CN107915765B - Glucopyranosyl-substituted EGCG compound and preparation method and application thereof - Google Patents
Glucopyranosyl-substituted EGCG compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of drug therapy, and particularly relates to a glucopyranosyl-substituted compound EGCG, and a preparation method and application thereof. The glucopyranosyl-substituted EGCG compound has the general formula I
The compound and the optically active body or racemate of the salt thereof, and the application of the monomer or mixture of diastereoisomers in preparing the anti-Alzheimer disease medicine.
Description
Technical Field
The invention belongs to the field of drug therapy, and particularly relates to a glucopyranosyl-substituted compound EGCG, and a preparation method and application thereof.
Background
Tea contains a large amount of polyphenol compounds, which are collectively called Tea Polyphenol (TP), accounting for 18-36% of the dry weight of the tea, and a large amount of researches show that the tea polyphenol has strong antioxidant capacity and is always used as a natural food antioxidant additive (Pujian et al, university of Anhui agriculture, 2011,38(2): 156-163.). The chemical component research of tea polyphenol shows that the main components of tea polyphenol are catechin (C), Epicatechin (EC), epicatechin gallate (ECG), Epigallocatechin (EGC), epigallocatechin gallate (EGCG) and other active substances. Wherein, the content of EGCG is the highest and accounts for about 50 to 60 percent of the total content of catechin. A great deal of research at present shows that EGCG has the biological activities of resisting cancer, mutation, aging, blood fat, blood pressure, blood sugar and radiation, preventing and treating cardiovascular and cerebrovascular diseases, regulating endocrine, immune system and the like (strongness and the like, Chinese experimental diagnostics, 2010,14(2): 170-.
The antioxidation has been an important function of tea polyphenols such as EGCG and the like, and is widely used as a food additive. In addition, the main components in tea polyphenol can eliminate free radicals in vivo and delay aging of organism. Research shows that EGCG can reduce CCl in liver4Induced hepatitis, oxidative stress and fibrosis, whose mechanism of action is to reduce the transcriptional expression of inflammatory and fibrosis regulators (Zhenmc, et al. journal of nutritional biochemistry,2007,18:795-805.TipoeGL, et al. toxicology,2010,273(1/3): 45-52.). In addition, more researches find that the EGCG has good effects on treating and interfering the nervous system diseases. Monoamine oxidase B, an important enzyme in brain tissue, can cause brain tissue lipid peroxidation to be exacerbated, and EGCG can tissue-specifically inhibit the activity of this enzyme (XieJ, et al. neuroscience Letter,2010,497(1): 26-30.). There are a number of studies that have shown that EGCG can protect neurons from damage in neurodegenerative diseases (alzheimer's disease, parkinson, etc.). EGCG has obvious effect on various tumor cells, and induces the apoptosis of the tumor cells by interfering different cell signal pathways in the cells. In recent years, more research has been conducted on EGCG against colon cancer, and in human colon cancer cells HCT-116, hepatocyte growth factor can induce phosphorylation of Met receptor tyrosine kinase, thereby regenerating tumor tissue vessels and generating metastasis of tumor cells in vivo, while EGCG inhibits the phosphorylation process in a concentration-dependent manner (LarsencA, et al. archives of biochemistry and biochemistry, 2010,501(1): 52-30.). Meanwhile, research shows that EGCG can also reduce the solubility of cholesterol and change chylomicron, thereby inhibiting the absorption of lipid by the body to reduce the lipid level in plasma and further protecting the cardiovascular and cerebrovascular systems (RaedestorffDG, et al. journal of Nutritional Biochemistry,2003,14: 326-. As an important system for preventing diseases and regulating body homeostasis, the immune and endocrine systems of the body have become hot of research. In terms of the effects of EGCG on the immune and endocrine systems, some parts of the literature have been reported. Monocyte chemotactic protein-1 (MCP-1) is known to be an inflammatory disease of the bodyEGCG, an important mediator in the disease process, can inhibit the increase of MCP-1 expression induced by phorbol ester, thereby having important influence on the anti-inflammatory action of the body (hongMH, actual. Life Sciences,2007,80(1): 1957-1965.). In addition to the above-mentioned various biological activities, some studies show that EGCG also has various activities such as antibacterial activity, hair growth promotion activity and bone cell growth promotion activity. EGCG is a compound entity of great research value.
