CN101735286B - Amino acid modified glucosamine as well as preparation method and application thereof - Google Patents
Amino acid modified glucosamine as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses an amino acid modified glucosamine shown as the general formula I. By detection, the amino acid modified glucosamine has more favorable PPAR agonist activity and potential and wide application prospect in the field of treatment of diabetes, is a favorable diabetes resistant leading compound and can be further developed to prepare a diabetes resistant medicament. The invention also provides a preparation method of the amino acid modified glucosamine. An intermediate 2-amino-1,3,4,6-four-O-acetyl-beta-D-glucosamine sulfate is synthesized in one step by adopting D-amino glucosamine hydrochloride as an initial raw material through an improved acetic anhydride-sulfuric acid method, and the intermediate is coupled with protected amino acid under the action of a condensing agent to obtain the amino acid modified glucosamine. The invention has short reaction step, mild reaction condition, convenient post processing, high yield and low cost.
Description
Technical field
The present invention relates to a kind of GS verivate, particularly amino acid modified GS also relates to its preparation method and the application aspect medical.
Background technology
Mellitus be because of hypoinsulinism cause with carbohydrate metabolism disturbance, blood sugar is too high is the chronic disease of principal character, is the healthy the third-largest disease of harm humans after cardiovascular disorder and cancer.Show that according to the IDF latest data whole world had 2.46 hundred million diabetic subjects approximately in 2007, estimates will reach 3.8 hundred million in 2025, promptly 7.1% of adult population, wherein the type ii diabetes patient accounts for 90%.The antidiabetic medicine type of listing is a lot of at present, but all has heavy or light spinoff, as: trypsin class medicine possibly cause hypoglycemia, anaphylaxis, insulin resistant etc.; There is former relatively poor, the easy secondary failure of effect in sulfonylureas, the shortcomings such as danger of hypoglycemia and weight increase is arranged; Biguanides can cause untoward reactions such as lactic acidosis, vomiting, diarrhoea; Alpha-glucosidase inhibitors such as acarbose possibly produce gastrointestinal side effects such as abdominal distension, gasteremphraxis, epigastrium cusalgia, diarrhoea or constipation; Thiazolidinediones medicines such as troglitazone have liver toxicity.Therefore, finding and screen the diabetes medicament with novel chemical structure, high-efficiency low-toxicity is the vital task in the diabetes control work.
D-glucosamine (being 2-amino-2-deoxy-D-glucose) participates in constituting tissue and cytolemma as the eventual degradation product of chitin, is the intermediate material of protein-polysaccharide macromole preparation.Its verivate has multiple important biological, in field of medicaments, has a wide range of applications.As: the salt derivative of D-glucosamine such as D-glucosamine hydrochloride have pharmacologically actives such as participating in the detoxifcation of liver kidney, anti-inflammatory, protect liver, be antibiotic; Can treat rheumatic arthritis, and Glucosamine Sulphate can be used for treatment and diseases such as prevention osteoarthritis and stomach ulcer; The coordination compound of D-glucosamine and metal platinum has antitumour activity; The acylated derivatives of D-glucosamine such as N-acetylaminohydroxyphenylarsonic acid 2-deoxy-D-glucose are the essentially consist units of many important polysaccharide in the biomass cells; Being the important as precursors of preparation bifidus factor, is the good medicine of treatment rheumatic and rheumatoid arthritis clinically; The phosphoric acid ester derivant of D-glucosamine has antitumor, antiviral, antibiotic and the immunomodulatory isoreactivity.
Doherty etc. (J.Am.Chem.Soc., 1953,75:3466-3468) utilize amino acid whose carbobenzyloxy derivative in pyridine with 1; 3; 4,6-is tetra-acetylated-the D-glucosamine effect, prepared the amino acid derivative of D-glucosamine again through deacetylation and hydrogenolytic cleavage; But the report of the amino acid derivative of the D-glucosamine of other type seldom, and do not see that so far the amino acid derivative of D-glucosamine has the relevant report of anti-diabetic activity.
