CN108640898A - 1,3- dioxane -4,6- cyclohexadione compounds, preparation method, pharmaceutical composition and its application - Google Patents

1,3- dioxane -4,6- cyclohexadione compounds, preparation method, pharmaceutical composition and its application Download PDF

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CN108640898A
CN108640898A CN201810643494.3A CN201810643494A CN108640898A CN 108640898 A CN108640898 A CN 108640898A CN 201810643494 A CN201810643494 A CN 201810643494A CN 108640898 A CN108640898 A CN 108640898A
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substituted
unsubstituted
alkyl
sirt1
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刘东祥
柳红
王敏
李淳朴
杨利生
陈凯先
蒋华良
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Shanghai Institute of Materia Medica of CAS
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Abstract

The invention discloses a kind of 4,6 cyclohexadione compounds of 1,3 dioxane, preparation method, pharmaceutical composition and its applications, and the structure of such compound is shown in formula I, and the definition of each substituent group is as described in specification and claims.The compound of the present invention, which has, inhibits SIRT1 albumen deacetylation enzymatic activitys; can be used for treating with SIRT1 albumen deacetylase unconventionality expressions or with the horizontal relevant various diseases of its enzyme activity, such as the purposes in the drug of neurodegenerative disease, metabolic disease, cancer disease.

Description

1,3- dioxane -4,6- cyclohexadione compounds, preparation method, pharmaceutical composition And its application
Technical field
The present invention relates to 1,3- dioxane -4,6- cyclohexadione compounds, preparation method, pharmaceutical composition and its answer With.
Background technology
Sirtuin is a kind of NAD+The albumen deacetylase of dependence, they have on amino acid sequence and structure The homology of height.Sirtuin albumen is widely present in a variety of life entities such as ancient bacterium, nematode, drosophila, yeast and mammal It is interior, regulated and controled including cell ageing, transcription, Apoptosis, inflammation, stress, mitochondria synthesis and body biological clock including A variety of important bioprocess.
Yeast Sir2 genes are the first sirtuin albumen being found.Early in 20th century the seventies, people find that Sir2 genes can maintain the generation of the length of yeast telomere, the repetitive dna sequence for adjusting rDNA codings.Sir2 bases are found later Because that can extend the service life of yeast by the unstability of suppressor group, ferment can be obviously shortened by knocking out yeast Sir2 genes Female service life, and the service life of yeast about 40% can be extended by being overexpressed Sir2 genes then.Equally, Sir2.1 is overexpressed in online polypide (homologous gene of Sir2) can extend the service life of nematode about 50%, also there is similar phenomenon in drosophila.These find to make More heated door is become to the research of sirtuin family proteins.
Mammalian genome encodes seven kinds of sirtuin albumen, is respectively designated as SIRT1-7, they contain, and there are one by NAD+Calmodulin binding domain CaM and enzyme activity catalysis region composition, highly conserved nucleus and length, the sequence variable ends N- and C- End.The difference at Sirtuin n-end of albumen and the ends C- can influence combination, mediating proteins and other sirtuin of albumen and ligand The interaction of hypotype or the subcellular localization for influencing them.Existing result of study shows that SIRT1, SIRT6 and SIRT7 are Nucleoprotein, but SIRT1 can also be entered from nucleus in cytoplasm by nucleo-cytoplasmic transport, to in cytoplasm stress reaction Target protein be adjusted.SIRT2 is predominantly located in cellular matrix, but SIRT2 can enter cell by nucleo-cytoplasmic transport In core, and SIRT3, SIRT4 and SIRT5 are predominantly located in mitochondria.The sirtuin of mammal is distributed in different subcellulars Layer, this is closely related with the substrate and biological function of their effects.
SIRT1 be in mammal sirtuin family proteins in sequence closest to yeast Sir2 and mammal Member studied earliest in sirtuin families.SIRT1 adjusts different dyeing by deacetylation H1K26, H3K9 and H4K16 The formation of matter, in addition, SIRT1 also assists in nonhistones deacetylation.The nonhistones substrate of SIRT1 can be divided into three classes：(1) Transcription factor：Such as p53, FOXO3a, E2F2, BCL6；(2) DNA repair protein：Such as Ku70 and MRE11-RAD50-NBS1 (MRN) etc.；(3) signal factor：Smad7 etc..SIRT1 by the deacetylation to histone substrates and nonhistones substrate, It participates in adjusting the different physiological roles including gene expression, energetic supersession and aging.
SIRT1 and generation, the development of a variety of diseases are closely related, it can pass through the P65/RelA of deacetylation NF- κ B Subunit inhibits A beta-aggregations in microglia, to control the development of alzheimer's disease (AD).SIRT1 can also pass through Deacetylation PGC-1 α simultaneously increase PGC-1 alpha actives, and nerve cell is protected in Huntingdon disease (HD) disease model.Known cancer Inhibiting factor p53 albumen participates in the various physiological processes including DNA reparations, cell growth arrest, aging and apoptosis, has become For one of the important target for the treatment of of cancer.And SIRT1 can be with the 382nd lysine residue of deacetylation p53, deacetylation P53 can lead oncogenic generation.SIRT1 can also pass through deacetylation DNA reparative factors Ku70 and plug transcription factor FOXOs enhances cell DNA repair, inhibits Apoptosis caused by DNA damage.Studies have shown that inhibiting SIRT1 activity can With inducing tumor cell growth retardation, and promote apoptosis of tumor cells.In addition, SIRT1 can pass through deacetylation histone h1 26th, the 9th of H3, the 16th lysine of H4 adjust the transcription of tumor suppressor gene, to participating in tumour cell week The adjusting of phase.The study found that existing in most of solid tumor and including breast cancer, colon cancer, prostate cancer, liver cancer and leukaemia The overexpression of SIRT1 albumen is all detected in interior Malignancy.Overexpression due to SIRT1 and cancer Correlation occurs, so inhibiting the activity of SIRT1 that can effectively inhibit cancer cell multiplication, while cancer cell specific induction of apoptosis.Therefore, SIRT1 is likely to become the novel targets of oncotherapy, and SIRT1 inhibitor can become potential anticancer drug candidate.
Invention content
It is an object of the present invention to provide 1,3- dioxane -4,6- diones chemical combination shown in a kind of logical formula (I) Object, its pharmaceutical salt, enantiomter, diastereoisomer or racemic modification.
It is another object of the present invention to provide a kind of preparation methods of compound shown in above-mentioned logical formula (I).
It is yet a further object of the present invention to provide a kind of one or more above-mentioned logical formula (I) institutes including therapeutically effective amount Show compound or the pharmaceutical composition of its pharmaceutical salt.
A further object of the present invention is to provide compound shown in above-mentioned logical formula (I) and is preparing for treating SIRT1 Acetylase running water equals the purposes in relevant disease, such as the drug of cancer, immune disorders and inflammation.
The first aspect of the present invention provides compound shown in Formulas I or its pharmaceutically acceptable salt, hydrate, solvation Object, enantiomter, diastereoisomer or racemic modification or their mixture：
Wherein,
R1And R7It is each independently hydrogen, C1-C6 alkyl or C2-C12 unsaturated alkyls；
R2、R3、R4、R5、R6It is each independently hydrogen, halogen, cyano, nitro, amino, hydroxyl, carboxyl, substitution or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 unsaturated alkyls, substituted or unsubstituted C1-C6 alkoxies, substitution or Unsubstituted C1-C6 acyl groups, substituted or unsubstituted C3-C12 cyclic hydrocarbon radicals ,-L1- (CH2) the substituted or unsubstituted C6-C12 of m- Aryl ,-L1- (CH2) the substituted or unsubstituted 3-12 circle heterocyclic rings bases of m- ,-L1- (CH2) m-C (=O)-N (R8)(R9), wherein L1 For nothing ,-O- or-S-；M is 0,1,2,3,4 or 5；R8And R9It is each independently selected from：Hydrogen, substituted or unsubstituted C1-C6 alkyl, Substituted or unsubstituted C3-C8 naphthenic base, substituted or unsubstituted 3-12 circle heterocyclic rings base or substituted or unsubstituted C6-C12 virtues Base；
The substitution refers to comprising one or more substituent groups selected from the group below：Halogen, hydroxyl, phenyl, C1-C12 alkyl, C1-C12 halogenated alkyls, C2-C12 unsaturated alkyls, C1-C6 alkoxies, C1-C6 halogenated alkoxies, C3-C12 cyclic hydrocarbon radicals, 3-12 Circle heterocyclic ring base, cyano, nitro, methylol, carboxyl, sulfydryl；
And R6Quantity be 1-3.
