CN1293199A - Saponin library of rhammose-substituted beta-o-gluco-diosgenin and its preparing process and application - Google Patents
Saponin library of rhammose-substituted beta-o-gluco-diosgenin and its preparing process and application Download PDFInfo
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Abstract
A saponin library of 5-16 monorhamnose-or polyrhamnose-substituted beta-D-gluco-diosenins containing beta-D-gluco-diosgenin is prepared from easily available aglycone and monose through one-step ramdom glycosidation reaction or two-step randomization reaction including random acylation and random glycosidation, and further removing protective group. It is a compound library with physiological activity for medicine screening.
Description
The invention relates to a saponin library of β -D-glucosyl-dioscin substituted by rhamnose, in particular to a saponin library of monosaccharide saponin to pentasaccharide saponin containing one to five glycosyl groups.
Saponins are active compounds with complex structures, which are widely distributed in plants, and many saponins have been proved to have various physiological activities and good pharmacological effects, such as anticancer, antibacterial, anti-inflammatory, blood pressure lowering, immunity regulating and the like. However, the synthesis of saponins has been limited to the conventional stepwise method of protecting group-deprotecting group [ high layer efficient glycosylation of sapogenins, Shaojiang Deng, Biao Yu, Jianming Xie, Yongzheng Hui.J.org.Chem., 1999, 64, 7265-7266], which has greatly limited the synthesis and screening process of saponin compounds. The effective components of traditional Chinese herbal medicines such as ginseng, polygala root, ophiopogon root and the like contain saponin, and the effective components consist of multiple saponin homologues with similar structures, which can play pharmacological roles simultaneously. Hindsgaul et al have recently developed a process for preparing trisaccharide libraries using random glycosylation [ A strategy of random glycosylation "for the production of oligosaccharide library Kanie, Frank Barresi, Yili Ding, Jill Labbe, Albin otter, L.Scott Forsberg, Beaternst, Ole Hindsgaul, Angew.chem.End.Engl., 1995, 34, 2720-2722], but there has been no report on the preparation of saponin libraries to date. It is therefore of interest to develop a method for combinatorial chemistry that allows simple preparation of saponin libraries containing all possible homologues starting from readily available aglycones and monosaccharides.
The invention aims to provide a saponin library containing 5-16 kinds of β -D-glucosyl-dioscin substituted by monorhamnose or polyrhamnose.
Another object of the present invention is to provide a method for preparing the above saponin library containing 5-16 kinds of mono-rhamnose-substituted or poly-rhamnose-substituted β -D-glucosyl-dioscin.
The invention also provides the application of the saponin library containing 5 to 16 kinds of the β -D-glucosyl-dioscin substituted by monorhamnose or polyrhamnose, namely providing a compound library with physiological activity for drug screening.
The invention adopts a small group of random glycosylation method, prepares a saponin mixture library of disaccharide, trisaccharide, tetrasaccharide and pentasaccharide with all possibilities by a one-step or two-step randomization reaction starting from easily available aglycone and monosaccharide and then by a protective group removing reaction, and characterizes the composition by using an analysis method of gas chromatography-mass spectrometry combination, wherein the saponin library contains 5-16 kinds of saponins a-p, a) β -D-glucosyl-dioscin with a relative molar percentage of 0-20%, b) rhamnosyl (1 → 2) - β -D-glucosyl-dioscin with a relative molar percentage of 0-35%, c) rhamnosyl (1 → 3) - β -D-glucosyl-dioscin with a relative molar percentage of 0-35%, D) rhamnosyl (1 → 3) -5-D-glucosyl- → 1 → 4) -631-D-glucosyl- → 6 → 1 → 7%, D → 7-5-D → 7% of saponins 1-15%, 0-5-15% of saponins 1-15%, 3-5-D → 7% of saponins 1-5-D-glucosyl-3 → 7%, 0-3 → 1 → 4 → 7%, 0-5-D → 3 → 4 → 1 → 4% of a relative molar percentage of saponin → 0-3 → 1 → 4 → 15%, 0-D → 7% of a relative molar percentage of a relative percentage of a weight → 7%, 0-3-D → 7%, 0-D → 7% of a relative percentage of a weight of a-D → 7% of a weight of a rhamnosyl-D → 7% of a-D → 7%, a-D → 7% of a weight of a rhamnosylglucosyl-3-D → 7%, a rhamnosyld → 7-1-3 → 1 → 7%, a relative to a-3-1-3-1 → 0%, a weight of a relative molar percentage of a weight of a rhamnosyld → 7% of a rhamnosylof a rhamnosyld → 7% of a rhamnosyld → 0-3 → 7% of a rhamnosyld → 7% of a weight of a rhamnosyld → 7-3 → 0-1 → 0-3 → 0-1 → 7% of a rhamnosyld → 7% of a 1 → 7% of a rhamnosylof a 1 → 7% of a 1 → 0-3 → 1 → 0.