The D-glucosamine molecule contains 4 hydroxyls and 1 amino, and its selective protection product 1,3,4,6-four-O-ethanoyl-β-D-glucosamine are the important intermediate of preparation GS verivate.Its preparation method mainly contains three types: the first kind is that the hydroxyl in the D-glucosamine molecule is protected with ethanoyl with amino simultaneously; The ethanoyl on the deaminize optionally again; Like salt method etc., but this class methods reagent costliness, severe reaction conditions, productive rate are low; Second type is that earlier protection is amino, protects hydroxyl again, the protection base on the deaminize then, and like Tetra hydro Phthalic anhydride method, aubepine method etc., but this class methods reactions step is long, and productive rate is lower; The 3rd type is that direct selectivity is protected hydroxyl with ethanoyl under acidic conditions, like diacetyl oxide-sulfuric acid process etc.
Summary of the invention
In view of this, one of the object of the invention is to provide a kind of amino acid modified GS; Two of purpose is to provide the preparation method of said amino acid modified GS; Three of purpose is to provide the application of said amino acid modified GS aspect medical.
For achieving the above object, the present invention adopts following technical scheme:
1, amino acid modified GS has structure shown in the general formula I:
Wherein: R
1For H, methyl, sec.-propyl, isobutyl-, sec.-butyl, benzyl ,-CH
2OC (CH
3)
3,-CH (CH
3) O (CH
3)
3,-CH
2CH
2SCH
3,-CH
2CH
2CO
2C (CH
3)
3Or-CH
2CO
2C (CH
3)
3R
2Be the amido protecting group; Ac representes ethanoyl.
Further, said R
1Be methyl, sec.-propyl, isobutyl-or benzyl;
Further, said R
1Be sec.-propyl;
Further, said R
2For 9-fluorenylmethyloxycarbonyl (Fmoc), carbobenzoxy-(Cbz), p-toluenesulfonyl, to chlorobenzene alkylsulfonyl or p-bromobenzenesulfonyl;
Further, said R
2Be Fmoc.
2, the preparation method of said amino acid modified GS may further comprise the steps:
A, D-glucosamine hydrochloride and diacetyl oxide are reacted under sulphuric acid catalysis, intermediate II be that 2-is amino-1,3,4,6-four-O-ethanoyl-β-D-glucosamine sulphate salt; Reaction formula is following:
B, be that 2-is amino-1,3,4 with intermediate II, 6-four-O-ethanoyl-β-D-glucosamine sulphate salt and the coupling under the effect of coupling agent of amino protected amino acid promptly get amino acid modified GS; Reaction formula is following:
Wherein, R
1And R
2Has the aforementioned definition of giving.
Further, the mol ratio of D-glucosamine hydrochloride, diacetyl oxide and the vitriol oil described in the step a is 1: 11.5: 1.6;
Further, coupling agent described in the step b is N, N '-DIC (DIC), 1-hydroxyl-benzo-triazole (HOBt) and N, N '-diisopropylethylamine (DIPEA);
Further, linked reaction described in the step b is carried out in solvents tetrahydrofurane (THF).
3, the said amino acid modified application of GS in the preparation antidiabetic medicine.
Beneficial effect of the present invention is: the invention provides a kind of amino acid modified GS; Has PPAR agonist activity preferably through detecting; It is good anti-diabetic lead compound; Further development and preparation becomes antidiabetic medicine, has potential, wide application prospect in the treating diabetes field; The present invention also provides the preparation method of said amino acid modified GS, is starting raw material with the D-glucosamine hydrochloride, adopts improved diacetyl oxide-sulfuric acid process one-step synthesis midbody 2-amino-1; 3,4,6-four-O-ethanoyl-β-D-glucosamine sulphate salt; Obtain amino acid modified GS with the coupling under the effect of condensing agent of protection amino acid again, reactions step is short, and reaction conditions is gentle; Convenient post-treatment, productive rate is high, and cost is low.
Embodiment
In order to make the object of the invention, technical scheme and advantage clearer, carry out detailed description in the face of the preferred embodiments of the present invention down.
Main agents and instrument: D-glucosamine hydrochloride (CP, Shanghai chemical reagents corporation of Chinese Medicine group); Diacetyl oxide (AR, Chongqing Chuan Dong chemical industry ltd); Fmoc-Ala-OH, Fmoc-Val-OH, Fmoc-Leu-OH, Fmoc-Phe-OH, HOBt (Chengdu triumphant safe new technology Ltd); DIC (Shandong Zibo is smooth along industry and trade ltd), DIPEA (new Dehua, Zhejiang worker ltd); Melting point detector (X-6 type, Beijing Fu Kai Instr Ltd.); NMR (AV-300 type, German Bruker company; TMS is interior mark); FTIR Spectrometer FTIR (Spectrum GX type, U.S. Perkin Elmer company); Normal atmosphere electric spray ion source (API-ES); Mass spectrograph (LC-MSD-1100 type, U.S. Agilent company).
