CN109705189B - Triterpene derivative with structure shown in formula I, preparation method and application thereof - Google Patents
Triterpene derivative with structure shown in formula I, preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a triterpene derivative with a structure shown in a formula I, belonging to the technical field of organic synthesis. The triterpene derivative with the structure shown in the formula I has specific selective anti-HIV activity.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a triterpene derivative with a structure shown in a formula I, a preparation method and application thereof.
Background
Acquired Immune Deficiency Syndrome (AIDS), also known as Acquired Immunodeficiency Syndrome, is a serious disease that seriously threatens Human health and affects social development due to infection with Human Immunodeficiency Virus (HIV). Currently, no drug capable of curing aids has yet been developed, so that a large number of patients die of complications; meanwhile, the public health problem increases the national financial pressure and delays the development of economy. Therefore, the prevention and treatment of AIDS is urgently needed to be solved.
To date, no ideal drug has been found that can completely cure HIV infection, and the treatment of aids is mainly aimed at delaying the course of the disease and eliminating complications. Highly active antiretroviral therapy (HAART), also known as "cocktail therapy", is a combination of two or more reverse transcriptase inhibitors with one or more protease inhibitors to inhibit the replication of HIV in humans. The HAART combined medicine has a plurality of toxic and side effects in clinical application: nucleoside reverse transcriptase inhibitors can induce mitochondrial toxicity by blocking DNA polymerase, which may cause serious side effects such as neuromuscular toxicity, pancreatitis, hyperlactacidemia, anemia, and neutropenia; non-nucleoside reverse transcriptase inhibitors have hepatotoxicity, can cause liver damage, and can cause severe rash and adverse reactions of central neurotoxicity during use; the long-term application of the protease inhibitor can cause lipid metabolism disorder, and then induce cardiovascular and cerebrovascular diseases such as atherosclerosis and myocardial infarction. Adverse reactions caused by interaction of the drugs can be more prominent in the process of combined medication, and because of long-term medication, the incidence rate of drug resistance is higher, and the treatment is continued by replacing a new drug combination after a period of time.
The theory system of the traditional Chinese medicine in China has a long history, and people accumulate abundant experience on the aspects of curative effect, toxicity and the like of various traditional Chinese medicines in long-term clinical practice. Through modern scientific and technical means, the material basis of the action of the traditional Chinese medicine is gradually excavated, and then organic synthesis is applied to modify the structure of the lead compound so as to improve the activity of the effective components, reduce toxic and side effects, improve the absorption, distribution, metabolism and excretion of the effective components, improve the stability and further obtain the monomer medicine for production. It has been reported in the literature that the natural cycloartane triterpenoids Astragaloside IV and cycloastragenol can promote the proliferation of CD8+ T lymphocytes of HIV patients by modulating the activity of telomerase (Yung LY, Lam WS, Ho MK, et al, Astragaloside IV and cyclodextragen kinase in multiple cell types. planta Med, 2012,78(2): 115-121.); a series of cycloartane triterpenoids with anti-HIV activity are also found in the plants of the family Schisandraceae [ honeysuckle, Yanshi, Liujunxia, and the like.
Disclosure of Invention
In view of the above, the present invention aims to provide a triterpene derivative having a structure shown in formula I, and a preparation method and application thereof. The triterpene derivative with the structure shown in the formula I has specific selective anti-HIV activity.
In order to achieve the above object, the present invention provides the following technical solutions:
a triterpene derivative having a structure shown in formula I.
The invention also provides a preparation method of the triterpene derivative in the technical scheme, which comprises the following steps:
mixing a triterpenoid saponin compound, namely Beesioside I, a hydrolase molsin and a disodium hydrogen phosphate-citric acid buffer solution for reaction to obtain aglycone of the Beesioside I;
and (2) mixing the aglycone of the Beesioside I with 2, 2-dimethylsuccinic anhydride, 2-dimethylglutaric anhydride and diglycolic anhydride respectively to perform microwave reaction to obtain the triterpene derivative with the structure shown in the formula I.
Preferably, the mass ratio of the triterpenoid saponin compound beesioside I to the hydrolase molsin is 1: 1-1: 10.
Preferably, the pH of the disodium phosphate-citric acid buffer is 4.0.
