CN110551169A - Glycyrrhetinic acid derivative and preparation method and application thereof - Google Patents
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Abstract
, wherein R 1 and R 2 independently represent H or OH, the number of R 1 is 1-5, and the number of R 2 is 1-3 under the condition of OH.
Description
Technical Field
The invention relates to a glycyrrhetinic acid derivative, in particular to an 18-beta-glycyrrhetinic acid derivative containing a flavone structure, a preparation method thereof and application thereof as an anticancer drug.
Background
Glycyrrhetinic Acid (GA) is a pentacyclic triterpenoid compound extracted from the rhizome of traditional Chinese herbal medicine liquorice, and mainly takes 18-beta-Glycyrrhetinic Acid as a main component. Through continuous research, the glycyrrhetinic acid and the derivatives thereof have the effects of resisting inflammation, ulcer, virus, tumor, allergy, blood fat and insulin absorption.
flavones are a widely-occurring natural polyphenol compound, usually exist in many common fruits, vegetables, grains, Chinese herbal medicines and fruit juices, and are classified into flavones, isoflavones, flavonones, chalcones, flavonols, flavonones and the like due to the complexity and diversity of the chemical structure of flavones. Because of the special chemical structure of the flavonoid compound, the flavonoid compound has the biological activities of resisting oxidation, cancer, virus and inflammation, and treating cardiovascular diseases, osteoporosis and other diseases. Among them, 5' -hydroxyflavone compounds are natural compounds which are present in large amounts in the natural world and show various biological activities.
the C3 position of glycyrrhetinic acid is connected with the 5 '-hydroxyl of the 5' -hydroxyflavone structure through the ethyl ester structure, so that various biological activities of glycyrrhetinic acid can be enhanced, and a new route is provided for research, development and application of glycyrrhetinic acid derivatives.
Disclosure of Invention
The invention aims to provide a novel glycyrrhetinic acid derivative which has obvious inhibition effect on cancer cells; the invention also provides a preparation method of the novel glycyrrhetinic acid derivative, and the provided method is scientific, reasonable, simple and feasible, has few reaction steps and high yield, and is suitable for industrial production.
the technical scheme of the invention is as follows:
a novel glycyrrhetinic acid derivative has the following structural formula:
Wherein R is1、R2Each independently represents H or OH; in the case of OH, R1May be 1-5, R2the number of (c) may be 1-3.
in one embodiment, the general formula (I) may be selected from the following compounds:
the compounds of the above general formula of the present invention can be prepared by using the following starting materials as starting materials.
The invention further provides a preparation method of the novel glycyrrhetinic acid derivative, which comprises the following steps:
(A) dissolving 5-hydroxyflavone compounds (such as one or more of luteolin, quercetin, apigenin, prunetin, chrysin, etc.) and alkali (such as potassium hydroxide or sodium hydroxide) with different substituents in solvent (such as ketone solvent such as acetone), adding diethyl sulfate dropwise, and stirring for reaction;
(B) Collecting solid precipitated from the reaction solution obtained in the step (A), washing with alkali (such as 5-30% aqueous solution of sodium hydroxide) to neutrality, and recrystallizing to obtain intermediate product;
(C) dissolving glycyrrhetinic acid in a solvent (such as an alcohol solvent such as methanol), and then dropwise adding concentrated sulfuric acid for reaction;
(D) Evaporating the reaction liquid obtained in the step (C) to dryness under reduced pressure, extracting, collecting an organic layer, concentrating and drying to obtain a crude product, and then recrystallizing to obtain methyl glycyrrhetinate;
(E) dissolving the product methyl glycyrrhetinate in a solvent (such as dichloromethane), and then slowly dropwise adding bromoacetyl bromide for reaction;
(F) Evaporating the reaction solution obtained in the step (E) to dryness under reduced pressure, extracting an organic layer, drying, evaporating the solvent to dryness under reduced pressure, and recrystallizing the obtained crude product to obtain bromoacetyl methyl glycyrrhetinate;
(G) Dissolving bromoacetyl glycyrrhetinic acid methyl ester and the intermediate product obtained in the step (B) in a solvent (such as acetonitrile), adding potassium carbonate as a catalyst, and carrying out reflux reaction;
(H) And (G) filtering the reaction liquid, evaporating the filtrate under reduced pressure, extracting an organic layer, drying, evaporating the solvent under reduced pressure, and recrystallizing the obtained crude product to obtain the final product, namely the novel glycyrrhetinic acid derivative.
