CN119751537A - A triterpenoid phenolic acid ester derivative and its preparation method and application - Google Patents
A triterpenoid phenolic acid ester derivative and its preparation method and application Download PDFInfo
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Abstract
The invention relates to a triterpene phenolic acid ester derivative, a preparation method and application thereof, belonging to the field of pharmaceutical chemistry. The main structure R of the triterpene phenolic acid ester derivative is cucurbitane type triterpene compound residues, wherein at least one of the cucurbitane type triterpene compound residuesTo which phenolic groups are attached, otherAnd each of the phenolic acid groups is independently connected with hydroxyl, methyl or methoxy, wherein X is 0, C1-C3 saturated alkyl or C1-C3 unsaturated alkyl, and R 1、R2、R3 is independently selected from hydrogen, hydroxyl or methoxy. The triterpene phenolic acid ester derivative has remarkable effect of regulating and controlling the metabolism of glycolipid, and can be used for preventing or treating the occurrence and the development of glycolipid metabolic disorder diseases.
Description
Technical Field
The invention relates to a triterpene phenolic acid ester derivative, a preparation method and application thereof, belonging to the field of pharmaceutical chemistry.
Background
Large-scale epidemiological investigation, clinical data analysis, molecular gene research and experimental evidence of large animals approaching human disease models indicate that metabolic syndrome, which is represented by glycolipid metabolic disorder as a center, is the largest risk factor for diseases such as hyperlipidemia, fatty liver, diabetes, hypertension, atherosclerosis, cardiovascular and cerebrovascular diseases and the like. Glycolipid metabolic disorders are due to their broad nature, pathogenicity and susceptibility.
The balance of glycolipid metabolism plays a vital role in maintaining the basic vital activity of a cell or organism. Disruption of glycolipid homeostasis will lead to the development of various metabolic diseases such as obesity, diabetes, fatty liver, cardiovascular disease. Studies have shown that polyphenols regulate carbohydrate metabolism by mechanisms that regulate enzyme activity, stimulate insulin secretion, regulate insulin sensitivity, enhance glucose uptake in tissues and secretion of gut hormones. And some polyphenols have been shown to reduce the levels of total blood cholesterol (total cholesterol, TC), triglycerides (TRIGLYCERIDES, TG) and low density lipoprotein cholesterol (low density lipoprotein cholesterol, LDL-C), inhibit the absorption of fat in the intestine, etc. by modulating the expression of genes associated with lipid metabolism.
Triterpenes have a wide range of physiological activities, and some triterpenes have been found to have a significant effect of regulating glycolipid metabolism. More and more researches and data show that after the polyphenol components are combined with certain drug molecules through chemical means, the antioxidant activity of the drug molecules can be obviously enhanced, and the drug effect is improved. Therefore, it is necessary to develop a conjugate of polyphenol and triterpene and derivatives thereof as a lead compound for regulating glycolipid metabolism.
Disclosure of Invention
Aiming at the technical problems existing in the preparation of medicines for treating glycolipid metabolic diseases in the prior art, the invention provides a triterpene phenolic acid ester derivative, and a preparation method and application thereof. The triterpene phenolic acid ester derivative provided by the invention can be used as a lead compound for developing novel efficient low-toxicity glycolipid metabolism regulation and control, and provides a synthetic template for developing glycolipid metabolism regulation and control drugs.
A triterpene phenolic acid ester derivative is characterized in that the main structure R of the triterpene phenolic acid ester derivative is cucurbitane type triterpene compound residue, and the specific structural formula is as follows:
Wherein at least one of To which phenolic groups are attached, otherEach independently connecting hydroxyl, methyl or methoxy, wherein the phenolic acid group has the following structure:
Wherein,
X is 0, C1-C3 saturated alkyl or C1-C3 unsaturated alkyl;
R 1、R2、R3 is independently selected from hydrogen, hydroxy or methoxy.
Further, at least one of the cucurbitane-type triterpene compound residuesBy linking phenolic groups is meant that the phenolic acid groups can be mono-substituted, non-aligned poly-substituted or fully substituted.
Further, the other of the cucurbitane-type triterpene compound residuesEach independently of the other, is bound to a hydroxy, methyl or methoxy groupWhen phenolic groups are not attached, each may be independently selected from hydroxy, methyl or methoxy.
