A triterpenoid phenolic acid ester derivative, and a preparation method and application thereof

Abstract

The present application relates to a triterpene phenolic acid ester derivative, a preparation method and application thereof, and belongs to the field of medicinal chemistry. The main structure R of the triterpene phenolic acid ester derivative is a cucurbitane type triterpene compound residue, wherein at least one phenolic acid group is connected in the cucurbitane type triterpene compound residue, and each of the other hydroxyl groups, methyl groups or methoxy groups is independently connected; the phenolic acid group, X is 0, a C1-C3 saturated alkyl group or a C1-C3 unsaturated alkyl group, R1, R2 and R3 are each independently selected from hydrogen, a hydroxyl group or a methoxy group. The triterpene phenolic acid ester derivative has a significant effect of regulating glycolipid metabolism, and can be used for preventing or treating the occurrence and development of glycolipid metabolism disorder diseases.

Description

Technical Field

[0001] This invention relates to a triterpenoid phenolic ester derivative, its preparation method and application, belonging to the field of medicinal chemistry. Background Technology

[0002] Large-scale epidemiological surveys, clinical data analysis, molecular genetic studies, and large animal experiments closely resembling human disease models have demonstrated that metabolic syndrome, centered on disorders of glucose and lipid metabolism, is the greatest risk factor for diseases such as hyperlipidemia, fatty liver, diabetes, hypertension, and atherosclerotic cardiovascular and cerebrovascular diseases. Disorders of glucose and lipid metabolism are particularly prevalent due to their widespread impact, pathogenicity, and susceptibility.

[0003] Glucose and lipid homeostasis plays a crucial role in maintaining basic cellular and biological life activities. Disruption of glucose and lipid homeostasis leads to various metabolic diseases, such as obesity, diabetes, fatty liver, and cardiovascular disease. Studies have shown that polyphenolic compounds regulate glucose metabolism through mechanisms such as modulating enzyme activity, stimulating insulin secretion, regulating insulin sensitivity, enhancing glucose uptake in tissues, and regulating intestinal hormone secretion. Furthermore, some polyphenolic compounds have been shown to lower total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) levels and inhibit intestinal fat absorption by regulating the expression of lipid metabolism-related genes.

[0004] Triterpenoids possess a wide range of physiological activities, and some triterpenoids have been found to significantly regulate glucose and lipid metabolism. Increasing research and data indicate that the chemical binding of polyphenols with certain drug molecules can significantly enhance the antioxidant activity of the drug molecules and increase their efficacy. Therefore, it is currently essential to develop conjugates of polyphenols and triterpenoids and their derivatives as lead compounds for regulating glucose and lipid metabolism. Summary of the Invention

[0005] To address the technical problems existing in the preparation of drugs for treating glucose and lipid metabolism disorders using current technologies, this invention provides a triterpenoid phenolic ester derivative, its preparation method, and its applications. The triterpenoid phenolic ester derivative provided by this invention can serve as a lead compound for developing novel, highly efficient, and low-toxicity drugs for regulating glucose and lipid metabolism, and also provides a synthetic template for developing drugs that regulate glucose and lipid metabolism.

[0006] A triterpenoid phenolic ester derivative, characterized in that: the main structure R of the triterpenoid phenolic ester derivative is a cucurbitane-type triterpenoid compound residue, with the specific structural formula as follows:

[0007]

[0008]

[0009] At least one of them Connecting phenolic acid groups, others Each phenolic acid group is independently linked to a hydroxyl, methyl, or methoxy group; the phenolic acid group has the following structure:

[0010]

[0011] in,

[0012] X is a 0- or C1-C3 saturated alkyl group or a C1-C3 unsaturated alkyl group;

[0013] R1, R2, and R3 are each independently selected from hydrogen, hydroxyl, or methoxy.

[0014] Furthermore, at least one residue of the cucurbitane-type triterpenoid compound... The connection of phenolic acid groups means that phenolic acid groups can be monosubstituted, non-positioned polysubstituted, or fully substituted.

[0015] Furthermore, other residues in the cucurbitane-type triterpenoid compound... Each independently linked hydroxyl, methyl, or methoxy group means "other". When no phenolic acid group is attached, each group can be independently selected from hydroxyl, methyl, or methoxy groups.