In another preferred example, R1And R7It is each independently hydrogen, C1-C4 alkyl or C2-C4 unsaturated alkyls.
In another preferred example, R2、R3、R4、R5It is each independently hydrogen, halogen, cyano, nitro, amino, hydroxyl, carboxylic Base, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C6 unsaturated alkyls, substituted or unsubstituted C1-C4 Alkoxy, substituted or unsubstituted C1-C4 acyl groups, substituted or unsubstituted C3-C6 cyclic hydrocarbon radicals ,-L1- (CH2) m- substitution or not Substituted C6-C12 aryl ,-L1- (CH2) the substituted or unsubstituted 4-10 circle heterocyclic rings bases of m- ,-L1- (CH2) m-C (=O)-N (R8) (R9), wherein L1 is nothing ,-O- or-S-；M is 0,1,2,3,4 or 5；R8And R9It is each independently selected from：Hydrogen, substitution or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 naphthenic base, substituted or unsubstituted 3-6 circle heterocyclic rings base or substitution or do not take The C6-C12 aryl in generation；
The substitution refers to comprising one or more substituent groups selected from the group below：Halogen, hydroxyl, phenyl, C1-C4 alkyl, C1-C4 halogenated alkyls, C2-C4 unsaturated alkyls, C1-C4 alkoxies, C1-C4 halogenated alkoxies, C3-C6 cyclic hydrocarbon radicals, 3-6 members are miscellaneous Ring group, cyano, nitro, methylol, carboxyl, sulfydryl.
In another preferred example, R3For hydrogen, halogen, hydroxyl ,-L1- (CH2) m-3-10 circle heterocyclic rings base ,-L1- (CH2)m-C6- C10 aryl ,-L1- (CH2) m-C6-C10 aryl-carboxyl, C1-C4 alkoxies, 3-6 circle heterocyclic rings base ,-L1- (CH2) m-C (=O)-N (R8)(R9), wherein L1 is nothing ,-O- or-S-；M is 0,1,2 or 3；R8And R9It is each independently selected from：Hydrogen, C1-C4 alkyl or Phenyl.
In another preferred example, R2、R4It is each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxies or-L1- (CH2) m-C6-C10 aryl, wherein L1 is nothing ,-O- or-S-；M is 0,1,2 or 3.
In another preferred example, R5For hydrogen or C1-C4 alkoxies.
In another preferred example, the compound is：
The second aspect of the present invention provides the preparation method of the compound described in second aspect, includes the following steps：
A) malonic acid obtains compound I with substituted benzaldehyde or reactive ketonea；
B) compound IaCompound shown in Formulas I is obtained with substituted benzaldehyde or reactive ketone,
Wherein, R1、R2、R3、R4、R5、R6、R7Definition as described in relation to the first aspect.
In another preferred example, the preparation method of the compound includes the following steps：
A) malonic acid and substituted benzoyl aldehydes or ketones are dissolved in a solvent, reacts to obtain compound I in heating stirringa, described Solvent is aceticanhydride；
B) by compound IaIt is dissolved in methanol with substituted benzoyl aldehydes or ketones, is stirred to react to obtain final product at room temperature.
The third aspect of the present invention, provides a kind of pharmaceutical composition, and the composition includes the chemical combination described in first aspect Object or its pharmaceutically acceptable salt, hydrate, solvate, enantiomter, diastereoisomer or racemic modification, or Their mixture；And pharmaceutically acceptable carrier.
" pharmaceutically acceptable carrier " refers to：One or more biocompatible solids or liquid filler or gelatinous mass, They are suitable for people's use and it is necessary to have enough purity and sufficiently low toxicity." compatibility " referred to herein as composition The active constituent of middle each component energy and the present invention and they between mutually admix, and significantly reduce the drug effect of active constituent. Pharmaceutically acceptable carrier part example have cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, Cellulose ethanoate etc.), gelatin, talcum, kollag (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soya-bean oil, Sesame oil, peanut oil, olive oil etc.), polyalcohol (such as propylene glycol, glycerine, mannitol, sorbierite), emulsifier (such as ), wetting agent (such as lauryl sodium sulfate), colorant, flavoring agent, stabilizer, antioxidant, preservative, apirogen water.
The fourth aspect of the present invention provides the compound described in first aspect or its pharmaceutically acceptable salt, hydration The purposes of object, solvate, enantiomter, diastereoisomer or racemic modification or their mixture, (a) is for making The inhibitor of standby SIRT1 deacetylases；Or (b) it is used to prepare treatment and the expression of SIRT1 abnormal proteins or horizontal with its enzyme activity The drug of relevant disease.
In another preferred example, the SIRT1 abnormal proteins are expressed or are selected from its enzyme activity level-related disease：Nerve moves back Row disease, cancer, metabolic disease, immune disorders and inflammation.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment) It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.Institute in specification The each feature disclosed can be replaced by any alternative characteristics for providing identical, impartial or similar purpose.As space is limited, exist This is no longer repeated one by one.
Description of the drawings
Fig. 1 is external SIRT1 enzyme activity experimental result picture, illustrates that compound S3 inhibits SIRT1 to live in a manner of concentration dependant Property
Fig. 2 is compound S3 to the inhibition type map of SIRT1 albumen, A), B) be respectively fixed NAD+Concentration changes substrate When peptide concentration, Michaelis constant curves and double reciprocal curve of the detection compound S3 to substrate A bz polypeptides.C), D) it is respectively solid Determine substrate A bz peptide concentrations, changes NAD+When concentration, detection compound S3 is to NAD+Michaelis constant curve and double reciprocal curve. Illustrate that compound S3 is the competitive inhibitor of substrate polypeptide Abz, is NAD+Noncompetitive inhibitor.
Fig. 3 is the binding curve figure of dynamic experiment (MST) the detection compound S3 and albumen of micro thermophoresis.Illustrate that compound S3 is competing The result figure of the binding site of striving property bound substrates polypeptide A bz.
A in Fig. 4) the molecular simulation result figures that are combined with SIRT1 of compound S3；B) SIRT1 mutant enzymes dynamic experiment knot Fruit is schemed.
Specific implementation mode
The present inventor is based on for a long time and in-depth study, is prepared for a kind of compound with structure shown in Formulas I, and find It is with SIRT1 inhibitory activity.And the compound generates inhibiting effect to SIRT1 at low concentrations, inhibitory activity is suitable It is excellent, thus can be used for treat with SIRT1 activity or the relevant disease of expression quantity for example neurodegenerative disease, metabolic disease, Tumour.On this basis, the present invention is completed.