EGCG molecules have a polyhydroxy chemical structure and good water solubility, however, after EGCG enters organisms such as mice, rats, human beings and the like, due to poor fat solubility (HuoCD, et al. tetrahedron Letter,2011,52(42):5478-5483.CelizG, et al. Process Biochemistry,2011,46(1):94-100.), the problems of instability in the physiological environment of organisms (Chiou YS, et al. Carbonogenesis, 2013,34(6): 1315-.
Therefore, the change of the molecular structure of EGCG becomes a problem to be solved at present by adopting a molecular modification means.
Disclosure of Invention
The invention relates to a glucopyranosyl-substituted epigallocatechin gallate compound, pharmaceutically acceptable salts thereof, application and a preparation method thereof, which can enhance the anti-senile dementia activity of the compound, and simultaneously ensure that the compound has higher stability, quicker absorption in vivo and higher bioavailability.
In order to achieve the above object, the present invention is realized by: a glucopyranosyl-substituted epigallocatechin gallate (EGCG) compound characterized in that the compound has the following general formula I:
R1is any one of the following groups: an unsubstituted or variously substituted amino group,c1-6 alkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, C1-6 cyanoalkyl, C1-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylsulfonyl, C2-6 alkenylsulfonyl, C2-6 alkynylsulfonyl, C1-6 alkylcarbonyl, C2-6 alkenylcarbonyl, C2-6 alkynylcarbonyl.
Preferably, in the general formula I of the compound, R1Is any one of the following groups: amino, methylamino, propylamino, cyclopropylamino, 2-hydroxyethylamino, 2-cyanoethylamino, benzenesulfonylamino, p-methoxybenzenesulfonylamino, acetylamino, benzoylamino, p-methoxybenzoylamino, acrylamido. The chemical formula of the compound is:
preferably, the compound is any pharmaceutically acceptable salt.
Preferably, the compound is in any pharmaceutically therapeutically acceptable dosage form.
Preferably, the compound is in any pharmaceutically therapeutically acceptable dose.
A method for preparing a glucopyranosyl-substituted epigallocatechin gallate (EGCG) compound, comprising the steps of:
takes epigallocatechin gallate (EGCG) as a starting material, 4-Dimethylaminopyridine (DMAP) as a catalyst, and acetic anhydride for acetylation protection to obtain an intermediate A-1, wherein the chemical formula of the intermediate A-1 is
Dissolving the intermediate A-1 in N-methylpyrrolidone (NMP), adding imidazole and thiophenol, and selectively removing acetyl protecting group at 7-position to obtain intermediate A-2, wherein the chemical formula of A-2 is
The intermediate A-2 reacts with the end group brominated trichloroethyl chloroformate protected peracetylglucosamine to obtain an intermediate A-3, wherein the chemical formula of the intermediate A-3 is
Under the action of zinc powder and acetic acid, the intermediate A-3 is subjected to the removal of the protection of trichloroethyl chloroformate (Troc) to obtain an intermediate A-4, wherein the chemical formula of the intermediate A-4 is shown in the specification
The intermediate A-4 can be deacylated in the presence of sodium methoxide to obtain G-1, or the intermediate A-4 is firstly linked with substituent R1 through reaction to obtain intermediate A-5,
g-1 has the formula
A-5 has the formula
Then deacylation protection is carried out in the presence of sodium methoxide to obtain the compound shown in the general formula I.
Compared with the prior art, the invention has the following advantages and positive effects:
1. experiments show that the glucopyranosyl-substituted epigallocatechin gallate compound provided by the invention has stronger inhibition A β than EGCG1-42The stimulated SH-SY5Y cytotoxicity provides a reliable basis for the compounds to have the effect of resisting senile dementia. Suggesting that such compounds have potential advantages over EGCG.