Preferably, the temperature of the microwave reaction is 150-160 ℃, and the time of the microwave reaction is 1-3 h.
The invention also provides application of the triterpene derivative with the structure shown in the formula I in the technical scheme in preparing anti-AIDS drugs.
Preferably, the anti-AIDS drug comprises effective dose of triterpene derivatives with the structure shown in formula I, derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers, auxiliary materials, excipients and diluents.
Preferably, the anti-AIDS drug comprises tablets, injections, capsules, granules, pills, powder, oral liquid, sustained release preparations, controlled release preparations or nano preparations which are pharmaceutically acceptable.
Preferably, when R is a 1 group, the triterpene derivative with the structure shown in the formula I has remarkable in-vitro anti-HIV-1 effect on HIV-1NL4-3In virus-infected MT-4 cells, the inhibitor has obvious inhibiting effect on HIV virus, and half effective inhibiting concentration EC500.025 μ M and a therapeutic index TI of greater than 800.
The invention provides a triterpene derivative with a structure shown in a formula I, which has specific selective anti-HIV activity.
Drawings
FIG. 1 is a schematic diagram of a process for producing a triterpene derivative having a structure represented by formula I according to the present invention.
Detailed Description
The invention provides a triterpene derivative with a structure shown in a formula I,
in the invention, when R is 1, the chemical name of the triterpene derivative with the structure shown in the formula I is (20S,24S) -15 β,16 β -diacetoxy-18,24,20, 24-diacetoxy-9, 19-cyclolanostane-3 β,25-diol 3-O-3 ', 3' -dimethyluccinate, when R is 2, the chemical name of the triterpene derivative with the structure shown in the formula I is (20S,24S) -15 β,16 β -diacetoxy-18, 24; 20, 24-diacetoxy-9, 19-cyclolanostane-3 β,25-diol 3-O-4 ', 4' -dimethylglutamate, when R is 3, the chemical name of the triterpene derivative with the structure shown in the formula I is (20S,24S) -15, 8663, 16-diacetoxy-6718, 16-cyclolanostane-3, 20-dimethylglycollate, 363-369, 19-cyclolanostane-3, 25-dimethylglycollate, 3-dimethylglycollate.
The invention also provides a preparation method of the triterpene derivative in the technical scheme, which comprises the following steps:
mixing a triterpenoid saponin compound, namely Beesioside I, a hydrolase molsin and a disodium hydrogen phosphate-citric acid buffer solution for reaction to obtain aglycone of the Beesioside I;
and mixing the aglycone of the Beesioside I with 2, 2-dimethylsuccinic anhydride, 2-dimethylglutaric anhydride and diglycolic anhydride respectively to perform microwave reaction to obtain the triterpene derivative with the structure shown in the formula I.
The triterpenoid saponin compound, i.e., the Beesioside I, the hydrolase molsin and the disodium hydrogen phosphate-citric acid buffer solution are mixed and react to obtain the aglycone of the Beesioside I.
In the invention, the triterpenoid saponin compound beesioside I has a structure shown in a formula II:
the triterpene saponin compound beesioside I is prepared by a preparation method which is well known to a person skilled in the art without special limitation on the source. In the embodiment of the present invention, the triterpenoid saponin compound beesioside I is preferably obtained by the following steps:
drying and crushing panax notoginseng Souliea vagena (Maxim.) Franch.10Kg, performing reflux or cold-leaching extraction by using ethanol/water, methanol/water or acetone/water in different times and different proportions, recovering a solvent under reduced pressure to obtain 220g of an extract, dissolving the extract in water, sequentially extracting by using petroleum ether, trichloromethane, ethyl acetate and n-butanol, performing silica gel (100-200 meshes) column chromatography on 35g of an ethyl acetate extraction part, eluting by using petroleum ether/ethyl acetate (100: 0-1: 1) and dichloromethane/methanol (50: 1-1: 1) to obtain fractions with different polarities, taking 8g of a medium-polarity fraction, performing silica gel column chromatography (200-300 meshes) on the petroleum ether/ethyl acetate (10: 1-1: 1) and dichloromethane/methanol (20: 1-5: 1), and eluting by using reverse phase column chromatography methanol/water (50: 50-100: 0), eluting with gel LH-20 methanol to obtain crude active precursor compound, and recrystallizing with methanol to obtain triterpenoid saponin compound beesioside I.