[0016] Furthermore, the phenolic acid group in With cucurbitane-type triterpenoid residues Connected.

[0017] Preferably, X in the phenolic acid group is 0, or X is -C=C-.

[0018] Furthermore, the structure of the phenolic acid group where X is 0 is as follows:

[0019]

[0020] Preferably, the triterpenoid phenolic ester derivative has the following structural formula:

[0021]

[0022]

[0023] Another object of the present invention is to provide a method for preparing the above-mentioned triterpenoid phenolic ester derivatives.

[0024] The triterpenoid phenolic ester derivatives of the present invention can be prepared by the following method: phenolic acid (A) and triterpenoid compound (B) are esterified in a solvent containing an esterification catalyst at a temperature of 10-150°C to obtain the total product. The product is filtered, the filtrate is concentrated and dissolved in an organic solvent, extracted with water, and the organic phase is subjected to silica gel column chromatography or preparative liquid chromatography to obtain the triterpenoid phenolic ester derivative (Ia).

[0025]

[0026] In the above technical solution, the molar ratio of phenolic acid to triterpenoid compound is 1:1 to 3.

[0027] In the above technical solution, the organic solvent is one or more of dichloromethane, ethyl acetate, or acetone.

[0028] In the above technical solution, the solvent system for silica gel column chromatography is any two or a combination of three of dichloromethane, ethyl acetate, acetone, methanol, and water.

[0029] In the above technical solution, the preparative liquid chromatography separation is performed using methanol and 0.5% formic acid aqueous solution at a volume ratio of 60:40, or using acetonitrile and 0.5% formic acid aqueous solution at a volume ratio of 70:30.

[0030] Furthermore, the triterpenoid phenolic ester derivatives of the present invention can be prepared by the following method: phenolic acid is reacted with acetic anhydride in a solvent containing an acid or an esterification catalyst at a temperature of 10–150°C to generate hydroxyl-substituted acetylated phenolic acid. Then, it undergoes an esterification reaction with a triterpenoid compound in a solvent containing an esterification catalyst to obtain acetoxy-substituted triterpenoid phenolic esters. Finally, hydrazine hydrate is added to undergo a deprotection reaction to obtain the triterpenoid phenolic ester derivative.

[0031] In the above technical solution, the molar ratio of phenolic acid to acetic anhydride is 1:1 to 3.

[0032] In the above technical solution, the molar ratio of acetylated phenolic acid to triterpenoid compound is 1:3 to 5.

[0033] In the above technical solutions, the methods for carrying out the esterification reaction include: direct esterification of N,N'-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP), acetylation protection-acyl chloride-esterification-deacetylation, benzylation protection-acyl chloride or DCC esterification-hydrogen debenzylation.

[0034] Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a triterpenoid phenolic ester derivative.

[0035] Another object of the present invention is to provide the use of the aforementioned triterpenoid phenolic ester derivatives or the pharmaceutical compositions obtained above in the preparation of pharmaceuticals having the effect of regulating glucose and lipid metabolism.

[0036] The beneficial effects of this invention are as follows: Based on the natural regulatory effects of polyphenols and triterpenoids on glucose and lipid metabolism, this invention combines the two through ester bonds and uses structure-activity relationship analysis in medicinal chemistry to fully explore potential target compounds. The triterpenoid phenolic ester derivatives provided by this invention have the advantages of highly efficient and low-toxicity regulation of glucose and lipid metabolism, and at the same time provide a development template for candidate drugs with regulatory effects on glucose and lipid metabolism. Detailed Implementation

[0037] The following non-limiting embodiments are intended to enable those skilled in the art to more fully understand the invention, but do not limit the invention in any way.

[0038] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; the reagents and materials described are commercially available unless otherwise specified.