The saponin libraries of the present invention may contain amounts of saponins a-p that vary within the above ranges, as shown for example in the following libraries: a library I comprising: a library II comprising: saponin b, 0-30% by mol; saponin a, the mol percentage content is 3-20%; saponin c, the mol percentage content is 0-30%; saponin b, 3-35% of mol percentage; saponin d, 0-30% by mol; saponin c, 5-15% by mol; saponin e, 15-35% by mol of saponin d, 2-12% by mol; saponin f, the mol percentage content is 0-6%; saponin e, the mol percentage content is 1-7%; saponin g, the mol percentage content is 0-6%; saponin f, the mol percentage content is 3-15%; saponin h, the mol percentage content is 5-25%; saponin g, the mol percentage content is 3-15%; saponin j, the mol percentage content is 5-25%; saponin h, the mol percentage content is 1-12%; saponin i, the mol percentage content is 0-10%; saponin i, the mol percentage content is 2-7%; saponin k, 5-12% by mol; saponin j, the mol percentage content is 1-12%; saponin m, 0-20% by mol; saponin k, the mol percentage content is 2-4%; saponin n, the mol percentage content is 0-7%; saponin l, the mol percentage content is 0-15%; saponin o, 0-30% by mol; saponin m, the mol percentage content is 1-12%;
saponin n, the mol percentage content is 2-15%;
saponin o, 3-20% by mol;
saponin p, 3-7% by mol;
a library III comprising: a library IV comprising:
saponin f, the mol percentage content is 0-3%; saponin b, 5-35% by mol;
saponin g, the mol percentage content is 0-3%; saponin c, the mol percentage content is 2-35%;
saponin h, the mol percentage content is 5-10%; saponin d, 5-20% by mol;
saponin j, the mol percentage content is 5-10%; 7-25% of saponin f by mole percentage;
saponin i, the mol percentage content is 0-5%; saponin g, the mol percentage content is 7-25%;
saponin m, 10-30% by mol; saponin i, the mol percentage content is 2-5%;
saponin n, the mol percentage content is 5-35%; saponin l, the mol percentage content is 0-35%;
saponin o, 10-30% by mol;
saponin p, 15-25% by mol;
the saponin library of the present invention may have physiological activity.
Specifically, β -D-glucosyl dioscin or a derivative thereof is used as a starting material, rhamnosyl is randomly connected to any one or more of hydroxyl groups at positions 2, 3, 4 and 6 of glucosyl to obtain glycosylation products of the same series, or β -D-glucosyl dioscin or a derivative thereof is randomly acylated with an acyl donor, the product after random acylation is used as the starting material for glycosylation, and further subjected to random glycosylation reaction, and the random glycosylation reaction product is reduced by using a monovalent metal to remove a protecting group to obtain β -D-glucosyl dioscin, monorhamnosyl substituted β -D-glucosyl dioscin, polysaccharyl substituted β -D-glucosyl saponin or a mixture thereof, thus obtaining the dioscin library.
The process of the present invention can be represented by the following reaction formula:
in the above reaction formula, n =0, 1, 2, 3 or 4, m =1, 2, 3 or 4, and m.gtoreq.n,
R1= Formyl (Formyl), acetyl (Ac), succinyl monomethylate (COCH)2CH2COOCH3) Benzoyl (Bz) or pivaloyl (Piv), and the like.
R2= rhamnosyl radical with fully protected hydroxyl group, fraction thereofThe subformula is:in the formula R5Is an acyl or benzyl group having 1 to 7 carbon atoms.