2. The structural characteristics of polyphenol hydroxyl of EGCG lead the EGCG to easily deteriorate at normal temperature, and the application of the EGCG is limited.
Drawings
FIG. 1 is a scheme for the preparation of compounds of general formula I according to the invention.
FIG. 2 is a chromatogram of example 13, wherein A is EGCG; b is a compound G1 according to the invention.
The specific implementation mode is as follows:
the compounds of the present invention and their preparation will be better understood in connection with the following examples, which are intended to illustrate, but not to limit, the scope of the invention.
Example 1, 7- [ O- (2-amino) -glucoside ] -epigallocatechin gallate (G1)
Epigallocatechin gallate (0.44g,1mmol), 4-dimethylaminopyridine (1.22g,1mmol) and triethylamine (0.15g,1.5mmol) were sequentially added to 15ml of dichloromethane at room temperature, stirred at room temperature for 4 hours, and after the reaction was completed, the solvent was evaporated to dryness to obtain an oily substance. This oil was dissolved in ethyl acetate and subjected to column chromatography (developing solvent conditions: petroleum ether: acetone: 2:1) to isolate intermediate a-1(0.68g) in 93% yield.
Intermediate A-1(0.68g,0.93mmol) was added to 10ml of methylpyrrolidone, reacted in ice bath for 1 hour, and then diluted with 20ml of ethyl acetate, and the organic phase was washed with 1M aqueous hydrochloric acid and saturated aqueous NaCl solution. The organic phase was dried over anhydrous sodium sulfate overnight. The next day, a cold 30ml solution of anhydrous ether was added to give a white precipitate which was filtered off with suction to give intermediate A-2(0.47g) as a white solid in 72% yield.
Intermediate A-3(0.47g,0.67mmol), Troc-protected terminal bromoperacetamidoglucose (0.73g,1.34mmol) and potassium carbonate (0.93g,6.7mmol) were added to 30ml of DMF in this order, reacted at room temperature for 10 hours, the reaction mixture was poured into 100ml of water, extracted with ethyl acetate (20 ml. times.3), the organic phases were combined and dried over anhydrous sodium sulfate overnight. The next day, ethyl acetate was evaporated to dryness to give an oil which was subjected to column chromatography (conditions of developing solvent: petroleum ether: acetone: 2:1) to give intermediate a-3(0.48g) in 62% yield.
Intermediate a-3(0.48g,0.42mmol) was added to 10ml of acetic acid, a catalytic amount of zinc powder was further added, the mixture was stirred at room temperature for 5 hours, and the reaction solution was evaporated to dryness to obtain an oily substance, which was subjected to column chromatography (developing solvent conditions: petroleum ether: acetone: 3:1) to obtain intermediate a-4(0.35g) with a yield of 85%.
