (VLDL), low density lipoprotein, LDL and high density lipoprotein are separately.
The experiment of abdominal cavity glucose tolerance experiment-oral glucose tolerance.IPGTT and OGTT carry out on the mice of (12 hours) fasting that spends the night.Adopt 20% glucose Sterile Saline (0.9%NaCl) solution, mice is carried out lumbar injection (IPGTT) or oral perfusion (OGTT) with the dosage of 2g glucose/kg body weight.Be monitoring glucose and insulin, before giving glucose solution and after 15,30,45,75,90,120,150,180 minutes, from tail vein blood.The incremental area of the glucose curve of calculating can be used as the measured value of insulin sensitivity, and corresponding insulin level is then represented the reserves of insulin secretion.
Abdominal cavity insulin sensitivity experiment.Iletin II (Lilly) (0.5-1.0IU/kg to fasting animal lumbar injection routine; Lilly, Indianapolis, IN).The blood sampling after 0,15,30,45,60,90 minute of injection back is with above-mentioned methods analyst glucose.Behind the insulin injection, the slope that descends in time with glucose is as the measured value of insulin sensitivity.
Energy expenditure.(Columbus Instruments, Columbus OH) measure oxygen consumption in 12 hours, promptly estimate energy expenditure by indirect calorimetry to utilize Oxymax equipment.This system is made up of the open loop that has the plastics cage (mice of each cage) that air can pass in and out.Animal can freely be taken food and drink water.If the air mass flow that enters in the cage is constant, then utilize a point-device carbon dioxide and oxygen sensor to measure the difference of oxygen and gas concentration lwevel in the air volume, promptly obtain the oxygen consumption in the certain hour.The data that obtain from this equipment show through coupled Computer Processing, analysis and with the form of exportable Excel document.Numerical value is with ml kg
-1h
-1Expression, promptly common known VO
2
Double energy X-ray absorption measurement method is measured body fat content.Dexa analysis employing ultrahigh resolution PIXIMUS Series Densitometer (0.18 * 0.18mm pixel, GE MedicalSystems, Madison, WI USA) carries out.(BMD is with g/cm to utilize PIXIMUS software (version 1.4x, GEMedical Systems) to measure the skeleton mineral density
2Represent) and the health composition.
Noninvasive blood pressure and heart rate measurement
Visitech BP-2000 analysis of blood pressure system is tail cover (tail cuff) system of computer controlled automatic, and this system is used under the situation that no operator intervene 4 clear-headed mices being taken multiple measurements simultaneously.The tail of mice is penetrated the tail cover, put into the independently darkroom on the platform of heating.This system measures blood pressure by measuring cover pressure, and the blood flow that enters afterbody here is eliminated.Photoelectric sensor detects the pulse of animal subject.The result that system produces shows that applicant (Applicant) has shown the intra-arterial average pressure of measuring at carotid artery with the while substantial connection is arranged.Can obtain repeatably systolic pressure and heart rate value like this.This need be to one week of animal training in this system.
The circadian rhythm activity
The mensuration of spontaneous autonomic activities will adopt independently chest (boxes), and each chest is made up of sliding floor, dismountable cage, and is equipped with infrared grabber and is used for measuring the activity and the back leg of walking about stand (rears).(Imetronic, Pessac France) link to each other chest with computer to utilize electronic interface.Mice is carried out 32 hours experiment, to measure habituation and the activity in night and daytime of mice to this equipment.Experimental session uses automatic lickometer to measure the water yield that consumes.
The metabolic activity of sirtuin activator in the embodiment 2:Zucker diabetes rat model
Give Zucker lipogenous diabetes rat (ZOF/Gmicrl-fa/fa) 2 (accumulated dose 400mg/kg/ days) oral resveratrols every day (200mg/kg), metformin (200mg/kg), both combination (each 200mg/kg) or carrier (2% Tween 80 10ml/kg) reaches 42 days.8 rats of every group of use (six ages in week, 190+10g).Animal carried out the oral glucose tolerance experiment, and (glucose dosage was 2g/kg, and PO) fasting before is 24 hours at the 43rd day.Collect blood sample in afterwards 90 minutes of glucose load (glucoseload) (fasting glucose) 35 minutes before and oral glucose load (oral glucose load) from the posterior orbit hole.Measure serum level of glucose by Hitachi Model 750 automatic analyzers.This result of experiment is seen Figure 23.Equally body weight and the food intake through every day of 43 days proves no difference of science of statistics between 4 groups.In addition, also indifference between four groups the fasting blood glucose level (the 8th, 15,22,29,36,43 day).
Embodiment 3: the biochemistry and the histologic analysis of the obesity of diet induced (DIO) mouse model
The obesity that causes diet induced in the mice that is described in according to the foregoing description 1.The mice that adds the raising of 400mg/kg/ days resveratrols (HF+R400) with control diet (C), high fat diet (HF) or high fat diet is carried out biochemistry and histologic analysis (referring to embodiment 1).
Figure 24 represents that the body weight change of carrying out as the description of above-mentioned embodiment 1 is tested, food ration is tested and body fat content result of experiment.Adopt control diet (C), control diet to add resveratrol (C+R400), high fat diet (HF) or high fat diet in 400mg/kg/ days and add 400mg/kg/ days resveratrol (HF+R400) nursing 9 weeks of mice.The upper left side shows the body weight change curve chart through the mice of four diet groups of 9 time-of-weeks.The upper right side shows the curve chart of four diet groups with the mice food ration of expression in kcal/24 hour.The below has shown the comparison at the mice body fat content of four diet groups utilizing the analysis of double energy X-ray absorption scanning method the 9th week of treatment.Numerical value is represented with meansigma methods ± standard error of mean (SEM n=10).BAT is brown adipose tissue (lower right); InguinalWAT is a groin white adipose tissue (lower left); Retroperitoneal WAT is white adipose tissue behind the peritoneum (middle below); The result demonstrates significant difference (p value).
Figure 25 represents to add with control diet (C), high fat diet (HF) or high fat diet the serum biochemistry analysis result of 400mg/kg/ days resveratrols (HF+R400) nursing 16 week back animals.The numerical value that shows is based on the average measurement value of 10 animals in each diet group.The level of T-CHOL, HDL-C, low-density lipoprotein cholesterol, triglyceride, free fatty, aspartate transaminase (ASAT), alanine aminotransferase (ALAT) and alkaline phosphate (ALP) all adopts standard method to measure.ASAT, ALP and ALAT are by dynamic ultraviolet and color experiment measuring, and the method to the recommendation of OlympusAU-400 automated laboratory work station based on International Federation of Clinical Chemistry (IFCC) has been used in above-mentioned experiment.Utilize the OSR6109 reagent system quantitative to AST, this system is based on the transamination generation L-glutamic acid of AST catalysis aspartic acid and 2-oxoglutaric acid and the activity of oxaloacetic acid.Oxaloacetic acid is reduced to L MALIC ACID by malic dehydrogenase subsequently, causes NADH to be converted into NAD.Because the consumption of NADH, the absorption value that 340nM measures down descends and is proportional with the AST activity in the sample.Utilize the OSR6107 reagent system quantitative to ALT, this system is based on ALT 2-oxoglutaric acid is arrived in the transamination of alanine, generates the activity of acetone acid and glutamic acid.Acetone acid is reacted by lactic acid dehydrogenase catalysis then, causes NADH to be converted into NAD.AST is the same with measuring, and in the consumption of the measuring N ADH of 340nm place, the active amount of ALT is proportional in itself and the sample.Measure ALP by measuring p-nitrophenyl phosphate to the conversion ratio of paranitrophenol (pNP).Because the generation of pNP is carried out the bitintability measurement at the 410/480nM place to absorbing rate of change, the ALP activity is directly proportional in this rate of change and the sample.The value of all serum biochemistry labels of each diet group is all in range of normal value.