Term
As used herein, term " C1-C12 alkyl " refers to the linear or branched alkyl group with 1-12 carbon atom, such as first Base, ethyl, propyl, isopropyl, butyl, isobutyl group, sec-butyl, tertiary butyl, n-pentyl, isopentyl, n-hexyl and isohesyl, or Similar group." C1-C6 alkyl " refers to the linear or branched alkyl group with 1,2,3,4,5 or 6 carbon atom, " C1-C4 alkyl " Refer to the linear or branched alkyl group with 1,2,3 or 4 carbon atom, and so on.Term " C1-C12 halogenated alkyls " refers to by 1, 2, the linear or branched alkyl group with 1-12 carbon atom of 3 or more halogens substitution, such as trifluoromethyl.
Term " C2-C12 unsaturated alkyls " refers to the linear chain or branched chain alkenyl or alkynyl for having 2-12 carbon atom, such as Vinyl, propinyl etc..
Term " C1-C6 alkoxies " refers to the straight or branched alkoxyl with 1-6 carbon atom, such as methoxyl group, ethoxy Base, propoxyl group, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy or similar group." the C1-C6 Alkoxy " definition includes " C1-C4 alkoxies ".
Term " C3-C12 cyclic hydrocarbon radicals " is saturation or unsaturated alkyl with 3-12 carbon atom on finger ring, such as ring third Base, cyclobutyl, cyclohexyl, cyclohexenyl group etc..Term " C3-C8 naphthenic base " is the saturated hydrocarbons with 3-8 carbon atom on finger ring Base, such as cyclopropyl, cyclobutyl, cyclohexyl.
Term " C6-C12 aryl " refers to monocycle or condensed-bicyclic with 6-12 carbon atom, has the pi-electron body of conjugation The substituent group of system, such as phenyl and naphthalene, or similar group.Described " C6-C12 aryl " definition includes " C6-C10 virtues Base ".
Term " 3-12 circle heterocyclic rings base " refers to monocycle or condensed-bicyclic with 3-12 annular atom, and in ring system there are one tools Or multiple (preferably 1-5) are selected from the hetero atoms of O, S, N or P, such as piperidyl, pyrrolidinyl, piperazinyl, tetrahydrofuran base, Morpholinyl, benzdioxolanyl, nafoxidine base or similar group.Described " the 3-12 circle heterocyclic rings base " definition includes " 4- 10 circle heterocyclic ring bases ".
Term " halogen " refers to fluorine, chlorine, bromine or iodine.
Herein, it removes and illustrates that place, term " substitution " refer to one or more hydrogen atoms on group by under The substituent group substitution of group：Halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C2-C6 acyl groups, does not take carboxyl Generation or halogenated C1-C6 alkyl-hydroxyls.
Unless stated otherwise, in the present invention, the compound occurred is intended to including all possible optical isomer, Such as the compound of single chiral or the mixture (i.e. racemic modification) of various different chipal compounds.All chemical combination of the present invention Among object, each asymmetric carbon atom can be optionally the mixture of R configurations or S configurations or R configurations and S configurations.
As used herein, term " the compounds of this invention " refers to Formulas I compound represented.The term further includes and Formulas I chemical combination Various crystalline forms, pharmaceutically acceptable salt, hydrate or the solvate of object.
As used herein, term " pharmaceutically acceptable salt " refers to the compounds of this invention and acid or alkali is formed by suitable use Make the salt of drug.Pharmaceutically acceptable salt includes inorganic salts and organic salt.A kind of preferred salt is the compounds of this invention and acid The salt of formation.The acid for suitably forming salt includes but is not limited to：Hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid etc. are inorganic Acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, The organic acids such as picric acid, methanesulfonic acid, benzene methanesulfonic acid, benzene sulfonic acid；And the acidic amino acids such as aspartic acid, glutamic acid.
Compound of formula I
Formula Compound I structure is as follows：
Each substituent group is defined as described above.
Preferred compound is as shown in the table：
Table 1, compound number, title and chemical structural formula
SIRT1 activitys inhibitor and its application
The compounds of this invention can inhibit the activity of one or more sirtuin albumen.For example, the compounds of this invention can The activity of the enzyme in cell for inhibiting to inhibit sirtuin enzyme activity or in patient, by by the chemical combination of the present invention of amount of suppression Object is applied to the cell, individual or patient and realizes the inhibition to sirtuin protein functions.
Through to the compounds of this invention to the inhibitory activity data analysis of SIRT1, SIRT2, SIRT3 and SIRT5 it is found that this hair Bright compound is the selective depressant of SIRT1, and selectivity is more preferable compared with for positive compound EX527.
As SIRT1 inhibitor, the compounds of this invention is suitable for treatment and SIRT1 unconventionality expressions or activity are relevant various Disease.Activity or the relevant dysproliferative disease of expression quantity with SIRT1 include but unlimited with following disease：Histiocytic Lymthoma, oophoroma, neck phosphor shaped epithelial cell cancer, gastric cancer, breast cancer, children's hepatocellular carcinoma, colorectal cancer, cervical carcinoma, It is lung cancer, sarcoma, nasopharyngeal carcinoma, cancer of pancreas, spongioblast cancer, prostate cancer, Small Cell Lung Cancer, non-small cell lung cancer, multiple Myeloma, thyroid cancer, carcinoma of testis, cervical carcinoma, adenocarcinoma of lung, colon cancer, Papillary Renal Cell Carcinoma, spongioblastoma, uterus Endometrial carcinomas, cancer of the esophagus, leukaemia, clear-cell carcinoma, carcinoma of urinary bladder, liver cancer and astrocytoma, glioma, non-malignant cutaneum carcinoma etc.. The Malignancy being more preferably used in including treatment breast cancer, colon cancer, prostate cancer, liver cancer and leukaemia.
The compound of the present invention and composition are for treating, preventing or regulating and controlling metabolism related diseases, including diabetes, high blood Fat, obesity, hyperglycemia hyperosmolality syndrome.
The compound of the present invention and composition are for treating, preventing or regulating and controlling neurodegenerative disease, including alzheimer ' Silent disease, parkinsonism, Huntingdon disease, amyotrophic lateral sclerosis, spinocerebellar ataxia and Duchenne-Arandisease Disease.
The invention has the beneficial effects that：
1,3- dioxane -4,6- cyclohexadione compounds toxicity of the present invention is low, and dissolubility is good.
1,3- dioxane -4,6- the cyclohexadione compounds of the present invention and its preparation method of derivative have reaction condition Mildly, abundant raw material is easy to get, operates and post-processes the advantages that simple, corresponding selection is good.
1,3- dioxane -4,6- the cyclohexadione compounds and its derivative of the present invention have very well SIRT deacetylases Inhibitory activity and excellent selectivity.
Therefore, the compound of the present invention can be used for treating and SIRT1 abnormal proteins are expressed or the relevant various diseases of activity, Such as neurodegenerative disease, diabetes, tumour disease.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip Part or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are weight percent and weight Number.
Unless otherwise defined, all professional and scientific terms used in text and meaning known to one skilled in the art Justice is identical.In addition, any method and material similar or impartial to described content can be applied to the method for the present invention.Wen Zhong The preferred implement methods and materials are for illustrative purposes only.