In the invention, the mass ratio of the triterpenoid saponin compound beesioside I to the hydrolase molsin is preferably 1: 1-1: 10.
In the present invention, the pH of the disodium hydrogen phosphate-citric acid buffer is preferably 4.0.
In the present invention, the mixing is preferably performed in anhydrous ethanol. In the present invention, the mixing is preferably carried out by dissolving the triterpenoid saponin compound beesioside I in anhydrous ethanol, and adding the hydrolase molsin (Aspergillus saitoi) dissolved in pure water and 0.2M disodium hydrogen phosphate-0.1M citric acid buffer (pH 4.0) to the solution.
In the present invention, the temperature of the reaction is preferably 37 ℃ and the time of the reaction is preferably 2 days.
After the reaction is finished, preferably, the obtained reaction solution is extracted for 3 times by using ethyl acetate with the same volume, the ethyl acetate parts are combined, dried and concentrated by using anhydrous sodium sulfate, subjected to silica gel column chromatography (200-300 meshes), eluted by using n-hexane/acetone (10: 1-1: 1), and recrystallized by using methanol to obtain the aglycone of the Beesioside I.
In the invention, the structure of the aglycone of the Beesioside I is shown as a formula III:
after obtaining the aglycone of the Beesioside I, the aglycone of the Beesioside I is respectively mixed with 2, 2-dimethylsuccinic anhydride, 2-dimethylglutaric anhydride and diglycolic anhydride to carry out microwave reaction, so as to obtain the triterpene derivative with the structure shown in the formula I.
When the aglycone of the Beesioside I and 2, 2-dimethyl succinic anhydride are subjected to microwave reaction, a triterpene derivative with a structure shown in a formula I and a group R of 1 is obtained; when the aglycone of the Beesioside I and 2, 2-dimethyl glutaric anhydride are subjected to microwave reaction, a triterpene derivative with a structure shown in a formula I and R being a group of 2 is obtained; when the daisioside I aglycone and diglycolic anhydride are subjected to microwave reaction, the triterpene derivative with the structure shown in the formula I and the group R of3 is obtained.
In the present invention, the microwave reaction is preferably carried out in anhydrous pyridine and 4-Dimethylaminopyridine (DMAP).
In the invention, the mole ratio of the aglycone of the Beesioside I to the 2, 2-dimethyl succinic anhydride, the 2, 2-dimethyl glutaric anhydride and the diglycolic anhydride is preferably 1: 1-1: 10.
In the invention, the temperature of the microwave reaction is preferably 150-160 ℃, and the time of the microwave reaction is preferably 1-3 h.
And (5) after the microwave reaction is finished. According to the invention, the reaction solution is preferably added with 1N hydrochloric acid for neutralization, then ethyl acetate is added for extraction for 3 times, the ethyl acetate part is washed for 3 times by using brine, anhydrous magnesium sulfate is added for drying, and after silica gel column (200-300 meshes) chromatography and N-hexane/acetone gradient elution (10: 1-1: 1), the triterpene derivative with the structure shown in formula I is obtained.
The invention also provides application of the triterpene derivative with the structure shown in the formula I in the technical scheme in preparing anti-AIDS drugs.
In the present invention, the anti-aids drug preferably comprises an effective amount of a triterpene derivative having a structure represented by formula I, a derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, excipient and diluent.
In the invention, the anti-AIDS drug preferably comprises tablets, injections, capsules, granules, pills, powder, oral liquid, sustained-release preparations, controlled-release preparations or nano preparations which are pharmaceutically acceptable.
In the invention, when R is a 1 group, the triterpene derivative with the structure shown in the formula I has remarkable in-vitro anti-HIV-1 effect on HIV-1NL4-3In virus-infected MT-4 cells, the inhibitor has obvious inhibiting effect on HIV virus, and half effective inhibiting concentration EC500.025 μ M and a therapeutic index TI of greater than 800.
The triterpene derivative having the structure shown in formula I and the preparation method and application thereof provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
FIG. 1 is a schematic diagram of a process for producing a triterpene derivative having a structure represented by formula I according to the present invention.