Figure 26 and 27 shows the h and E dyeing to the liver of the animal that adds 400mg/kg/ days resveratrol (HF+R400) 16 weeks of nursing with control diet (C), high fat diet (HF) or high fat diet, epididymis white adipose tissue (WAT), brown adipose tissue (BAT) and gastrocnemius part.Tissue is fixed with 4% paraformaldehyde after collecting, and handles and paraffin embedding before section (10 microns) and dyeing.The dyeing of the h and E of organized processing, paraffin embedding, tissue slice and tissue slice all adopt the program of standard and be purchased reagent carry out (referring to, for example McManus J.F.A. and Mowry, R.W., Staining Methods.Histologic andHistochemcial, Harper and Row, New York 1960; Luna L.G., HitopathologicalMethods and Color Atlas of Special Stains and Tissue Artifacts, JohnsonPrinters, Downers Grove, IL 1992; Gabe M., Techniques histologiques.Masson, Paris 1968; And the statlab.com of World Wide Web).As shown in the figure, not observing the histology in any tissue of different diet groups changes.
Figure 28 has shown and has carried out the painted result of succinate dehydrogenase to add 400mg/kg/ days resveratrol (HF+R400) brown adipose tissue and the muscular tissue (musculus soleus and gastrocnemius) of feeding the mice after 16 weeks with high fat diet (HF) or high fat diet.Succinate dehydrogenase is the label of mitochondria activity, produces black-dyeing in photo.Collection organization, freezing in methybutane immediately, then the section and dyeing before-80 ℃ of preservations.Succinate dehydrogenase dyeing be adopt standard method and be purchased that reagent carries out (referring to, for example Reichmann H and Wildenauer D, Histochemistry, 96:251-3 (1991)).As shown in figure 28, accept high fat diet add 400mg/kg/ days resveratrol (HF+R400) the brown adipose tissue of mice and the succinate dehydrogenase dyeing of gastrocnemius tissue obviously darker, explanation is after giving resveratrol, and mitochondria activity is stronger in these tissues.On the contrary, accept high fat diet (HF) and high fat diet add 400mg/kg/ days resveratrol (HF+R400) the succinate dehydrogenase dyeing of musculus soleus tissue of mice in do not observe variation.
Figure 29 has shown that the gastrocnemius of feeding the mice in 16 weeks with control diet (C), high fat diet (HF) or the higher fatty acid 400mg/kg/ of adding days resveratrol (HF+R400) diet amplifies 10,000 and 20,000 times result through the transmitted electron fibrescope.Transmission electron microscope adopts the standard method operation that describes below.The Z-shaped line of darker rectangle of the leap I shape line that can see is a mitochondrion.As shown in the figure, add the mice that the mice comparison of feeding of 400mg/kg/ days resveratrols (HF+R400) feeds according to diet or high fat diet with high fat diet and contain more mitochondrion.
Figure 30 shows that adding the mice brown adipose tissue in 400mg/kg/ days resveratrol (HF+R400) 16 weeks of nursing with control diet (C), high fat diet (HF) or high fat diet amplifies 4,000 and 20,000 times result through transmission electron microscope.Transmission electron microscope adopts the standard method operation that describes below.Can observe under two kinds of amplifications and present white or light grey particulate lipochondrion, more high-amplification-factor can be observed the mitochondrion that presents round striated structure down.High fat diet adds the resveratrol domesticated animal and contains less lipochondrion (last figure) and more mitochondrion (figure below).
The preparation of transmission electron microscope microscopy/sample: in the biopsy of gastrocnemius and brown adipose tissue, slice thickness 1mm uses Karnovsky fixative (glutaraldehyde is dissolved in dimethyl arsenic acid buffer liquid) fixing, 4 ℃ of preservations, no time limit immediately after the sampling.Second step was to fix 1 hour after 4 ℃ of following Osmic acid .s that are dissolved in 0.1M dimethyl arsenic acid buffer liquid with 1% carry out.To organize then by successive gradient ethanol (graded alcohol) bath and the bath of expoxy propane afterwards and dewater, handle with the mixture of expoxy propane and resin then, again it is embedded in after 48 hours, change under 60 ℃ solid pure epoxy resin (epoxy resin, Epon812) in.Be cut into the thick semithin section Toluidine blue staining of 2 μ m, utilize optical microscope to carry out histologic analysis.Be cut into the thick ultrathin section of 70nm and form contrast, with Philips 208 electron microscope examinations with uranyl acetate and lead citrate.
Figure 31 shows the level that adds the Sirtl mRNA that measures in mice brown adipose tissue, liver and the muscle of the nursing of 400mg/kg/ days resveratrols (HF+R400) with control diet (C), high fat diet (HF) or high fat diet.Shown in numerical value be based on the meansigma methodss of 6 animals in each diet group.Numerical value is to represent with respect to house-keeping gene 18s and with respect to normal diet (being customized for 1) form.The relative expression of gene be utilize Sybrgreen incorporation (
Roche Applied Science, Indianapolis IN) is undertaken by real-time quantitative PCR.Protein expression level and protein active have also been measured.Separate the liver nuclear extract by the SDS-polyacrylamide gel electrophoresis, utilize the specificity one of Sirtl to resist then (the anti-Sir2 of rabbit igg,
Biotechnology, Lake Placid NY) carries out immunoblotting to determine protein expression level.With liver nuclear extract and anti--PGC1 Alpha antibodies (PGC1 H300:sc-13063; Santa CruzBiotecnology; Inc., Santa Cruz CA) carries out co-immunoprecipitation; separate with SDS-PAGE afterwards; with anti--acetylation lysine antibody (Cell Signaling Technology, Inc., Beverly; MA) carry out immunoblotting, thereby determine the activity of Sirt1.
Figure 32 shows PCK (PEPCK), G-6-Pase (G6Pase), Foxol, PGC1-α (the peroxisome proliferation activated receptor in the liver; γ; the co-activation factor 1; α), Sirt1; uncoupling protein 1 (UCP1) in the brown adipose tissue, acyl group-coenzyme A oxidase (ACO), Foxol, PGC1-α, Sirt1, and the relative gene expression of the uncoupling protein in the muscle 3 (UCP3), muscularity carnitine palmitoyltransferase (mCPT), Foxol, PGC1-α, Sirt1.The relative expression of gene be utilize Sybrgreen incorporation (
Roche Applied Science, Indianapolis IN) is undertaken by real-time quantitative PCR.