R3= rhamnosyl, its formula:
R4= rhamnose with full protection of the remaining hydroxyl groups activated at the anomeric carbon position, whose molecular formula is:
wherein X is halogen, -SEt, -Sph,
For example: the fully benzylated rhamnose thioglycoside has a molecular formula as follows:the molecular formula of the fully acetylated rhamnose thioglycoside is as follows:
the total benzoylated rhamnose trichloroimino ester has a molecular formula as follows:the total benzoylated rhamnose bromoglycoside has the molecular formula:
the process of the invention can be further described as follows:
acyl donor β -D-glucosyl dioscin is acylated with or without polar solvent under catalysis of organic base at-20 deg.c to room temperature for 0.5-25 hr to partially acylate the hydroxyl groups of the glucosyl saponin, wherein the molar ratio of β -D-glucosyl dioscin to acyl donor to organic base is 1: 0.5-5: 1-1000, and the acyl donor is acid anhydride or acyl halide containing 1-8 carbon atoms, such as acetic anhydride, propionic anhydride, succinic anhydride, butenedioic anhydride, phthalic anhydride, acetyl chloride, acetyl bromide, n-butyl chloride, trimethyl acetyl chloride, benzoyl halide, p-nitrobenzoyl chloride, etc.
In polar solvent, using the acylation product or directly using β -D-glucosyl dioscin or its derivative as glycosyl acceptor, and activating hydroxyl group at anomeric carbon position to completely protect rhamnose R4As glycosyl donor and addingAdding a small amount of activated molecular sieve, silica gel, diatomite or ion exchange resin as water absorbent, and performing random glycosylation reaction under the action of promoter and water absorbent to make non-acylated hydroxyl on glucosyl group in glycosyl acceptor and glycosyl donor perform glycosylation. The reaction time is 0.5-25 hours, and the reaction temperature is-20 ℃ to room temperature. Wherein the molar ratio of the glycosyl acceptor or the acylation product, the glycosyl donor and the accelerator is 1: 0.5-8: 0-5 in sequence.
The organic base used for random acylation is an organic base containing at least one nitrogen atom, such as triethylamine (Et)3N), pyridine (Py), Diisopropylethylamine (DIEA), 4-Dimethylaminopyridine (DMAP), and the like. The polar solvent used for the random acylation or glycosylation reaction is Tetrahydrofuran (THF), N-Dimethylformamide (DMF), pyridine, dichloromethane or dioxane, etc. The accelerator used for the random glycosylation is C1-C6Halogenated amide of (1), C1-C6Halogenated hydrocarbyl sulfonic acid of (2), C1-C6Halogenated hydrocarbyl sulfonate of (A), C1-C6Halogenated hydrocarbyl sulfonate of (A), C1-C6Trimethylsilyl halosulfonate, boron trifluoride-diethyl ether or mixtures thereof, such as N-iodosuccinimide (NIS), N-iodosuccinimide (NIS) -silver trifluoromethanesulfonate (AgOTf) mixture, N-iodosuccinimide (NIS) -trifluoromethanesulfonic acid (TfOH) mixture, trimethylsilyl trifluoromethanesulfonate (TMSOTf), silver trifluoromethanesulfonate (AgOTf), boron trifluoride-diethyl ether (BF)3·Et2O), and the like. This type of reaction can also be quenched by addition of a weak base, usually NH3、(CH3)3N、(C2H5)3N, etc. quench the reaction.
Then taking random glycosylation reaction products, reducing the products in polar solvent and liquid ammonia by using monovalent metal reducing agent, and reducing acyl groups connected with random acylation on glucosyl groups and protecting groups on rhamnosyl groups connected with random glycosylation into hydroxyl groups by removing the acyl groups and the protecting groups to obtain the final product, namely a saponin library. The mol ratio of the random glycosylation product to the reducing agent in the reduction reaction is 1: 1-500, 1-1000ml of liquid ammonia is used for each gram of random glycosylation product, and the reaction is not influenced by adopting more liquid ammonia. The reduction reaction time is 0.1-2 h, and the monovalent metal is lithium, sodium, potassium, rubidium or cesium.
The obtained saponin library is derivatized to prepare partially methylated alditol acetate, and then gas chromatography-mass spectrometry (GC-MS) analysis is carried out, and the relative molar mass of each component can be calculated from a gas chromatogram. Comparing the chromatogram corresponding to each group of chromatogram peaks with the standard mass spectrogram, the chemical composition of each component can be known, and the specific structure of the corresponding saponin can be deduced.
The invention provides a randomized saponin library with physiological activity for the first time. The randomization reaction expands the synthesis and screening process of saponin compound, and the raw material is easy to obtain, the method is simple, the efficiency of synthesizing the compound is greatly improved, an efficient and convenient method is provided for discovering and screening new saponin compound, compared with the method of extracting from natural plant, the method has industrialization prospect. Through one-step or two-step randomization reaction, not only various types of saponin libraries can be obtained, but also a new compound library with physiological activity can be provided for drug screening.