Example 1
Preparation of triterpenoid saponin compound beesioside I
Taking 10Kg of radix notoginseng Souliea vagena (Maxim.) Franch, drying and crushing, extracting with ethanol/water, methanol/water or acetone/water in different times and different proportions by refluxing or cold soaking, recovering solvent under reduced pressure to obtain 220g of extract, dissolving the extract in water, sequentially extracting with petroleum ether, trichloromethane, ethyl acetate and n-butanol, separating 35g of ethyl acetate extract part by silica gel (100-200 meshes, 200g) column chromatography, eluting with petroleum ether/ethyl acetate (100: 0-1: 1) and dichloromethane/methanol (50: 1-1: 1) to obtain fractions with different polarities, taking 8g of the fraction with medium polarity, eluting with silica gel column chromatography (200-300 meshes, 150g) petroleum ether/ethyl acetate (10: 1-1: 1), dichloromethane/methanol (20: 1-5: 1) and eluting with reverse phase column chromatography methanol/water (50: 50-100: 0), and eluted by gel LH-20 methanol to obtain an active precursor compound crude product, and finally recrystallized by methanol to obtain 1.1g of a monomer compound, which is determined to be a triterpenoid saponin I by nuclear magnetic resonance spectroscopy and mass spectrometry and comparison with a reference document (N.Sakurai, M.Nagai, T.goto, T.Inoue, P.G.Xiao, Studies on the society of Beesia caalefolia and Souliea vagenata. IV.1) Beesioside I, a cyclolanonoxylosyloside from the rhizophile of Beesia, chem.Pharm.Bull.,1993,41, 272-275).
Beesioside I, white powder, ESI-MS M/z 743[ M + Na]+；1H-NMR(pyridine-d5,600MHz)δH:1.16(1H,m,H-1),1.58(1H,m,H-1),2.06(1H,m,H-2),2.75(1H, m,H-2),3.50(2H,dd,J＝4.2,12.0Hz,H-3),1.28(1H,m,H-5),0.57(1H,dd, H-6a),1.36(1H,m,H-6b),1.05(1H,H-7a),1.26(1H,H-7b),1.60(1H,dd,J＝ 12.0,4.8Hz,H-8),1.16(1H,m,H-11),2.00(1H,m,H-11),1.54(1H,m,H-12a), 2.94(1H,m,H-12b),5.65(1H,d,J＝9.0Hz,H-15),5.90(1H,dd,J＝10.2,8.4 Hz,H-16),2.69(1H,d,J＝11.4Hz,H-17),4.45(1H,d,J＝13.2Hz,H-18),4.56 (1H,d,J＝13.2Hz,H-18),0.15(1H,d,J＝4.2Hz,H-19),0.48(1H,d,J＝3.6 Hz,H-19),1.31(3H,s,H-21),3.65(1H,d,J＝10.5Hz,H-22),2.40(1H,m, H-23a),1.90(1H,m,H-23b),1.53(3H,s,H-26),1.64(3H,s,H-27),1.25(3H,s, H-28),1.17(3H,s,H-29),1.00(3H,s,H-30),4.86(1H,d,J＝7.8Hz,H-1′),4.02 (1H,m,H-2′),4.15(1H,t,J＝8.4Hz,H-3′),4.22(1H,m,H-4′),3.70(1H,t,J＝ 10.8Hz,H-5′a),4.34(1H,dd,J＝11.4,5.4Hz,H-5′b),2.12(3H,COCH3),2.09 (3H,COCH3)；13C-NMR(pyridine-d5,150MHz)δC:32.7(C-1),31.2(C-2),88.6 (C-3),41.7(C-4),47.5(C-5),20.8(C-6),26.4(C-7),47.6(C-8),19.5(C-9),28.0 (C-10),26.6(C-11),28.4(C-12),46.2(C-13),51.9(C-14),82.4(C-15),75.5 (C-16),56.6(C-17),66.8(C-18),31.8(C-19),87.2(C-20),32.8(C-21),38.6 (C-22),30.4(C-23),114.6(C-24),73.1(C-25),26.0(C-26),26.1(C-27,28),15.8 (C-29),15.7(C-30),108.0(C-1′),76.0(C-2′),79.0(C-3′),71.6(C-4′),67.5(C-5′), 21.6(COCH3),171.3(COCH3),21.6(COCH3),171.0(COCH3).