Figure 33 shows the result of immunoblotting, and it shows that resveratrol has improved the deacetylation of PGC1 α.Gastrocnemius by the mice individuality that adds 400mg/kg resveratrol (HF+R400) 15 weeks of nursing with high fat diet (HF) or high fat diet prepares nuclear extract.With PGC1 Alpha antibodies (Santa CruzBiotechnology, cat #SC-13067) co-precipitation together, with acetylation lysine specific monoclonal (Cell Signaling Technology, cat #9441; The upper left side) or PGC1 Alpha antibodies (Santa CruzBiotechnology, cat #SC-13067; The lower left) carries out secondary western trace for probe.Exposure is scanned, add the PGC1 α acetylation level that total PGC1 α of 400mg/kg resveratrol (HF+R400) domesticated animal compares with high fat diet (HF) or high fat diet and be presented at right-hand component.
Embodiment 4: the analysis of fat absorption in diet induced obesity (Dio) mouse model
For studying the fat absorption of the mice that different way of dinings raise, as mentioned above, measure normal diet (C), high fat diet (HF) or high fat diet and add the 400mg/kg/ days lipid contents in resveratrol (HF+R400) stool in mice of feeding.In order to carry out the analysis of feces lipid content, mice is placed metabolic cage, this cage comprises the metal grid net bottom plate that has replaced the mice bedding.Monitor the food ration in 24 hours, determining the equilibrated feces of collecting simultaneously of fat.Place 70 ℃ in vacuum drying oven dry down in feces, carefully remove the pollutant of mice bedding and/or food debris then.(2: 1, v/v) under 60 ℃, continuous stirring extracted lipid in 30 minutes with chloroform/methanol from the 100mg feces of five equilibrium.The cooling sample uses Whatman No.1 filter paper filtering then in teat glass.Add a certain amount of chloroform/methanol again, add water reextraction sample, the thermal agitation mixing.Low-speed centrifugal makes and is separated, then with the chloroform phase transfer of lower floor in new test tube.The evaporate to dryness sample is resuspended with chloroform/triton earlier then, and last water is resuspended.Utilize method that zymetology detection kit and manufacturer provide according to T-CHOL (Biomerieux, enzymatic colour test CHOD-PAP) and triglyceride (Biomerieux, enzymatic colour test, GPO-PAP) content is distinguished the fat-extraction thing.The amount of lipid in the heavy total amount of each feces of data representation.The result of feces lipid content analysis sees Figure 34.
Embodiment 5: the endurance in diet induced obesity (Dio) mouse model and the analysis of fat absorption
Press described in the foregoing description 1, second treated animal has been comprised the research of the diet induced obesity of 16 all high fat diets.Animal in this research is divided into following four diet groups:
1: normal diet
2: normal diet adds resveratrol (400mg/kg/ days)
3: high fat diet
4: high fat diet adds resveratrol (400mg/kg/ days)
Body weight analysis through the mice in all four diet groups in 16 weeks is seen Figure 35.
Diet shown in pressing is fed 14-15 after week, and mice is carried out endurance research.The standard detecting method of estimating motor capacity is to utilize treadmill (treadmill), promptly a kind of system that forms by the speed belt that is sealed in the lucite chamber, and it also has the stimulating apparatus that comprises metal electric shock net that is positioned at belt back.In the previous day of running experiment, begin to utilize acclimation method to make mice adapt to treadmill.According to this method, mice is placed in the chamber, runs 10 minutes with the speed of 5 ° of inclination angle 27cm/s.For real running experiment, use two kinds to increase the methods of moving, a kind ofly be used for the high fat diet domesticated animal, a kind ofly be used for the normal diet domesticated animal.To the animal of normal diet, speed is 25cm/s during the experiment beginning, and the inclination angle is 5 °, gathers way then, adjusts the inclination angle according to mode shown in Figure 36.Usually, the big and difficult high fat diet domesticated animal that moves for body weight, starting velocity is 18cm/s, the inclination angle is 0 °, increases according to Figure 36 then.Write down 5 minutes at interval the running distance and the number of times that is shocked by electricity.When mice suffered about 100 electric shocks (2mA shocks by electricity) in 5 minutes at every turn, think that then mice is exhausted, it is removed from experiment.With persistent period of running and relate to the performance (Figure 37) that total distance evaluation is represented mice.All mice fasting are 2 hours before running; The domestication scheme is carried out in the afternoon, the experiment of running morning next day.
Embodiment 6: resveratrol is to the effect of insulin resistant
At present, the gold standard method of measurement insulin resistant is the euglycemia tongs technology.In the method, by at the insulin of fixing irrigation rate with variable bit rate titration glucose (the glucose rate of flooding: GIR) make glucose by " pincers " at predetermined value (euglycemia value 5mmol/L).Study preceding two to three days, under anesthesia (ketamine and xylazine), in femoral vein place intubate, this conduit is attached to the mouse head back, in the subcutaneous supply of mice.After the operation, mice is fed separately, made it restore to few 48 hours, this is preferably to be enough to make them to recover the time of body weight.The blood glucose clamping method clear-headed, footloose, stress not, the photoperiod puts upside down, carry out on 5 hours the mice of fasting.Mice is through the top of domestication (1 hour) adaptation cage, and their conduits on one's body link to each other with syringe-charge pump.Mice conduit on one's body is divided into two branches, is used for distinguishing constant speed and speed change insulin injection and glucose simultaneously.Before insulin injection, detect glucose baseline value from the sampling of tail vein.Before the flow velocity with insulin/kg/ minute 2 μ l/min being equivalent to 18mU continues the perfusion insulin, with the short time booster dose (6 μ l/ minutes, 1min) intubate is estimated.In whole experiment, blood glucose value was monitored in per five minutes, blood glucose reduces in 15 minutes, begins to pour into glucose (20% saline solution).The irrigation rate that changes glucose is up to reaching and keeping euglycemia level (± 15%).At this moment, animal has been lived by " pincers ", and it is oppositely relevant that the amount of the glucose that the degree of insulin resistant is essential with keeping required blood sugar concentration is.GIR (mg glucose/kg animal * minute) calculates with the meansigma methods in vise last 60 minutes.When the average GIR of an animal is higher than the another animal, shown that preferably insulin sensitivity or glucose remove faster from blood plasma.
Figure 38 demonstration utilizes the effect of the resveratrol of hyperinsulinism (18mU/kg/ minute) euglycemia pincers (5.5mmol/l) commercial measurement to insulin sensitivity.Left-hand component shows that adding 400mg/kg resveratrol (C+R400), high fat diet (HF) or high fat diet with control diet (C), control diet adds the glucose irrigation rate (GIR) that 400mg/kg resveratrol (HF+R400) is fed the animal groups in 14 weeks.Right-hand component shows the average GIR when reaching blood glucose pincers stable state.
Equivalent
The present invention provides sirtuin activating compounds and using method thereof especially.Specific specific embodiments of the present invention is through discussing, and above-mentioned description is used to illustrate and nonrestrictive.Those skilled in the art are after reading this description, and multiple variation of the present invention is conspicuous for those skilled in the art.Four corner of the present invention should pass through with reference to claim and whole equivalent thereof, and description changes next definite with these.
Quoting of list of references
Used publication and the patent mentioned among the present invention comprise that those clauses and subclauses of listing below all introduce the present invention as a reference, and are considered as each independent publication or patent clearly and individually is incorporated herein by reference.If any conflict, the application comprises that any definition of the present invention will be restricted.