The above-mentioned solvent may be selected from ketone solvents such as acetone, nitrile solvents such as acetonitrile, ester solvents such as ethyl acetate, and the like.
preferably, in step (A), the molar ratio of the 5-hydroxyflavone compound with different substituents to the base (potassium hydroxide) to the diethyl sulfate is in the range of 1:0.3-0.8:2-6, such as 1:0.5:3, and the amount of the solvent (e.g. acetone) used in step (A) may be 1.5-5 times the total mass of the 5-hydroxyflavone compound with different substituents to the base (potassium hydroxide) to the diethyl sulfate.
Preferably, in the step (C), the molar ratio between the glycyrrhetinic acid and the concentrated sulfuric acid may be 1:20-35, and the amount of the solvent may be 3-15 times of the total mass of the glycyrrhetinic acid and the concentrated sulfuric acid.
Preferably, in step (E), the molar ratio of methyl glycyrrhetinate to bromoacetyl bromide may be 1: 1.1-2.5, the dosage of the solvent (dichloromethane) can be 2-10 times of the total mass of the methyl glycyrrhetinate and the bromoacetyl bromide.
Preferably, in the step (G), the molar ratio of bromoacetyl glycyrrhetinic acid methyl ester, the intermediate product, and potassium carbonate may be 1: 0.5-2: 1.1-2.5, the dosage of the solvent acetonitrile can be 2-10 times of the total mass of bromoacetyl glycyrrhetinic acid methyl ester and potassium carbonate.
in a more specific embodiment, the preparation method of the present invention comprises:
(A) dissolving 5-hydroxyflavone compounds with different substituents and potassium hydroxide in acetone, then dropwise adding diethyl sulfate, and violently stirring and reacting at room temperature for 3-4 hours;
(B) Pouring the reaction solution of (A) into distilled water, standing for 1-4h, such as 2h, collecting the precipitated solid, washing with alkali to neutrality to obtain crude product, and recrystallizing with ethanol to obtain pure intermediate product.
(C) Dissolving glycyrrhetinic acid in methanol, and then dropwise adding concentrated sulfuric acid to react for 20-40h, such as 24 h;
(D) Evaporating the reaction solution of the step (C) to dryness under reduced pressure, extracting with ethyl acetate/distilled water, collecting an organic layer, drying, concentrating to obtain a crude product, and then recrystallizing with ethanol to obtain methyl glycyrrhetinate;
(E) Dissolving the product methyl glycyrrhetinate in dichloromethane, and slowly adding bromoacetyl bromide dropwise at low temperature of 1-6 deg.C (such as 4 deg.C) to react for 1-4h (such as 2 h);
(F) evaporating the reaction solution obtained in the step (E) to dryness under reduced pressure, extracting with ethyl acetate/distilled water, drying the organic layer with anhydrous sodium sulfate, evaporating the solvent to dryness under reduced pressure, and recrystallizing the obtained crude product with acetone to obtain bromoacetyl methyl glycyrrhetinate;
(G) dissolving bromoacetyl glycyrrhetinic acid methyl ester and the intermediate product obtained in the step (B) in acetonitrile, adding potassium carbonate as a catalyst, and carrying out reflux reaction for 4-10h, such as 6 h;
(H) and (G) filtering the reaction solution, evaporating the filtrate under reduced pressure, extracting with ethyl acetate/distilled water, drying the organic layer with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and recrystallizing the obtained crude product with acetone to obtain the final product, namely the novel glycyrrhetinic acid derivative.