Example 2
1) Preparation of aglycones of beesioside I
Beesioside I (1.1g, 1.53mmol) was dissolved in 100mL of anhydrous ethanol, and 2.2g of a hydrolase molsin (Aspergillus saitoi) dissolved in 100mL of pure water and 1000mL of a 0.2M disodium hydrogenphosphate-0.1M citric acid buffer solution (pH 4.0) were added to the solution, and the solution was stirred at 37 ℃ for 2 days. Extracting the reaction solution for 3 times by using equal volume of ethyl acetate, combining ethyl acetate parts, drying the ethyl acetate parts, concentrating the ethyl acetate parts, performing chromatography by using a silica gel column (200-300 meshes), eluting by using n-hexane/acetone (10: 1-1: 1), recrystallizing by using methanol to obtain a monomer compound, and comparing the monomer compound with a reference (N.Sakurai, M.Nagai, T.goto, T.Inoue, P.G.Xaao, Studies on the constraints of Beesia caalevia and Soulia varginata.IV.1) Beesioside I, acetolanosol hydrolysate of Beesia caalevia, chem.Bull, 1993,41,272 and 275) to determine that the aglycone is a colorless crystal of the Beesioside I; ESIMS M/z 589[ M + H ]]+；1H NMR(400MHz,pyridine-d5)δH0.23(1H,d,J＝4.0Hz, H-19),0.56(1H,d,J＝4.0Hz,H-19),0.66(1H,q,J＝12.0Hz,H-6a),1.06(3H, s,H3-30),1.23(6H,s,H3-28,29),1.27(3H,m,H-1,7a,11a),1.30(3H,s,H3-21), 1.36(1H,m,H-5),1.47(1H,m,H-6b),1.56(3H,m,H-8,11b,12a),1.57(3H,s, H3-27),1.58(1H,m,H-1b),1.68(3H,s,H3-26),1.85(1H,m,H-2a),1.97(1H, m,H-22a),2.01(1H,m,H-2b),2.05(1H,m,H-7b),2.08(1H,m,H-23a),2.13 (3H,s,COCH3),2.14(3H,s,COCH3),2.73(1H,d,J＝11.2Hz,H-17),2.79(1H, m,H-23b),2.96(1H,m,H-12b),2.99(1H,m,H-22b),3.54(1H,dd,J＝11.2,4.0 Hz,H-3),4.52(1H,d,J＝13.2Hz,H-18a),4.64(1H,d,J＝13.2Hz,H-18b), 5.71(1H,d,J＝8.8Hz,H-15),5.94(1H,dd,J＝11.2,8.8Hz,H-16)；13C NMR (pyridine-d5,100MHz)δC15.2(C-30),15.9(C-29),19.5(C-9),21.1(C-6),21.6 (COCH3),21.7(COCH3),26.0(C-27),26.2(C-26),26.5(C-11),26.6(C-28), 26.7(C-7),28.3(C-10),28.4(C-12),31.3(C-23),31.6(C-2),32.0(C-19),32.9 (C-1,21),38.6(C-22),41.5(C-4),46.2(C-13),47.4(C-5),47.6(C-8),51.9 (C-14),56.6(C-17),66.8(C-18),73.1(C-25),75.6(C-16),78.2(C-3),82.4 (C-15),87.2(C-20),114.7(C-24),171.0(COCH3),171.3(COCH3).
2) Preparation of Compounds 1 to 3
Adding beesioside I aglycone (0.06 mmol) obtained in the step into 10mL of anhydrous pyridine, adding 10 times of equivalent of 4-Dimethyllaminopyradine (DMAP), respectively adding 10 times of equivalent of 2, 2-dimethylsuccinic anhydride, 2-dimethylglutaric anhydride and diethylene glycol anhydride, carrying out microwave reaction at 155 ℃ for 2h, after the reaction is stopped, adding 1mL of 1N hydrochloric acid into the reaction liquid for neutralization, then adding 10mL of ethyl acetate for extraction for 3 times, washing the ethyl acetate part for 3 times by using brine, adding anhydrous magnesium sulfate for drying, carrying out silica gel column (200-300 meshes) chromatography and N-hexane/acetone gradient elution (10: 1-1: 1) to obtain (20S,24S) -15 β,16 β -diacetoxy-18, 24; 20, 24-diacetoxy-9, 19-cyclolactone-3 β,25-di 3-O-3 ', 3 ' -dimethyllactone yield (1, 2.19-24% of the diacetoxy-3 ', 3 ' -dimethyllactone (1, 37.19-24%) and carrying out (3-24%) yield of the diepoxy-3 ', 3 ' -dimethyllactone (19-20, 19-24%) and the yield of the diepoxy-3 ', 3-20-60% of the diepoxy-15% of the diepoxide (20S-3-15-5-dioxolane) (20-15% of the yield of the total dioxolane) obtained by using anhydrous pyridine (20S-3-24% of the anhydrous pyridine).