Embodiment 1,2-amino-1,3,4, the preparation of 6-four-O-ethanoyl-β-D-glucosamine sulphate salt (intermediate II)
In round-bottomed flask, add diacetyl oxide, cryosel was bathed cooling after 15 minutes, slowly added the D-glucosamine hydrochloride, fast magnetic agitation; Slowly drip the vitriol oil again, after dropwising, stirring reaction under the room temperature, stopped reaction after 24 hours; Cryosel is bathed and is slowly dripped absolute ethyl alcohol down, separates out a large amount of white solids, and after dropwising, cryosel is bathed and stirred 30 minutes; Suction filtration, to there not being tart flavour, 25 ℃ of vacuum-dryings get white solid to filter cake with the ETHYLE ACETATE washing; M.p.168～172 ℃;
1H NMR (300MHz, DMSO-d
6) δ: 6.01 (d, 1H, J=3.32Hz, H-1), 5.17 (t, 1H, J=9.51Hz, H-3), 4.97 (t, 1H, J=9.51Hz, H-4), 4.37～4.13 (m, 3H, H-5, H-6), 3.92 (m, 1H, H-2), 2.19,2.09,2.02,1.99 (s, 12H, 4 * CH
3); IR (KBr, cm
-1): 2986,2908 (v
C-H), 1754 (v
C=O), 1236 (s, br, v
C-O-C), 1044 (s, v
C-O-C); ESI MS:347.4 (M-98).
Preparation condition and experimental result are seen table 1.Can know that by table when the mol ratio of D-glucosamine hydrochloride, diacetyl oxide and the vitriol oil was 1: 11.5: 1.6, product yield was the highest.This reaction is solvent with the diacetyl oxide, if the amount of diacetyl oxide very little, is unfavorable for reactants dissolved and stirs difficulty; When the mol ratio of diacetyl oxide and D-glucosamine hydrochloride during greater than 11.5 times, product yield changes little, but when aftertreatment, will use more ETHYLE ACETATE cleaning product, causes aftertreatment complicated, and the product loss increases.
The preparation condition of table 1 intermediate II and experimental result
Embodiment 2, N-[N-(9-fluorenylmethyloxycarbonyl) alanyl]-1,3,4, the preparation of 6-four-O-ethanoyl-β-D-glucosamine (compound I-1)
Fmoc-Ala-OH is dissolved among the THF, and ice bath, stirring add DIC, HOBt and DIPEA down successively, stir 30 minutes, and be subsequent use; Intermediate II is dissolved among the THF, adds triethylamine (Et
3N), stir, subsequent use; Above-mentioned two kinds of solution are mixed, and stirring reaction under the room temperature is with tlc (TLC) monitoring reaction process; After reaction finished, THF was removed in underpressure distillation, in residual solution, adds entry; Use ethyl acetate extraction, collect water layer and organic layer respectively, water layer is used ethyl acetate extraction again; Merge all organic layers, use concentration to wash as sodium bicarbonate aqueous solution, the saturated sodium-chloride water solution of 0.5mol/L successively, use anhydrous sodium sulfate drying again as aqueous citric acid solution, the concentration of 0.5mol/L; Concentrate, column chromatography purification gets white solid; M.p.198.6～202.3 ℃;
1H NMR (300MHz, DMSO-d
6) δ: 7.94 (d, 1H, J=8.3Hz, H-9), 7.89 (d, 2H, J=7.4Hz, H-20), 7.72 (d, 2H, J=7.3Hz; H-17), 7.48 (d, 1H, J=8.0Hz, H-12), 7.42 (t, 2H, J=7.4Hz, H-19), 7.33 (t; 2H, J=7.3Hz, H-18), 5.92 (d, 1H, J=3.0Hz, H-1), 5.20 (t, 1H, J=10.1Hz; H-3), 5.02 (t, 1H, J=9.5Hz, H-4), 4.26～4.01 (m, 8H, H-2, H-5, H-6; H-11, H-14, H-15), 2.19,2.02,1.99,1.93 (s, each 3H, H-8), 1.5 (d, 3H, J=6.8Hz, H-22);