The invention will be understood by the following examples, which are not intended to limit the scope of the invention:
example 1
General procedure for random acylation
Adding trillin 230mg (0.4 mmol) into 1.5-3 ml Py or DMAP, slowly dropping Ac under ice-bath cooling2O19-188. mu.l (0.2-2.0 mmol). The ice bath is maintained for 0.5 h and then removed, and the reaction is continued to be stirred at the temperature of minus 20 ℃ to room temperature for 0.5-24 h. The post-treatment was as follows: py or DMAP was mostly removed under reduced pressure. The residue was taken up in 70ml of CH2Cl2Extraction, washing with saturated NaCl three times and drying. The solvent was evaporated under reduced pressure to give a white solid.
Example 2
General procedure for random glycosylation
Taking 0.16 mmol of random acylation product (or trillin), and total benzyl protected rhamnose thioglycoside or total benzeneFormylated rhamnose trichloroimidate 0.32 mmol-0.64 mmol is dissolved in dioxane 3-5ml and transferred to a fire dried branched tube (containing 1-5 angstrom molecular sieve 160 mg). Stirring at-20 deg.C to room temperature under argon protection for 30min, adding NIS or BF3·Et2The amount of O was 0.35 mmol to 0.70 mmol, and 0.33 to 0.67 ml of AgOTf toluene solution (0.19M) was added quickly. Reacting at-20 deg.C to room temperature for 0.5-24 h, adding Et3The reaction was quenched by N1 ml. The reaction mixture was filtered and washed with CH2Cl2The filter cake is washed. The filtrate is combined with the washing solution, CH2Cl2100ml of the solution was diluted, followed by saturated Na2S2O3Saturated NaCl water wash, MgSO4And (5) drying. The solvent was evaporated under reduced pressure, and the residue was applied to a column with a crude silica gel and purified by silica gel H column chromatography. With petroleum ether (10: 1) gradient elution, collecting CH2Cl2And CH2Cl2-CH3Concentrating the eluate eluted with OH (20: 1) under reduced pressure to obtain brown solid or oily substance.
Example 3
Li／NH3General procedure for reduction
180mg of the random glycosylation product was dissolved in 3ml of THF for further use. Let NH react3Condensed in a three-necked flask. After drying, it is distilled to about 0.2-180 ml in a 50ml reaction flask, added with 300mg of Li or K wire and stirred. The reduction was carried out by slowly adding dropwise a THF solution of the random glycosylation product. After dripping, continuously reacting for 0.1-2 h at about-70 ℃ to naturally raise the temperature to room temperature until NH is formed3After the essential evaporation, CH was added under ice-bath3The OH quenches the reaction and adjusts the pH of the system to acidity. The methanol was distilled off under reduced pressure to leave an oily substance, which was diluted with about 70ml of n-butanol and washed thoroughly with distilled water. After the organic phase and the aqueous phase are fully separated, n-butyl is addedThe alcohol was separated and concentrated to a small volume under reduced pressure from an oil pump in a water bath atroom temperature-35 ℃. Adding a large amount of anhydrous ether to generate white precipitate, and filtering to obtain Li/NH3And (4) reducing the product.