[0039] Example 1

[0040] The preparation method of compound I-1 (3-O-galloyl-23E-5β,19-epoxy-cucurbita-6,23-dien-25-ol) includes the following steps:

[0041] (1) Preparation of 3,4,5-triacetylgallic acid

[0042] In a 1000 mL three-necked flask equipped with an electric stirrer, water bath cooling, a reflux condenser with a drying tube, and a thermometer, 26 mol of acetic anhydride and concentrated sulfuric acid (2% catalyst) were added. Gallic acid (0.5 mol) was added in portions with stirring, maintaining the reaction temperature below 60 °C. After the addition was complete, stirring continued for 10–20 min. The reaction system was then heated at 90 °C for 10 h. The reaction progress was monitored by thin-layer chromatography. After cooling, filtration, and vacuum drying, 0.46 mol of 3,4,5-triacetylgallic acid (92% yield) was obtained as a white solid.

[0043] (2) Preparation of compound I-1

[0044] Take 0.01 mol of the above-obtained 3,4,5-triacetylgallic acid into a 250 mL Erlenmeyer flask, add 50 mL of acetonitrile to dissolve it, add 0.01 mol of 23E-5β,19-epoxy-cucurbita-6,23-dien-25-ol (structure shown below) and 0.01 mol of DCC, and reflux for 24 hours. After the reaction is complete, cool and filter the insoluble N,N'-dicyclohexylurea (DCU) white byproduct. Add 0.03 mol of hydrazine hydrate to the filtrate, react at room temperature for half an hour, add 0.03 mol of acetic acid and 100 mL of water, extract three times with 100 mL of ethyl acetate, combine the organic phases, wash with water until neutral, dry with anhydrous magnesium sulfate, and evaporate the solvent under reduced pressure to obtain the total product. The total product was separated on 200-300 mesh silica gel and eluted with a gradient of petroleum ether-ethyl acetate (volume ratios of 100:0, 50:1, 30:1, 10:1, 8:1, 5:1, 3:1, 2:1, 1:1, 0:1), with 5 column volumes for each gradient. The product was then qualitatively analyzed by silica gel thin-layer chromatography. Identical fractions were combined and eluted with petroleum ether-ethyl acetate at a volume ratio of 2:1. The collected fraction was recrystallized to give compound I-1, which was dried under vacuum to obtain 0.0029 mol, a yield of 29%.

[0045]

[0046] 23E-5β,19-epoxy-cucurbita-6,23-dien-25-ol

[0047] Example 2

[0048] The preparation method of compound I-2 (3-O-dicaffeoyl-23E-5β,19-epoxy-cucurbita-6,23,25-triene-3β-ol) includes the following steps:

[0049] (1) Preparation of 3,4-diacetaconic acid

[0050] In a 1000 mL three-necked flask equipped with an electric stirrer, water bath cooling, a reflux condenser with a drying tube, and a thermometer, 26 mol of acetic anhydride and concentrated sulfuric acid (2% catalyst) were added. 0.5 mol of caffeic acid was added in portions with stirring, maintaining the reaction temperature below 60°C. After the addition was complete, stirring continued for 10–20 min. The reaction system was then heated at 90°C for 10 h. Samples were taken for thin-layer chromatography to monitor the reaction progress. After cooling, filtration, and vacuum drying, 0.44 mol of 3,4-diacetaconic acid (88% yield) was obtained as a white solid.

[0051] (2) Preparation of compound I-2

[0052] 0.01 mol of 3,4-diacetaconic acid was dissolved in 50 mL of acetonitrile in a 250 mL Erlenmeyer flask. 0.01 mol of 23E-5β,19-epoxy-cucurbita-6,23,25-triene-3β-ol (structure shown below) and 0.01 mol of DCC were added, and the mixture was refluxed for 24 hours. After the reaction was complete, the mixture was cooled and filtered to obtain an insoluble white byproduct of N,N'-dicyclohexylurea (DCU). 0.03 mol of hydrazine hydrate was added to the filtrate, and the mixture was reacted at room temperature for half an hour. 0.03 mol of acetic acid and 100 mL of water were added, and the mixture was extracted three times with 100 mL of ethyl acetate. The combined organic phases were washed with water until neutral, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the total product. The total product was separated on 200-300 mesh silica gel and eluted with a petroleum ether-ethyl acetate gradient (volume ratios of 100:1, 50:1, 10:1, 8:1, 5:1, 1:1, 0:1), with 5 column volumes eluted for each gradient. Qualitative analysis was performed using silica gel thin-layer chromatography. Identical fractions were combined, and the ethyl acetate elution fraction was collected and recrystallized to give compound I-2. Vacuum drying yielded 0.0017 mol, a yield of 17%.