13CNMR (75MHz, DMSO-d
6) δ: 173.4 (C-10), 170.1,169.9,169.2,169.1 (C-7), 155.6 (C-13), 144.0,143.8 (C-16), 140.7 (C-21); 127.7 (C-17), 127.1 (C-20), 125.3 (C-18), 120.1 (C-19), 89.7 (C-1); 70.1 (C-3), 69.1 (C-5), 67.9 (C-4), 65.6 (C-14), 61.4 (C-6); 49.9 (C-2), 49.7 (C-11), 46.7 (C-15), 20.9,20.5,20.4 (C-8), 18.3 (C-22); IR (KB r, cm
-1): 3341 (v
N-H), 3068 (v
=C-H), 2986,2908 (v
C-H), 1754 (v
C=O), 1676 (v
O=C-N), 1604,1451 (v
C=C), 1236 (s, br, v
C-O-C), 1044 (s, v
C-O-C); ESI MS:663.3 ([M+Na]
+), 679.2 ([M+K]
+).
Preparation condition and experimental result are seen table 2.
The preparation condition of table 2 compound I-1 and experimental result
Amino acid whose linked reaction common solvent has methylene dichloride (DCM), acetonitrile, THF, N, dinethylformamide (DMF), CCl
4, benzene etc., different solvents is different to dissolubility of reactants on the one hand, different on the other hand solvents is required time of reaction and to obtain the amount of by product also different down, the yield of the finished product is also different.The present invention investigates the linked reaction solvent of DIC/HOBt/DIPEA catalysis intermediate II and Fmoc-Ala-OH, and the result is as shown in table 3.When reaction solvent was THF, product yield was the highest and speed of reaction is very fast; Though in DMF the reaction times also shorter, by product is more.
The influence of solvent in table 3 linked reaction
The present invention also investigates the coupling agent of the linked reaction of intermediate II and Fmoc-Ala-OH, and the result sees table 4, finds that the effect of linked reaction of DIC/HOBt/DIPEA system's catalysis intermediate II and Fmoc-Ala-OH is best.TLC monitors discovery, and the catalysis of DIC/HOBt/DIPEA system can make Fmoc-Ala-OH be converted into the active ester midbody preferably, and the speed that obtains the active ester midbody is the fastest, and it is also the most complete to generate active ester.
Influence of coupling agents in table 4 linked reaction
Embodiment 3, N-[N-(9-fluorenylmethyloxycarbonyl) is valyl]-1,3,4, the preparation of 6-four-O-ethanoyl-β-D-glucosamine (compound I-2)
Fmoc-Val-OH is dissolved among the THF, and ice bath, stirring add DIC, HOBt and DIPEA down successively, stir 30 minutes, and be subsequent use; Intermediate II is dissolved among the THF, adds Et
3N stirs, and is subsequent use; Above-mentioned two kinds of solution are mixed, and stirring reaction under the room temperature is with TLC method monitoring reaction process; After reaction finished, THF was removed in underpressure distillation, in residual solution, adds entry; Use ethyl acetate extraction, collect water layer and organic layer respectively, water layer is used ethyl acetate extraction again; Merge all organic layers, use concentration to wash as sodium bicarbonate aqueous solution, the saturated sodium-chloride water solution of 0.5mol/L successively, use anhydrous sodium sulfate drying again as aqueous citric acid solution, the concentration of 0.5mol/L; Concentrate, column chromatography purification gets white solid; M.p.199.6～204.8 ℃;