Example 4
Experiment knotFruit table 1 reaction conditions and distribution of saponin library
TABLE 2 relative mol% of each saponin in the saponin library
Example 5
Evaluation of the results of in vitro screening experiments of antitumor bioactivity: and (4) invalidation: l0-5 mol/l<85%
Weak effect: l0-5 mol/l is more than or equal to 85 percent or 10-6 mol/l is more than or equal to 50 percent
The strong effect is as follows: 10-6 mol/l is more than or equal to 85 percent or 10-7 mol/l is more than 50 percent
Table 3 screening method: sulforhodamine B (SRB) protein staining method cell line: a-549 human lung adenocarcinoma action time: 72h
Inhibition of tumor cell growth%
Table 4 screening methods: tetrazolium salt (MTT) reduction cell line: p388 mouse leukemia duration of action: 48h
Inhibition of tumor cell growth%
Claims (11)
1. A saponin library comprising rhamnosyl-substituted β -D-glucosyl-dioscin, which contains 5-16 kinds of saponins a-p as follows:
a) β -D-glucosyl-dioscin, with a relative molar percentage of 0-20%;
b) rhamnosyl (1 → 2) - β -D-glucosyl-dioscin, the relative molar percentage content is 0-35%;
c) rhamnosyl (1 → 3) - β -D-glucosyl-dioscin, the relative molar percentage content is 0-35%;
d) rhamnosyl (1 → 4) - β -D-glucosyl-dioscin, the relative molar percentage content is 0-30%;
e) rhamnosyl (1 → 6) - β -D-glucosyl-dioscin, the relative molar percentage content is 0-35%;
f) dirhamnosyl (1 → 2, 1 → 3) - β -D-glucosyl-dioscin, the relative molar percentage content is 0-25%;
g) dirhamnosyl (1 → 2, 1 → 4) - β -D-glucosyl-dioscin, relative molar percentage content is 0-25%;
h) dirhamnosyl (1 → 2, 1 → 6) - β -D-glucosyl-dioscin, the relative molar percentage content is 0-20%;
i) dirhamnosyl (1 → 3, 1 → 4) - β -D-glucosyl-dioscin, the relative molar percentage content is 0-10%;
j) dirhamnosyl (1 → 3, 1 → 6) - β -D-glucosyl-dioscin, the relative molar percentage content is 0-20%;
k) dirhamnosyl (1 → 4, 1 → 6) - β -D-glucosyl-dioscin, the relative molar percentage content is 0-15%;
l) trihamniosyl (1 → 2, 1 → 3, 1 → 4) - β -D-glucosyl-dioscin, the relative molar percentage content is 0-35%;
m) trihamniosyl (1 → 2, 1 → 3, 1 → 6) - β -D-glucosyl-dioscin, the relative molar percentage content is 0-30%;
n) trihamniosyl (1 → 2, 1 → 4, 1 → 6) - β -D-glucosyl-dioscin, the relative molar percentage content is 0-35%;
o) trihamniosyl (1 → 3, 1 → 4, 1 → 6) - β -D-glucosyl-dioscin, in a relative molar percentage of 0-30%;
p) tetrarhamnosyl (1 → 2,1 → 3, 1 → 4, 1 → 6) - β -D-glucosyl-dioscin, the relative molar percentage content is 0-25%.
2. The relative mole percentage content range of the saponins in the saponin library is as follows: 0-30% of saponin b, 0-30% of saponin c, 0-30% of saponin d, 15-35% of saponin e, 0-6% of saponin f, 0-6% of saponin g, 5-25% of saponin h, 0-10% of saponin I, 5-25% of saponin j, 5-12% of saponin k, 0-20% of saponin m, 0-7% of saponin n and 0-30% of saponin o.
3. The relative mole percentage content range of the saponins in the saponin library is as follows: 3-20% of saponin a, 3-35% of saponin b, 5-15% of saponin c, 2-12% of saponin d, 1-7% of saponin e, 3-15% of saponin f, 3-15% of saponin g, 1-12% of saponin h, 2-7% of saponin i, 1-12% of saponin j, 2-4% of saponin k, 0-15% of saponin l, 1-12% of saponin m, 2-15% of saponin n, 3-20% of saponin o and 3-7% of saponin p.
4. The relative mole percentage content range of the saponins in the saponin library is as follows: 0-3% of saponin f, 0-3% of saponin g, 5-10% of saponin h, 0-5% of saponin i, 5-10% of saponin j, 10-30% of saponin m, 5-35% of saponin n, 10-30% of saponin o and 15-25% of saponin p.
5. The relative mole percentage content range of the saponins in the saponin library is as follows: 5-35% of saponin b, 2-35% of saponin c, 5-20% of saponin d, 7-25% of saponin f, 7-25% of saponin g, 2-5% of saponin I and 0-35% of saponin l.
