CN101919835B - Application of 2-acetylamino gentisic acid to preparing insulin sensitizer - Google Patents
Application of 2-acetylamino gentisic acid to preparing insulin sensitizer Download PDFInfo
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Abstract
The invention discloses application of a 2-acetylamino gentisic acid compound with protein tyrosine phosphatase 1B inhibitory activity to preparing an insulin sensitizer. The 2-acetylamino gentisic acid can be used for preparing drugs for treating diabetes, obesity and complications thereof caused by insulin resistance and is obtained by fermenting and separating deep-sea streptomyces sp. 220225.
Description
Technical field
The invention belongs to the microbial medicine field.Be particularly related to a kind of purposes that protein-tyrosine-phosphatase 1B (PTP 1B) suppresses active chemical compound 2-acetylamino gentisic acid (2-Acetylaminogentisic acid) conduct preparation euglycemic agent that has.
Background technology
Diabetes (Diabetes Mellitus; DM) being is chronic disease, the frequently-occurring disease of characteristic with the chronic hyperglycemia, is that absolute or relative deficiency and target tissue cell reduce a series of metabolism disorders such as the sugar that causes, fat, protein, electrolyte to insulin sensitivity owing to insulin secretion in the body.Along with improving constantly of human living standard, the sickness rate of diabetes increases year by year, has become the chronic disease of the 3rd serious threat human health after cancer, cardiovascular disease at present.WHO estimates, because aged tendency of population, obesity, unsound diet and the life style that lacks motion, will rise to 3.0 hundred million by 1.35 hundred million of nineteen ninety-five to the number of diabetics in 2025.Therefore, diabetes and complication thereof have become the worldwide public health problem of serious threat human health.
Generally diabetes are divided into two types of insulin-dependent (IDDM, I type) and non-insulin-depending types (NIDDM, II type) clinically.Wherein 90% diabetics all belongs to type ii diabetes.Type ii diabetes (DM2) is a kind of multi-factor disease, by environmental factors and inherited genetic factors both sides decision, and is significant heterogeneity, the various complicacy of its pathogenesis, and exist than big-difference between each patient.Generally speaking can be summarized as the relative deficiency and the insulin resistant of insulin secretion.To the type ii diabetes people, especially a series of researchs of obese diabetic patient confirm, insulin resistant is the key factor in type ii diabetes generation, the evolution.Therefore, designing and developing euglycemic agent, to improve the insulin resistant state, is the emphasis of present type ii diabetes new drug research, also is one of its main direction.
The characteristic of type ii diabetes is the opposing to insulin action of insulin sensitivity tissue such as skeletal muscle, fatty tissue.Though its mechanism of action is still indeterminate, insulin signaling weakening even blocking in its pathway must be direct factor.Insulin is through combining the intrinsic tyrosine kinase activity of β subunit in the activated receptor born of the same parents with the outer α subunit of its receptor born of the same parents; Cause tyrosine residue autophosphorylation crucial in the adjustment structure territory; Thereby activate the insulin receptor tyrosine kinase activity fully, insulin receptor tyrosine kinase hands on signal through its substrate of phosphorylation again.Along with the intensification of reversibility tyrosine phosphorylation understanding in the insulin action path in the pair cell, protein-tyrosine-phosphatase (PTPases) is the more importance attached in the GAP-associated protein GAP tyrosine phosphorylation level in this path of balance.PTPases possibly act on a plurality of links in this path, thus path behind the negative regulation insulin action receptor.The active imbalance of EGFR-TK glucose-6-phosphate dehydrogenase possibly be the reason that causes the type ii diabetes insulin resistant in specific PTPases and the insulin path.Therefore, suppress its activity, strengthen and the prolongation insulin signaling, become the new way of more and more valued treatment type ii diabetes through the inhibitor of seeking selectively acting PTPases in this path.
PTPases comprises that extended familys stride (non-receptor type) enzyme in film (receptor type) and the born of the same parents, participates in the serial important life process of regulation and control.Though multiple PTPases expresses in the insulin sensitivity tissue, like CD45, LAR-PTPase, SHPTP-1, SHPTP-2, PTP 1B etc., have only several kinds of PTPases maybe be in the insulin path receptor or receptor metasomite influence normal insulin action.Present research mainly concentrates on LAR-PTPase, SHPTP-2 and PTP 1B.