1H NMR (300MHz, DMSO-d
6) δ: 7.96 (d, 1H, J=8.2Hz, H-9), 7.88 (d, 2H, J=7.4Hz, H-20), 7.73 (d, 2H, J=7.3Hz; H-17), 7.50 (d, 1H, J=8.0Hz, H-12), 7.42 (t, 2H, J=7.4Hz, H-19), 7.33 (t, 2H; J=7.3Hz, H-18), 6.01 (d, 1H, J=3.1Hz, H-1), 5.17 (t, 1H, J=10.1Hz, H-3), 4.97 (t; 1H, J=9.5Hz, H-4), 4.37～4.03 (m, 8H, H-2, H-5, H-6, H-11, H-14, H-15); 2.21～2.32 [m, 1H, H-22], 2.16,2.01,1.96,1.94 (s, each 3H, H-8), 0.92 [d, 6H, J=5.93Hz, H-23];
13CNMR (75MHz, DMSO-d
6) δ: 173.3 (C-10), 170.0,169.8,169.2,169.1 (C-7), 155.7 (C-13), 144.0 (C-16), 140.8 (C-21), 127.7 (C-17); 127.1 (C-20), 125.3 (C-18), 120.1 (C-19), 89.5 (C-1), 70.0 (C-3); 69.1 (C-5), 68.0 (C-4), 65.6 (C-14), 61.4 (C-6), 51.4 (C-2); 51.1 (C-11), 46.7 (C-15), 31.6 (C-22), 20.9,20.5,20.4 (C-8), 19.0,17.8 (C-23); IR (KBr, cm
-1): 3334 (v
N-H), 3072 (v
=C-H), 2989,2904 (v
C-H), 1753 (v
C=O), 1674 (v
O=C-N), 1601,1454 (v
C=C), 1237 (s, br, v
C-O-C), 1036 (s, v
C-O-C); ESI MS:691.3 ([M+Na]
+), 707.3 ([M+K]
+).
Preparation condition and experimental result are seen table 5.
The preparation condition of table 5 compound I-2 and experimental result
Embodiment 4, N-[N-(9-fluorenylmethyloxycarbonyl) leucyl]-1,3,4, the preparation of 6-four-O-ethanoyl-β-D-glucosamine (compound I-3)
Fmoc-Leu-OH is dissolved among the THF, and ice bath, stirring add DIC, HOBt and DIPEA down successively, stir 30 minutes, and be subsequent use; Intermediate II is dissolved among the THF, adds Et
3N stirs, and is subsequent use; Above-mentioned two kinds of solution are mixed, and stirring reaction under the room temperature is with TLC method monitoring reaction process; After reaction finished, THF was removed in underpressure distillation, in residual solution, adds entry; Use ethyl acetate extraction, collect water layer and organic layer respectively, water layer is used ethyl acetate extraction again; Merge all organic layers, use concentration to wash as sodium bicarbonate aqueous solution, the saturated sodium-chloride water solution of 0.5mol/L successively, use anhydrous sodium sulfate drying again as aqueous citric acid solution, the concentration of 0.5mol/L; Concentrate, column chromatography purification gets white solid; M.p.211.5～215.2 ℃;
1H NMR (300MHz, DMSO-d
6) δ: 8.01 (d, 1H, J=8.3Hz, H-9), 7.89 (d, 2H, J=7.4Hz, H-20), 7.72 (d, 2H, J=7.3Hz; H-17), 7.48 (d, 1H, J=8.0Hz, H-12), 7.42 (t, 2H, J=7.3Hz, H-19), 7.33 (t, 2H; J=7.2Hz, H-18), 5.94 (d, 1H, J=3.3Hz, H-1), 5.19 (t, 1H, J=10.2Hz, H-3), 5.02 (t; 1H, J=9.6Hz, H-4), 4.28～4.02 (m, 8H, H-2, H-5, H-6, H-11, H-14, H-15); 2.19,2.03,1.98,1.91 (s, each 3H, H-8), 1.39～1.57 (m, 3H, H-22, H-23), 0.87～0.92 (m, 6H, H-24);
13C NMR (75MHz, DMSO-d
6) δ: 173.2 (C-10), 170.0,169.7,169.2,169.0 (C-7), 155.8 (C-13), 144.1,143.7 (C-16), 140.7 (C-21), 127.6 (C-17); 127.1 (C-20), 125.3 (C-18), 120.1 (C-19), 89.5 (C-1), 69.8 (C-3), 69.1 (C-5); 68.1 (C-4), 65.5 (C-14), 61.4 (C-6), 52.2 (C-2), 50.1 (C-11); 46.7 (C-15), 40.6 (C-22), 22.8,21.6 (C-24), 21.1 (C-23), 20.9,20.5,20.4 (C-8); IR (KBr, cm
-1): 3322 (v
N-H), 2960,2901 (v
C-H), 1754 (v
C=O), 1602,1468 (v
C=C), 1236 (s, br, v
C-O-C), 1032 (s, v
C-O-C); ESI MS:705.3 ([M+Na]
+), 721.2 ([M+K]
+).