3) Structural determination of Compounds
Compound 1, colorless crystal, melting point 221-]20D–12.0(c 0.10, MeOH)；ESIMS:m/z 717[M+H]+,739[M+Na]+；1H NMR(400MHz, pyridine-d5)δH0.17(1H,d,J＝4.0Hz,H-19),0.48(1H,d,J＝4.0Hz,H-19), 0.55(1H,q,J＝12.0Hz,H-6a),0.97(6H,s,H3-28,29),1.11(1H,m,H-7a),1.12 (1H,m,H-1a),1.16(1H,m,H-11a),1.18(3H,s,H3-30),1.23(1H,m,H-5),1.28 (3H,s,H3-21),1.31(2H,m,H-6b,7b),1.47(1H,m,H-1b),1.54(1H,m,H-12a),1.55(3H,s,H3-27),1.56(6H,s,H3-3'),1.59(1H,m,H-8),1.66(3H,s,H3-26), 1.69(1H,m,H-2a),1.96(1H,m,H-11b),1.97(2H,m,H-2b,22a),2.08(1H,m, H-23a),2.12(3H,s,COCH3),2.14(3H,s,COCH3),2.73(1H,d,J＝11.2Hz, H-17),2.79(1H,m,H-23b),2.89(1H,d,J＝15.6Hz,H-2'a),2.96(1H,m, H-12b),2.98(1H,d,J＝15.6Hz,H-2'b),2.99(1H,m,H-22b),4.49(1H,d,J＝ 13.2Hz,H-18a),4.58(1H,d,J＝13.2Hz,H-18b),4.86(1H,dd,J＝12.0,4.0Hz, H-3),5.67(1H,d,J＝8.8Hz,H-15),5.94(1H,dd,J＝11.2,8.8Hz,H-16)；13CNMR(pyridine-d5,100MHz)δC15.8(C-29,30),19.6(C-9),20.6(C-6),21.6 (2×COCH3),26.0(3'-2×CH3),26.2(C-26,27),26.3(C-11),26.6(C-7,28),27.5 (C-2),27.8(C-10),28.3(C-12),31.2(C-23),31.7(C-19),32.2(C-1),32.8(C-21), 38.6(C-22),40.0(C-4),41.2(C-3'),45.6(C-2'),46.1(C-13),47.2(C-5),47.4 (C-8),51.8(C-14),56.5(C-17),66.7(C-18),73.1(C-25),75.5(C-16),80.8(C-3), 82.4(C-15),87.2(C-20),114.7(C-24),171.0(COCH3),171.3(COCH3),171.9 (C-1'),179.7(C-4').