PTP 1B is one of non-receptor type PTP of classics in the PTPases family.It is a kind of PTPase of wide expression; Be positioned at cell; C-end structure territory through catalytically inactive links to each other with endoplasmic reticulum, and can be through the dephosphorylation downward modulation insulin signaling to IRS-1 (IRS-1) and IRS-2 (IRS-2).Research shows that PTP 1B is wide expression in the insulin sensitivity tissue, and protein expression and phosphate esterase active level all are higher than matched group in the skeletal muscle of the obese people of insulin resistant and rodent and adipose cell.Therefore we infer, two subject matters of PTP 1B and metabolism syndrome, and impaired glucose tolerance and obesity have substantial connection.A large amount of experiments prove; PTP 1B is the potential target spot of treatment diabetes and obesity; Its correlated inheritance is learned the not only insulin sensitivity enhancing of mice that evidence is a PTP 1B gene knockout; And, make mice obesity or insulin resistant under the high fat diet condition, also not occur owing to removed the inhibition of PTP 1B to insulin and leptin signal transduction.Therefore, suppress PTP 1B level, improve the sensitivity of insulin signaling pathway, can treat insulin resistant, diabetes and obesity effectively.PTP 1B inhibitor also becomes " new talent " that scientists is sought metabolic disease medicaments such as diabetes, obesity gradually in recent years.
Though the research of PTP 1B selective depressant has obtained certain progress.But great majority are confined to some peptide classes or type peptide compounds, though these peptide inhibitors have the active and higher selectivity of stronger inhibition, they self physicochemical property makes it be difficult to become drug candidate compound.In recent years, screening is sought micromolecule PTP 1B selective depressant and is received people's generally attention from natural product and synthesis of chemicals, is one of important channel of finding new treatment diabetes, obesity and complication medicine thereof.
Summary of the invention
In order to solve the weak point that exists in the above-mentioned prior art; Primary and foremost purpose of the present invention is to provide a kind of to be had protein-tyrosine-phosphatase (PTP) 1B and suppresses active chemical compound 2-acetylamino gentisic acid (2-Acetylaminogentisic acid) (structure is as follows), as the purposes of preparation euglycemic agent.
The object of the invention is realized through following technical proposals: a kind of have protein-tyrosine-phosphatase 1B and suppress active chemical compound 2-acetylamino gentisic acid, as the purposes of preparation euglycemic agent.
Said euglycemic agent is applied to prepare diabetes, obesity and the complication medicine thereof that treatment is caused by insulin resistant.
Said 2-acetylamino gentisic acid is to separate through deep-sea streptomycete (Streptomyces sp.) 220225 fermentations to obtain;
Said deep-sea streptomycete 220225 is preserved in Chinese typical culture collection center on July 15th, 2009, and deposit number is CCTCC M209154.
Said 2-acetylamino gentisic acid prepares by following method:
(1) deep-sea streptomycete 220225 is inoculated in after slant activation in the FM3 culture medium, under 26～30 ℃ with 180～250rmin
-1Shaken cultivation 1～3d is inoculated in the FM3 culture medium according to 2～10% inoculum concentrations again, and 26～30 ℃, 160～250rmin
-1Shaken cultivation 7～10d obtains fermented product;
(2) fermented product is evaporated to extractum, adds the methanol account for fermented product volume 1/30～5/30 and extract, leach extracting solution, extracting solution is concentrated into dried, obtain CE;
(3) CE is suspended with methanol aqueous solution, use isopyknic cyclohexane extraction, chloroform and ethyl acetate extraction more successively, obtain cyclohexane extraction extract layer (A), chloroform extraction layer (B), ethyl acetate extraction layer
(C) and water layer position (D); Ethyl acetate extraction layer (C) is carried out Sephadex LH-20 column chromatography; The use volume ratio is 1: 1 a chloroform/methanol eluting; Obtain 025C-B1,025C-B2,025C-B3,025C-B4,025C-B5,025C-B6 and 025C-B7 totally 7 fractions successively according to eluted sequencing; 025C-B4 is carried out the SephadexLH-20 column chromatography once more, and the use volume ratio is 1: 1 a chloroform/methanol eluting, obtains chemical compound 2-acetylamino gentisic acid.
The said FM3 culture medium of step (1) is made up of the component of the following meter of volume ratio by weight: soluble starch 20g/L, yeast powder 5g/L, analysis for soybean powder 15g/L, peptone 2g/L, calcium carbonate 4g/L, sea salt 18g/L; The pH value of said FM3 culture medium is 7.0.
The temperature of the said concentrating under reduced pressure of step (2) is 40～100 ℃; The number of times of said extraction is 2～3 times.
The mass volume ratio of said CE of step (3) and methanol aqueous solution is 1～10g/L.