Further, the phenolic acid group in the phenolic acid groupWith cucurbitane-type triterpene compounds residuesAre connected.
Preferably, X in the phenolic acid group is 0, or X is-c=c-.
Further, the phenolic acid group structure with X being 0 is
Preferably, the triterpene phenolic acid ester derivative has the structural formula shown as follows:
another object of the present invention is to provide a process for preparing the above triterpene phenolic acid ester derivative.
The triterpene phenolic acid ester derivative can be prepared by the following method, wherein phenolic acid (A) and triterpene compound (B) are subjected to esterification reaction in a solvent containing an esterification catalyst at the temperature of 10-150 ℃ to obtain a total product, the total product is filtered, filtrate is concentrated and then is dissolved in an organic solvent, water is added for extraction, and a triterpene phenolic acid ester derivative (I-a) is obtained from an organic phase through silica gel column chromatography or preparative liquid chromatography.
In the technical scheme, the molar ratio of the phenolic acid to the triterpene compound is 1:1-3.
In the above technical scheme, the organic solvent is one or more of dichloromethane, ethyl acetate or acetone.
In the above technical scheme, the solvent system of the silica gel column chromatography is any two or a combination of three of dichloromethane, ethyl acetate, acetone, methanol and water.
In the technical scheme, the preparation liquid chromatography is separated by using methanol and 0.5% formic acid aqueous solution in a volume ratio of 60:40, or by using acetonitrile and 0.5% formic acid aqueous solution in a volume ratio of 70:30.
Further, the triterpene phenolic acid ester derivative of the invention can be prepared by reacting phenolic acid and acetic anhydride in a solvent containing acid or an esterification catalyst at the temperature of 10-150 ℃ to generate hydroxyl-substituted acetylated phenolic acid, then carrying out esterification reaction with a triterpene compound in the solvent containing the esterification catalyst to obtain acetoxy-substituted triterpene phenolic acid ester, adding hydrazine hydrate to carry out deprotection reaction to obtain the triterpene phenolic acid ester derivative
In the technical scheme, the molar ratio of the phenolic acid to the acetic anhydride is 1:1-3.
In the technical scheme, the molar ratio of the acetylated phenolic acid to the triterpene compound is 1:3-5.
In the technical scheme, the method for carrying out the esterification reaction comprises an N, N' -Dicyclohexylcarbodiimide (DCC) method, a 4-Dimethylaminopyridine (DMAP) direct esterification method, an acetylation protection-acyl chlorination-esterification-deacetylation method, a benzyl protection-acyl chlorination or DCC esterification-hydrogenolysis debenzylation method.
It is a further object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of a triterpene phenolic acid ester derivative.
It is still another object of the present invention to provide the use of said triterpene phenolic acid ester derivative or the pharmaceutical composition obtained as described above for the preparation of a medicament having a glycolipid metabolism regulating effect.
The invention has the beneficial effects that the natural regulation and control glycolipid metabolism efficacy based on polyphenols and triterpenes is realized, the polyphenols and the triterpenes are combined through ester bonds, the analysis of the structure-activity relationship of pharmaceutical chemistry is carried out, and the potential target compounds are fully excavated. The triterpene phenolic acid ester derivative provided by the invention has the advantages of high efficiency and low toxicity for regulating and controlling the metabolism of glycolipid, and provides a development template for researching candidate medicaments with the function of regulating the metabolism of glycolipid.
Detailed Description
The following non-limiting examples will enable those of ordinary skill in the art to more fully understand the invention and are not intended to limit the invention in any way.
The test methods described in the examples below, unless otherwise indicated, are conventional, and the reagents and materials, unless otherwise indicated, are commercially available.
Example 1
A process for the preparation of compound I-1 (3-O-galloyl-23E-5 beta, 19-epoxy-cucurbita-6, 23-dien-25-ol) comprising the steps of:
(1) Preparation of 3,4, 5-triacetylgallantoin
26Mol of acetic anhydride and 2 percent of catalyst concentrated sulfuric acid (catalytic amount) are added into a 1000mL three-port bottle provided with an electric stirring, a water bath cooling, a reflux condenser protected by a drying pipe and a thermometer, 0.5mol of gallic acid is added in batches under stirring, the temperature of a reaction system is not more than 60 ℃, the stirring is continued for 10-20 min after the addition, the reaction system is placed at 90 ℃ for heating reaction for 10h, and the reaction progress is detected and tracked by thin layer chromatography. Cooling, filtering and vacuum drying to obtain 0.46mol of 3,4, 5-triacetyl gallic acid with a yield of 92% and a white solid.
