CN101250212A - 20(S) or 20(R)-dammarane-3 beta,12 beta, 20,25-tetraalcohol derivative, its salt and use thereof - Google Patents
20(S) or 20(R)-dammarane-3 beta,12 beta, 20,25-tetraalcohol derivative, its salt and use thereof Download PDFInfo
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Abstract
The invention provides a 20(S)/20(R)-dammarane-3beta, 12beta, 20, 25-tetraol derivative, relative salt and anti-tumor application, belonging to medical technical field, wherein the 20(S)/20(R)-dammarane-3beta, 12beta, 20, 25-tetraol derivative and relative salt are respresented as below, the 20(S)/20(R)-dammarane-3beta, 12beta, 20, 25-tetraol derivative and relative salt can be combined with medical acceptable carrier into drug compound, to prepare anti-virus and anti-tumor drugs. The 20(S)/20(R)-dammarane-3beta, 12beta, 20, 25-tetraol derivative and relative salt have stronger anti-viruse and anti-tumor activity than dammarane-3beta, 12beta, 20, 25-tetraol, which can improve the activity of other anti-virus and anti-tumor drugs and reduce the toxicity.
Description
Technical field
The invention belongs to medical technical field, relate to 20 (S) or 20 (R)-dammarane-3 β, 12 β, 20,25-tetraalcohol derivative, its salt and uses thereof.20 (S) or 20 (R)-dammarane-3 β of containing provided by the invention, 12 β, 20, the medicine of 25-tetraalcohol derivative and salt thereof has stronger antitumour activity than 20 (S) and 20 (R)-protopanoxadiols, can strengthen more obviously also simultaneously that other is antiviral, cancer therapy drug active and reduce these poisonous side effect of medicine.
Background technology
20 (R)-dammarane-3 β, 12 β, 20,25-tetrol [20 (R)-25-OH-PPD] has stronger antitumour activity, can suppress human tumor cells (human breast carcinoma, human small cell lung carcinoma, people's cancer of the stomach, human colon carcinoma, the human neuroglia cancer, Humanmachine tumour, the human cervical carcinoma, people's liver cancer, early young grain leukemia, sarcoma S-180, liver ascites, mouse cervical cancer-14 and ehrlich carcinoma etc.) growth and propagation, the inducing tumor cell differentiation, apoptosis suppresses tumor neogenetic blood vessels and generates, suppressing invading of tumour moistens and transfer, anti-tumor activities such as enhancing body immunizing power and reduction toxic and side.Than the ginsenoside derivative Rg that is widely used at present cancer therapy drug at home
3Growth of tumor is suppressed active high 5-15 doubly.25-OH-PPD can also induce the apoptosis of lung cancer cell line H838 (p53 wild-type) and H358 (p53 absence type) and suppress cell proliferation in the interdependent mode of dosage, and can make cell-cycle arrest in the G1 phase, this compound of different concns all demonstrates the activity stronger than other ginsenosides.In addition, 25-OH-PPD (when 50 μ M and 100 μ M) effectively reduces the survival rate of prostate cancer cell line LNCaP (p53 wild-type) and PC3 (p53 absence type), but does not influence inoblast; This compound can also be induced the apoptosis of these two kinds of cells, suppresses the propagation of cell, and makes cell-cycle arrest in the G1 phase.In the LNCaP and PC3 cell that 25-OH-PPD handled, the expression of cancer suppressor gene p21, p27 and Bax improves, and the expression of proto-oncogene MDM2, Bcl2, E2F1, cdk2, CDK4 and CyclinD1 all reduces.25-OH-PPD can also suppress the growth of prostate gland transplanted tumor, and increases the susceptibility of tumour to chemicotherapy.For 20 (S) or 20 (R)-dammarane-3 β, 12 β, 20, derivative of 25-tetrol and uses thereof has not yet to see report.
Summary of the invention
20 (S) or 20 (R)-dammarane-3 β have been the purpose of this invention is to provide, 12 β, 20,25-tetraalcohol derivative, its salt and anticancer usage thereof.