Preparation condition and experimental result are seen table 6.
The preparation condition of table 6 compound I-3 and experimental result
Embodiment 5, N-(N-(9-fluorenylmethyloxycarbonyl) phenylalanyl)-1,3,4, the preparation of 6-four-O-ethanoyl-β-D-glucosamine (compound I-4)
Fmoc-Phe-OH is dissolved among the THF, and ice bath, stirring add DIC, HOBt and DIPEA down successively, stir 30 minutes, and be subsequent use; Intermediate II is dissolved among the THF, adds Et
3N stirs, and is subsequent use; Above-mentioned two kinds of solution are mixed, and stirring reaction under the room temperature is with TLC method monitoring reaction process; After reaction finished, THF was removed in underpressure distillation, in residual solution, adds entry; Use ethyl acetate extraction, collect water layer and organic layer respectively, water layer is used ethyl acetate extraction again; Merge all organic layers, use concentration to wash as sodium bicarbonate aqueous solution, the saturated sodium-chloride water solution of 0.5mol/L successively, use anhydrous sodium sulfate drying again as aqueous citric acid solution, the concentration of 0.5mol/L; Concentrate, column chromatography purification gets white solid; ℃ m.p.207.5.～209.1;
1H NMR (300MHz, DMSO-d
6) δ: 8.17 (d, 1H, J=8.7Hz, H-9), 7.88 (d, 2H, J=7.50Hz, H-20), 7.65～7.61 (m; 2H, H-25), 7.43～7.19 (m, 10H, H-12and other ArH), 5.98 (d, 1H, J=3.3Hz, H-1); 5.24 (t, 1H, J=10.1Hz, H-3), 5.03 (t, 1H, J=9.8Hz, H-4), 4.29～3.99 (m; 8H, H-2, H-5, H-6, H-11, H-14, H-15), 2.89～2.84 (m; 1H, H-22), 2.78～2.51 (m, 1H, H-22), 2.21,2.03,1.99,1.91 (s, each 3H, H-8);
13C NMR (75MHz, DMSO-d
6) δ: 173.4 (C-10), 170.0,169.8,169.2,169.1 (C-7), 155.7 (C-13), 143.8 (C-16), 140.6 (C-21), 137.7,129.1,128.0,126.3 (C23～C26); 127.6 (C-17), 127.0 (C-20), 125.2 (C-18), 120.0 (C-19), 89.5 (C-1); 69.9 (C-3), 69.1 (C-5), 68.0 (C-4), 65.6 (C-14), 61.3 (C-6); 55.6 (C-11), 50.1 (C-2), 46.5 (C-15), 38.3 (C-22), 20.8,20.5,20.4 (C-8); IR (KBr, cm
-1): 3341 (v
N-H), 3071 (v
=C-H), 2984,2914 (v
C-H), 1756 (v
C=O), 1676 (v
O=C-N), 1608,1457 (v
C=C), 1238 (s, br, v
C-O-C), 1045 (s, v
C-O-C); ESI MS:739.3 ([M+Na]
+), 755.3 ([M+K]
+).
Preparation condition and experimental result are seen table 7.
The preparation condition of table 7 compound I-4 and experimental result
With reference to embodiment 1～5 said method; With intermediate II is 2-amino-1,3,4; 6-four-O-ethanoyl-β-D-glucosamine sulphate salt and other protection amino acid coupling under the effect of coupling agent DIC/HOBt/DIPEA can make other amino acid modified GS of the present invention.