Intermediate A-4(0.35g,0.36mmol) was added to 10ml of anhydrous methanol, sodium methoxide (0.02g,0.36mmol) was added, stirring was carried out at room temperature for 5 hours, a small amount of water was added and the solvent was evaporated to dryness. Water (30 ml) was added thereto, extraction was performed with ethyl acetate (15 ml. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate overnight. The next day, ethyl acetate was evaporated to dryness to give an oil which was subjected to column chromatography (developing solvent conditions: petroleum ether: acetone: 3:1) to give intermediate G-1(0.18G) in 85% yield. ESI-MS 602.2[ M + H ]]+；1H NMR(300MHz,DMSO-d6)δ6.97(S,2H),6.93(S,1H),6.75(d,J＝8.1Hz,1H),6.71(d，J＝8.1Hz,1H),6.20(d,J＝1.2Hz,1H),6.05(d,J＝1.2Hz,1H),5.56(d,J＝6.1Hz,1H),5.35(S,6H),5.23(m,1H),5.11(S,2H),3.65(dd,J＝11.5,6.5Hz,1H),3.62(d,J＝13Hz,1H),3.58(m,2H),3.49(m,1H),3.45(m,1H),3.37(d,J＝13Hz,1H),3.10(dd,J＝12.0,6.5Hz,1H),3.05(m,1H),2.85(dd,J＝12.0,6.5Hz,1H),2.47(dd,J＝5.2,6.0Hz,1H),1.82(dd,J＝11.5,6.5Hz,1H),1.38(d,J＝3.3Hz,1H),0.86(d,J＝3.3Hz,1H)。
Example 2, 7- [ O- (2-methylamino) -glucoside ] -epigallocatechin gallate (G2)
The preparation method is the same as the above, and the total yield is 28%. ESI-MS 616.2[ M + H ]]+；1H NMR(300MHz,DMSO-d6)δ6.97(S,2H),6.93(S,1H),6.75(d,J＝7.5Hz,1H),6.71(d，J＝7.5Hz,1H),6.20(d,J＝1.2Hz,1H),6.05(d,J＝1.2Hz,1H),5.56(d,J＝6.1Hz,1H),5.35(S,6H),5.23(m,1H),3.65(dd,J＝11.5,6.5Hz,1H),3.62(dd,J＝13.0Hz,1H),3.58(m,2H),3.49(m,1H),3.45(m,1H),3.37(dd,J＝13.0,7.5Hz,1H),3.26(S,3H),3.10(dd,J＝12.0,6.5Hz,1H),3.05(m,1H),2.85(dd,J＝12.0,6.5Hz,1H),2.03(d,1H),2.0(q,1H),1.82(m,1H),1.38(t,J＝7.5Hz,1H),0.86(m,1H)。
Example 3, 7- [ O- (2-propylamino) -glucoside ] -epigallocatechin gallate (G3)
The preparation method is the same as the above, and the total yield is 22%. ESI-MS 644.2[ M + H ]]+；1H NMR(300MHz,DMSO-d6)δ6.97(S,2H),6.93(S,1H),6.75(d,J＝7.5Hz,1H),6.71(d，J＝7.5Hz,1H),6.20(d,J＝1.2Hz,1H),6.05(d,J＝1.2Hz,1H),5.56(d,J＝6.1Hz,1H),5.35(S,6H),5.23(m,1H),3.65(dd,J＝11.5,6.5Hz,1H),3.62(dd,J＝13.0Hz,1H),3.58(m,2H),3.49(m,1H),3.45(m,1H),3.37(dd,J＝13.0,7.5Hz,1H),3.10(dd,J＝12.0,6.5Hz,1H),3.05(m,1H),2.85(dd,J＝12.0,6.5Hz,1H),2.55(m,2H),2.03(d,1H),2.0(q,1H),1.82(m,1H),1.45(m,2H),1.38(t,J＝7.5Hz,1H),0.90(m,3H),0.86(m,1H)。
Example 4, 7- [ O- (2-cyclopropylamino) -glucoside ] -epigallocatechin gallate (G4)