(2) Preparation of Compound I-1
Taking 0.01mol of the obtained 3,4, 5-triacetyl gallic acid, putting the 3,4, 5-triacetyl gallic acid into a 250mL Erlenmeyer flask, adding 50mL of acetonitrile to dissolve the 3,4, 5-triacetyl gallic acid, adding 0.01mol of 23E-5 beta, 19-epoxy-cucurbita-6,23-dien-25-ol (with the structure shown as the following) and 0.01mol of DCC, carrying out reflux reaction for 24 hours, cooling, filtering insoluble N, N' -Dicyclohexylurea (DCU) white byproducts after the reaction, adding 0.03mol of hydrazine hydrate into the filtrate, reacting for half an hour at room temperature, adding 0.03mol of acetic acid and 100mL of water, extracting three times by using 100mL of ethyl acetate, merging organic phases, washing to be neutral by using water, drying by using anhydrous magnesium sulfate, and evaporating the solvent under reduced pressure to obtain a total product. Separating the total product by 200-300 mesh silica gel, gradient eluting by using petroleum ether-ethyl acetate (volume ratio of 100:0,50:1,30:1,10:1,8:1,5:1,3:1,2:1,1:1, 0:1), eluting 5 column volumes by each gradient, qualitatively separating the silica gel thin layers, combining the same components, eluting and collecting the part by using petroleum ether-ethyl acetate with volume ratio of 2:1, recrystallizing to obtain the compound I-1, and vacuum drying to obtain 0.0029mol, wherein the yield is 29%.
23E-5β,19-epoxy-cucurbita-6,23-dien-25-ol
Example 2
A process for the preparation of compound I-2 (3-O-dicaffeoyl-23E-5 beta, 19-epoxy-cucurbita-6,23,25-triene-3 beta-ol) comprising the steps of:
(1) Preparation of 3, 4-diacetyl caffeic acid
26Mol of acetic anhydride and 2 percent of catalyst concentrated sulfuric acid (catalytic amount) are added into a 1000mL three-port bottle provided with an electric stirring, a water bath cooling, a reflux condenser protected by a drying pipe and a thermometer, 0.5mol of caffeic acid is added in batches under stirring, the temperature of a reaction system is not more than 60 ℃, the stirring is continued for 10-20 min after the addition, the reaction system is placed at 90 ℃ for heating reaction for 10h, and the reaction progress is detected and tracked by using thin layer chromatography. Cooling, filtering and vacuum drying to obtain 0.44mol of 3, 4-diacetyl caffeic acid with 88 percent of yield and white solid.
(2) Preparation of Compound I-2
Taking 0.01mol of 3, 4-diacetyl caffeic acid in a 250mL Erlenmeyer flask, adding 50mL of acetonitrile to dissolve the 3, 4-diacetyl caffeic acid, adding 0.01mol of 23E-5 beta, 19-epoxy-cucurbita-6,23,25-triene-3 beta-ol (with the structure shown as the following) and 0.01mol of DCC, carrying out reflux reaction for 24 hours, cooling, filtering insoluble N, N' -Dicyclohexylurea (DCU) white byproducts, adding 0.03mol of hydrazine hydrate into the filtrate, carrying out reaction for half an hour at room temperature, adding 0.03mol of acetic acid and 100mL of water, extracting three times by using 100mL of ethyl acetate, merging the organic phases, washing the organic phases to be neutral by using water, drying by using anhydrous magnesium sulfate, and evaporating the solvent under reduced pressure to obtain a total product. Separating the total product by 200-300 mesh silica gel, performing gradient elution by using petroleum ether-ethyl acetate (volume ratio is 100:1,50:1,10:1,8:1,5:1,1:1, 0:1), performing gradient elution by 5 column volumes each, performing thin-layer characterization on the silica gel, combining the same components, eluting and collecting the part by using ethyl acetate, and performing recrystallization to obtain the compound I-2. Vacuum drying to obtain 0.0017mol, yield 17%.