All introduce the present invention as a reference also comprise any polynucleotide and peptide sequence, they have the relevant public database that enters, for example by (the The Institute for GenomicResearch of Joint Genome Institute, TIGR) (www.tigr.org) and the U.S. state-run biotechnology information centre (the NationalCenter for Biotechnology Information, NCBI) (www.ncbi.nlm.nih.gov) data base's of safeguarding accession number.
It is following also comprising as a reference to introduce the present invention: the open WO2005/002672,2005/002555 and 2004/016726 of PCT.
Claims (123)
1. pharmaceutical dosage form, it comprises a certain amount of sirtuin activating compounds with the sirtuin activation that is equal to or greater than the 200mg resveratrol.
2. pharmaceutical dosage form according to claim 1, wherein said pharmaceutical dosage form comprise a certain amount of sirtuin activating compounds with the sirtuin activation that is equal to or greater than the 500mg resveratrol.
3. pharmaceutical dosage form according to claim 2, wherein said pharmaceutical dosage form comprise a certain amount of sirtuin activating compounds with the sirtuin activation that is equal to or greater than the 1g resveratrol.
4. pharmaceutical dosage form according to claim 3, wherein said pharmaceutical dosage form comprise a certain amount of sirtuin activating compounds with the sirtuin activation that is equal to or greater than the 2g resveratrol.
5. pharmaceutical dosage form according to claim 1, described sirtuin activating compounds is naturally occurring.
6. pharmaceutical dosage form according to claim 5, wherein said sirtuin activating compounds are resveratrol or nicotiamide nucleoside.
7. pharmaceutical dosage form according to claim 1, wherein said sirtuin activating compounds right and wrong are naturally occurring.
8. pharmaceutical dosage form according to claim 1, wherein said sirtuin activating compounds is represented by one of general formula 1-25,30,32-65 and 69-88.
9. pharmaceutical dosage form according to claim 1 also comprises blood fat reducing, obesity or antidiabetic medicine or its combination.
10. pharmaceutical dosage form according to claim 9, wherein said obesity or antidiabetic medicine are selected from chromium, fat-binding polymers, saccharide conjugated polymer, lipase inhibitor, heat generating agent, catecholamine reuptake inhibitor, thyroxin, Statins, nicotinic acid, Cannibinoid receptor modulators, anticonvulsant and combination thereof.
11. pharmaceutical dosage form according to claim 9, wherein said obesity or antidiabetic medicine improve blood pressure, heart rate or its both.
12. pharmaceutical dosage form according to claim 1, wherein said pharmaceutical dosage form is suitable for oral administration.
13. pharmaceutical dosage form according to claim 1, wherein said pharmaceutical dosage form are slow release formulation.
14. pharmaceutical dosage form according to claim 1, wherein said pharmaceutical dosage form are instant.
15. one kind to there being the fat experimenter who needs of treatment to carry out the method for Bariatric, it comprises and gives the experimenter a certain amount of sirtuin activating compounds with the sirtuin activation that is equal to or greater than the 18mg/kg resveratrol every day.
16. the method that the experimenter who has the treatment insulin resistance disorders to need is carried out the insulin resistance disorders treatment, it comprises and gives the experimenter a certain amount of sirtuin activating compounds with the sirtuin activation that is equal to or greater than the 18mg/kg resveratrol every day.
17. one kind to there being the fat experimenter who needs and consume high fat diet of treatment to carry out the method for Bariatric, it comprises and gives the experimenter a certain amount of sirtuin activating compounds.
18. method according to claim 17, wherein caloric at least 30% of experimenter's mean consumption every day is lipid.
19. method according to claim 18, wherein caloric at least 40% of experimenter's mean consumption every day is lipid.
20. method according to claim 19, wherein caloric at least 50% of experimenter's mean consumption every day is lipid.
21. body weight that is used to alleviate the experimenter that the needs that lose weight are arranged or prevention have the experimenter's of prevention weight increase needs the method for weight increase, it comprises and gives the experimenter a certain amount of sirtuin activating compounds with the sirtuin activation that is equal to or greater than the 18mg/kg resveratrol every day.
22. method according to claim 21, wherein said experimenter is just because of the medicine weight increase.
23. one kind to there being the fat experimenter's who needs of treatment the method for carrying out Bariatric, it comprises the sirtuin activating compounds that gives experimenter's effective dose, wherein said experimenter can not make calorie minimizing, active increase or its combination that consume reach the degree that is enough to cause the body weight reduction under the non-existent situation of sirtuin activating compounds.
24. one kind is carried out body temperature to the experimenter who has the reduction of treatment body temperature to need and reduces the method for the treatment of, it comprises the sirtuin activating compounds that gives experimenter's effective dose.
25. a protection has the method for the experimenter's who protects the pancreatic beta cell needs pancreatic beta cell, it comprises the sirtuin activating compounds that gives experimenter's effective dose.
26. according to each described method among the claim 15-25, wherein said sirtuin activating compounds is naturally occurring.
27. method according to claim 26, wherein said sirtuin activating compounds are resveratrol or nicotiamide nucleoside.
28. according to each described method among the claim 15-25, wherein said sirtuin activating compounds right and wrong are naturally occurring.
29. according to each described method among the claim 15-25, wherein said sirtuin activating compounds is by representative one of among general formula 1-25,30,32-65 and the 69-88.
30. according to each described method among the claim 15-25, it also comprises and gives experimenter's blood fat reducing, obesity or antidiabetic medicine or its combination.
31. method according to claim 30, wherein said obesity or antidiabetic medicine are selected from chromium, fat-binding polymers, saccharide conjugated polymer, lipase inhibitor, heat generating agent, catecholamine reuptake inhibitor, thyroxin, Statins, nicotinic acid, Cannibinoid receptor modulators, anticonvulsant and combination thereof.
32. method according to claim 31, wherein said obesity or antidiabetic medicine improve blood pressure, heart rate or its both.
33. according to each described method among the claim 15-25, wherein said experimenter is the people.
34. according to each described method among the claim 15-25, wherein said experimenter is farming animals or companion animals.
35. according to each described method among the claim 15-25, wherein said sirtuin activating compounds is administered once every day.
36. according to each described method among the claim 15-25, wherein said sirtuin activating compounds is administered twice or three times every day.
37. according to each described method among the claim 15-25, wherein said sirtuin activating compounds is with the slow release form administration.
A 38. food or beverage that is applicable to that mammal consumes, wherein said food or beverage comprise the additive of one or more sirtuin activating compounds, and the concentration of one or more sirtuin activating compounds in wherein said food or the beverage has the sirtuin activation that is equal to or greater than the 11mg/g resveratrol.
A 39. food or beverage that is applicable to that mammal consumes, wherein said food or beverage comprise the additive of one or more sirtuin activating compounds, and wherein said food or beverage do not comprise Fructus Vitis viniferae, Fructus Mori, blue berry, Fructus Rubi, Semen arachidis hypogaeae, milk, yeast or its extract.
40. beverage that is applicable to that mammal consumes, the beverage of a copy of it 8 ounce fluid ounces comprises the sirtuin activating compounds of a certain amount of sirtuin of having activation, and described sirtuin activation is equal to or greater than the sirtuin activation of 25mg resveratrol.