The preparation of 1 compound 5- of embodiment (4- chlorine benzal) -2- phenyl -1,3- dioxane -4,6- diketone (S1)
Reaction equation 1.1
Step 1:Prepare 2- phenyl -1,3- dioxane -4,6- diketone
Malonic acid (10.4g, 100mmol) is placed in round-bottomed flask, acetic anhydride (28.4mL, 300mmol) is added, room temperature is stirred It mixes, the dense H of 0.1mL is added2SO4, it is stirred overnight.At room temperature, it is slowly added to benzaldehyde (10.2mL, 100mmol), at 5 DEG C mistake Night reacts, after reaction.About 30mL toluene is added, is concentrated under reduced pressure and removes acetic anhydride, white solid is precipitated, is used after suction filtration 200mL water washing filter cakes, obtain crude product.Crude product is dissolved in acetone, solid is precipitated after suitable quantity of water is added, after stirring 15 minutes It filters, washes filter cake, obtain 2- phenyl -1,3- dioxies -4,6- diketone (10.2g, yield 53%).1H NMR(400MHz, DMSO-d6) δ 7.56 (dtd, J=10.2,5.1,2.0Hz, 5H), 7.13 (s, 1H), 4.56 (d, J=18.4Hz, 1H), 3.61 (d, J=18.4Hz, 1H) .MS (ESI, m/z):191(M-H)。
Reaction equation 1.2
Step 2:Prepare S1
2- phenyl -1,3- dioxy -4,6- diketone (0.3g, 1.56mmol) is dissolved in anhydrous DMSO, acetic anhydride is added Sodium (90mg, 1.09mmol) stirs to dissolve at room temperature, and 4- chlorobenzaldehydes (0.22g, 1.56mmol) are added, are stirred overnight, About 30mL water is added into solution, stirring makes solid be precipitated, and filters, and water washing filter cake obtains crude product, methanol/stone after drying Oily ether is recrystallized to give sterling 310mg, yield 63%.1H NMR(400MHz,CDCl3)δ8.32(s,1H),8.08-7.94(m, 2H),7.65-7.58(m,2H),7.56-7.40(m,5H),6.76(s,1H).
2 compound 5- of embodiment (the iodo- 5- benzylidenes of 4- hydroxyls -3-) -2- methyl -2- phenyl -1,3- dioxies six The preparation of ring -4,6- diketone (S2)
Reaction equation 2.1
Step 1:Prepare 2- methyl -2- phenyl -1,3- dioxane -4,6- diketone
Malonic acid (15.6g, 150mmol) is placed in round-bottomed flask, acetic anhydride (55.5mL, 585mmol) is added, room temperature is stirred It mixes, the dense H of 0.2mL is added2SO4, it is stirred overnight.At room temperature, it is slowly added to acetophenone (35mL, 300mmol), is reacted 1 hour Afterwards, it is concentrated under reduced pressure and removes acetic anhydride, production is isolated and purified to obtain through quick separating column chromatography (petrol ether/ethyl acetate=15/1, v/v) Object 2- methyl -2- phenyl -1,3- dioxy -4,6- diketone (9.3g, yield 30%).MS(ESI,m/z):205(M-H)。
Reaction equation 2.2
Step 2:Prepare S2
2- methyl -2- phenyl -1,3- dioxy -4,6- diketone (0.3g, 1.45mmol) is dissolved in anhydrous DMSO, nothing is added Water acetic acid sodium (84mg, 1.02mmol) stirs to dissolve at room temperature, and the iodo- 5- methoxybenzaldehydes of 4- hydroxyls -3- are added (0.41g, 1.45mmol), is stirred overnight, and about 30mL water is added into solution, and stirring makes solid be precipitated, and filters, water washing filter Cake, obtains crude product after drying, methanol/petroleum ether is recrystallized to give sterling 340mg, yield 50%.1H NMR(400MHz, DMSO-d6)δ10.59(s,1H),7.78-7.68(m,4H),7.42-7.22(m,4H),3.78(s,3H),1.86(s,3H).
3 compound 5- of embodiment (the bromo- 4- hydroxy-5-methyls oxygroup benzals of 3-) -2- phenyl -1,3- dioxane -4,6- The preparation of diketone (S3)
Other than replacing 4- chlorobenzaldehydes with the bromo- 4- hydroxy-5-methyls oxygroup benzaldehydes of 3-, with same as Example 1 Mode prepare compound S3, final step reaction yield 56%.1H NMR(400MHz,DMSO-d6) δ 8.17 (d, J=6.8Hz, 2H),7.91(s,1H),7.64–7.40(m,5H),7.08(s,1H),3.82(s,3H).MS(ESI,m/z):404(M-H)。
4 compound 5- of embodiment [4- (1,3- benzodioxolane -5- alkyl methoxyl group) -3- benzylidenes) -2- The preparation of phenyl -1,3- dioxane -4,6- diketone (S4)
In addition to replacing 4- chlorobenzaldehydes with 4- (phendioxin, 3- dioxolanes -5- alkyl methoxyl group)-m-methoxybenzaldehyde Except, prepare compound S4 in the same manner as example 1, final step reaction yield 68%.1H NMR(400MHz, CDCl3)δ8.34(s,1H),8.22-8.18(m,1H),7.64-7.42(m,6H),6.99-6.76(m,4H),6.70(s,1H), 5.96(s,2H),5.18(s,2H),3.90(s,3H)。
5 compound 3- of embodiment ({ 4- [(4,6- dioxy -2- phenyl -1,3- dioxanes -5- bases subunit) methyl] phenoxy group } Methyl) benzoic acid (S5) preparation
Other than replacing 4- chlorobenzaldehydes with 3- ((4- formyls phenoxy group) methyl) benzoic acid, with same as Example 1 Mode prepare compound S5, final step reaction yield 23%.1H NMR(400MHz,DMSO-d6)δ8.24(s,1H), 8.08-7.92(m,2H),8.05-8.01(m,1H),7.95-7.85(m,1H),7.62-7.50(m,3H),7.48-7.38(m, 4H),7.10-7.01(m,2H),6.88(s,1H),5.20(s,2H)。
6 5- of embodiment (the iodo- 5- benzylidenes of 4- hydroxyls -3-) -2- phenyl -1,3- dioxane -4,6- diketone (S6) preparation
Other than replacing 4- chlorobenzaldehydes with the iodo- 5- methoxybenzaldehydes of 4- hydroxyls -3-, with same as Example 1 Mode prepare compound S6, final step reaction yield 70%.1H NMR(400MHz,DMSO-d6)δ10.65(s,1H),8.14 (s,1H),8.08-7.92(m,2H),7.56-7.48(m,2H),7.42-7.38(m,3H),6.82(s,1H),3.83(s,3H)。
7 5- of embodiment (3- ethyoxyl -4- hydroxyls benzal) -2- methyl -2- phenyl -1,3- dioxane -4,6- diketone (S7) preparation
In addition to vanirom replace the iodo- 5- methoxybenzaldehydes of 4- hydroxyls -3- other than, with reality Apply 2 identical mode prepare compound S7 of example, final step reaction yield 46%.1H NMR(400MHz,CDCl3)δ8.08- 8.01(m,2H),7.54-7.25(m,5H),6.91-6.84(m,1H),6.35(s,1H),4.22-4.10(m,2H),1.56(s, 3H),1.50-1.42(m,3H)。
The preparation of 8 5- benzal -2- methyl -2- phenyl -1,3- dioxane -4,6- diketone (S8) of embodiment
Other than replacing the iodo- 5- methoxybenzaldehydes of 4- hydroxyls -3- with benzaldehyde, in the same way as in example 2 Prepare compound S8, final step reaction yield 62%.1H NMR(400MHz,CDCl3)δ8.06(s,1H),7.74-7.68(m, 2H),7.58-7.28(m,8H),1.98(s,3H)。
9 3- of embodiment ({ 2- methoxyl groups -4- [(2- methyl -4,6- dioxy -2- phenyl -1,3- dioxanes -5- bases subunit) Methyl] phenoxy group methyl) benzoic acid (S9) preparation