The invention provides a kind of 20 (S) or 20 (R)-dammarane-3 β, 12 β, 20,25-tetraalcohol derivative and salt thereof have following constitutional features:
Wherein, R
1, R
2, R
3And R
4Can singly replace, can two replace, can three replace, also can replace simultaneously;
R
1, R
2, R
3And R
4Can be alkyl, alkylene, fatty acyl group, aromaticacyl radical, assorted aromaticacyl radical, substituted aroma acyl group, di-carboxylic acid monoacyl M1OOC-M2-CO-, inorganic acidic group or-CO-(CH2) nR; M2 among the M1OOC-M2-CO-is alkylidene group, aromatic base, substituted aromatic base, heterocyclic radical, substituted heterocyclic radical or alkylene; M1 is H or alkali metal; The integer of n=1-20 among-CO-(CH2) nR, R are halogen or pharmaceutically acceptable anti-tumor activity group;
Described salt is sylvite, sodium salt, ammonium salt, magnesium salts or calcium salt.
20 (S) provided by the invention or 20 (R)-dammarane-3 β, 12 β, 20, in 25-tetraalcohol derivative and the salt thereof,
Described alkyl is the alkyl with 1-20 carbon atom;
Described alkylene is the alkylene with 2-20 carbon atom;
Described fatty acyl group is the fatty acyl group with 1-20 carbon atom;
Described aromaticacyl radical is the aromaticacyl radical with 6 carbon atoms;
Described assorted aromaticacyl radical is the aromaticacyl radical with pyridine ring;
Described substituted aroma acyl group is to have the substituted aroma acyl group that has different substituents on the phenyl ring of aromaticacyl radical of 6 carbon atoms, and substituting group wherein is hydroxyl, methoxyl group, amino or halogen; Substituent position is 2,3,4,5 of a phenyl ring, and single replacement of 6, two replacement or three replace;
M2 among the described di-carboxylic acid monoacyl M1OOC-M2-CO-is the alkyl of C1-5 carbon atom or the alkylene that C2-5 carbon atom arranged;
Described inorganic acidic group is phosphate or sulfonic group;
Among described-CO-(CH2) nR, R is: mustargen, endoxan, 5 FU 5 fluorouracil, Rimantadine, purinethol, acyclovir, didanosine, fixed, the lamifudin of the many furans of department.
20 (S) provided by the invention or 20 (R)-dammarane-3 β, 12 β, 20, in 25-tetraalcohol derivative and the salt thereof,
Described alkyl is methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl;
Described fatty acyl group is ethanoyl, propionyl, butyryl radicals, pentanoyl, caproyl, oenanthyl, capryloyl, nonanoyl, decanoyl, palmitoyl, unsaturated fatty acyl group;
Described aromaticacyl radical is benzoyl, phenylacetyl, phenylpropenoyl (cinnamoyl);
Described substituted aroma acyl group is benzoyl, to methoxybenzoyl base, cinnamoyl, asafoetide acyl group;
Described assorted aromaticacyl radical is 2-pyridine formyl radical, 3-pyridine formyl radical, 4-pyridine formyl radical;
Described di-carboxylic acid monoacyl M1OOC-M2-CO-is Succinic Acid monoacyl, maleic acid monoacyl or phthalic acid monoacyl;
Among described-CO-(CH2) nR ,-(CH2) n is ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, ethanoyl, positive propionyl, propionyl, positive butyryl radicals.
The invention provides 20 (S) or 20 (R)-dammarane-3 β, 12 β, 20, the application in preparation cancer therapy drug, antiviral of 25-tetraalcohol derivative and salt thereof.
20 (S) provided by the invention or 20 (R)-dammarane-3 β, 12 β, 20,25-tetraalcohol derivative and salt thereof can be mixed and made into pharmaceutical composition with pharmaceutically acceptable carrier and be used to prepare cancer therapy drug, antiviral.
Dammarane-3 β that contains provided by the invention, 12 β, 20, the medicine of 25-tetraalcohol derivative and salt thereof can be used for treating virus disease and tumour.