Compound 2, colorless crystals, m.p.228-230 deg.C (MeOH) [ α ]]20D–13.6(c 0.15, MeOH)；ESIMS:m/z 731[M+H]+,753[M+Na]+；1H NMR(400MHz, pyridine-d5)δH：0.18(1H,d,J＝3.2Hz,H-19),0.49(1H,d,J＝3.2Hz,H-19), 0.60(1H,q,J＝12.0Hz,H-6a),0.91(6H,s,H3-28,29),1.11(1H,m,H-7a),1.12 (1H,m,H-1a),1.16(1H,m,H-11a),1.18(3H,s,H3-30),1.23(1H,m,H-5),1.29 (3H,s,H3-21),1.30(2H,m,H-7b),1.38(6H,s,H3-3'),1.43(1H,m,H-1b),1.47(1H,m,H-6b),1.54(3H,s,H3-27),1.55(1H,m,H-12a),1.59(1H,m,H-8),1.65 (3H,s,H3-26),1.69(1H,m,H-2a),1.96(1H,m,H-11b),1.97(2H,m,H-2b,22a), 2.08(1H,m,H-23a),2.13(3H,s,COCH3),2.14(3H,s,COCH3),2.27(2H,m, H-3'),2.72(2H,m,H-2'),2.73(1H,d,J＝11.2Hz,H-17),2.74(2H,s,H-4'), 2.79(1H,m,H-23b),2.96(1H,m,H-12b),2.99(1H,m,H-22b),4.50(1H,d,J＝ 13.2Hz,H-18a),4.59(1H,d,J＝13.2Hz,H-18b),4.83(1H,dd,J＝11.2,4.0Hz, H-3),5.67(1H,d,J＝8.8Hz,H-15),5.94(1H,dd,J＝11.2,8.8Hz,H-16)；13CNMR(pyridine-d5,100MHz)δC15.9(C-29,30),19.7(C-9),20.8(C-6),21.8 (2×COCH3),26.0(4'-2×CH3),26.1(C-26,27),26.3(C-11),26.4(C-28),27.6 (C-2),27.9(C-10),28.4(C-12),31.4(C-23),31.8(C-19,2'),32.3(C-1),33.0 (C-21),36.6(C-3'),38.7(C-22),40.2(C-4),42.4(C-4'),46.2(C-13),47.3(C-5), 47.5(C-8),52.0(C-14),56.7(C-17),66.9(C-18),73.3(C-25),75.6(C-16),80.8 (C-3),82.5(C-15),87.3(C-20),114.8(C-24),171.2(COCH3),171.6(COCH3), 174.0(C-1'),180.4(C-5').
Compound 3, colorless crystals, m.p.197-199 deg.C (MeOH) [ α ]]20D–1.9(c 0.16, MeOH)；ESIMS:m/z 727[M+Na]+；1H NMR(400MHz,pyridine-d5)δH0.19 (1H,d,J＝4.0Hz,H-19),0.52(1H,d,J＝4.0Hz,H-19),0.55(1H,q,J＝12.0 Hz,H-6a),0.90(3H,s,H3-29),0.92(3H,s,H3-28),1.11(1H,m,H-7a),1.12(1H, m,H-1a),1.16(1H,m,H-11a),1.21(3H,s,H3-30),1.23(1H,m,H-5),1.29(3H, s,H3-21),1.31(2H,m,H-6b,7b),1.47(1H,m,H-1b),1.54(1H,m,H-12a),1.56 (3H,s,H3-27),1.59(1H,m,H-8),1.68(3H,s,H3-26),1.69(1H,m,H-2a),1.96 (1H,m,H-11b),1.97(2H,m,H-2b,22a),2.08(1H,m,H-23a),2.13(3H,s, COCH3),2.15(3H,s,COCH3),2.73(1H,d,J＝11.6Hz,H-17),2.79(1H,m, H-23b),2.96(1H,m,H-12b),2.99(1H,m,H-22b),4.49(1H,d,J＝13.2Hz, H-18a),4.58(1H,d,J＝13.2Hz,H-18b),4.70(2H,s,H-3'),4.71(2H,s,H-2'), 4.90(1H,dd,J＝12.0,4.0Hz,H-3),5.69(1H,d,J＝8.8Hz,H-15),5.94(1H,dd, J＝11.6,8.8Hz,H-16)；13C NMR(pyridine-d5,100MHz)δC15.8(C-29,30),19.7(C-9),20.6(C-6),21.6(2×COCH3),26.0(C-26,27),26.2(C-11,28),26.6 (C-7),27.5(C-2),27.9(C-10),28.3(C-12),31.2(C-23),31.6(C-19),32.1(C-1), 32.8(C-21),38.6(C-22),40.1(C-4),46.1(C-13),47.1(C-5),47.3(C-8),51.7 (C-14),56.6(C-17),66.8(C-18),68.9(C-2'),69.0(C-3'),73.0(C-25),75.5 (C-16),81.3(C-3),82.3(C-15),87.2(C-20),114.7(C-24),170.7(C-1'),171.0 (COCH3),171.3(COCH3),173.2(C-4').