In addition to replacing the iodo- 5- methoxies of 4- hydroxyls -3- with 3- ((4- formoxyl -2- methoxyphenoxies) methoxyl group) benzoic acid Except benzaldehyde, prepare compound S9 in the same way as in example 2, final step reaction yield 45%.1H NMR (400MHz,CDCl3)δ8.18-8.02(m,3H),7.88(s,1H),7.70-7.65(m,1H),7.55-7.46(m,3H), 7.40-7.28(m,4H),6.88-6.82(m,1H),5.22(s,2H),3.86(s,3H),1.90(s,3H)。
10 5- of embodiment (3- chloro-4-hydroxyl -5- benzylidenes) -2- phenyl -1,3- dioxane -4,6- diketone (S10) preparation
Other than replacing 4- chlorobenzaldehydes with 4- hydroxyl -3- chloro-5-methoxyl benzaldehydes, with same as Example 1 Mode prepare compound S10, final step reaction yield 72%.1H NMR(400MHz,DMSO-d6)δ8.15(s,1H),7.90- 7.82(m,1H),7.80-7.74(m,1H),7.58-7.45(m,2H),7.42-7.36(m,3H),6.82(s,1H),3.84(s, 3H)。
11 5- of embodiment (2,5- dimethoxybenzylidenegroup groups) -2- methyl -2- phenyl -1,3- dioxane -4,6- diketone (S11) preparation
In addition to 2,5- dimethoxy benzaldehydes replace the iodo- 5- methoxybenzaldehydes of 4- hydroxyls -3- except, with embodiment 2 identical mode prepare compound S11, final step reaction yield 54%.1H NMR(400MHz,CDCl3)δ8.50(s,1H), 7.58-7.50(m,2H),7.43-7.30(m,3H),7.25-7.20(m,1H),7.05-7.02(m,1H),6.80-6.75(m, 1H),3.78(s,3H),3.76(s,3H),1.96(s,3H)。
12 5- of embodiment (3- ethyoxyl -4- hydroxyls benzal) -2- phenyl -1,3- dioxane -4,6- diketone (S12) Preparation
Other than replacing 4- chlorobenzaldehydes with vanirom, make in the same manner as example 1 Standby compound S12, final step reaction yield 43%.1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),8.20-8.04 (m,2H),7.60-7.38(m,6H),6.90-6.82(m,2H),4.14-4.02(m,2H),1.43-1.38(m,3H)。
13 5- of embodiment (2- benzylidenes) -2- methyl -2- phenyl -1,3- dioxane -4,6- diketone (S13) Preparation
In addition to Benzaldehyde,2-methoxy replace the iodo- 5- methoxybenzaldehydes of 4- hydroxyls -3- other than, with 2 phase of embodiment Same mode prepare compound S13, final step reaction yield 76%.1H NMR(400MHz,CDCl3)δ8.51(s,1H), 7.58-7.52(m,3H),7.44-7.30(m,4H),6.91-6.82(m,2H),3.80(s,3H),1.98(s,3H)。
The preparation of 14 5- of embodiment (2- isopropoxies benzal) -2- phenyl -1,3- dioxane -4,6- diketone (S14)
Other than replacing 4- chlorobenzaldehydes with 2- isopropoxide benzaldehydes, preparation in the same manner as example 1 Close object S12, final step reaction yield 43%.1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),8.20-8.04(m, 2H),7.60-7.38(m,6H),6.90-6.82(m,2H),4.14-4.02(m,2H),1.43-1.38(m,3H)。
15 5- of embodiment (bis- chloro-4-hydroxyl benzals of 3,5-) -2- phenyl -1,3- dioxane -4,6- diketone (S15) Preparation
In addition to being replaced except 4- chlorobenzaldehydes with 3,5-, bis- chloro- 4- hydroxy benzaldehydes, make in the same manner as example 1 Standby compound S15, final step reaction yield 68%.1H NMR(400MHz,DMSO-d6)δ8.15-8.07(m,3H),7.58- 7.39(m,6H),6.93(s,1H)。
16 5- of embodiment (4- hydroxyls benzal) -2- methyl -2- phenyl -1,3- dioxane -4,6- diketone (S16) It prepares
Other than replacing the iodo- 5- methoxybenzaldehydes of 4- hydroxyls -3- with 4- hydroxy benzaldehydes, with same as Example 2 Mode prepare compound S16, final step reaction yield 76%.1H NMR(400MHz,CDCl3)δ8.07(s,1H),7.93- 7.82(m,2H),7.56-7.44(m,2H),7.40-7.28(m,3H),6.87-6.80(m,2H),5.93(s,1H),1.94(s, 3H)。
17 5- of embodiment [4- (1,3- benzodioxolane -5- alkyl methoxyl group) benzal] -2- phenyl -1,3- dioxies The preparation of six ring -4,6- diketone (S17)
In addition to 4- (phendioxin, 3- dioxolanes -5- ylmethoxies) benzaldehyde replace 4- chlorobenzaldehydes except, with reality Apply 1 identical mode prepare compound S17 of example, final step reaction yield 41%.1H NMR(400MHz,CDCl3)δ8.37(s, 1H),8.23-8.16(m,2H),7.64-7.58(m,2H),7.51-7.42(m,3H),7.08-6.80(m,5H),6.70(s, 1H),5.96(s,2H),5.06(s,2H)。
The preparation of 18 5- of embodiment (4- hydroxyls benzal) -2- phenyl -1,3- dioxane -4,6- diketone (S18)
Other than replacing 4- chlorobenzaldehydes with 4- hydroxy benzaldehydes, prepare compound in the same manner as example 1 S18, final step reaction yield 55%.1H NMR(400MHz,DMSO-d6)δ10.56(s,1H),8.19(s,1H),8.10- 8.02(m,2H),7.55-7.43(m,2H),7.42-7.35(m,3H),6.85-6.75(m,3H)。
Embodiment 19 2- phenyl -5- (2,3,4- trimethoxies benzal) -1,3- dioxane -4,6- diketone (S19) It prepares
In addition to being replaced except 4- chlorobenzaldehydes with 2,3,4- trimethoxybenzaldehyde, make in the same manner as example 1 Standby compound S19, final step reaction yield 58%.1H NMR(400MHz,CDCl3)δ8.78(s,1H),8.28-8.20(m, 1H),7.63-7.40(m,5H),6.78-6.68(m,2H),4.01(s,3H),3.95(s,3H),3.84(s,3H)。
20 2- phenyl -5- of embodiment [4- (1- nafoxidines base) benzal] -1,3- dioxane -4,6- diketone (S20) Preparation
Other than replacing 4- chlorobenzaldehydes with 4- (1- nafoxidines base) benzaldehyde, in the same manner as example 1 Prepare compound S20, final step reaction yield 22%.1H NMR(400MHz,CDCl3)δ8.32(s,1H),8.28-8.19 (m,2H),7.68-7.58(m,2H),7.52-7.40(m,3H),6.64-6.52(m,3H),3.58-3.40(m,4H),2.18- 1.97(m,4H)。
21 2- of embodiment { 4- [(4,6- dioxy -2- phenyl -1,3- dioxanes -5- bases benzal) methyl] phenoxy group }-N- The preparation of phenyl acetamide (S21)
Other than replacing 4- chlorobenzaldehydes with 2- (4- formvlphenoxvs)-N- phenyl acetamides, with same as Example 1 Mode prepare compound S21, final step reaction yield 36%.1H NMR(400MHz,DMSO-d6)δ9.98(s,1H), 8.25(s,1H),8.20-8.01(m,2H),7.62-7.50(m,4H),7.49-7.40(m,3H),7.28-7.20(m,2H), 7.18-6.97(m,4H),4.78(s,2H)。
22 5- of embodiment (the bromo- 2,4- dimethoxys base benzals of 5-) -2- phenyl -1,3- dioxane -4,6- diketone (S22) preparation
In addition to being replaced except 4- chlorobenzaldehydes with bromo- 2, the 4- dimethoxy benzaldehydes of 5-, in the same manner as example 1 Prepare compound S22, final step reaction yield 65%.1H NMR(400MHz,CDCl3)δ8.66(s,1H),8.01(s,1H), 7.59 (ddd, J=7.3,2.0,1.0Hz, 2H), 7.44 (s, 1H), 7.42-7.34 (m, 2H), 7.37-7.29 (m, 1H), 6.75 (s, 1H), 3.89 (d, J=10.1Hz, 6H)