The preparation method is the same as the above, and the total yield is 32%. ESI-MS 642.2[ M + H ]]+；1H NMR(300MHz,DMSO-d6)δ6.97(S,2H),6.93(S,1H),6.75(d,J＝7.5Hz,1H),6.71(d，J＝7.5Hz,1H),6.20(d,J＝1.2Hz,1H),6.05(d,J＝1.2Hz,1H),5.56(d,J＝6.1Hz,1H),5.35(S,6H),5.23(m,1H),3.65(dd,J＝11.5,6.5Hz,1H),3.62(dd,J＝13.0Hz,1H),3.58(m,2H),3.49(m,1H),3.45(m,1H),3.37(dd,J＝13.0,7.5Hz,1H),3.10(dd,J＝12.0,6.5Hz,1H),3.05(m,1H),2.85(dd,J＝12.0,6.5Hz,1H),2.03(d,1H),2.0(q,1H),1.82(m,1H),1.38(t,J＝7.5Hz,1H),1.35(m,1H),0.69(m,2H),0.44(m,2H),0.86(m,1H)。
Example 5, 7- [ O- (2-hydroxyethylamino) -glucoside ] -epigallocatechin gallate (G5)
The preparation method is the same as the above, and the total yield is 19%. ESI-MS 646.2[ M + H ]]+；1H NMR(300MHz,DMSO-d6)δ6.97(S,2H),6.93(S,1H),6.75(d,J＝7.5Hz,1H),6.71(d，J＝7.5Hz,1H),6.20(d,J＝1.2Hz,1H),6.05(d,J＝1.2Hz,1H),5.56(d,J＝6.1Hz,1H),5.35(S,6H),5.23(m,1H),3.65(dd,J＝11.5,6.5Hz,1H),3.65(m,2H),3.65(t,1H),3.62(dd,J＝13.0Hz,1H),3.58(m,2H),3.49(m,1H),3.45(m,1H),3.37(dd,J＝13.0,7.5Hz,1H),3.10(dd,J＝12.0,6.5Hz,1H),3.05(m,1H),2.85(dd,J＝12.0,6.5Hz,1H),2.74(m,2H),2.03(d,1H),2.0(q,1H),1.82(m,1H),1.38(t,J＝7.5Hz,1H),0.86(m,1H)。
Example 6, 7- [ O- (2-cyanoethylamino) -glucoside ] -epigallocatechin gallate (G6)
The preparation method is the same as the above, and the total yield is 24%. ESI-MS 655.2[ M + H ]]+；1H NMR(300MHz,DMSO-d6)δ6.97(S,2H),6.93(S,1H),6.75(d,J＝7.5Hz,1H),6.71(d,J＝7.5Hz,1H),6.20(d,J＝1.2Hz,1H),6.05(d,J＝1.2Hz,1H),5.56(d,J＝6.1Hz,1H),5.35(S,6H),5.23(m,1H),3.65(dd,J＝11.5,6.5Hz,1H),3.62(dd,J＝13.0Hz,1H),3.58(m,2H),3.49(m,1H),3.45(m,1H),3.37(dd,J＝13.0,7.5Hz,1H),3.10(dd,J＝12.0,6.5Hz,1H),3.05(m,1H),2.92(t,J＝7.5Hz,2H),2.85(dd,J＝12.0,6.5Hz,1H),2.53(t,J＝7.5Hz,2H),2.03(d,1H),2.0(q,1H),1.82(m,1H),1.38(t,J＝7.5Hz,1H),0.86(m,1H)。
Example 7, 7- [ O- (2-benzenesulfonylamino) -glucoside ] -epigallocatechin gallate (G7)
The preparation method is the same as the above, and the total yield is 34%. ESI-MS 742.2[ M + H ]]+；1H NMR(300MHz,DMSO-d6)δ7.86(dd,J＝7.1,2.5Hz,2H),7.74(dd,J＝6.6,6.3Hz,1H),7.71(m,1H),7.62(dd,J＝7.1,7.5Hz,2H),6.97(S,2H),6.93(S,1H),6.75(d,J＝7.5Hz,1H),6.71(d,J＝7.5Hz,1H),6.20(d,J＝1.2Hz,1H),6.05(d,J＝1.2Hz,1H),5.56(d,J＝6.1Hz,1H),5.35(S,6H),5.23(m,1H),3.65(dd,J＝11.5,6.5Hz,1H),3.62(dd,J＝13.0Hz,1H),3.58(m,2H),3.49(m,1H),3.45(m,1H),3.37(dd,J＝13.0,7.5Hz,1H),3.10(dd,J＝12.0,6.5Hz,1H),3.05(m,1H),2.85(dd,J＝12.0,6.5Hz,1H),2.47(dd,J＝6.3,5.8Hz,1H),1.82(m,1H),1.38(t,J＝7.5Hz,1H),0.86(m,1H)。
Example 8, 7- [ O- (2-p-methoxyphenylsulfonylamino) -glucoside ] -epigallocatechin gallate (G8)