[0053]

[0054] 23E-5β,19-epoxy-cucurbita-6,23,25-triene-3β-ol

[0055] Example 3

[0056] The preparation method of compound I-3 (3-O-galloyl-3β,7β,25-trihydroxy-cucurbita-5,(23E)-diene-19-ol) includes the following steps:

[0057] 0.01 mol of 3,4,5-triacetylgallic acid obtained in Example 1 was placed in a 250 mL Erlenmeyer flask and dissolved in 50 mL of acetonitrile. 0.01 mol of 3β,7β,25-trihydroxy-cucurbita-5,(23E)-diene-19-ol (structure shown below) and 0.01 mol of DCC were added, and the mixture was refluxed for 24 hours. After the reaction was completed, the mixture was cooled and filtered to obtain an insoluble white byproduct of N,N'-dicyclohexylurea (DCU). 0.03 mol of hydrazine hydrate was added to the filtrate, and the mixture was reacted at room temperature for half an hour. 0.03 mol of acetic acid and 100 mL of water were added, and the mixture was extracted three times with 100 mL of ethyl acetate. The combined organic phases were washed with water until neutral, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the total product. The total product was separated on 200-300 mesh silica gel and eluted with a petroleum ether-acetone gradient (volume ratios of 100:1, 50:1, 10:1, 8:1, 5:1, 3:1, 1:1, 0:1), with 5 column volumes eluted for each gradient. Qualitative analysis was performed using silica gel thin-layer chromatography. Identical fractions were combined and eluted with petroleum ether-acetone at a 3:1 ratio. The collected fraction was recrystallized to give compound I-3. Vacuum drying yielded 0.0016 mol, a yield of 16%.

[0058]

[0059] 3β,7β,25-trihydroxy-cucurbita-5,(23E)-diene-19-ol

[0060] Example 4

[0061] The preparation method of compound I-4 (3-O-feruloyl-charantadiol A) includes the following steps:

[0062] (1) Preparation of 4-acetylferulic acid

[0063] In a 1000 mL three-necked flask equipped with an electric stirrer, water bath cooling, a reflux condenser with a drying tube, and a thermometer, 26 mol of acetic anhydride and concentrated sulfuric acid (2% catalyst) were added. Ferulic acid (0.5 mol) was added in portions with stirring, keeping the reaction temperature below 60 °C. After the addition was complete, stirring continued for 10–20 min. The reaction system was then heated at 90 °C for 10 h. Thin-layer chromatography was used to monitor the reaction progress. After cooling, filtration, and vacuum drying, 0.43 mol of 4-acetylferulic acid (86% yield) was obtained as a white solid.

[0064] (2) Preparation of compound I-4

[0065] 0.01 mol of 4-acetylferulic acid was placed in a 250 mL Erlenmeyer flask and dissolved in 50 mL of acetonitrile. Then, 0.01 mol of charantadiol A (structure shown below) and 0.01 mol of DCC were added, and the mixture was refluxed for 24 hours. After the reaction was completed, the mixture was cooled and filtered to obtain an insoluble white byproduct of N,N'-dicyclohexylurea (DCU). 0.03 mol of hydrazine hydrate was added to the filtrate, and the mixture was reacted at room temperature for half an hour. Then, 0.03 mol of acetic acid and 100 mL of water were added, and the mixture was extracted three times with 100 mL of ethyl acetate. The combined organic phases were washed with water until neutral, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the total product. The total product was separated on 200-300 mesh silica gel and eluted with a chloroform-methanol gradient (volume ratios of 100:0, 50:1, 30:1, 10:1, 5:1, 3:1, 1:1, 0:1), with 5 column volumes eluted for each gradient. Qualitative analysis was performed using silica gel thin-layer chromatography. Identical fractions were combined and eluted with chloroform-methanol at a volume ratio of 10:1. The collected fraction was recrystallized to give compound I-4. Vacuum drying yielded 0.0019 mol, a yield of 19%.