23 5- of embodiment (3- benzyl -4- hydroxy-5-methyl oxygroups benzal) -2- phenyl -1,3- dioxane -4,6- two The preparation of ketone (S23)
Other than replacing 4- chlorobenzaldehydes with 3- benzyl -4- hydroxy-5-methyl oxygroup benzaldehydes, with same as Example 1 Mode prepare compound S23, final step reaction yield 78%.1H NMR(400MHz,DMSO-d6)δ10.42(s,1H), 8.22(s,1H),8.04(s,1H),7.75(s,1H),7.69–7.45(m,5H),7.32–7.05(m,6H),3.92(s,2H), 3.85(s,3H).MS(ESI,m/z):415(M-H)。
24 5- of embodiment (4- hydroxyl -3,5- dimethoxybenzylidenegroup groups) -2- phenyl -1,3- dioxane -4,6- diketone (S24) preparation
In addition to being replaced except 4- chlorobenzaldehydes with 4- hydroxyl -3,5- dimethoxy benzaldehydes, with side same as Example 1 Formula prepare compound S24, final step reaction yield 82%.1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),8.28 (s,1H),7.79(s,2H),7.65–7.60(m,2H),7.57–7.49(m,3H),7.13(s,1H),3.82(s,6H).MS (ESI,m/z):355(M-H)。
The system of 25 5- of embodiment (the fluoro- 4- hydroxyls benzals of 3-) -2- phenyl -1,3- dioxane -4,6- diketone (S25) It is standby
Other than replacing 4- chlorobenzaldehydes with the fluoro- 4- hydroxy benzaldehydes of 3-, preparation in the same manner as example 1 Close object S25, final step reaction yield 74%.1H NMR(400MHz,DMSO-d6) δ 11.48 (s, 1H), 8.27 (dd, J= 13.4,1.8Hz, 2H), 7.89 (dd, J=8.6,2.1Hz, 1H), 7.62 (dd, J=6.8,3.0Hz, 2H), 7.54 (dd, J= 5.1,1.9Hz, 3H), 7.14 (s, 1H), 7.08 (t, J=8.8Hz, 1H) .MS (ESI, m/z):313(M-H)。
The system of 26 5- of embodiment (the bromo- 4- hydroxyls benzals of 3-) -2- phenyl -1,3- dioxane -4,6- diketone (S26) It is standby
Other than replacing 4- chlorobenzaldehydes with the bromo- 4- hydroxy benzaldehydes of 3-, preparation in the same manner as example 1 Close object S26, final step reaction yield 75%.1H NMR(400MHz,DMSO-d6) δ 11.81 (s, 1H), 8.60 (d, J= 2.2Hz, 1H), 8.23 (s, 1H), 8.04 (dd, J=8.7,2.2Hz, 1H), 7.65-7.59 (m, 2H), 7.57-7.50 (m, 3H), 7.15 (s, 1H), 7.06 (d, J=8.6Hz, 1H) .MS (ESI, m/z):374(M-H)。
27 5- of embodiment (bis- bromo- 4- hydroxyls benzals of 3,5-) -2- phenyl -1,3- dioxane -4,6- diketone (S27) Preparation
In addition to being replaced except 4- chlorobenzaldehydes with 3,5- dibromine-4-hydroxy benzaldehydes, make in the same manner as example 1 Standby compound S27, final step reaction yield 75%.1H NMR(400MHz,DMSO-d6)δ8.48(s,2H),8.18(s,1H), 7.66–7.58(m,2H),7.57–7.49(m,3H),7.11(s,1H).MS(ESI,m/z):453(M-H)。
28 5- of embodiment (bis- fluoro- 4- hydroxyls benzals of 3,5-) -2- phenyl -1,3- dioxane -4,6- diketone (S28) Preparation
In addition to being replaced except 4- chlorobenzaldehydes with 3,5-, bis- fluoro- 4- hydroxy benzaldehydes, make in the same manner as example 1 Standby compound S28, final step reaction yield 73%.1H NMR(400MHz,DMSO-d6)δ8.24(s,1H),8.08–8.03 (m,2H),7.64–7.59(m,2H),7.57–7.51(m,3H),7.15(s,1H).MS(ESI,m/z):331(M-H)。
29 5- of embodiment (4- hydroxyl -3,5- diiodo-s benzal) -2- phenyl -1,3- dioxane -4,6- diketone (S29) Preparation
In addition to being replaced except 4- chlorobenzaldehydes with 4- hydroxyl -3,5- diiodo- benzaldehydes, make in the same manner as example 1 Standby compound S29, final step reaction yield 80%.1H NMR(400MHz,DMSO-d6)δ7.75(s,1H),7.62–7.55 (m,2H),7.52–7.45(m,3H),7.08(s,3H),6.81(s,1H).MS(ESI,m/z):547(M-H)。
Pharmacological experiment
The present invention determines 1,3- dioxane -4,6- cyclohexadione compounds and lives to the inhibition of SIRT deacetylation enzyme activity Property, experiment material used in pharmacological experiment are commercially available unless otherwise specified.
One, SIRT1 enzyme activities detect
With DMSO by polypeptide A bz-GVLK(Ac)AY(NO2)GV-NH2 is configured to the storing liquid of 10mM, is frozen in -80 after packing In DEG C refrigerator；NAD+With enzyme activity reaction buffer (25mM Tris, pH 8.0,137mM sodium chloride, 2.7mM potassium chloride, 1mM chlorine Change magnesium) it is configured to the storing liquid of 50mM；Micromolecular compound is configured to the storing liquid of 10mM with DMSO.
Measure compound IC50When, gradient dilution is carried out to compound.Reaction system is 100 μ L, contains 1 μM in system SIRT1、500μM NAD+, 10 μM of substrate polypeptides and respective concentration compound, 3 secondary orifices of each reaction condition are each to test It is repeated 3 times.After 37 DEG C of oscillating reactions 30min, the final concentration of 10mM niacinamide of 50 μ L and 0.01mg/mL pancreases are added into every hole Protease come terminate reaction and carry out digestion.After 37 DEG C of reaction 15min, fluorescent value, excitation wavelength and transmitting are read with microplate reader Wavelength is respectively 320nm and 420nm.
As shown in table 1, this kind of compound be all 1,3- dioxane -4,6- diketone the positions C2 connect a phenyl, C5 Connect a benzal based structures.With SIRT1 enzyme activity test experiences, has detected this batch of compound and inhibit SIRT1 deacetylations The IC of enzymatic activity50(table 2) shows that such compound has inhibiting effect to SIRT1 deacetylation enzyme activity.
Since each hypotype of sirtuin families has very important effect in life entity, so in design SIRT1 When micromolecular inhibitor, to consider inhibiting effect of the inhibitor to other hypotypes of sirtuin, select several reactive compounds, inspection Their inhibitory activity to SIRT2, SIRT3 and SIRT5 are surveyed.In this experiment, select SIRT1 inhibitor EX527 as sun Property compound.According to measurement micromolecular compound to the IC of SIRT1 inhibiting effect50Detection method and the concentration of each component are matched Than detecting inhibiting effect of these compounds to SIRT1 homologous proteins.As shown in table 3, such compound is the selection of SIRT1 Property inhibitor, and selectivity is more preferable compared with for positive compound EX527.It can be seen that the compound of the present invention has SIRT1 Good inhibitory activity, and have preferable selectivity.