The concentration of volume percent of the said methanol aqueous solution of step (3) is 60～90%.
(13 ° of 24.987 ' N separate in 110 ° of 9.202 ' E) sample said deep-sea streptomycete 220225 from picking up from South China Sea deep-sea sea mud.This deep-sea streptomycete 220225 belongs to cinder ash monoid, and cell wall contains LL-DAP and glycine, does not have the characteristic saccharide.Optimum growh NaCl concentration is 1%, the highest 25%NaCl concentration that tolerates.
The present invention is with respect to prior art; Have following advantage and beneficial effect: the present invention shows that through the biological activity test experiment chemical compound 2-acetylamino gentisic acid has strong inhibition PTP 1B activity; As PTP1B inhibitor and euglycemic agent, can be used as the medicine that is used to treat the diabetes, obesity and the complication thereof that cause by insulin resistant.
The specific embodiment
Below in conjunction with embodiment the present invention is described in further detail, but embodiment of the present invention is not limited thereto.
In the following example, mass spectrograph is the LCQ-Advantage mass spectrograph that U.S. Finnigan company produces.NMR spectrometer with superconducting magnet is Bruker AV-400.Thin layer chromatography is Haiyang Chemical Plant, Qingdao's product with silica GF254 and column chromatography silica gel (200-300 order).Anti-phase ODS filler (40-63 μ m) is a U.S. Merck Company products.Sephadex LH 20 is the Pharmacia Company products.Phase chromatography-use methanol is chromatographically pure, and water is dual distilled water, and other reagent are analytical pure.In the biological activity test experimental example, the construction method of PTP 1B high flux screening model is with reference to " molecular cloning experimental technique ".PNPP (p-nitrophenyl phosphoric acid) purchases in Shanghai the biological company limited of living worker.
Embodiment 1:
The sea mud from the South China Sea deep-sea (13 ° of 24.987 ' N, the separation of 110 ° of 9.202 ' E) middle employing Gao Shi culture medium obtains deep-sea streptomycete bacterial strain 220225, and this deep-sea streptomyces is in cinder ash monoid, and cell wall contains LL-DAP and glycine, does not have the characteristic saccharide.Optimum growh NaCl concentration is mass percent 1%, the highest mass percent 25%NaCl concentration that tolerates.The GenBank accession number of the 16S rRNA gene order of this bacterial strain is FJ429837, and its sequence is:
GCGTGGGCGT?GCTTACCATG?CAAGTCGAAC?GATGAACCAC?TTCGGTGGGG?ATTAGTGGCG
AACGGGTGAG?TAACACGTGG?GCAATCTGCC?CTGCACTCTG?GGACAAGCCC?TGGAAACGGG
GTCTAATACC?GGATACTGAT?CATCTTGGGC?ATCCTTGGTG?ATCGAAAGCT?CCGGCGGTGC
AGGATGAGCC?CGCGGCCTAT?CAGCTTGTTG?GTGAGGTAAT?GGCTCACCAA?GGCGACGACG
GGTAGCCGGC?CTGAGAGGGC?GACCGGCCAC?ACTGGGACTG?AGACACGGCC?CAGACTCCTA
CGGGAGGCAG?CAGTGGGGAA?TATTGCACAA?TGGGCGAAAG?CCTGATGCAG?CGACGCCGCG
TGAGGGATGA?CGGCCTTCGG?GTTGTAAACC?TCTTTCAGCA?GGGAAGAAGC?GAAAGTGACG
GTACCTGCAG?AAGAAGCGCC?GGCTAACTAC?GTGCCAGCAG?CCGCGGTAAT?ACGTAGGGCG