41. food that is applicable to that mammal consumes, wherein independent serving comprises the sirtuin activating compounds of a certain amount of sirtuin of having activation, and described sirtuin activation is equal to or greater than the sirtuin activation of 100mg resveratrol.
42. according to the described food of claim 41, wherein said every portion of food provides 100 to 500kcal heats.
43. according to each described food or beverage among the claim 32-36, wherein said sirtuin activating compounds is naturally occurring.
44. according to described food of claim 37 or beverage, wherein said sirtuin activating compounds is resveratrol or nicotiamide nucleoside.
45. according to each described food or beverage among the claim 38-42, wherein said sirtuin activating compounds right and wrong are naturally occurring.
46. according to each described food or beverage among the claim 38-42, wherein said sirtuin activating compounds is by representative one of among general formula 1-25,30,32-65 and the 69-88.
47. a food or a beverage that is applicable to that mammal consumes, wherein said food or beverage comprise the additive of one or more stable sirtuin activating compounds.
48. according to described food of claim 47 or beverage, wherein said stable sirtuin activating compounds is not contact light, oxygen or both sirtuin activating compounds through physical protection.
49. according to described food of claim 47 or beverage, wherein said stable sirtuin activating compounds comprises the mixture of one or more sirtuin activating compounds and one or more antioxidants.
50. according to claim 48 or 49 described food or beverages, wherein said sirtuin activating compounds is naturally occurring.
51. according to described food of claim 50 or beverage, wherein said sirtuin activating compounds is resveratrol or nicotiamide nucleoside.
52. according to claim 48 or 49 described food or beverages, wherein said sirtuin activating compounds right and wrong are naturally occurring.
53. according to claim 48 or 49 described food or beverages, wherein said sirtuin activating compounds is by representative one of among general formula 1-25,30,32-65 and the 69-88.
54. according to described food of claim 47 or beverage, wherein said stable sirtuin activating compounds comprises the chemoproection group that is attached on one or more oxygen or the photosensitivity part.
55. according to each described food or beverage in the claim 38,39,40,41 and 47, it also comprises one or more blood fat reducings, obesity or antidiabetic medicine or its combination.
56. according to described food of claim 55 or beverage, wherein said obesity or antidiabetic medicine are selected from chromium, fat-binding polymers, saccharide conjugated polymer, lipase inhibitor, heat generating agent, catecholamine reuptake inhibitor, thyroxin, Statins, nicotinic acid, Cannibinoid receptor modulators, anticonvulsant and combination thereof.
57. according to described food of claim 55 or beverage, wherein said obesity or antidiabetic medicine improve blood pressure, heart rate or its both.
58. one kind is used for the treatment of the experimenter's who benefits from the mitochondria activity increase the disease or the method for obstacle, it comprises a certain amount of sirtuin activating compounds with the sirtuin activation that is equal to or greater than the 18mg/kg resveratrol of experimenter that these treatment needs are arranged every day.
59. according to the described method of claim 58, wherein said sirtuin regulates chemical compound and improves mitochondria activity and do not increase mitochondrial mass.
60. according to the described method of claim 58, wherein said sirtuin regulates chemical compound increases mitochondrial mass.
61. according to the described method of claim 58, wherein said sirtuin regulates chemical compound and improves the proteic deacetylase activity of sirtuin.
62. according to the described method of claim 61, wherein said sirtuin activating compounds increases the deacetylated effect of PGC-1 α.
63. according to the described method of claim 58, it is naturally occurring that wherein said sirtuin regulates chemical compound.
64. according to the described method of claim 63, wherein said sirtuin activating compounds is resveratrol or nicotiamide nucleoside.
65. according to the described method of claim 58, wherein said sirtuin activating compounds right and wrong are naturally occurring.
66. according to the described method of claim 65, wherein said sirtuin activating compounds is by representative one of among general formula 1-25,30,32-65 and the 69-88.
67. according to the described method of claim 58, it also comprises and gives the experimenter one or more following materials: vitamin, cofactor or antioxidant.
68. according to the described method of claim 58, it also comprises and gives the experimenter one or more following materials: ubiquinone
10, L-carnitine, thiamine, riboflavin, nicotiamide, folic acid, vitamin E, selenium, thioctic acid or prednisone.
69. according to the described method of claim 58, its also comprise give the experimenter one or more palliate a disease or the medicine of the symptom of obstacle.
70. according to the described method of claim 69, wherein said medicine alleviates epilepsy, neuropathic pain or heart dysfunction.
71. according to the described method of claim 58, wherein said obstacle is relevant with the medicine that reduces mitochondria activity.
72. according to the described method of claim 71, wherein said medicine is reverse transcriptase inhibitors, protease inhibitor or dihydroorate dehydrogenase (DHOD) inhibitor.
73. according to the described method of claim 58, wherein said experimenter is the people.
74. according to the described method of claim 58, wherein said sirtuin activating compounds is administered once every day.
75. according to the described method of claim 58, wherein said sirtuin activating compounds is administered twice or three times every day.
76. according to the described method of claim 58, wherein said sirtuin activating compounds is with the slow release form administration.
77. one kind be used for strengthening motor capacity or muscular endurance, minimizing is tired or the method accelerating to recover from fatigue, it comprises the sirtuin activating compounds that gives at least a treatment effective dose of experimenter.
78. according to the described method of claim 77, wherein said sirtuin regulates chemical compound and improves mitochondria activity.
79. according to the described method of claim 77, wherein said sirtuin regulates chemical compound increases mitochondrial mass.
80. according to the described method of claim 77, wherein said sirtuin activating compounds improves the proteic deacetylase activity of sirtuin.
81. 0 described method according to Claim 8, wherein said sirtuin activating compounds increases the deacetylated effect of PGC-1 α.
82. according to the described method of claim 77, it is naturally occurring that wherein said sirtuin regulates chemical compound.
83. 2 described methods according to Claim 8, wherein said sirtuin activating compounds is resveratrol or nicotiamide nucleoside.
84. according to the described method of claim 77, wherein said sirtuin activating compounds right and wrong are naturally occurring.
85. 4 described methods according to Claim 8, wherein said sirtuin activating compounds is by representative one of among general formula 1-25,30,32-65 and the 69-88.
86. according to the described method of claim 77, wherein said experimenter is the people.
87. 6 described methods according to Claim 8, wherein said people is the athlete.
88. according to the described method of claim 77, wherein said treatment effective dose is meant the amount of the sirtuin activating compounds with the sirtuin activation that is equal to or greater than the 18mg/kg resveratrol.
89. 8 described methods according to Claim 8, wherein said sirtuin activating compounds is administered once every day.
90. 8 described methods according to Claim 8, wherein said sirtuin activating compounds is administered twice or three times every day.
91. according to the described method of claim 77, wherein said sirtuin activating compounds is with the form administration of slow release.
92. according to the described method of claim 77, wherein said fatigue is with to give chemotherapeutic relevant.
93. a method that is used for the treatment of or prevents the disease of motor capacity or muscular endurance reduction, it comprises a certain amount of sirtuin activating compounds with the sirtuin activation that is equal to or greater than the 18mg/kg resveratrol of experimenter that this treatment or prevention needs are arranged every day.