Example 3
Compounds of formula I in HIV-1NL4-3Assay for HIV inhibition in infected MT-4 cells
Drugs to be tested for activity:
(20S,24S)-15β,16β-diacetoxy-18,24；20,24-diepoxy-9,19-cyclolanostane-3β, 25-diol 3-O-3′,3′-dimethylsuccinate(1)
(20S,24S)-15β,16β-diacetoxy-18,24；20,24-diepoxy-9,19-cyclolanostane-3β, 25-diol 3-O-4′,4′-dimethylglutarate(2)
(20S,24S)-15β,16β-diacetoxy-18,24；20,24-diepoxy-9,19-cyclolanostane-3β, 25-diol 3-O-diglycolate(3)
the test method comprises the following steps:
in vitro evaluation of HIV-1 inhibition by samples test reference is made to the Z.Dang, L.Zhu, W.Lai, H.Bogerd, K.H.Lee, L.Huang, C.H.Chen, allergy and its derivatives as a new class of HIV-1entry inhibitors ACS. Medium. chem.Lett.7(2016)240-NL4- 3The Nanoluc-sec virus is a reporter virus, has secNluc as a reporter gene, and after a compound is dissolved in DMSO, the replication of the virus is detected by detecting the activity of fluorescein kinase using the Promega Nano-Glo luciferase assay System. The results are shown in Table 1. From Table 1 can seeIt is recognized that (20S,24S) -15 β,16 β -diacetoxy-18, 24; 20, 24-diacetoxy-9, 19-cyclolanostane-3 β,25-diol 3-O-3 ', 3' -dimethyluccinate (1) is the most effective anti-HIV agent, inhibiting HIV concentration EC in half50The value is 0.025 mu M, the therapeutic index TI value is more than 800, and the HIV mature stage inhibitor 3-O- (3 ', 3' -dimethyluccinnanyl) -beta inic acid (DSB) entering the first phase II clinical test is almost the same as the HIV mature stage inhibitor, and the HIV mature stage inhibitor is likely to be developed into an anti-HIV-1 medicament of natural source.
TABLE 1 test results of HIV-1 inhibition activity of samples and positive drugs on MT-4 cellsa
aThe inhibition of the HIV-1 virus was tested using a method of multicycle virus replication.
bEC50Half of the effective inhibitory HIV concentrations (mean +/-SD of3tests).
cCC50Half the effective inhibitory cell concentration
d*-No selectivity (CC)50/EC50<5).
eTI:CC50/EC50.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (9)
1. A triterpene derivative having a structure shown in formula I,
2. The method for producing a triterpene derivative according to claim 1, comprising the steps of:
mixing a triterpenoid saponin compound, namely Beesioside I, a hydrolase molsin and a disodium hydrogen phosphate-citric acid buffer solution for reaction to obtain aglycone of the Beesioside I;
and (2) mixing the aglycone of the Beesioside I with 2, 2-dimethylsuccinic anhydride, 2-dimethylglutaric anhydride and diglycolic anhydride respectively to perform microwave reaction to obtain the triterpene derivative with the structure shown in the formula I.
3. The preparation method of claim 2, wherein the mass ratio of the triterpenoid saponin compound beesioside I to the hydrolase molsin is 1: 1-1: 10.
4. The method according to claim 2 or 3, wherein the pH of the disodium hydrogen phosphate-citric acid buffer is 4.0.
5. The preparation method according to claim 2, wherein the temperature of the microwave reaction is 150-160 ℃, and the time of the microwave reaction is 1-3 h.
6. Use of the triterpene derivative with the structure shown in the formula I in the claim 1 or the triterpene derivative with the structure shown in the formula I prepared by the preparation method in any one of the claims 2 to 5 in the preparation of anti-AIDS drugs.
7. The use of claim 6, wherein the anti-AIDS drug comprises an effective amount of a triterpene derivative having a structure shown in formula I, a stereoisomer, a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, excipient and diluent.
8. The use of claim 6 or 7, wherein the anti-AIDS drug is in the form of tablet, injection, capsule, granule, pill, powder, oral liquid, sustained release preparation, controlled release preparation or nano-preparation pharmaceutically acceptable dosage form.
9. The use according to claim 6 or 7, wherein when said R is a 1 group, said triterpene derivative having the structure shown in formula I has a significant in vitro anti-HIV-1 effect on HIV-1NL 4-3In virus-infected MT-4 cells, the inhibitor has obvious inhibiting effect on HIV virus, and half effective inhibiting concentration EC50At 0.025 μ M and a therapeutic index TI of greater than 800, the 1 group having the following structure:
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