[0066]

[0067] charantadiol A

[0068] Tests on the hypoglycemic activity of the triterpenoid phenolic ester derivatives obtained in Examples 1-4:

[0069] (I) Experiments on the inhibitory activity of triterpenoid phenolic acid ester derivatives, proto-triterpenoid compounds, and proto-phenolic acids on α-glucosidase obtained in Examples 1-4.

[0070] 1. Experimental materials and reagents

[0071] Multiskan MK3 (ELISA reader, Thermo Electron, USA); α-glucosidase (Sigma-Aldrich, USA); p-nitrophenyl-α-D-glucopyranoside (PNPG, 99% purity) purchased from Sigma-Aldrich, USA; acarbose (trade name: Glucobay) purchased from Bayer AG, Germany; dimethyl sulfoxide (DMSO) from Laiyang Chemical Experimental Plant; all other chemical reagents used were commercially available analytical grade and purchased from Sinopharm Group.

[0072] 2. Reagent preparation

[0073] a. Preparation of phosphate buffer: Na2HPO4·3H2O (35.82g) + NaH2PO4 (15.61g) are used as solutes and dissolved in double-distilled water. The solution is then diluted to 500mL in a volumetric flask. The solution is slightly acidic at this point. The pH is adjusted to 6.8 with NaOH (2mol / L) solution. Store in the dark.

[0074] b. Preparation of α-glucosidase solution: Weigh an appropriate amount and dissolve it in double-distilled water to ensure the enzyme activity unit of the solution is 0.02 U / μL. After preparation, freeze and store it at -4℃ in the dark as a stock solution.

[0075] c. Preparation of substrate solution: Weigh 30 mg of solid 4-nitrophenyl-β-D-glucopyranoside (PNPG) and dissolve it in 5 mL of phosphate buffer (6 μg / μL). The substrate is difficult to dissolve and needs to be sonicated for about 20 min. After dissolving, wrap it in aluminum foil and store it in the dark.

[0076] d. Preparation of Na2CO3 stop solution: Dissolve 21.2g of Na2CO3 in distilled water to prepare a 0.2mol / L solution.

[0077] e. Preparation and formulation of test solutions: Triterpenoid phenolic ester derivatives are all white powders. They are dissolved in DMSO to prepare a stock solution, which is then stored at -20°C. Before use, they are diluted with the appropriate culture medium. The final concentration of DMSO should be ≤1‰.

[0078] 3. Experimental Methods

[0079] Add 30 μL of α-glucosidase solution and 20 μL of prepared triterpenoid phenolic acid ester derivative solution to a test tube, incubate at 37°C for 5 min, then add 150 μL of PNPG and 800 μL of phosphate buffer. Seal and incubate at 37°C for 30 min. Stop the reaction by adding 2 mL of 2M Na₂CO₃. Measure the OD value at 405 nm using a microplate reader. Use acarbose as a positive control. The inhibition rate is calculated according to the following formula, where A... 空白 A represents the absorbance after the reaction without adding a sample. 样品 This represents the absorbance value after the sample is added and reacted.

[0080]

[0081] The inhibition rate corresponding to each concentration is represented by the ordinate Y, and the logarithm of the administered concentration is represented by the abscissa X. A linear regression is performed, and the administered concentration at which the inhibition rate is 50% is calculated based on the resulting equation, thus obtaining the IC50 of the drug. 50 .

[0082] The concentrations of compound I-1 were prepared as follows: 10, 3, 0.3, and 0.03 μM; the concentrations of 23E-5β,19-epoxy-cucurbita-6,23-dien-25-ol were prepared as follows: 50, 10, 1, and 0.1 μM; the concentrations of gallic acid were prepared as follows: 100, 50, 10, and 1 μM; and the concentrations of the positive control drug acarbose were prepared as follows: 30, 10, 3, and 0.3 μM. The activity inhibition experiments of α-glucosidase were conducted according to the above method. The activity inhibition experiments of compounds I-2 to I-4 were similar to those described above, except that the types of triterpenoids and phenolic acids were different. The results are shown in Table 1.