23E-5β,19-epoxy-cucurbita-6,23,25-triene-3β-ol
Example 3
The preparation method of the compound I-3 (3-O-galloyl-3 beta, 7 beta, 25-trihydroxy-cucurbita-5, (23E) -diene-19-ol) comprises the following steps:
0.01mol of 3,4, 5-triacetyl gallic acid obtained in example 1 is taken in a 250mL Erlenmeyer flask, 50mL of acetonitrile is added to dissolve the 3, 7 beta, 25-trihydroxy-cucurbita-5, (23E) -diene-19-ol (the structure is shown as follows) and 0.01mol of DCC are added to carry out reflux reaction for 24 hours, after the reaction is completed, insoluble N, N' -Dicyclohexylurea (DCU) white byproducts are cooled and filtered, 0.03mol of hydrazine hydrate is added to filtrate to carry out reaction for half an hour at room temperature, 0.03mol of acetic acid and 100mL of water are added, the mixture is extracted three times by 100mL of ethyl acetate, the organic phase is combined to be neutral by water, and then dried by anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure, thus obtaining the total product. Separating the total product by 200-300 mesh silica gel, gradient eluting by using petroleum ether-acetone (volume ratio of 100:1,50:1,10:1,8:1,5:1,3:1,1:1, 0:1), performing gradient elution for 5 column volumes each, performing silica gel thin layer characterization, combining the same components, eluting a collecting part by using petroleum ether-acetone 3:1, and performing recrystallization to obtain the compound I-3. Vacuum drying to obtain 0.0016mol, and the yield is 16%.
3β,7β,25-trihydroxy-cucurbita-5,(23E)-diene-19-ol
Example 4
A process for the preparation of compound I-4 (3-O-feruloyl-charantadiol A) comprising the steps of:
(1) Preparation of 4-acetyl ferulic acid
26Mol of acetic anhydride and 2 percent of catalyst concentrated sulfuric acid (catalytic amount) are added into a 1000mL three-port bottle provided with an electric stirring, a water bath cooling, a reflux condenser protected by a drying pipe and a thermometer, 0.5mol of ferulic acid is added in batches under stirring, the temperature of a reaction system is not more than 60 ℃, the stirring is continued for 10-20 min after the addition, the reaction system is placed at 90 ℃ for heating reaction for 10h, and the reaction progress is tracked by sampling and thin-layer detection. Cooling, filtering and vacuum drying to obtain 0.43mol of 4-acetyl ferulic acid, with a yield of 86% and a white solid.
(2) Preparation of Compound I-4
Dissolving 0.01mo 4-acetyl ferulic acid in 250mL Erlenmeyer flask, adding 50mL acetonitrile to dissolve, adding 0.01mol charantadiol A (structure shown below) and 0.01mol DCC, reflux reacting for 24 hours, cooling, filtering insoluble N, N' -Dicyclohexylurea (DCU) white byproduct, adding 0.03mol hydrazine hydrate into filtrate, reacting for half an hour at room temperature, adding 0.03mol acetic acid and 100mL water, extracting with 100mL ethyl acetate for three times, combining organic phases, washing with water to be neutral, drying with anhydrous magnesium sulfate, evaporating solvent under reduced pressure, and obtaining total product. Separating the total product by 200-300 mesh silica gel, gradient eluting by chloroform-methanol (volume ratio of 100:0,50:1,30:1,10:1,5:1,3:1,1:1, 0:1), eluting 5 column volumes by each gradient, qualitatively separating by silica gel thin layer, combining the same components, eluting the collecting part by chloroform-methanol volume ratio of 10:1, and recrystallizing to obtain the compound I-4. Vacuum drying to obtain 0.0019mol, yield 19%.
charantadiol A
Test of hypoglycemic activity of triterpene phenolic acid ester derivatives obtained in examples 1 to 4:
(one) an experiment of the activity of the triterpene phenolic acid ester derivative, prototype triterpene compound and prototype phenolic acid in inhibiting alpha-glucosidase obtained in examples 1 to 4
1. Experimental materials and reagents
MultiskanMK3 (enzyme-labeled instrument, thermo Electron Co., U.S.A.), alpha-glucosidase (Sigma Co., U.S.A.), p-nitrophenyl-alpha-D-glucopyranoside (PNPG, 99% purity) was purchased from Sigma Co., U.S.A.), acarbose (trade name: bayer Tang Ping) was purchased from Bayer Germany, dimethyl sulfoxide (DMSO) was purchased from Lyyang chemical laboratory, and the other chemicals used were all commercially available analytical pure and were purchased from the national pharmaceutical group.