Table 2：Compound is to the active inhibiting effect of SIRT1 deacetylases
Compound IC50(μM) Compound IC50(μM)
S1 18.81±0.42 S15 1.20±0.09
S2 2.45±0.37 S16 7.06±0.10
S3 1.31±0.26 S17 3.41±0.19
S4 8.14±0.97 S18 6.33±0.21
S5 10.04±0.57 S19 15.79±1.36
S6 0.89±0.01 S21 4.51±1.17
S7 7.92±1.79 S22 4.89±0.35
S8 >50 S23 2.47±0.10
S9 12.88±2.09 S24 11.90±2.62
S10 1.90±0.53 S25 4.65±0.05
S11 16.75±0.71 S26 1.40±0.43
S12 5.49±0.95 S27 0.70±0.03
S13 14.38±1.86 S28 4.54±0.03
S14 14.01±2.01 S29 0.46±0.09
Table 3：Inhibiting effect of the part of compounds to the deacylated enzymatic activity of SIRT1, SIRT2, SIRT3, SIRT5
Two, enzyme kinetics reaction test
External SIRT1 enzyme activity experiment shows that compound S3 inhibits SIRT1 enzyme activity (see Fig. 1), S3 with concentration dependant manner Inhibit the IC of SIRT150It is 1.31 ± 0.26 μM, next selects compound S3, using Michaelis constant curve (Michaelis- Menten plot) and double reciprocal curve (Lineweaver-Burk plot) detect the inhibition type of this kind of inhibitor.
Since the deacetylation enzyme reaction of SIRT1 needs acetylated polypeptides, NAD+As Double bottom object, so dynamic carrying out enzyme It when mechanics reacts, needs to fix a reaction substrate concentration and change another reaction substrate concentration, judges inhibitor respectively To the substrate acetyl polypeptide and NAD of SIRT1+Inhibition type：
1) fixed NAD+A concentration of 1mM measures inhibition type of the inhibitor to acetylated polypeptides：Fixed SIRT1 albumen is dense Degree is 0.5 μM, and the concentration of acetylated polypeptides is respectively 50 μM, 25 μM, 12.5 μM, 6.25 μM, 3.125 μM, 1.5625 μM, is inhibited The concentration of agent S3 distinguishes 1.875 μM, 0.9375 μM, 0.46875 μM and 0 μM.After 37 DEG C of oscillating reactions 15min, digestion 15min is detected with microplate reader.
2) a concentration of 30 μM of fixed acetylated polypeptides measure inhibitor to NAD+Inhibition type：Fixed SIRT1 albumen A concentration of 0.5 μM, NAD+Concentration be respectively 1000 μM, 500 μM, 250 μM, 125 μM, 62.5 μM and 31.25 μM, inhibitor S3 Concentration distinguish 1.875 μM, 0.9375 μM, 0.46875 μM and 0 μM.After 37 DEG C of oscillating reactions 15min, digestion 15min is used Microplate reader is detected.
Experimental result is as shown in Figure 2.
A, B are respectively fixed NAD in Fig. 2+When concentration, change substrate A bz peptide concentrations, compound S3 is to Abz polypeptides Michaelis constant curve and double reciprocal curve.C, D are respectively fixed Abz peptide concentrations, change NAD in Fig. 2+When concentration, compound S3 is to NAD+Michaelis constant curve and double reciprocal curve.B can be seen that when mapping to substrate A bz polypeptides from Fig. 2, Different compound concentration lower curves meet at third quadrant, illustrate to increase with compound S3 concentration, initial velocity V0Reduce, apparent rice Family name's constant Km' reduce, so compound S3 is that mixed type inhibits, and the combination of compound S3 and SIRT1 may to substrate polypeptide In the binding site of substrate polypeptide.And to NAD+When mapping (D in Fig. 2), under different compound concentrations, curve meets at horizontal axis, Illustrate to increase with compound S3 concentration, initial velocity V0Reduce, apparent K_m Km' constant, so compound S3 is to NAD+It is Noncompetition inhibition, S3 are combined with SIRT1 not in NAD+Binding site.
Three, (Microscale Thermophoresis, MST) experiment is moved in micro thermophoresis
After mini-hSIRT1 albumen high speed centrifugation (12,000rpm, 10min) is removed gas, it is stored at room temperature 30min.To The TCEP (PB buffer dissolvings) of 100 100 times of albumen molar concentrations of μ L is added in 1mL mini-hSIRT1 albumen, uses nitrogen Centrifuge tube is covered rapidly after rinsing the centrifuge tube equipped with albumen, and 10min is placed after thorough mixing.50 μ L are added into centrifuge tube again The Cy5 of 10 times of albumen molar concentrationsTMDye solution (DMSO dissolvings), is purged with nitrogen after the centrifuge tube equipped with albumen and covers rapidly Centrifuge tube is placed after thorough mixing.Incubation at room temperature 2 hours, and it is primary every half an hour mixing, 4 DEG C are placed later overnight.Claim 2g SM-2 adsorbents (Bio-Rad), with the methanol Activation filling of 1~2 times of column volume, then with water and buffer solution (20mM HEPES, pH 7.2,200mM sodium chloride, 5% glycerine) it rinses.After above-mentioned protein liquid is flowed through filler, with wash buffer filler, collection flows through Liquid measures SIRT1 albumen concentration.
Before carrying out MST experiments, by labeled SIRT1Cy5Albumen high speed centrifugation (13,000rpm, 5min) removes Aggregation.The SIRT1 of labelCy5Albumen optimizes buffer solution (50mM Tris, pH 7.4,150mM sodium chloride, 10mM chlorinations with MST Magnesium, 0.05% Tween-20) to be diluted to 200nM spare.In reaction system, fixed SIRT1Cy5A concentration of 100nM, compound setting For 16 500 μM of initial concentration, doubling dilution gradients, and DMSO contents are 10% in holding system.Use Monolith NT115 (Nano Temper Technologies) measures MST curves (the Monolith NT115 parameter settings under the conditions of three kinds For 20%Red, MST Power 40.0%, excitation power 20%)：
1)SIRT1Cy5With compound S3 Curves of Interaction
2) in 500 μM of polypeptide A bz-GVLK(Ac)AY(NO2)GV-NH2Under participation, SIRT1Cy5It is bent with compound S3 interactions Line
3) in 5mM NAD+Under participation, SIRT1Cy5With compound S3 Curves of Interaction.
Experimental data is analyzed with MO.Affinity Analysis softwares, obtains MST binding curves.As shown in figure 3, Under the participation of Abz polypeptides, the binding curve of compound S3 and SIRT1 albumen moves to right, KdValue increases, and illustrates S3 pairs of compound Abz polypeptides are competitive inhibitors.And in NAD+When participation, the binding curve of compound S3 and SIRT1 albumen does not occur bright Aobvious variation, illustrates compound S3 to NAD+It is noncompetitive inhibitor.
Four, molecular simulation and mutant are tested
From the compound crystal composite structure for downloading SIRT1/EX527 in RCSB-PDB databases (www.rcsb.org) (PDB ID：4I5I), EX527 molecules in structure are removed, extracts the coordinate of a SIRT1 protein molecular, save as pdb texts Part.Compound S3 is docked in SIRT1 protein structures, and according to Structure-activity analysis binding model.As shown in A in Fig. 4, change Close object S3 and the 273rd phenylalanine of SIRT1,346 asparagines, 347 isoleucines, 348 aspartic acids and 414 Position phenylalanine has combination, so carrying out rite-directed mutagenesis to this 5 amino acid residues, and has detected compound S3 to these Inhibition constant (the K of SIRT1 mutant proteinsi).It can be seen that Ks of the compound S3 to SIRT1 wild types from B in Fig. 4iValue is 0.16 μM, compound S3 is to mutant SIRT1F273L、SIRT1N346A、SIRT1I347A、SIRT1D348A、SIRT1F414AInhibiting rate Constant KiRespectively 0.85 μM, 2.47 μM, 0.67 μM, 4.33 μM and 25.5 μM, it can be seen that, compound is to mutant protein Inhibition constant increases, wherein mutant SIRT1F414AMaximum is influenced on compound inhibitory activity, is based on binding model, hair There is hydrophobic effect between the C2 position phenyl and the 414th phenylalanine of existing compound, these all illustrate the 414th phenylpropyl alcohol of SIRT1 Propylhomoserin is the critical amino acid residues that " albumen/S3 micromolecular compounds " combines, and prompting can be appropriate in next step structure of modification The hydrophobicity for increasing compound phenyl, to further increase compound activity.In addition, being found according to binding model, compound C5 The 346th asparagicacid residue of the hydroxyl of position benzal R3 and SIRT1 forms hydrogen bond, and to the 346th asparagicacid residue After being mutated, compound S3 reduces the sensibility of mutant protein, illustrates that the site is also the crucial position that compound combines Point.