Dammarane-3 β, 12 β, 20 contained provided by the invention, 25-tetraalcohol derivative and salt thereof are not only than dammarane-3 β, 12 β, 20, the 25-tetrol has stronger antiviral, antitumour activity, can strengthen more obviously also simultaneously that other is antiviral, cancer therapy drug active and reduce these drug toxicities.
Embodiment
Give further instruction below by embodiment to the present invention, certainly, the present invention is not limited only to following embodiment.
Embodiment 1: preparation dammarane-3 β, 12 β, 20,25-tetrol-12 β-monomethyl ether and dammarane-3 β, 12 β, 20,25-tetrol-3 β, 12 β-two methyl ethers
0.3g dammarane-3 β, 12 β, 20, the 25-tetrol adds 15ml DMF dissolving, adds 0.3g sodium hydride (60%).Sodium hydride all dissolves the back and adds the 0.2ml methyl iodide, is heated to 70 ℃, refluxes 8 hours.Add suitable quantity of water in the reaction solution, separate out white solid.Solid is separated out in filtration, and drying is through silica gel column chromatography, use sherwood oil: acetone (3: 1) wash-out, obtain two components: component 1 is white oily matter dammarane-3 β, 12 β, 20,25-tetrol-3 β, 12 β-two methyl ethers (69.7%), component 2 is white solid dammarane-3 β, 12 β, 20,25-tetrol-12 β-monomethyl ether (48.6%).Embodiment 2: preparation dammarane-3 β, 12 β, 20,25-tetrol-12 β-single ether and dammarane-3 β, 12 β, 20,25-tetrol-3 β, 12 β-two ether
0.5g dammarane-3 β, 12 β, 20, the 25-tetrol adds 15ml DMF dissolving, adds 0.5g sodium hydride (60%).Sodium hydride all dissolves the back and adds the 0.4ml monobromethane, is heated to 75 ℃, refluxes 10 hours.Add suitable quantity of water in the reaction solution, separate out white solid.Solid is separated out in filtration, and drying is through silica gel column chromatography, use sherwood oil: ethyl acetate (4: 1) wash-out, obtain two components: component 1 is white oily matter dammarane-3 β, 12 β, 20,25-tetrol-3 β, 12 β-two ether (25.2%), component 2 is white solid dammarane-3 β, 12 β, 20,25-tetrol-12 β-single ether (47.3%).
Embodiment 3: preparation dammarane-3 β, 12 β, 20,25-tetrol-12 β-n-amylether
0.4g dammarane-3 β, 12 β, 20, the 25-tetrol adds 18ml DMF dissolving, adds 0.4g sodium hydride (60%).Sodium hydride all dissolves the back and adds the positive bromine alkane of 0.3ml bromo, is heated to 80 ℃, refluxes 5 hours.Add suitable quantity of water in the reaction solution, separate out oily matter, placement is spent the night.Inclining supernatant liquor, and chloroform extraction oily matter, extracting solution anhydrous magnesium sulfate drying are once used in washing.Removal of solvent under reduced pressure obtains faint yellow oily thing dammarane-3 β, 12 β, 20,25-tetrol-3 β, 12 β-n-amylether (89.5%).
Embodiment 4: preparation dammarane-3 β, 12 β, 20,25-tetrol-12 β-propionic ester
0.3g dammarane-3 β, 12 β, 20, the 25-tetrol adds 15ml DMF dissolving, adds the 0.5g propionyl chloride.Be cooled to 0 ℃.Under agitation drip the 0.3ml triethylamine.Drip to finish and shift out ice bath, continue reaction 5 hours.Removal of solvent under reduced pressure, the residue silica gel column chromatography is refining.Get dammarane-3 β with the chloroform wash-out, 12 β, 20,25-tetrol-12 β-propionic ester (45.9%).