The preparation method is the same as the above, and the total yield is 24%. ESI-MS 772.2[ M + H ]]+；1H NMR(300MHz,DMSO-d6)δ7.74(dd,J＝6.6,6.3Hz,1H),7.64(dd,J＝7.1,2.5Hz,2H),7.12(dd,J＝7.1,7.5Hz,2H),6.97(S,2H),6.93(S,1H),6.75(d,J＝7.5Hz,1H),6.71(d,J＝7.5Hz,1H),6.20(d,J＝1.2Hz,1H),6.05(d,J＝1.2Hz,1H),5.56(d,J＝6.1Hz,1H),5.35(S,6H),5.23(m,1H),3.83(S,3H),3.65(dd,J＝11.5,6.5Hz,1H),3.62(dd,J＝13.0Hz,1H),3.58(m,2H),3.49(m,1H),3.45(m,1H),3.37(dd,J＝13.0,7.5Hz,1H),3.10(dd,J＝12.0,6.5Hz,1H),3.05(m,1H),2.85(dd,J＝12.0,6.5Hz,1H),2.47(dd,J＝6.3,5.8Hz,1H),1.82(m,1H),1.38(t,J＝7.5Hz,1H),0.86(m,1H)。
Example 9, 7- [ O- (2-acetylamino) -glucoside ] -epigallocatechin gallate (G9)
The preparation method is the same as the above, and the total yield is 29%. ESI-MS 644.2[ M + H ]]+；1H NMR(300MHz,DMSO-d6)8.03(dd,J＝6.6,6.3Hz,1H),6.97(S,2H),6.93(S,1H),6.75(d,J＝7.5Hz,1H),6.71(d，J＝7.5Hz,1H),6.20(d,J＝1.2Hz,1H),6.05(d,J＝1.2Hz,1H),5.56(d,J＝6.1Hz,1H),5.35(S,6H),5.23(m,1H),3.65(dd,J＝11.5,6.5Hz,1H),3.62(dd,J＝13.0Hz,1H),3.58(m,2H),3.49(m,1H),3.45(m,1H),3.37(dd,J＝13.0,7.5Hz,1H),3.10(dd,J＝12.0,6.5Hz,1H),3.05(m,1H),2.85(dd,J＝12.0,6.5Hz,1H),2.47(dd,J＝6.3,5.8Hz,1H),1.84(S,3H),1.82(m,1H),1.38(t,J＝7.5Hz,1H),0.86(m,1H)。
Example 10, 7- [ O- (2-benzoylamino) -glucoside ] -epigallocatechin gallate (G10)
The preparation method is the same as the above, and the total yield is 19%. ESI-MS 706.2[ M + H ]]+；1H NMR(300MHz,DMSO-d6)8.03(dd,J＝6.6,6.3Hz,1H),8.03(dd,J＝7.1,2.5Hz,2H),7.63(dd,J＝7.1,7.5Hz,2H),7.70(dd,J＝7.5,2.4Hz,1H),6.97(S,2H),6.93(S,1H),6.75(d,J＝7.5Hz,1H),6.71(d,J＝7.5Hz,1H),6.20(d,J＝1.2Hz,1H),6.05(d,J＝1.2Hz,1H),5.56(d,J＝6.1Hz,1H),5.35(S,6H),5.23(m,1H),3.65(dd,J＝11.5,6.5Hz,1H),3.62(dd,J＝13.0Hz,1H),3.58(m,2H),3.49(m,1H),3.45(m,1H),3.37(dd,J＝13.0,7.5Hz,1H),3.10(dd,J＝12.0,6.5Hz,1H),3.05(m,1H),2.85(dd,J＝12.0,6.5Hz,1H),2.47(dd,J＝6.3,5.8Hz,1H),1.82(m,1H),1.38(t,J＝7.5Hz,1H),0.86(m,1H)。
Example 11, 7- [ O- (2-p-methoxybenzoylamino) -glucoside ] -epigallocatechin gallate (G11)
The preparation method is the same as the above, and the total yield is 24%. ESI-MS:736.2[ M + H ]]+；1H NMR(300MHz,DMSO-d6)8.03(dd,J＝6.6,6.3Hz,1H),7.92(dd,J＝7.4,2.8Hz,2H),7.17(dd,J＝7.4,2.8Hz,2H),6.97(S,2H),6.93(S,1H),6.75(d,J＝7.5Hz,1H),6.71(d,J＝7.5Hz,1H),6.20(d,J＝1.2Hz,1H),6.05(d,J＝1.2Hz,1H),5.56(d,J＝6.1Hz,1H),5.35(S,6H),5.23(m,1H),3.83(S,3H),3.65(dd,J＝11.5,6.5Hz,1H),3.62(dd,J＝13.0Hz,1H),3.58(m,2H),3.49(m,1H),3.45(m,1H),3.37(dd,J＝13.0,7.5Hz,1H),3.10(dd,J＝12.0,6.5Hz,1H),3.05(m,1H),2.85(dd,J＝12.0,6.5Hz,1H),2.47(dd,J＝6.3,5.8Hz,1H),1.82(m,1H),1.38(t,J＝7.5Hz,1H),0.86(m,1H)。