94. according to the described method of claim 93, wherein said disease is that muscular dystrophy, neuromuscular disorder, Mai Kadeershi disease (McArdle ' s disease), myasthenia gravis, muscle injury, multiple sclerosis, amyotrophic lateral sclerosis or the skeletal muscle relevant with the age reduce disease.
95. one kind is used for the treatment of or the method for the muscle tissue damage that prevention is relevant with anoxia or ischemia, it comprises a certain amount of sirtuin activating compounds with the sirtuin activation that is equal to or greater than the 18mg/kg resveratrol of experimenter that this treatment or prevention needs are arranged every day.
96. a method that is used to increase experimenter's muscle ATP level, it comprises and gives the sirtuin activating compounds that the experimenter treats effective dose.
97. according to the described method of claim 96, wherein said treatment effective dose is meant the amount of the sirtuin activating compounds with the sirtuin activation that is equal to or greater than the 18mg/kg resveratrol.
98. a method that is used for the treatment of or prevents among the experimenter with cell death or old and feeble diseases associated or obstacle, it comprises a certain amount of sirtuin activating compounds with the sirtuin activation that is equal to or greater than the 18mg/kg resveratrol of experimenter that this treatment or prevention needs are arranged every day.
99. according to the described method of claim 98, wherein said and old and feeble diseases associated is apoplexy, cardiovascular disease, arthritis, hypertension or Alzheimer's disease.
100. one kind is used to prolong experimenter's method of life, it comprises and gives the experimenter a certain amount of sirtuin activating compounds with the sirtuin activation that is equal to or greater than the 18mg/kg resveratrol every day.
101. a method that is used for the treatment of or prevents experimenter's neurological sexual disorders, it comprises a certain amount of sirtuin activating compounds with the sirtuin activation that is equal to or greater than the 18mg/kg resveratrol of experimenter that this treatment or prevention needs are arranged every day.
102. according to the described method of claim 101, wherein said neurodegenerative diseases is selected from: Alzheimer (AD), parkinson (PD), Huntington Chorea (HD), amyotrophic lateral sclerosis (ALS; LouGehrig ' s disease), diffusivity lewy body disease, chorea acanthocytosis, primary lateral sclerosis, multiple sclerosis (MS) and family ataxia disease.
103. a method that is used for the treatment of or prevents experimenter's blood coagulation disorders, it comprises a certain amount of sirtuin activating compounds with the sirtuin activation that is equal to or greater than the 18mg/kg resveratrol of experimenter that this treatment or prevention needs are arranged every day.
104. according to the described method of claim 103, wherein said blood coagulation disorders is selected from: thromboembolism, deep venous thrombosis, pulmonary infarction, apoplexy, myocardial infarction, miscarriage, lack relevant thrombosis with Antithrombin III, the C hypoproteinosis, the S hypoproteinosis, to the proteic resistance of activatory C, dysfibrinogenemia, the fibrinolysis obstacle, homocystinuria, gestation, the inflammation obstacle, myelosis sexual disorders, arteriosclerosis, angina pectoris, disseminated inravascular coagulation, thrombotic thrombocytopenic purpura, cancer metastasis, drepanocytosis, glomerulonephritis, drug-induced thrombocytopenia and therapeutic clot dissolution or as during angioplasty or the operation technique or afterwards closed again.
105. a method that is used for the treatment of or prevents ocular disease or obstacle, it comprises a certain amount of sirtuin activating compounds with the sirtuin activation that is equal to or greater than the 18mg/kg resveratrol of experimenter that this treatment or prevention needs are arranged every day.
106. according to the described method of claim 105, wherein said ocular disease or obstacle are selected from: visual disorder, glaucoma, optic neuritis, degeneration of macula or anterior ischemic optic neuropathy AION.
107. according to the described method of claim 106, wherein said visual disorder is caused by optic nerve or central nervous system injury.
108. according to the described method of claim 107, wherein said damage is caused by high intraocular pressure, optic nerve swelling or ischemia.
109. according to the described method of claim 106, wherein said visual disorder is caused by retina injury.
110. according to the described method of claim 109, wherein said damage enters the disturbed or macula lutea of retina by blood flow and destroys and cause.
111. a method that is used for the treatment of or prevents the inductive sacred disease of chemotherapeutic, it comprises a certain amount of sirtuin activating compounds with the sirtuin activation that is equal to or greater than the 18mg/kg resveratrol of experimenter that this treatment or prevention needs are arranged every day.
112. according to the described method of claim 111, wherein said chemotherapeutic comprises vinka alkaloid or cisplatin.
113. one kind is used for the treatment of or the method for the sacred disease that prevention is relevant with ischemic event or disease, it comprises a certain amount of sirtuin activating compounds with the sirtuin activation that is equal to or greater than the 18mg/kg resveratrol of experimenter that this treatment or prevention needs are arranged every day.
114. according to the described method of claim 113, wherein said ischemic event is apoplexy, coronary heart disease (comprising congestive heart failure or myocardial infarction), apoplexy, emphysema, hemorrhagic shock, arrhythmia (for example atrial fibrillation), peripheral blood vessel or the damage relevant with transplanting.
115. a method that is used for the treatment of or prevents polyglutamic amide disease, it comprises a certain amount of sirtuin activating compounds with the sirtuin activation that is equal to or greater than the 18mg/kg resveratrol of experimenter that this treatment or prevention needs are arranged every day.
116. according to the described method of claim 115, wherein said polyglutamic amide disease is: spinal cord bulbar muscular atrophy (Kennedy disease), Huntington Chorea, dentatorubral-pallidoluysian atrophy (dentatorubralpallidoluysian atrophy, Haw River syndrome), spinocerebellar ataxia 1 type, spinocerebellar ataxia 2 types, spinocerebellar ataxia 3 types (horse is looked into many-Joseph disease), spinocerebellar ataxia 6 types, spinocerebellar ataxia 7 types or spinocerebellar ataxia 17 types.
117. according to the described method of claim 115, wherein said method also comprises the HDAC I/II inhibitor for the treatment of effective dose.
118. according to each described method among the claim 98-117, wherein said chemical compound improves proteic level of a kind of sirtuin or activity at least.
119. according to the described method of claim 118, wherein said chemical compound improves the proteic deacetylase activity of sirtuin.
120. according to the described method of claim 118, wherein said sirtuin albumen is mammalian proteins.
121. according to the described method of claim 118, wherein said sirtuin albumen is human SIRT1.
122. according to the described method of claim 118, wherein said sirtuin albumen is human SIRT3.