2. Reagent preparation
A. The preparation of phosphate buffer solution, na 2HPO4·3H2O(35.82g)+NaH2PO4 (15.61 g) is taken as a solute, dissolved in double distilled water, and the solution is slightly acidic at the moment in a 500mL volumetric flask, and is adjusted to pH=6.8 by NaOH (2 mol/L) solution, and then the solution is preserved in a dark place.
B. the preparation of the alpha-glucosidase solution comprises weighing a proper amount, dissolving with double distilled water, and ensuring the activity unit of the enzyme solution to be 0.02U/. Mu.L. After preparation, the mixture was frozen at-4 ℃ and stored in a dark place as a mother solution.
C. the preparation of substrate solution comprises weighing 30mg of solid 4-nitrophenyl-beta-D-glucopyranoside (PNPG), dissolving in 5mL of phosphoric acid buffer solution (6 μg/μl), dissolving the substrate difficultly, taking ultrasound for about 20min, and wrapping with tinfoil paper for light-shielding storage.
And d, preparing Na 2CO3 stopping solution, namely dissolving 21.2g of Na 2CO3 into distilled water to prepare 0.2mol/L solution.
E. the preparation and preparation of the sample of the test solution are that the triterpene phenolic acid ester derivative is white powder, and the triterpene phenolic acid ester derivative is dissolved by DMSO to prepare mother solution which is stored in a refrigerator at-20 ℃. The experiment was performed by diluting it with the corresponding culture solution before use. The final concentration of DMSO is less than or equal to 1 per mill.
3. Experimental method
Mu.L of alpha-glucosidase solution, 20. Mu.L of the prepared solution triterpene phenolic acid ester derivative was added to a test tube, and the mixture was incubated at 37℃for 5 minutes, and 150. Mu.L of PNPG and 800. Mu.L of phosphate buffer were added. Sealing, and placing in a 37 ℃ warm bath for 30min. The reaction was quenched by the addition of 2mL of 2M Na 2CO3. OD was measured with a microplate reader at a wavelength of 405 nm. Acarbose was used as a positive control. The inhibition rate was calculated according to the following formula, wherein A Blank space is the absorbance after the reaction without addition of sample, and A Sample of is the absorbance after the reaction with addition of sample.
The inhibition ratio corresponding to each concentration is on the ordinate Y, the logarithm of the administration concentration is on the abscissa X, and linear regression is performed to obtain the administration concentration at an inhibition ratio of 50% according to the obtained equation, that is, to obtain the drug IC 50.
The concentration of the compound I-1 is 10, 3, 0.3 and 0.03 mu M in sequence, the concentration of the 23E-5 beta, 19-epoxy-cucurbita-6,23-dien-25-ol is 50, 10, 1 and 0.1 mu M in sequence, the concentration of the gallic acid is 100, 50, 10 and 1 mu M in sequence, and the concentration of the positive drug acarbose is 30, 10, 3 and 0.3 mu M in sequence. An experiment for inhibiting the activity of alpha-glucosidase was performed as described above. The activity test of the compound I-2~I-4 for inhibiting alpha-glucosidase is similar to the above method, except that the triterpene compound and the phenolic acid are different, and the results are shown in Table 1.
TABLE 1 investigation of the inhibition of alpha-glucosidase activity by Compound I-1~I-4
The alpha-glucosidase activity research shows that the triterpene phenolic acid ester derivative has extremely strong inhibition activity on alpha-glucosidase, and the activity is stronger than that of the prototype triterpene compound, phenolic acid and acarbose as a positive control drug.