The raw material ratio in each step may be as described above.
the invention also relates to application of the glycyrrhetinic acid derivatives containing different flavone structures in preparation of anti-cancer (especially breast cancer, liver cancer and the like) medicaments.
effects of the invention
The glycyrrhetinic acid derivative containing the flavone structure has an obvious inhibiting effect on cancer cells, so that the glycyrrhetinic acid derivative containing the flavone structure can be used for preparing an anti-cancer medicament.
Detailed Description
The present invention is further illustrated by the following examples, but the scope of the present invention is not limited to these examples.
Example 1:
preparation of (Ia)
(1) luteolin (2mmol, 0.572g) and potassium hydroxide (1.0mmol,2.8g) were dissolved in acetone 60mL, then diethyl sulfate (6mmol,0.924g) was added dropwise and the reaction was stirred vigorously at room temperature for 3-4 hours.
(2) the reaction solution of (1) was poured into distilled water and allowed to stand for 2h, the precipitated solid was collected and washed with base to neutrality to give the crude product which was recrystallized from ethanol to give pure intermediate 2a (1.9mmol, 0.66 g).
1H NMR(400MHz,CDCl3)δ16.47(s,1H),7.71(s,1H),7.69(d,J＝8.0Hz,1H),6.97(d,J＝8.0Hz,1H),6.71(s,1H),6.50(s,1H),6.17(s,1H),4.13-4.06(m,6H),1.42-1.34(m,9H).
(3) Glycyrrhetinic acid (3mmol,1.41g) was dissolved in 150mL of methanol, and then 4.5mL of concentrated sulfuric acid was added dropwise for reaction for 24 h.
(4) And (3) evaporating the reaction solution under reduced pressure, extracting with ethyl acetate/distilled water, collecting an organic layer, drying, concentrating to obtain a crude product, and then recrystallizing with ethanol to obtain methyl glycyrrhetinate (2.94mmol, 1.41 g).
(5) The product, methyl glycyrrhetinate (2mmol,0.968g), was dissolved in 60mL of dichloromethane, and bromoacetyl bromide (3.0mmol,0.604g) was slowly added dropwise at 4 ℃ and then reacted for 2 h.
(6) The reaction solution was evaporated to dryness under reduced pressure, extracted with ethyl acetate/distilled water, the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated to dryness under reduced pressure, and the resulting crude product was recrystallized from acetone to give bromoacetyl methyl glycyrrhetinate (1.9mmol,1.14 g).
(7) bromoacetyl glycyrrhetinic acid methyl ester (1mmol,0.6g) and intermediate 2a (1mmol,0.37g) were dissolved in acetonitrile 50mL, and potassium carbonate (1.5mmol,0.2g) was added as a catalyst, followed by reflux reaction for 6 h;
(8) And (3) filtering the reaction solution in the step (7), evaporating the filtrate under reduced pressure, extracting with ethyl acetate/distilled water, drying the organic layer with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and recrystallizing the obtained crude product with acetone to obtain a final product, namely the novel glycyrrhetinic acid derivative (0.7mmol,0.57 g).
The product was a white powder with a yield of 70%. M.p.219-222 ℃;1H NMR(400MHz,CDCl3)δ10.29(s,1H),9.48(s,2H),7.04-6.52(m,4H),6.17(s,2H),4.90(s,2H),4.61(d,J＝4.8Hz,1H),3.64(s,3H),2.88-2.66(m,6H),2.37(s,1H),1.85-1.53(m,8H),1.38-1.29(m,6H),1.16(d,J＝5.7Hz,6H),1.13(d,J＝3.11Hz,3H),0.88(s,7H),0.81(s,3H).
Example 2:
(Ib) preparation of
the preparation method is the same as example 1. Quercetin was used instead of luteolin, and intermediate product was 2b, to give the target compound (0.73mmol,0.6 g).