6. A process for the preparation of a saponin library according to claim 1, wherein the library is prepared by the following steps of random glycosylation (2) in one step or by two steps of randomization using acylation (1) followed by glycosylation (2), and then subjecting the glycosidation product to a protecting group removal reaction (3):
(1) random acylation reaction of β -D-glucosyl dioscin or its derivative and acyl donor in polar solvent or not in polar solvent and with organic base containing at least one nitrogen atom, wherein the molar ratio of β -D-glucosyl dioscin to acyl donor to organic base is 1: 0.5-5: 1-1000, and the acyl donor is acid anhydride or acyl halide containing 1-8 carbon atoms;
(2) random glycosylation reaction, β -D-glucosyl dioscin or its derivative or acylation product of the above (1) as glycosyl acceptor with the carbon position of anomeric as carbon atomThe rhamnose which is over-activated and fully protected by the rest hydroxyl groups is taken as glycosyl donor, and random glycosylation reaction is carried out in a polar solvent under the action of an accelerant and a water absorbent, wherein the molar ratio of the glycosyl acceptor, the glycosyl donor and the accelerant is 1: 0.5-8: 0-5 in sequence, and the accelerant is C1-C6Halogenated amide of (1), C1-C6Halogenated hydrocarbyl sulfonic acid of (2), C1-C6Halogenated hydrocarbyl sulfonate of (A), C1-C6Halogenated hydrocarbyl sulfonate of (A), C1-C6The water absorbent is molecular sieve, silica gel, diatomite or ion exchange resin,
the rhamnose R4 with the activated hydroxyl group at the anomeric carbon position fully protected has the molecular formula:wherein X is halogen, -SEt, -Sph,
R5Is an acyl or benzyl group having 1 to 7 carbon atoms.
(3) Removing the protecting group: reducing the product of the step (2) in a polar solvent and liquid ammonia by using a monovalent metal reducing agent, wherein the molar ratio of the random glycosylation product to the reducing agent is 1: 1-5, and the reaction time is 0.1-2 h; the reaction time of the random acylation (1) or glycosylation (2) is 0.5 to 25 hours, and the reaction temperature is-20 ℃ to room temperature.
7. A process for the preparation of a saponin library according to claim 6, characterized in that the polar solvent is tetrahydrofuran, N dimethylformamide, pyridine, dichloromethane or dioxane.
8. A process for preparing the saponin library as claimed in claim 6, wherein the organic base used for random acylation is triethylamine, pyridine, diisopropylethylamine, 4-dimethylaminopyridine or bipyridine.
9. A process for the preparation of a saponin library according to claim 6, characterized in that the acyl donor is acetic anhydride, propionic anhydride, succinic anhydride, maleic anhydride, phthalic anhydride, acetyl chloride, acetyl bromide, n-butyryl chloride, trimethylacetyl chloride, benzoyl halide or p-nitrobenzoyl chloride.
10. A process for the preparation of a saponin library as claimed in claim 6 characterized in that the accelerator used for random glycosylation is N-iodosuccinimide, a mixture of N-iodosuccinimide-silver triflate, a mixture of N-iodosuccinimide-trifluoromethanesulfonic acid, trimethylsilyl trifluoromethanesulfonate, silver trifluoromethanesulfonate or boron trifluoride-diethyl ether.
11. Use of a saponin library according to claim 1, characterized in that a library of physiologically active compounds is provided for drug screening.
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Cited By (3)
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| WO2003022287A1 (en) * | 2001-08-24 | 2003-03-20 | Jilin Tianyao Science And Technology Co. Ltd. | USE OF 3β-HYDROXY-5-SPIROSTENE AS DRUGS FOR PREVENTION OR TREATMENT OF CARDIOVASCULAR DISEASES OR CONDITIONS FOR INHIBITION OF TUMORS AND DECREASING OF BLOOD LIPIDS |
| CN104395333A (en) * | 2012-05-23 | 2015-03-04 | 肿瘤学研究国际有限公司 | Improved synthesis |
| CN114644679A (en) * | 2020-12-18 | 2022-06-21 | 百极优棠(广东)医药科技有限公司 | Glucuronic acid glucoside compound, preparation method and application thereof |
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| WO2003022287A1 (en) * | 2001-08-24 | 2003-03-20 | Jilin Tianyao Science And Technology Co. Ltd. | USE OF 3β-HYDROXY-5-SPIROSTENE AS DRUGS FOR PREVENTION OR TREATMENT OF CARDIOVASCULAR DISEASES OR CONDITIONS FOR INHIBITION OF TUMORS AND DECREASING OF BLOOD LIPIDS |
| CN104395333A (en) * | 2012-05-23 | 2015-03-04 | 肿瘤学研究国际有限公司 | Improved synthesis |
| CN104395333B (en) * | 2012-05-23 | 2018-01-02 | 肿瘤学研究国际有限公司 | Improved synthesis |
| CN114644679A (en) * | 2020-12-18 | 2022-06-21 | 百极优棠(广东)医药科技有限公司 | Glucuronic acid glucoside compound, preparation method and application thereof |
| CN114644679B (en) * | 2020-12-18 | 2024-01-09 | 百极优棠(广东)医药科技有限公司 | Glucuronide compound, preparation method and application thereof |
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