All references mentioned in the present invention is all quoted in this application, as a reference, just as each document coverlet It is solely incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art The present invention can be made various changes or modifications, such equivalent forms are equally fallen within defined by the application the appended claims Range.

Claims (10)

1. compound shown in Formulas I or its pharmaceutically acceptable salt, hydrate, solvate, enantiomter, diastereomeric are different Structure body or racemic modification or their mixture：
Wherein,
R1And R7It is each independently hydrogen, C1-C6 alkyl or C2-C12 unsaturated alkyls；
R2、R3、R4、R5、R6It is each independently hydrogen, halogen, cyano, nitro, amino, hydroxyl, carboxyl, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 unsaturated alkyls, substituted or unsubstituted C1-C6 alkoxies, substitution or not Substituted C1-C6 acyl groups, substituted or unsubstituted C3-C12 cyclic hydrocarbon radicals ,-L1- (CH2) the substituted or unsubstituted C6-C12 virtues of m- Base ,-L1- (CH2) the substituted or unsubstituted 3-12 circle heterocyclic rings bases of m- ,-L1- (CH2) m-C (=O)-N (R8)(R9), wherein L1 is Nothing ,-O- or-S-；M is 0,1,2,3,4 or 5；R8And R9It is each independently selected from：Hydrogen, takes substituted or unsubstituted C1-C6 alkyl Generation or unsubstituted C3-C8 naphthenic base, substituted or unsubstituted 3-12 circle heterocyclic rings base or substituted or unsubstituted C6-C12 virtues Base；
The substitution refers to comprising one or more substituent groups selected from the group below：Halogen, hydroxyl, phenyl, C1-C12 alkyl, C1- C12 halogenated alkyls, C2-C12 unsaturated alkyls, C1-C6 alkoxies, C1-C6 halogenated alkoxies, C3-C12 cyclic hydrocarbon radicals, 3-12 members Heterocycle, cyano, nitro, methylol, carboxyl, sulfydryl；
And R6Quantity be 1-3.
2. compound as described in claim 1, which is characterized in that R1And R7It is each independently hydrogen, C1-C4 alkyl or C2-C4 Unsaturated alkyl.
3. compound as described in claim 1, which is characterized in that R2、R3、R4、R5It is each independently hydrogen, halogen, cyano, nitre Base, amino, hydroxyl, carboxyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C6 unsaturated alkyls, substitution Or unsubstituted C1-C4 alkoxies, substituted or unsubstituted C1-C4 acyl groups, substituted or unsubstituted C3-C6 cyclic hydrocarbon radicals ,-L1- (CH2) the substituted or unsubstituted C6-C12 aryl of m- ,-L1- (CH2) the substituted or unsubstituted 4-10 circle heterocyclic rings bases of m- ,-L1- (CH2) m-C (=O)-N (R8)(R9), wherein L1 is nothing ,-O- or-S-；M is 0,1,2,3,4 or 5；R8And R9It selects each independently From：Hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 naphthenic base, substituted or unsubstituted 3-6 members are miscellaneous Ring group or substituted or unsubstituted C6-C12 aryl；
The substitution refers to comprising one or more substituent groups selected from the group below：Halogen, hydroxyl, phenyl, C1-C4 alkyl, C1-C4 Halogenated alkyl, C2-C4 unsaturated alkyls, C1-C4 alkoxies, C1-C4 halogenated alkoxies, C3-C6 cyclic hydrocarbon radicals, 3-6 circle heterocyclic rings base, Cyano, nitro, methylol, carboxyl, sulfydryl.
4. compound as described in claim 1, which is characterized in that R3For hydrogen, halogen, hydroxyl ,-L1- (CH2) m-3-10 members are miscellaneous Ring group ,-L1- (CH2) m-C6-C10 aryl ,-L1- (CH2) m-C6-C10 aryl-carboxyl, C1-C4 alkoxies, 3-6 circle heterocyclic rings Base ,-L1- (CH2) m-C (=O)-N (R8)(R9), wherein L1 is nothing ,-O- or-S-；M is 0,1,2 or 3；R8And R9It is respectively independent Ground is selected from：Hydrogen, C1-C4 alkyl or phenyls.
5. compound as described in claim 1, which is characterized in that R2、R4Be each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxies or-L1- (CH2) m-C6-C10 aryl, wherein L1 is nothing ,-O- or-S-；M is 0,1,2 or 3.
6. compound as described in claim 1, which is characterized in that R5For hydrogen or C1-C4 alkoxies.
7. compound as described in claim 1, which is characterized in that the compound is：
8. the preparation method of compound as described in claim 1, which is characterized in that include the following steps：
A) malonic acid obtains compound I with substituted benzaldehyde or reactive ketonea；
B) compound IaCompound shown in Formulas I is obtained with substituted benzaldehyde or reactive ketone,
Wherein, R1、R2、R3、R4、R5、R6、R7Definition it is as described in claim 1.
9. a kind of pharmaceutical composition, which is characterized in that the composition includes compound described in claim 1 or its pharmacy Upper acceptable salt, hydrate, solvate, enantiomter, diastereoisomer or racemic modification or their mixing Object；And
Pharmaceutically acceptable carrier.
10. compound as described in claim 1 or its pharmaceutically acceptable salt, hydrate, solvate, enantiomerism The purposes of body, diastereoisomer or racemic modification or their mixture, which is characterized in that (a) is used to prepare SIRT1 and goes The inhibitor of acetylase；Or (b) it is used to prepare treatment and SIRT1 albumen deacetylase unconventionality expressions or horizontal with its enzyme activity The drug of relevant disease.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019242687A1 (en) * 2018-06-21 2019-12-26 中国科学院上海药物研究所 1,3-dioxane-4,6-dione compound, and preparation method, pharmaceutical composition, and application thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0578849A1 (en) * 1992-07-17 1994-01-19 Biogal Gyogyszergyar Process for the preparation of 1,3-dioxane-4,6-dione derivates

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108640898A (en) * 2018-06-21 2018-10-12 中国科学院上海药物研究所 1,3- dioxane -4,6- cyclohexadione compounds, preparation method, pharmaceutical composition and its application

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0578849A1 (en) * 1992-07-17 1994-01-19 Biogal Gyogyszergyar Process for the preparation of 1,3-dioxane-4,6-dione derivates

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AMERICAN CHEMICAL SOCIETY (ACS): "STNext Registry 数据库", 《HTTP://NEXT.STN.ORG》 *
CASADESUS，MERITXELL等: "Synthesis of 5-alkylidene-1，3-dioxane-4，6-diones， an easily accessible family of axially chiral alkenes: preparation in non-racemic form and platinum binding studies.", 《ORGANIC & BIOMOLECULAR CHEMISTRY》 *
刘瑞环等: "ＳＩＲＴ１抑制剂的研究进展", 《中南药学》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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