(II) Activity experiments of triterpene phenolic acid ester derivatives, prototype triterpene Compounds and prototype phenolic acid obtained in examples 1-4 for inhibiting PTP1B
1. Experimental materials, reagents and instruments
Nichipet EX pipette (Nichiryo), HH-B11 electrothermal incubator (Shanghai medical instruments Co., ltd.), HC-3518 low-speed centrifuge (Anhui middle Co., ltd.), BS-124S precision electronic balance (Sidoris Corp., germany), 450 type enzyme calibration tester (Bio-Rad Co., USA), EDTA, tris, HCl, beta-mercaptoethanol, naOH, na 3VO4·12H2 O (national pharmaceutical Co., chemical reagent Co., ltd.), PTP1B enzyme, DTT, pNPP (Sigma USA), dimethyl sulfoxide (DMSO) Laiyang chemical laboratory.
2. Reagent preparation
A. The stock solution was diluted to 20mL with 0.6055g Tris and 0.0584g EDTA, respectively, and the pH was adjusted to 7.5 with concentrated hydrochloric acid. The final concentration of Tris-HCl was 250mM and EDTA was 10mM.
B. Buffer 1mL of stock solution was diluted to 10mL with distilled water, and 0.0015g of Dithiothreitol (DTT) and 0.718. Mu.L of beta-mercaptoethanol were added. The buffer at this time contained 25mM Tris-HCl, 1mM EDTA, 1mM DTT, 2mM beta-mercaptoethanol. The solution needs to be prepared in situ.
C. Substrate solution 0.1856g of disodium 4-nitrophenylphosphate hexahydrate (pNPP) was weighed, diluted with 1mL of buffer solution, and split-charged with 1.5mL EP tube. Stored in a freezer at-20 ℃ protected from light.
D. And (3) taking 0.816g of sodium vanadate solution, adding 100mL of distilled water, heating and boiling the solution to be semitransparent, adjusting the pH value to be about 10, taking 1mL of the solution into a 100mL beaker by using a pipette, stirring and mixing uniformly by using a glass rod, heating again to be semitransparent, ensuring that the sodium vanadate is in a monomer form, cooling, sub-packaging in a 1.5mL EP tube, and freezing and preserving at-20 ℃.
E. stop solution 2M NaOH solution.
3. Experimental method
The triterpene phenolic acid ester derivative is prepared into stock solution with concentration of 10mM by DMSO and stored in dark place. At the time of use, the experiments were performed by dilution with PBS, and the final concentration of DMSO in the highest dose group was 1%.
Positive control group sodium vanadate solution preparation method was as above.
Triterpene phenolic acid ester derivatives inhibition of PTP1B enzyme activity experiments were performed in 96-well plates. The experimental group was sequentially added with 83. Mu.L of an enzyme-containing buffer solution (0.4. Mu.L of an enzyme), 10. Mu.L of a derivative solution and 4. Mu.L of a substrate solution, the positive control group was sequentially added with 83. Mu.L of an enzyme-containing buffer solution (0.4. Mu.L of an enzyme), 10. Mu.L of a sodium vanadate solution and 4. Mu.L of a substrate solution, the blank control group was sequentially added with 93. Mu.L of an enzyme-containing buffer solution (0.4. Mu.L of an enzyme) and 4. Mu.L of a substrate solution, the reagent control group was added with 83. Mu.L of an enzyme-containing buffer solution (0.4. Mu.L of an enzyme), 10. Mu.L of a DMSO solution and 4. Mu.L of a substrate solution, and after a reaction in a constant temperature incubator at 37℃for 30min, the reaction was terminated with 5. Mu.L of NaOH solution. The absorption intensity of the product at 405nm wavelength is measured by an enzyme-labeled instrument, and the relative inhibition rate of the derivative on PTP1B at different concentrations is calculated. The inhibition rate was calculated according to the following formula, wherein A Blank space is the absorbance after the reaction without addition of sample, and A Sample of is the absorbance after the reaction with addition of sample.
The inhibition ratio corresponding to each concentration is on the ordinate Y, the logarithm of the administration concentration is on the abscissa X, and linear regression is performed to obtain the administration concentration at an inhibition ratio of 50% according to the obtained equation, that is, to obtain the drug IC 50.