Intermediate 2b has the following structural formula:
1H NMR(400MHz,CDCl3)δ16.47(s,1H),7.71(s,1H),7.69(d,J＝8.0Hz,1H),6.97(d,J＝8.0Hz,1H),6.50(s,1H),6.17(s,1H),4.09-4.03(m,4H),4.13(m,4H),1.42-1.34(m,12H).
the product was a white powder in 73% yield. M.p.133-135 ℃;1H NMR(400MHz,CDCl3)δ10.68-10.29(m,2H),9.48(s,2H),7.04-6.54(m,3H),6.17(s,2H),4.90(s,2H),4.61(d,J＝4.8Hz,1H),3.64(s,3H),2.88-2.66(m,6H),2.37(s,1H),1.85-1.53(m,8H),1.38-1.29(m,6H),1.16(d,J＝5.7Hz,6H),1.13(d,J＝3.11Hz,3H),0.88(s,7H),0.81(s,3H).
example 3:
preparation of (Ic)
The preparation method is the same as example 1. Apigenin instead of luteolin, intermediate was 2c to give the title compound (0.72mmol,0.58 g).
Intermediate 2c has the formula1H NMR was as follows:
1H NMR(400MHz,CDCl3)δ16.47(s,1H),7.69(d,J＝8.0Hz,2H),6.97(d,J＝8.0Hz,2H),6.50(s,1H),6.17(s,1H),4.06-4.03(m,6H),1.42-1.34(m,9H).
The product was a white powder with a yield of 72%. M.p.172-174 ℃;1H NMR(400MHz,CDCl3)δ10.68-10.29(m,2H),9.68(s,1H),7.48(s,2H),6.65(s,2H),6.17(s,2H),4.90(s,2H),4.61(d,J＝4.8Hz,1H),3.64(s,3H),2.88-2.66(m,6H),2.37(s,1H),1.85-1.53(m,8H),1.38-1.29(m,6H),1.16(d,J＝5.7Hz,6H),1.13(d,J＝3.11Hz,3H),0.88(s,7H),0.81(s,3H).
example 4:
preparation of (Id)
the preparation method is the same as example 1. Oriental cherry flavin was used in place of luteolin, and intermediate product was 2d to give the title compound (0.79mmol,0.63 g).
Intermediate 2d has the following structural formula:
1H NMR(400MHz,CDCl3)δ16.47(s,1H),7.69(d,J＝8.0Hz,2H),6.97(d,J＝8.0Hz,2H),6.71(s,1H),6.50(s,1H),6.17(s,1H),4.06-4.03(m,4H),1.42-1.34(m,6H).
the product was a white powder with a yield of 79%. M.p.250-251 ℃;1H NMR(400MHz,CDCl3)δ10.29(s,1H),9.68(s,1H),8.68(s,1H),7.35(s,2H),6.65(s,2H),6.16(s,2H),4.90(s,2H),4.61(d,J＝4.8Hz,1H),3.64(s,3H),2.88-2.66(m,6H),2.37(s,1H),1.85-1.53(m,8H),1.38-1.29(m,6H),1.16(d,J＝5.7Hz,6H),1.13(d,J＝3.11Hz,3H),0.88(s,7H),0.81(s,3H).
Example 5:
preparation of (Ie)
The preparation method is the same as example 1. Chrysin was substituted for luteolin, intermediate 2e, to give the title compound (0.75mmol, 0.85 g).
Intermediate 2e has the following structural formula:
1H NMR(400MHz,CDCl3)δ16.47(s,1H),7.69(d,J＝8.0Hz,2H),7.46(s,1H),6.97(d,J＝8.0Hz,2H),6.71(s,1H),6.50(s,1H),6.17(s,1H),4.06(s,2H),1.36-1.34(m,3H).
the product was a white powder with a yield of 75%. M.p.144-145 ℃;1H NMR(400MHz,CDCl3)δ10.29(s,1H),7.77-7.48(m,5H),6.71(s,1H),6.17(s,2H),4.90(s,2H),4.61(d,J＝4.8Hz,1H),3.64(s,3H),2.88-2.66(m,6H),2.37(s,1H),1.85-1.53(m,8H),1.38-1.29(m,6H),1.16(d,J＝5.7Hz,6H),1.13(d,J＝3.11Hz,3H),0.88(s,7H),0.81(s,3H).
The following is a study for examining the anticancer activity of the novel glycyrrhetinic acid derivatives of examples 1 to 5.
1. Experimental Material
1.1 cell lines
human hepatoma cell line HepG 2; human breast cancer cell strain MCF-7.