[0083] Table 1. Studies on the inhibitory activity of compounds I-1 to I-4 on α-glucosidase.

[0084]

[0085]

[0086] Studies on α-glucosidase activity have shown that triterpenoid phenolic acid ester derivatives have extremely strong inhibitory activity against α-glucosidase, with stronger activity than the original triterpenoid compounds, phenolic acids, and the positive control drug acarbose.

[0087] (II) Activity experiments of triterpenoid phenolic acid ester derivatives, prototype triterpenoid compounds, and prototype phenolic acids in inhibiting PTP1B obtained in Examples 1-4

[0088] 1. Experimental materials, reagents and instruments

[0089] Nichipet EX pipette (Nichiryo); HH-B11 electric thermostatic incubator (Shanghai Yuejin Medical Instrument Co., Ltd.); HC-3518 low-speed centrifuge (Anhui Zhongke Zhongjia Scientific Instrument Co., Ltd.); BS-124S ​​precision electronic balance (Sartorius, Germany); 450 type enzyme-linked immunosorbent assay (ELISA) instrument (Bio-Rad, USA); EDTA, Tris, HCl, β-mercaptoethanol, NaOH, Na3VO4·12H2O (Sinopharm Chemical Reagent Co., Ltd.); PTP1B enzyme, DTT, pNPP (Sigma, USA); Dimethyl sulfoxide (DMSO) Laiyang Chemical Experimental Plant.

[0090] 2. Reagent preparation

[0091] a. Stock solutions: Dilute 0.6055 g Tris and 0.0584 g EDTA with distilled water to 20 mL, and adjust the pH to 7.5 with concentrated hydrochloric acid. The final concentrations are 250 mM for Tris-HCl and 10 mM for EDTA.

[0092] b. Buffer solution: Take 1 mL of the stock solution, dilute with distilled water to 10 mL, and add 0.0015 g of dithiothreitol (DTT) and 0.718 μL of β-mercaptoethanol. The buffer solution now contains 25 mM Tris-HCl, 1 mM EDTA, 1 mM DTT, and 2 mM β-mercaptoethanol. This solution should be prepared fresh before use.

[0093] c. Substrate solution: Weigh 0.1856 g of 4-nitrophenyl phosphate disodium hexahydrate (pNPP), dilute with 1 mL of buffer solution, and dispense into 1.5 mL EP tubes. Store in a freezer at -20°C, protected from light.

[0094] d. Sodium vanadate solution: Take 0.816g of sodium vanadate dodecahydrate, add 100mL of distilled water, heat the solution to boiling until translucent, and adjust the pH to about 10. Use a pipette to take 1mL of the solution into a 100mL beaker, stir and mix with a glass rod, and heat again to boiling until translucent to ensure that the sodium vanadate is in monomer form. After cooling, dispense into 1.5mL EP tubes and store frozen at -20℃.

[0095] e. Termination solution: 2M NaOH solution.

[0096] 3. Experimental Methods

[0097] Triterpenoid phenolic ester derivatives were prepared into a 10 mM stock solution using DMSO and stored protected from light. Before use, the solution was diluted with PBS for experiments, with the final concentration of DMSO in the highest dose group being 1‰.

[0098] Positive control group: Sodium vanadate solution was prepared in the same way as above.

[0099] The assay for the inhibition of PTP1B enzyme activity by triterpenoid phenolic ester derivatives was performed in 96-well plates. In the experimental group, 83 μL of enzyme-containing buffer (0.4 μL enzyme), 10 μL of derivative solution, and 4 μL of substrate solution were added sequentially; in the positive control group, 83 μL of enzyme-containing buffer (0.4 μL enzyme), 10 μL of sodium vanadate solution, and 4 μL of substrate solution were added sequentially; in the blank control group, 93 μL of enzyme-containing buffer (0.4 μL enzyme) and 4 μL of substrate solution were added sequentially; and in the reagent control group, 83 μL of enzyme-containing buffer (0.4 μL enzyme), 10 μL of DMSO solution, and 4 μL of substrate solution were added. The reaction was incubated at 37°C for 30 min, and then terminated with 5 μL of NaOH solution. The absorption intensity of the product at 405 nm was measured using a microplate reader, and the relative inhibition rate of the derivative against PTP1B at different concentrations was calculated. The inhibition rate was calculated according to the following formula, where A... 空白 A represents the absorbance after the reaction without adding a sample. 样品 This represents the absorbance value after the sample is added and reacted.