The concentration of the compound I-1 is 10, 3, 0.3 and 0.03 mu M in sequence, the concentration of the 23E-5 beta, 19-epoxy-cucurbita-6,23-dien-25-ol is 50, 10, 1 and 0.1 mu M in sequence, the concentration of the gallic acid is 100, 50, 10 and 1 mu M in sequence, and the concentration of the positive medicine sodium alum (Na 3VO4) is 50, 25, 10 and 1 mu M. The activity test of the compound I-2~I-4 for inhibiting PTP1B was similar to the above method, except that the triterpene compound and the phenolic acid were different, and the activity test for inhibiting PTP1B was performed according to the above method, and the results are shown in Table 2.
TABLE 2 investigation of the inhibition of PTP1B Activity by Compound I-1~I-4
The activity research of PTP1B shows that the triterpene phenolic acid ester compound has extremely strong inhibition activity on PTP1B, and the activity is stronger than that of prototype triterpene, phenolic acid and positive control medicine sodium alum.
Claims (10)
1. A triterpene phenolic acid ester derivative is characterized in that the main structure R of the triterpene phenolic acid ester derivative is cucurbitane type triterpene compound residue, and the specific structural formula is as follows:
Wherein at least one of To which phenolic groups are attached, otherEach of which is independently connected with hydroxyl, methyl or methoxy, wherein the phenolic acid group has the following structure:
Wherein,
X is 0, C1-C3 saturated alkyl or C1-C3 unsaturated alkyl;
R 1、R2、R3 is independently selected from hydrogen, hydroxy or methoxy.
2. The triterpene phenolic acid ester derivative according to claim 1, wherein X is 0 or X is-C=C-.
3. The triterpene phenolic acid ester derivative according to claim 1, wherein the triterpene phenolic acid ester derivative has the following structural formula:
4. A process for preparing a triterpene phenolic acid ester derivative according to any one of claims 1 to 3, which comprises the steps of subjecting phenolic acid (A) and triterpene compound (B) to esterification reaction in a solvent containing an esterification catalyst at a temperature of 10 to 150 ℃ to obtain a total product, filtering, concentrating the filtrate, dissolving in an organic solvent, extracting with water, and subjecting the organic phase to silica gel column chromatography or preparative liquid chromatography to obtain the triterpene phenolic acid ester derivative (I-a).
5. A process for preparing a triterpene phenolic acid ester derivative according to any one of claims 1 to 3, which comprises the steps of reacting a phenolic acid with acetic anhydride in a solvent containing an acid or an esterification catalyst at a temperature of 10 to 150 ℃ to produce an acetylated phenolic acid substituted with a hydroxyl group, then carrying out an esterification reaction with a triterpene compound in a solvent containing an esterification catalyst to obtain an acetoxy-substituted triterpene phenolic acid ester, and adding hydrazine hydrate to carry out a deprotection reaction to obtain the triterpene phenolic acid ester derivative.
6. The process according to claim 4 or 5, wherein the esterification reaction comprises N, N '-dicyclohexylcarbodiimide, 4-dimethylaminopyridine direct esterification, acetyl protection-acyl chloride-esterification-deacetylation, benzyl protection-acyl chloride or N, N' -dicyclohexylcarbodiimide esterification-hydrogenolysis debenzylation.
7. The preparation method of the composition of claim 4, wherein the molar ratio of the phenolic acid to the triterpene compound is 1:1-3, the organic solvent is one or more of dichloromethane, ethyl acetate or acetone, the solvent system of the silica gel column chromatography is any two or a combination of the dichloromethane, the ethyl acetate, the acetone, the methanol and the water, and the preparation liquid chromatography is separated by using methanol and 0.5% formic acid aqueous solution in a volume ratio of 60:40 or acetonitrile and 0.5% formic acid aqueous solution in a volume ratio of 70:30.
8. The method according to claim 5, wherein the molar ratio of the phenolic acid to acetic anhydride is 1:1-3, and the molar ratio of the acetylated phenolic acid to the triterpene compound is 1:3-5.
9. A pharmaceutical composition comprising a therapeutically effective amount of the triterpene phenolic acid ester derivative according to any one of claims 1 to 5.
10. Use of the triterpene phenolic acid ester derivative according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 9 for the preparation of a medicament having a glycolipid metabolism regulating effect.
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