CGAGCGTTGT?CCGGAATTAT?TGGGCGTAAA?GAGCTCGTAG?GCGGCTTGTC?GCGTCGGTTG
TGAAAGCCCG?GGGCTTAACC?CCGGGTCTGC?AGTCGATACG?GGCAGGCTAG?AGTTCGGTAG
GGGAGATCGG?AATTCCTGGT?GTAGCGGTGA?AATGCGCAGA?TATCAGGAGG?AACACCGGTG
GCGAAGGCGG?ATCTCTGGGC?CGATACTGAC?GCTGAGGAGC?GAAAGCGTGG?GGAGCGAACA
GGATTAGATA?CCCTGGTAGT?CCACGCCGTA?AACGGTGGGC?ACTAGGTGTG?GGCGACATTC
CACGTCGTCC?GTGCCGCAGC?TAACGCATTA?AGTGCCCCGC?CTGGGGAGTA?CGGCCGCAAG
GTTAAAACTC?AAAGGAATTG?ACGGGGGCCC?GCACAAGCGG?CGGAGCATGT?GGCTTAATTC
GACGCAACGC?GAAGAACCTT?ACCAAGGCTT?GACATACACC?GGAAAACCCT?GGAGACAGGG
TCCCCCTTGT?GGTCGGTGTA?CAGGTGGTGC?ATGGCTGTCG?TCAGCTCGTG?TCGTGAGATG
TTGGGTTAAG?TCCCGCAACG?AGCGCAACCC?TTGTCCCGTG?TTGCCAGCAG?GCCCTTGTGG
TGCTGGGGAC?TCACGGGAGA?CCGCCGGGGT?CAACTCGGAG?GAAGGTGGGG?AGGACGTCAA
GTCATCATGC?CCCTTATGTC?TTGGGCTGCA?CACGTGCTAC?AATGGCCGGT?ACAATGAGCT
GCGATACCGC?GAGGTGGAGC?GAATCTCAAA?AAGCCGGTCT?CAGTTCGGAT?TGGGGTCTGC
AACTCGACCC?CATGAAGTCG?GAGTCGCTAG?TAATCGCAGA?TCAGCATTGC?TGCGGTGAAT
ACGTTCCCGG?GCCTTGTACA?CACCGCCCGT?CACGTCACGA?AAGTCGGTAA?CACCCGAAGC
CGGT
Said bacterial strain is preserved in Chinese typical culture collection center on July 15th, 2009, and deposit number is CCTCC M209154.
Embodiment 2: bacterial strain 220225 bulk fermentations and fermented product sample-pretreating method thereof
Deep-sea streptomycete 220225 through slant activation, is inoculated in the FM3 culture medium 28 ℃, 220rmin
-1Shaken cultivation 3d is inoculated in the 30L FM3 culture medium according to 5% inoculum concentration, and 28 ℃, 220rmin
-1Shaken cultivation 7d obtains fermented product.Fermented product is evaporated to extractum under 60 ℃, add an amount of methanol (3L) and extract, and leaches extracting solution (repeating 2 times), and extracting solution is concentrated into dried CE.Said FM3 culture medium is made up of the component of following volume ratio by weight: soluble starch 20g/L, and yeast powder 5g/L, analysis for soybean powder 15g/L, peptone 2g/L, calcium carbonate 4g/L, sea salt 18g/L regulates pH to 7.0 (Garcia, G.D.; Romero, M.F.; Perez, B.J.; Garcia, D.T.Thiodepsipeptide isolated from a marine actinomycete WO9527730.1999, PatentNumber:US5681813.).
Embodiment 3: the separation of chemical compound
With of the methanol aqueous solution suspension (mass volume ratio of said CE and methanol aqueous solution be 10g/L) of embodiment 2 gained CEs with volumn concentration 90%; Use isopyknic cyclohexane extraction, chloroform and ethyl acetate extraction then successively; Obtain cyclohexane extraction extract layer (A), chloroform extraction layer (B), ethyl acetate extraction layer (C) and water layer position (D).Ethyl acetate extraction layer (C) is carried out Sephadex LH-20 column chromatography; The use volume ratio is 1: 1 a chloroform/methanol eluting; Obtain 025C-B1,025C-B2,025C-B3,025C-B4,025C-B5,025C-B6 and 025C-B7 totally 7 fractions successively according to eluted sequencing; 025C-B4 is carried out Sephadex LH-20 column chromatography once more, and the use volume ratio is 1: 1 a chloroform/methanol eluting, obtains chemical compound 1.