Example 12, 7- [ O- (2-Propenylamino) -glucoside ] -epigallocatechin gallate (G12)
The preparation method is the same as the above, and the total yield is 21%. ESI-MS 642.2[ M + H ]]+；1H NMR(300MHz,DMSO-d6)δ6.97(S,2H),6.93(S,1H),6.75(d,J＝7.5Hz,1H),6.71(d，J＝7.5Hz,1H),6.20(d,J＝1.2Hz,1H),6.05(d,J＝1.2Hz,1H),5.87(m,1H),5.56(d,J＝6.1Hz,1H),5.35(S,6H),5.23(m,1H),5.22(m,1H),5.19(m,1H),3.65(dd,J＝11.5,6.5Hz,1H),3.62(dd,J＝13.0Hz,1H),3.58(m,2H),3.49(m,1H),3.45(m,1H),3.37(dd,J＝13.0,7.5Hz,1H),3.22(m,2H),3.10(dd,J＝12.0,6.5Hz,1H),3.05(m,1H),2.85(dd,J＝12.0,6.5Hz,1H),2.03(d,1H),2.0(q,1H),1.82(m,1H),1.38(t,J＝7.5Hz,1H),0.86(m,1H)。
Example 13 compound stability test.
Except that the glucopyranosyl-substituted epigallocatechin gallate (EGCG) compound embodies certain antioxidant stress activity, the inventor simultaneously discovers that the stability of the compound is obviously improved. Due to the structural characteristics of polyphenol hydroxyl, EGCG is easy to deteriorate along with the time extension at normal temperature, and oxidation products are complex and have more impurity peaks. Detection of glucopyranosyl-substituted EGCG compounds G1-G12 shows that only a small amount of impurities are generated, and the content is obviously improved.
The chromatographic conditions were as follows:
a chromatographic column: shimpak C18(4.6 mm. times.150 mm, 5 μm); mobile phase: methanol: water: glacial acetic acid (20: 80: 0.2); detection wavelength: 280 nm; flow rate: 1.0 mL/min; column temperature: 30 ℃; the sample was taken in an amount of 5. mu.L, and the chromatogram was shown in FIG. 2.
The result shows that the color of the EGCG powder is obviously changed from white to pink when the EGCG powder is placed for the third day at the normal temperature, and the color of the glucopyranosyl-substituted EGCG compounds G1-G12 is not obviously changed; in addition, the high performance liquid phase result also shows that the EGCG is easy to deteriorate after being placed at normal temperature, a plurality of peaks are generated (as shown in figure 2A), and the glucopyranosyl-substituted EGCG compounds G1-G12 are all more excellent in stability, wherein the content of G1 is as high as 99.35% (as shown in figure 2B).
Example 14 pharmacological Activity test of Compounds.