Embodiment 5: preparation dammarane-3 β, 12 β, 20,25-tetrol-12 β-butyric ester and dammarane-3 β, 12 β, 20,25-tetrol-3 β-butyric ester
0.3g dammarane-3 β, 12 β, 20, the 25-tetrol adds 15ml DMF dissolving, adds the 0.5g butanic acid.Stir the solution under the DMF dissolving that adds DCC and DMAP down, drip Bi Jixu reaction 24 hours.Removal of solvent under reduced pressure adds acetic acid ethyl dissolution, filters, and filtrate is given a baby a bath on the third day after its birth inferior with 5% sodium bicarbonate, again with distillation washing five times, and removal of solvent under reduced pressure, the residue silica gel column chromatography obtains two components; Component 1 is white solid dammarane-3 β, 12 β, 20,25-tetrol-12 β-butyric ester (15.9%), component 2 is white solid dammarane-3 β, 12 β, 20,25-tetrol-3 β-butyric ester (33.9%) dammarane-3 β, 12 β, 20,25-tetrol-3 β-butyric ester nuclear magnetic resonance of carbon spectrum data:
13C-NMR (pyridine-d
5, 300MHz): δ 80.4 (C-3), 70.8 (C-12), 73.4 (C-20), 69.7 (C-25-OH); 50.8 (C-17), 22.9 (C-21), 44.1 (C-22), 38.6 (C-1), 28.1 (C-2), 38.1 (C-4), 56.4 (C-5), 18.5 (C-6), 35.1 (C-7), 40.1 (C-8), 50.3 (C-9), 37.2 (C-10), 32.2 (C-11), 49.3 (C-13), 51.8 (C-14), 31.5 (C-15), 26.7 (C-16), 16.3 (C-18-CH
3), 16.8 (C-19-CH
3), 18.7 (C-23), 45.6 (C-24), 30.0 (C-26-CH
3), 30.2 (C-27-CH
3), 24.1 (C-28-CH
3), 15.9 (C-29-CH
3), 17.4 (C-30-CH
3).
Embodiment 6: preparation dammarane-3 β, 12 β, 20,25-tetrol-12 β-n-caprylic acid ester and dammarane-3 β, 12 β, 20,25-tetrol-3 β-n-caprylic acid ester
0.3g dammarane-3 β, 12 β, 20, the 25-tetrol adds 15ml DMF dissolving, adds the 0.5g n-caprylic acid.Stir the solution under the DMF dissolving that adds DCC and DMAP down, drip Bi Jixu reaction 24 hours.Removal of solvent under reduced pressure adds acetic acid ethyl dissolution, filters, and filtrate is given a baby a bath on the third day after its birth inferior with 5% sodium bicarbonate, again with distillation washing five times, and removal of solvent under reduced pressure, the residue silica gel column chromatography obtains two components; Component 1 is white solid dammarane-3 β, 12 β, and 20,25-tetrol-12 β-n-caprylic acid ester (8.8%), component 2 is white solid dammarane-3 β, 12 β, 20,25-tetrol-3 β-n-caprylic acid ester (48.8%).Dammarane-3 β, 12 β, 20,25-tetrol-3 β-n-caprylic acid ester nuclear magnetic resonance of carbon spectrum data:
13C-NMR (pyridine-d
5, 300MHz): δ 80.4 (C-3), 70.7 (C-12), 73.4 (C-20), 69.7 (C-25-OH); 50.8 (C-17), 22.8 (C-21), 44.1 (C-22), 38.7 (C-1), 28.2 (C-2), 38.2 (C-4), 56.4 (C-5), 18.5 (C-6), 35.1 (C-7), 40.1 (C-8), 50.3 (C-9), 37.2 (C-10), 32.2 (C-11), 49.3 (C-13), 51.8 (C-14), 31.5 (C-15), 26.7 (C-16), 16.3 (C-18-CH
3), 16.8 (C-19-CH
3), 18.7 (C-23), 45.6 (C-24), 30.0 (C-26-CH
3), 30.2 (C-27-CH
3), 24.1 (C-28-CH
3), 15.9 (C-29-CH
3), 17.4 (C-30-CH
3).