Embodiment 4: the structure of chemical compound is identified
Through MS (comprising low distinguishing and high-resolution MS), NMR multiple Wave Spectrum means such as (comprising 1D, 2D NMR experiment), confirmed the structure of chemical compound, be accredited as 2-acetylamino gentisic acid (2-Acetylaminogentisic acid), its
1H,
13C NMR data are as shown in table 1 below:
Nuclear magnetic resonance data and the ownership of table 1 chemical compound 1-3
Embodiment 5: extract sample, fraction sample and Compound P TP 1B suppress activity test method
Experimental principle: the present invention adopts the light absorption detection method, in the flat transparent microwell plate in 96 holes, detects the activity of enzyme.Utilize molecular biology method at escherichia coli system expression people source protein matter tyrosine-phosphatase 1B (hPTP 1B) catalyst structure domain; HPTP 1B recombiant protein after purified can hydrolysis substrate pNPP the phospholipid key; The free product that obtains has very strong light absorption at the 410nm place, and variation that therefore can be through directly detecting 410nm place's light absorption is with the activity change of observation enzyme and the chemical compound inhibition situation to enzymatic activity.Observation index is the absorbance value at 410nm place for the dynamic measurement wavelength, and the time is 3min, and the slope of its kinetic curve first order reaction is as the activity index of enzyme.The active testing system of standard is following: 50mM Mops, PH 7.0,1mM EDTA, 2mM DTT, 2mM pNPP, 2%DMSO, 40nM hPTP 1B.The positive control chemical compound that adopts in the experiment is Na
3VO
4
Sample test and result treatment: primary dcreening operation is selected single concentration conditions 20 μ g/ml, and the activity of sample is tested.For under above-mentioned concentration, to show active sample be suppression ratio greater than 50%, test its active dose dependence, i.e. IC
50Value is carried out non-linear fitting through the sample activity to sample concentration and is obtained.Calculating used software is Graphpad Prism 4, and the employed model of match is sigmoidal dose-response (varible slope), and matched curve bottom and top are set at 0 and 100.Each sample all is provided with multiple hole (n >=2) in test, (Standard Deviation SD) representes with standard deviation in the result.The active result of chemical compound and positive control medicine is as shown in table 2 below:
It is active that the PTP1B of table 2 chemical compound suppresses
The foregoing description is a preferred implementation of the present invention; But embodiment of the present invention is not restricted to the described embodiments; Other any do not deviate from change, the modification done under spirit of the present invention and the principle, substitutes, combination, simplify; All should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (8)
- One kind have protein-tyrosine-phosphatase 1B suppress active chemical compound 2-acetylamino gentisic acid as the preparation euglycemic agent purposes.
- 2. purposes according to claim 1 is characterized in that: said euglycemic agent is applied to prepare diabetes, obesity and the complication medicine thereof that treatment is caused by insulin resistant.
- 3. purposes according to claim 1 is characterized in that: said 2-acetylamino gentisic acid is to separate through deep-sea streptomycete (Streptomyces sp.) 220225 fermentations to obtain;Said deep-sea streptomycete 220225 is preserved in Chinese typical culture collection center on July 15th, 2009, and deposit number is CCTCC M209154.
- 4. purposes according to claim 3 is characterized in that: said 2-acetylamino gentisic acid prepares by following method:(1) deep-sea streptomycete 220225 is inoculated in after slant activation in the FM3 culture medium, under 26～30 ℃ with 180～250rmin -1Shaken cultivation 1～3d is inoculated in the FM3 culture medium according to 2～10% inoculum concentrations again, and 26～30 ℃, 160～250rmin -1Shaken cultivation 7～10d obtains fermented product;(2) fermented product is evaporated to extractum, adds the methanol account for fermented product volume 1/30～5/30 and extract, leach extracting solution, extracting solution is concentrated into dried, obtain CE;(3) CE is suspended with methanol aqueous solution, use isopyknic cyclohexane extraction, chloroform and ethyl acetate extraction more successively, obtain cyclohexane extraction extract layer (A), chloroform extraction layer (B), ethyl acetate extraction layer (C) and water layer position (D); Ethyl acetate extraction layer (C) is carried out Sephadex LH-20 column chromatography; The use volume ratio is 1: 1 a chloroform/methanol eluting; Obtain 025C-B1,025C-B2,025C-B3,025C-B4,025C-B5,025C-B6 and 025C-B7 totally 7 fractions successively according to eluted sequencing; 025C-B4 is carried out Sephadex LH-20 column chromatography once more, and the use volume ratio is 1: 1 a chloroform/methanol eluting, obtains chemical compound 2-acetylamino gentisic acid.
- 5. purposes according to claim 4 is characterized in that: the said FM3 culture medium of step (1) is made up of the component of the following meter of volume ratio by weight: soluble starch 20g/L, yeast powder 5g/L; Analysis for soybean powder 15g/L; Peptone 2g/L, calcium carbonate 4g/L, sea salt 18g/L; The pH value of said FM3 culture medium is 7.0.
- 6. purposes according to claim 4 is characterized in that: the temperature of the said concentrating under reduced pressure of step (2) is 40～100 ℃; The number of times of said extraction is 2～3 times.
- 7. purposes according to claim 4 is characterized in that: the mass volume ratio of said CE of step (3) and methanol aqueous solution is 1～10g/L.
- 8. purposes according to claim 4 is characterized in that: the concentration of volume percent of the said methanol aqueous solution of step (3) is 60～90%.
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