123. according to the described method of claim 118; wherein said chemical compound is effectively improving under SIRT1 and/or the proteic deacetylated active compound concentration of SIRT3, does not have following one or more activity basically: suppress the PI3-kinases, suppress aldose reductase (aldoreductase), suppress tyrosine kinase, trans-activation EGFR tyrosine kinase, coronary dilation, spasmolytic activity.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US69744305P | 2005-07-07 | 2005-07-07 | |
| US60/697,443 | 2005-07-07 | ||
| US60/736,528 | 2005-11-14 | ||
| US60/753,606 | 2005-12-23 | ||
| US60/783,802 | 2006-03-16 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2013100114296A Division CN103055313A (en) | 2005-07-07 | 2006-07-07 | Methods and related compositions for treating or preventing obesity, insulin resistance disorders, and mitochondrial-associated disorders |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101257897A true CN101257897A (en) | 2008-09-03 |
Family
ID=39892163
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800330147A Pending CN101257897A (en) | 2005-07-07 | 2006-07-07 | Methods and related compositions for treating or preventing obesity, insulin resistance disorders, and mitochondrial-associated disorders |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101257897A (en) |
Cited By (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102300578A (en) * | 2008-12-01 | 2011-12-28 | 延寿有限责任公司 | Methods And Compositions For Altering Health, Wellbeing, And Lifespan |
| CN102395359A (en) * | 2009-03-16 | 2012-03-28 | Ipintl有限责任公司 | Treating alzheimer's disease and osteoporosis and reducing aging |
| CN102802626A (en) * | 2009-06-11 | 2012-11-28 | 帝斯曼知识产权资产管理有限公司 | Niacin and/or trigonelline as a muscle stimulant |
| CN103209968A (en) * | 2010-08-26 | 2013-07-17 | 国立大学法人京都大学 | Pluripotent stem cell cardiomyocyte differentiation-promoting agent |
| CN103837679A (en) * | 2014-02-20 | 2014-06-04 | 浙江大学医学院附属第二医院 | Sirt-1 protein applied in diagnosis and prediction of osteosarcoma transfer product |
| CN104622886A (en) * | 2015-03-05 | 2015-05-20 | 中国人民解放军第二军医大学 | Application of nicotinamide riboside in preparing drugs for treating non-alcoholic steatohepatitis |
| CN105030750A (en) * | 2011-12-23 | 2015-11-11 | 中国医学科学院医药生物技术研究所 | Application of longistyline structural analogues in prevention of hepatitis C virus and acquired immune deficiency syndrome (AIDS) virus |
| CN105343051A (en) * | 2015-08-07 | 2016-02-24 | 长庚大学 | Application of psoralen in preparing SIRT1 activator, medicine for treating diseases related to its activation and life prolonging medicine |
| CN105873937A (en) * | 2013-10-30 | 2016-08-17 | 可劳迈戴斯有限公司 | Nicotinamide riboside compositions for topical use in treating skin conditions |
| CN105963292A (en) * | 2016-06-10 | 2016-09-28 | 青岛科瑞元生物科技有限公司 | Pharmaceutical composition for myocardial infarction treatment and application thereof |
| CN105007943B (en) * | 2012-12-26 | 2017-07-14 | 中岛利博 | Function regulator, the conditioning agent of mitochondrial function, antiobesity agent and its screening methods of the β albumen of PGC 1 |
| CN107496410A (en) * | 2017-09-21 | 2017-12-22 | 上海华堇生物技术有限责任公司 | The medicinal usage of robinetin |
| CN107811997A (en) * | 2017-11-10 | 2018-03-20 | 大连医科大学附属第医院 | Application of the proteasome inhibitor resveratrol in angiocardiopathy is prevented and treated |
| CN109620819A (en) * | 2018-12-20 | 2019-04-16 | 西安交通大学 | (1,2,3- trimethoxy-benzene)-propenone improves the application in senile retinal macular degeneration drug in preparation |
| CN109890376A (en) * | 2016-10-27 | 2019-06-14 | 三得利控股株式会社 | Composition is used in PGC-1 α activation |
| CN110357789A (en) * | 2018-04-11 | 2019-10-22 | 华东理工大学 | N- substituted acrylamide derivative and its preparation and use as DHODH inhibitor |
| CN110621348A (en) * | 2017-04-20 | 2019-12-27 | 里波热姆斯国际股份公司 | Drug delivery system |
| CN110878294A (en) * | 2018-09-05 | 2020-03-13 | 广州溯原生物科技有限公司 | Application of rhodotorula glutinis deacetylase protein 4 for improving mitochondrial function |
| CN110879295A (en) * | 2018-09-05 | 2020-03-13 | 广州溯原生物科技有限公司 | Application of rhodotorula glutinis deacetylase protein 2 for improving mitochondrial function |
| CN111032037A (en) * | 2017-08-30 | 2020-04-17 | 大塚制药株式会社 | Compositions containing kaempferol analogs |
| CN111386111A (en) * | 2017-11-24 | 2020-07-07 | 奥塔哥创新有限公司 | Pharmaceutical combinations and methods of treating diabetes and related disorders |
| CN112773818A (en) * | 2020-12-23 | 2021-05-11 | 医微细胞生物技术(广州)有限公司 | Application of dental pulp stem cells in preparation of medicine for treating diabetes |
| CN113101295A (en) * | 2020-03-20 | 2021-07-13 | 上海疆云医疗健康科技有限公司 | Use of stilbene analogues in the treatment of diabetic renal disease |
| CN113908167A (en) * | 2021-10-28 | 2022-01-11 | 四川省畜牧科学研究院 | Veterinary drug composition and application thereof |
| WO2022094916A1 (en) * | 2020-11-06 | 2022-05-12 | 中国科学院深圳先进技术研究院 | Method for improving activity of nicotinamide phosphoribosyltransferase, and composition thereof |
| CN114668845A (en) * | 2022-04-06 | 2022-06-28 | 北京清华长庚医院 | Application of liver Sirt5 protein in preparation of products for inhibiting gluconeogenesis and improving sugar tolerance |
| CN115350191A (en) * | 2022-09-23 | 2022-11-18 | 温州医科大学 | New application of reagent BX-471 |
| CN116650471A (en) * | 2023-06-21 | 2023-08-29 | 成都自然素生物科技有限公司 | New application of morin, self-emulsifying drug delivery system and preparation method thereof |
-
2006
- 2006-07-07 CN CNA2006800330147A patent/CN101257897A/en active Pending
Cited By (37)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102300578A (en) * | 2008-12-01 | 2011-12-28 | 延寿有限责任公司 | Methods And Compositions For Altering Health, Wellbeing, And Lifespan |
| CN102395359A (en) * | 2009-03-16 | 2012-03-28 | Ipintl有限责任公司 | Treating alzheimer's disease and osteoporosis and reducing aging |
| CN102802626B (en) * | 2009-06-11 | 2015-11-25 | 帝斯曼知识产权资产管理有限公司 | As nicotinic acid and/or the trigonelline of muscular irritation agent |
| CN102802626A (en) * | 2009-06-11 | 2012-11-28 | 帝斯曼知识产权资产管理有限公司 | Niacin and/or trigonelline as a muscle stimulant |
| CN103209968B (en) * | 2010-08-26 | 2015-08-05 | 国立大学法人京都大学 | Pluripotent stem cell cardiomyocyte differentiation-promagent agent |
| CN103209968A (en) * | 2010-08-26 | 2013-07-17 | 国立大学法人京都大学 | Pluripotent stem cell cardiomyocyte differentiation-promoting agent |