[0100]

[0101] The inhibition rate corresponding to each concentration is represented by the ordinate Y, and the logarithm of the administered concentration is represented by the abscissa X. A linear regression is performed, and the administered concentration at which the inhibition rate is 50% is calculated based on the resulting equation, thus obtaining the IC50 of the drug. 50 .

[0102] The concentrations of compound I-1 were prepared as follows: 10, 3, 0.3, and 0.03 μM; the concentrations of 23E-5β,19-epoxy-cucurbita-6,23-dien-25-ol were prepared as follows: 50, 10, 1, and 0.1 μM; the concentrations of gallic acid were prepared as follows: 100, 50, 10, and 1 μM; and the concentrations of the positive control sodium vanadate (Na3VO4) were prepared as follows: 50, 25, 10, and 1 μM. The activity experiments of compounds I-2 to I-4 in inhibiting PTP1B were conducted similarly to the above methods, the difference being the different types of triterpenoids and phenolic acids. The results of the PTP1B activity experiments were performed according to the above methods and are shown in Table 2.

[0103] Table 2. Study on the inhibitory activity of compounds I-1 to I-4 against PTP1B

[0104]

[0105] PTP1B activity studies have shown that triterpenoid phenolic acid esters have extremely strong inhibitory activity against PTP1B, which is stronger than that of the original triterpenoids, phenolic acids, and the positive control drug sodium alum.

Claims

1. A triterpenoid phenolic ester derivative, characterized in that: The structural formula of the triterpenoid phenolic ester derivative is shown below: 。 2. The method for preparing the triterpenoid phenolic ester derivative according to claim 1, characterized in that: The preparation method of the derivatives includes the following steps: phenolic acid (A) and triterpenoid compound (B) are subjected to esterification reaction in a solvent containing an esterification catalyst at a temperature of 10~150℃ to obtain the total product. The product is filtered, the filtrate is concentrated and dissolved in an organic solvent, extracted with water, and the organic phase is subjected to silica gel column chromatography or preparative liquid chromatography to obtain triterpenoid phenolic acid ester derivatives (I-1~I-4), wherein the phenolic acid is gallic acid, ferulic acid or caffeic acid, and the triterpenoid compound has one of the following structures: 。 3. The preparation method according to claim 2, characterized in that: The preparation method of the derivative includes the following steps: at a temperature of 10~150℃, phenolic acid and acetic anhydride are reacted in a solvent containing an acid or an esterification catalyst to generate hydroxyl-substituted acetylated phenolic acid, which is then esterified with a triterpenoid compound in a solvent containing an esterification catalyst to obtain acetoxy-substituted triterpenoid phenolic ester, and hydrazine hydrate is added to undergo a deprotection reaction to obtain the triterpenoid phenolic ester derivative.

4. The preparation method according to claim 2, characterized in that: The molar ratio of the phenolic acid to the triterpenoid compound is 1:1~3; the organic solvent is one or more of dichloromethane, ethyl acetate, or acetone; the solvent system for the silica gel column chromatography is any combination of two or three of dichloromethane, ethyl acetate, acetone, methanol, and water; the preparative liquid chromatography separation is performed using methanol and a 0.5% formic acid aqueous solution at a volume ratio of 60:40, or using acetonitrile and a 0.5% formic acid aqueous solution at a volume ratio of 70:

30.

5. The preparation method according to claim 3, characterized in that: The molar ratio of the phenolic acid to the acetic anhydride is 1:1~3; the molar ratio of the acetylated phenolic acid to the triterpenoid compound is 1:3~5.

6. A pharmaceutical composition, characterized in that: The pharmaceutical composition contains a therapeutically effective amount of the triterpenoid phenolic ester derivative of claim 1.

7. The use of the triterpenoid phenolic ester derivative of claim 1 or the pharmaceutical composition of claim 6 in the preparation of a drug having the effect of regulating glucose and lipid metabolism.

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