The anti-diabetic activity of experimental example, amino acid modified GS detects
Nuclear peroxidase vegetation activated receptor (PPAR) is the part activating transcription factor, belongs to nuclear receptor gene family, plays crucial effects at aspects such as blood sugar regulation, insulin sensitivity, depot fat and metabolism.PPAR has 3 kinds of hypotypes: PPAR α, PPAR δ, PPAR γ, wherein the activation of PPAR γ can improve insulin sensitivity, reduces the generation of inflammation, reduces the lipid concentration of free fatty acids and brings high blood pressure down.Break through the substruction of traditional treatment medicine in recent years, development is the big focus that the antidiabetic thing of target spot has become drug research with PPAR.The amino acid modified GS that the present invention will prepare carries out the PPAR agonist activity and detects, and finds that this compounds has PPAR agonist activity preferably, is good anti-diabetic lead compound, and further development and preparation becomes antidiabetic medicine.The detected result of the GS that concrete detection method and partial amino-acid are modified is following:
With transfection contain the plasmid pPPRE-Luc of PPAR gene and Photinus pyralis LUC (Luc) reporter gene human liver cancer cell (HepG2) be inoculated in 96 orifice plates; Use the low sugar DMEM substratum that contains testing sample after the overnight cultures instead; Blank (not adding testing sample in the substratum) and positive control (adding PPAR γ receptor stimulant pioglitazone in the substratum) are set simultaneously; Establish two multiple holes for every group; Cultivate and detect uciferase activity (being chemiluminescence intensity L value) after 24 hours, replication twice calculates exciting rate: absolute exciting rate (%)=(L according to the following equation
Sample/ L
Blank-1) * 100; Absolute exciting rate * 100 of the absolute exciting rate/positive control of exciting relatively rate (%)=sample; Exciting relatively rate is further measured half effective concentration (EC50) greater than 70% testing sample, and the 4Parameter Logistic Model that uses in the Xlfit software calculates EC50.
The exciting rate of the GS that table 8, partial amino-acid are modified is measured the result
The EC50 of table 9, compound I-2 measures the result
Explanation is at last; Above embodiment is only unrestricted in order to technical scheme of the present invention to be described; Although through invention has been described with reference to the preferred embodiments of the present invention; But those of ordinary skill in the art should be appreciated that and can make various changes to it in form with on the details, and the spirit and scope of the present invention that do not depart from appended claims and limited.
Claims (7)
1. amino acid modified GS is characterized in that: have structure shown in the general formula I:
Wherein: R
1Be methyl, sec.-propyl, isobutyl-or benzyl, R
2Be 9-fluorenylmethyloxycarbonyl.
2. amino acid modified GS according to claim 1 is characterized in that: said R
1Be sec.-propyl.
3. the preparation method of the described amino acid modified GS of claim 1 is characterized in that: may further comprise the steps:
A, D-glucosamine hydrochloride and diacetyl oxide are reacted under sulphuric acid catalysis, intermediate II be that 2-is amino-1,3,4,6-four-O-ethanoyl-β-D-glucosamine sulphate salt; Reaction formula is following:
B, be that 2-is amino-1,3,4 with intermediate II, 6-four-O-ethanoyl-β-D-glucosamine sulphate salt and the coupling under the effect of coupling agent of amino protected amino acid promptly get amino acid modified GS; Reaction formula is following:
Wherein, R
1And R
2Has definition described in the claim 1.
4. the preparation method of amino acid modified GS according to claim 3, it is characterized in that: the mol ratio of the hydrochloride of D-glucosamine described in the step a, diacetyl oxide and the vitriol oil is 1: 11.5: 1.6.
5. the preparation method of amino acid modified GS according to claim 3, it is characterized in that: coupling agent described in the step b is DIC, HOBt and DIPEA.
6. the preparation method of amino acid modified GS according to claim 3, it is characterized in that: linked reaction described in the step b is carried out in solvents tetrahydrofurane.
7. the described amino acid modified application of GS in the preparation antidiabetic medicine of claim 1.
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| CN103059074B (en) * | 2013-01-11 | 2015-02-18 | 国家海洋局第三海洋研究所 | Glucosamine peptidomimetic compound as well as preparation method and application thereof |
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Non-Patent Citations (3)
| Title |
|---|
| David G.Doherty,et al.Amino Acid Derivatives of D-Glucosamine.《J.Am.Chem.Soc》.1953,第75卷(第14期), * |
| Rao Venkataramanarao,et al.An efficient synthetic route to N-glycosylamino acids using Na-Fmoc-Asp/Glu-5-oxazolidinone as internal protection.《synlett》.2007,第16卷 * |
| 林永成，等.甲壳质选择性降解和葡糖胺衍生物的合成.《中国海洋药物》.1996,(第3期), * |
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