| CN105030750A (en) * | 2011-12-23 | 2015-11-11 | 中国医学科学院医药生物技术研究所 | Application of longistyline structural analogues in prevention of hepatitis C virus and acquired immune deficiency syndrome (AIDS) virus |
| CN105030750B (en) * | 2011-12-23 | 2018-08-28 | 中国医学科学院医药生物技术研究所 | Application of one group of cajanin structurally similar compounds in anti-hepatitis C virus and anti AIDS virus |
| CN105007943B (en) * | 2012-12-26 | 2017-07-14 | 中岛利博 | Function regulator, the conditioning agent of mitochondrial function, antiobesity agent and its screening methods of the β albumen of PGC 1 |
| CN105873937A (en) * | 2013-10-30 | 2016-08-17 | 可劳迈戴斯有限公司 | Nicotinamide riboside compositions for topical use in treating skin conditions |
| CN103837679A (en) * | 2014-02-20 | 2014-06-04 | 浙江大学医学院附属第二医院 | Sirt-1 protein applied in diagnosis and prediction of osteosarcoma transfer product |
| CN103837679B (en) * | 2014-02-20 | 2016-06-08 | 浙江大学 | Sirt-1 albumen is in the application of diagnosis, prediction osteosarcoma transfer product |
| CN104622886A (en) * | 2015-03-05 | 2015-05-20 | 中国人民解放军第二军医大学 | Application of nicotinamide riboside in preparing drugs for treating non-alcoholic steatohepatitis |
| CN105343051A (en) * | 2015-08-07 | 2016-02-24 | 长庚大学 | Application of psoralen in preparing SIRT1 activator, medicine for treating diseases related to its activation and life prolonging medicine |
| CN105963292A (en) * | 2016-06-10 | 2016-09-28 | 青岛科瑞元生物科技有限公司 | Pharmaceutical composition for myocardial infarction treatment and application thereof |
| CN105963292B (en) * | 2016-06-10 | 2018-11-09 | 江苏霍氏医药科技有限公司 | A kind of pharmaceutical composition and its application for myocardial infarction treatment |
| CN109890376A (en) * | 2016-10-27 | 2019-06-14 | 三得利控股株式会社 | Composition is used in PGC-1 α activation |
| CN110621348A (en) * | 2017-04-20 | 2019-12-27 | 里波热姆斯国际股份公司 | Drug delivery system |
| CN111032037A (en) * | 2017-08-30 | 2020-04-17 | 大塚制药株式会社 | Compositions containing kaempferol analogs |
| CN107496410A (en) * | 2017-09-21 | 2017-12-22 | 上海华堇生物技术有限责任公司 | The medicinal usage of robinetin |
| CN107811997A (en) * | 2017-11-10 | 2018-03-20 | 大连医科大学附属第医院 | Application of the proteasome inhibitor resveratrol in angiocardiopathy is prevented and treated |
| CN111386111A (en) * | 2017-11-24 | 2020-07-07 | 奥塔哥创新有限公司 | Pharmaceutical combinations and methods of treating diabetes and related disorders |
| CN110357789A (en) * | 2018-04-11 | 2019-10-22 | 华东理工大学 | N- substituted acrylamide derivative and its preparation and use as DHODH inhibitor |
| CN110878294A (en) * | 2018-09-05 | 2020-03-13 | 广州溯原生物科技有限公司 | Application of rhodotorula glutinis deacetylase protein 4 for improving mitochondrial function |
| CN110879295A (en) * | 2018-09-05 | 2020-03-13 | 广州溯原生物科技有限公司 | Application of rhodotorula glutinis deacetylase protein 2 for improving mitochondrial function |
| CN110878294B (en) * | 2018-09-05 | 2024-01-02 | 广州弘润生物科技有限公司 | Application of rhodotorula glutinis deacetylase protein 4 for improving mitochondrial function |
| CN109620819A (en) * | 2018-12-20 | 2019-04-16 | 西安交通大学 | (1,2,3- trimethoxy-benzene)-propenone improves the application in senile retinal macular degeneration drug in preparation |
| CN109620819B (en) * | 2018-12-20 | 2021-06-22 | 西安交通大学 | Application of (1,2, 3-trimethoxy benzene) -acrylketone in preparing medicine for improving senile macular degeneration |
| CN113101295A (en) * | 2020-03-20 | 2021-07-13 | 上海疆云医疗健康科技有限公司 | Use of stilbene analogues in the treatment of diabetic renal disease |
| WO2022094916A1 (en) * | 2020-11-06 | 2022-05-12 | 中国科学院深圳先进技术研究院 | Method for improving activity of nicotinamide phosphoribosyltransferase, and composition thereof |
| CN112773818A (en) * | 2020-12-23 | 2021-05-11 | 医微细胞生物技术(广州)有限公司 | Application of dental pulp stem cells in preparation of medicine for treating diabetes |
| CN113908167A (en) * | 2021-10-28 | 2022-01-11 | 四川省畜牧科学研究院 | Veterinary drug composition and application thereof |
| CN114668845A (en) * | 2022-04-06 | 2022-06-28 | 北京清华长庚医院 | Application of liver Sirt5 protein in preparation of products for inhibiting gluconeogenesis and improving sugar tolerance |
| CN115350191A (en) * | 2022-09-23 | 2022-11-18 | 温州医科大学 | New application of reagent BX-471 |
| CN115350191B (en) * | 2022-09-23 | 2023-08-18 | 温州医科大学 | New application of reagent BX-471 |
| CN116650471A (en) * | 2023-06-21 | 2023-08-29 | 成都自然素生物科技有限公司 | New application of morin, self-emulsifying drug delivery system and preparation method thereof |
| CN116650471B (en) * | 2023-06-21 | 2023-09-22 | 成都自然素生物科技有限公司 | New application of morin, self-emulsifying drug delivery system and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101257897A (en) | Methods and related compositions for treating or preventing obesity, insulin resistance disorders, and mitochondrial-associated disorders | |
| CN103055313A (en) | Methods and related compositions for treating or preventing obesity, insulin resistance disorders, and mitochondrial-associated disorders | |
| US20070149466A1 (en) | Methods and related compositions for treating or preventing obesity, insulin resistance disorders, and mitochondrial-associated disorders | |
| ES2397275T3 (en) | Imidazopyridine derivatives as sirtuine modulating agents | |
| US20110009496A1 (en) | Resveratrol formulations | |
| CN101316853B (en) | Oxazolopyridine derivatives as SIRTUIN modulators | |
| JP2009521408A (en) | Modulator of Cdc2-like kinase (CLK) and method of use thereof | |
| US7998974B2 (en) | Fused heterocyclic compounds and their use as sirtuin modulators | |
| JP2008535790A (en) | N-phenylbenzamide derivatives which are sirtuin modulators | |
| US20100168084A1 (en) | Therapeutic compounds and related methods of use | |
| EP3152220A1 (en) | Nicotinamide riboside analogs and pharmaceutical compositions and uses thereof | |
| KR20170012449A (en) | Preparation and use of crystalline beta-d-nicotinamide riboside | |
| JP2008527002A (en) | Novel composition for preventing and treating neurodegenerative disorders and blood coagulation disorders | |
| WO2006094209A2 (en) | N-benzimidazolylalkyl-substituted amide sirtuin modulators | |
| WO2006094237A2 (en) | Acridine and quinoline dervatives as sirtuin modulators | |
| WO2006094210A2 (en) | Tetrahydroquinoxalinone sirtuin modulators | |
| WO2006094246A2 (en) | N-arylmethyl benzamide sirtuin modulators | |
| WO2006094233A1 (en) | N,n'-dicyclic isothiourea sirtuin modulators | |
| WO2006094248A1 (en) | Aryl-substituted cyclic sirtuin modulators |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20080903 |