1.2 reagents
DMEM medium (GIBCO), newborn bovine serum (hangzhou ilex bioengineering material), trypsin (Sigma),10000 units of diabody (GIBCO USA), PBS buffer (shanghai yuan culture biotechnology limited). Other common chemical reagents are all domestic analytical purifiers.
2. Experimental methods
2.1 preparation of the culture Medium
90mL of DMEM medium (Gibcio USA) is added with 10mL of inactivated newborn bovine serum (Hangzhou Chinese holly bioengineering material) and 1mL of 10000 units of double antibody (Gibco USA) to obtain a complete culture solution, and the complete culture solution is marked and stored at 4 ℃ for later use. Trypsin is prepared into 0.25% solution by PBS buffer solution, and the solution is stored at 4 ℃ for standby after filtration and sterilization.
2.2 preparation of the liquid medicine
Accurately weighing 1.0mg of the sample to be detected. The mixture was put into a sterilized 1.5mL centrifuge tube, and 1mL of DMSO was added to prepare a stock solution of 1mg/mL, which was then stored at-40 ℃ under refrigeration. The composition is thawed before use and diluted into corresponding concentration by using a proper amount of PBS flushing liquid for application.
2.3 cell culture and passage
culturing the cell strain in a cell culture bottle containing 10mL of complete culture solution in an adherent manner at 37 ℃ and 5% CO2And culturing under saturated humidity. Washing the cells with sterile PBS buffer twice after they have grown over the bottom of the flask, adding 0.25% trypsin to digest the cells for 1min, pouring offAnd (3) adding 30mL of complete culture solution after the cells are completely shed by gentle shaking by trypsin, blowing the cells by a pipette, subpackaging in 3 new cell culture bottles, and continuing to culture.
2.4 anti-cancer Activity assay
Collecting the cells which just grow into a complete monolayer in one bottle, collecting the cells after trypsinization, uniformly blowing and beating the cells by using a pipette, taking two drops of cell suspension Trypan Blue (Trypan Blue) for dyeing, and counting the number of living cells to 1 multiplied by 10 under a microscope4add 90. mu.L of cell suspension to each well of a 96-well plate, and place the plate in CO2culturing in incubator for 24h, taking out culture plate, adding 10 μ L solution containing samples to be tested with different concentrations into each well to make final concentration of drug be 50, 25, 12.5, 6.25, 3.125 μ M, setting 3 parallel wells for each concentration, and setting 6 wells as normal control well and positive control well. Adding the medicine, vibrating the culture plate on a microplate oscillator, mixing, and placing in CO2The incubator continues to culture for 24 h. The plate was removed, 10. mu.L of 5mg/mL MTT solution was added to each well, shaken and mixed, and the culture was continued for 4 hours. Add 150. mu.L of LDMSO per well and shake for 15 min. The microplate reader measured the light absorption (OD value) of each well and the measurement wavelength was 570 nm. The inhibition rate of the drug on the proliferation of both cells, i.e. IC, was calculated by SPSS software from the OD value of each well50The values, the results of the experiments are shown in Table 1,
As can be seen from the table above, the compound of the embodiment of the invention has good anti-tumor effect on liver cancer and breast cancer.
Claims (9)
1. A glycyrrhetinic acid derivative has a structural formula shown as the following general formula (I):
Wherein R is1、R2each independently represents H or OH.