Model cells: human neuroblastoma SH-SY5Y cell
The culture conditions are as follows: DMEM (Hyclone) + 10% fetal bovine serum (Clark), 37 ℃, 5% CO2The study shows that the abnormal accumulation of amyloid A β in the brain of a patient is an important cause for the pathogenesis of Alzheimer's Disease (AD), therefore, A β stimulates nerve cells to be used as a cell model for simulating the AD state in vitro;
the dosage is as follows: 200 u L/hole, conventional per plate three more holes, at least three test, usually five times.
The test method comprises the following steps: MTT method
The experimental process comprises the following steps:
1. the cells were digested, plated in 96-well plates at approximately 4000-.
2 adding proper concentration of aseptic drug EGCG, G1-G12 or blank control into the culture solution, and performing pre-treatment for 2 h.
3. Adding A β to each well1-42And molding at 10 mu M for 24 hours.
4. Completely sucking out the molding liquid, adding the complete culture solution and MTT into each well, and acting for 4-6 h.
5. The test was carried out with the results as given in the following table.
Wherein the low concentration, the medium concentration and the high concentration are respectively 1 micromole/liter, 5 micromole/liter and 10 micromole/liter.
Neuroprotective rate (%) ([ OD value (addition group) -OD value (group a β) ]/OD value (blank group) × 100%.
The result shows that compared with EGCG, the glucopyranosyl-substituted EGCG compound has better anti-AD activity.
Claims (6)
1. A glucopyranosyl-substituted EGCG compound, characterized in that the compound has the following structure:
G1：
G2：
G3：
；
G4：
G5：
G6：
G7：
；
G8：
G9：
G10：
；
G11：
；
G12：
2. a glucopyranosyl-substituted EGCG compound according to claim 1, characterized in that it is any pharmaceutically acceptable salt.
3. A glucopyranosyl-substituted EGCG compound according to claim 1, characterised in that it is in any pharmaceutically acceptable dosage form.
4. A glucopyranosyl-substituted EGCG compound according to claim 1, characterised in that it is in any pharmacotherapeutically acceptable dose.
5. The glucopyranosyl-substituted EGCG compound according to claim 1, characterized in that the optically active form or racemate of the compound and its salts, the monomer or mixture of diastereoisomers is used for preparing the anti-Alzheimer's disease drug.
6. A process for the preparation of a glucopyranosyl-substituted EGCG compound according to claim 1, characterized in that the process comprises the steps of: the method comprises the following steps of taking epigallocatechin gallate (EGCG) as a starting material, 4-Dimethylaminopyridine (DMAP) as a catalyst, and performing acetylation protection by using acetic anhydride to obtain an intermediate A-1, wherein the chemical formula of the intermediate A-1 is as follows:
dissolving the intermediate A-1 in N-methylpyrrolidone (NMP), adding imidazole and thiophenol, and selectively removing the acetyl protecting group at the 7-position to obtain an intermediate A-2, wherein the chemical formula of the intermediate A-2 is as follows:
the intermediate A-2 reacts with the end group brominated trichloroethyl chloroformate protected peracetylglucosamine to obtain an intermediate A-3, wherein the chemical formula of the intermediate A-3 is as follows:
under the action of zinc powder and acetic acid, removing the protection of trichloroethyl chloroformate (Troc) from the intermediate A-3 to obtain an intermediate A-4, wherein the chemical formula of the intermediate A-4 is as follows:
the intermediate A-4 can be deacylated under the existence of sodium methoxide to obtain G-1, or the intermediate A-4 is linked with substituent R1 through reaction to obtain intermediate A-5;
g-1 has the formula:
a-5 has the chemical formula:
then deacylation protection is carried out in the presence of sodium methoxide to obtain the compound of claim 1.
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| N-乙酰葡萄糖胺基糖化修饰与糖尿病、阿尔茨海默病及心脏病的关系;马晨丰 等;《药学服务与研究》;20130430;第13卷(第2期);第107-110页；第108页右栏第2段 * |
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