Embodiment 7: preparation dammarane-3 β, 12 β, 20,25-tetrol-12 β-cetylate and dammarane-3 β, 12 β, 20,25-tetrol-3 β-cetylate
0.3g dammarane-3 β, 12 β, 20, the 25-tetrol adds 15ml DMF dissolving, adds the 0.5g palmitinic acid.Stir the solution under the DMF dissolving that adds DCC and DMAP down, drip Bi Jixu reaction 24 hours.Removal of solvent under reduced pressure adds acetic acid ethyl dissolution, filters, and filtrate is given a baby a bath on the third day after its birth inferior with 5% sodium bicarbonate, again with distillation washing five times, and removal of solvent under reduced pressure, the residue silica gel column chromatography obtains two components; Component 1 is white solid dammarane-3 β, 12 β, and 20,25-tetrol-12 β-cetylate (20.7%), component 2 is white solid dammarane-3 β, 12 β, 20,25-tetrol-3 β-cetylate (66.7%).Dammarane-3 β, 12 β, 20,25-tetrol-3 β-cetylate nuclear magnetic resonance of carbon spectrum data:
13C-NMR (pyridine-d
5, 300MHz): δ 80.4 (C-3), 70.8 (C-12), 73.4 (C-20), 69.8 (C-25-OH); 50.8 (C-17), 22.9 (C-21), 44.1 (C-22), 38.7 (C-1), 28.2 (C-2), 38.1 (C-4), 56.1 (C-5), 18.5 (C-6), 35.1 (C-7), 40.1 (C-8), 50.3 (C-9), 37.2 (C-10), 32.2 (C-11), 49.3 (C-13), 51.8 (C-14), 31.5 (C-15), 26.7 (C-16), 16.4 (C-18-CH3), 16.9 (C-19-CH
3), 18.7 (C-23), 45.6 (C-24), 30.0 (C-26-CH
3), 30.2 (C-27-CH
3), 24.1 (C-28-CH
3), 15.9 (C-29-CH
3), 17.4 (C-30-CH
3).
Dammarane-3 β, 12 β, 20,25-tetrol-12 β-cetylate nuclear magnetic resonance of carbon spectrum data:
13C-NMR (pyridine-d
5, 300MHz): δ 77.9 (C-3), 75.5 (C-12), 73.7 (C-20), 69.7 (C-25-OH);
Embodiment 8: preparation dammarane-3 β, 12 β, 20,25-tetrol-3 β, 12 β-two laurates
0.3g dammarane-3 β, 12 β, 20, the 25-tetrol, the 0.5g cinnamyl chloride adds the dissolving of 15ml pyridine, and the 0.25g Dimethylamino pyridine adds in the reflection bottle successively.Reacted 96 hours.Removal of solvent under reduced pressure adds acetic acid ethyl dissolution, filters, and filtrate is given a baby a bath on the third day after its birth inferior with 5% sodium bicarbonate, wash five times with distillation again, removal of solvent under reduced pressure, the residue silica gel column chromatography obtains dammarane-3 β, 12 β, 20,25-tetrol-3 β, 12 β-two laurates (50.3%).
Embodiment 9: preparation dammarane-3 β, 12 β, 20,25-tetrol-3 β, 12 β-two succinate monoesters
0.3g dammarane-3 β, 12 β, 20, the 25-tetrol, the 0.5g Succinic anhydried adds the dissolving of 15ml pyridine, and the 0.25g Dimethylamino pyridine adds in the reaction flask successively.95-100 ℃ of reaction 96 hours.Removal of solvent under reduced pressure adds acetic acid ethyl dissolution, filters, and filtrate is given a baby a bath on the third day after its birth inferior with 5% sodium bicarbonate, wash five times with distillation again, removal of solvent under reduced pressure, the residue silica gel column chromatography obtains dammarane-3 β, 12 β, 20,25-tetrol-3 β, 12 β-two succinate monoesters (65.9%).