2. The glycyrrhetinic acid derivative according to claim 1, wherein the general formula (I) is selected from the following compounds:
3. The method for preparing glycyrrhetinic acid derivatives according to claim 1 or 2, comprising the steps of:
(A) Dissolving 5-hydroxyflavone compounds with different substituents and alkali (such as potassium hydroxide or sodium hydroxide) in a solvent (such as ketone solvent such as acetone), adding diethyl sulfate dropwise, and stirring for reaction;
(B) Collecting solid precipitated from the reaction solution obtained in the step (A), washing with alkali (such as 5-30% aqueous solution of sodium hydroxide) to neutrality, and recrystallizing to obtain intermediate product;
(C) Dissolving glycyrrhetinic acid in a solvent (such as an alcohol solvent such as methanol), and then dropwise adding concentrated sulfuric acid for reaction;
(D) Evaporating the reaction liquid obtained in the step (C) to dryness under reduced pressure, extracting, collecting an organic layer, concentrating and drying to obtain a crude product, and then recrystallizing to obtain methyl glycyrrhetinate;
(E) dissolving the product methyl glycyrrhetinate in a solvent (such as dichloromethane), and then slowly dropwise adding bromoacetyl bromide for reaction;
(F) evaporating the reaction solution obtained in the step (E) to dryness under reduced pressure, extracting an organic layer, drying, evaporating the solvent to dryness under reduced pressure, and recrystallizing the obtained crude product to obtain bromoacetyl methyl glycyrrhetinate;
(G) Dissolving bromoacetyl glycyrrhetinic acid methyl ester and the intermediate product obtained in the step (B) in a solvent (such as acetonitrile), adding potassium carbonate as a catalyst, and carrying out reflux reaction;
(H) And (G) filtering the reaction liquid, evaporating the filtrate under reduced pressure, extracting an organic layer, drying, evaporating the solvent under reduced pressure, and recrystallizing the obtained crude product to obtain the final product, namely the novel glycyrrhetinic acid derivative.
4. the process according to claim 3, wherein the molar ratio of 5-hydroxyflavone compound, base (potassium hydroxide) and diethyl sulfate of different substituents in step (A) is in the range of 1:0.3-0.8:2-6, for example 1:0.5:3, and the amount of solvent (for example acetone) used in step (A) is 1.5-5 times the total mass of 5-hydroxyflavone compound, base (potassium hydroxide) and diethyl sulfate of different substituents.
5. The production method according to claim 3 or 4, wherein in the step (C), the molar ratio between the glycyrrhetinic acid and the concentrated sulfuric acid is 1:20-35, and the amount of the solvent is 3-15 times of the total mass of the glycyrrhetinic acid and the concentrated sulfuric acid.
6. the production method according to any one of claims 3 to 5, wherein, in step (E), the molar ratio of methyl glycyrrhetinate to bromoacetyl bromide is 1: 1.1-2.5, the dosage of solvent methylene dichloride is 2-10 times of the total mass of the glycyrrhetinic acid methyl ester and the bromoacetyl bromide.
7. The production method according to any one of claims 3 to 6, wherein in step (G), the molar ratio of bromoacetyl glycyrrhetinic acid methyl ester, intermediate product, potassium carbonate is 1: 0.5-2: 1.1-2.5, and the dosage of the solvent acetonitrile is 2-10 times of the total mass of bromoacetyl glycyrrhetinic acid methyl ester and potassium carbonate.
8. The method according to any one of claims 2 to 7, wherein the 5-hydroxyflavone compound having different substituents is one or more selected from luteolin, quercetin, apigenin, prunetin and chrysin.
9. Use of the glycyrrhetinic acid derivative according to claim 1 or 2 or obtained by the preparation method according to any one of claims 3 to 7 for the preparation of an anticancer drug.
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| CN111606966A (en) * | 2020-05-13 | 2020-09-01 | 深圳市萱嘉生物科技有限公司 | Chloroquine glycyrrhetinate or hydroxychloroquine glycyrrhetinate, and preparation method and application thereof |
| CN112176018A (en) * | 2020-08-28 | 2021-01-05 | 河北仁心药业有限公司 | Method for preparing glycyrrhetinic acid and derivatives thereof based on honey-fried licorice root and application thereof |
| CN114014905A (en) * | 2021-12-03 | 2022-02-08 | 浙江科技学院 | PPAR gamma targeted glycyrrhetinic acid derivative and preparation method and application thereof |
| CN117105901A (en) * | 2023-08-30 | 2023-11-24 | 陕西中医药大学 | Chrysin derivative, preparation method and application thereof, and pharmaceutical composition |
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| CN117105901A (en) * | 2023-08-30 | 2023-11-24 | 陕西中医药大学 | Chrysin derivative, preparation method and application thereof, and pharmaceutical composition |
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