Embodiment 10: preparation dammarane-3 β, 12 β, 20,25-tetrol-3 β, 12 β-biconjugate methoxy benzoic acid ester
0.3g dammarane-3 β, 12 β, 20, the 25-tetrol, the 0.35g anisoyl chloride added the dissolving of 15ml anhydrous pyridine, 60-70 ℃ of reaction 3 hours.Removal of solvent under reduced pressure adds acetic acid ethyl dissolution, filters, and filtrate is given a baby a bath on the third day after its birth inferior with 5% sodium bicarbonate, wash five times with distillation again, removal of solvent under reduced pressure, the residue silica gel column chromatography obtains dammarane-3 β, 12 β, 20,25-tetrol-3 β, 12 β-biconjugate methoxy benzoic acid ester (69.6%).
Embodiment 11: preparation dammarane-3 β, 12 β, 20,25-tetrol-3 β, 12 β-two nicotinates
0.3g dammarane-3 β, 12 β, 20, the 25-tetrol, 0.5g nicotinoyl chlorine hydrochloride added the dissolving of 15ml pyridine, 60-70 ℃ of reaction 3 hours.Be cooled to room temperature, add water 20ml, separate out thick thing, placement is spent the night, and water-yielding stratum inclines, use the chloroform extraction coagulum, anhydrous magnesium sulfate drying, removal of solvent under reduced pressure, the residue silica gel column chromatography obtains dammarane-3 β, 12 β, 20,25-tetrol-3 β, 12 β-two nicotinates (82.8%).
Embodiment 12: preparation dammarane-3 β, 12 β, 20,25-tetrol-3 β, 12 β-two succinate monoester disodium salts
0.10g dammarane-3 β, 12 β, 20,25-tetrol-3 β, 12 β-two succinate monoesters add the 15ml dissolve with ethanol, dripping 30% sodium hydroxide transfers PH to 7.0. to steam partial solvent, add the 25ml acetone precipitation, filter and separate out solid, dammarane-3 β, 12 β, 20,25-tetrol-3 β, 12 β-two succinate monoester disodium salts (70.9%).
Embodiment 13: preparation dammarane-3 β, 12 β, 20,25-tetrol-3 β, 12 β-phthalic monoester
0.3g dammarane-3 β, 12 β, 20, the 25-tetrol, the 0.6g Tetra hydro Phthalic anhydride added the dissolving of 15ml anhydrous pyridine, 90 ℃ of reactions 10 hours.Removal of solvent under reduced pressure adds acetic acid ethyl dissolution, filters, and filtrate is given a baby a bath on the third day after its birth inferior with 5% sodium bicarbonate, wash five times with distillation again, removal of solvent under reduced pressure, the residue silica gel column chromatography obtains dammarane-3 β, 12 β, 20,25-tetrol-3 β, 12 β-phthalic monoester. (75.9%).
Embodiment 14: preparation dammarane-3 β, 12 β, 20,25-tetrol-3 β, 12 β-biphosphonate
The dissolving of 15ml anhydrous pyridine is cooled to 0 ℃ with ice-water bath, drips the 0.3ml Phosphorus Oxychloride, add to add 0.3g dammarane-3 β again, and 12 β, 20, the 25-tetrol is dissolved in the pyridine solution, reacts 24 hours.Add water and stirred 5 hours, transfer PH=3, separate out white solid, filter the solid of separating out, use anhydrous alcohol solution, filter, filtrate adds elutriation and goes out white solid.Placed 48 hours, inclining supernatant liquor, and natural filtration after the vacuum-drying, obtains dammarane-3 β, 12 β, 20,25-tetrol-3 β, 12 β-biphosphonate.Embodiment 15: preparation dammarane-3 β, 12 β, 20,25-tetrol-3 β, 12 β-maleic acid monoesters
0.3g dammarane-3 β, 12 β, 20, the 25-tetrol is dissolved in the chloroformic solution, adds the 0.75g maleic anhydride, adds the 0.5g Dimethylamino pyridine, reacts 48 hours.Removal of solvent under reduced pressure, adding distil water is transferred PH=3 again, uses ethyl acetate extraction, is washed to neutrality.Extracting solution adds activated carbon decolorizing after with anhydrous sodium sulfate drying, filters, and steams solvent and gets crude product.The crude product silica gel column chromatography is used the chloroform-methanol wash-out, obtains dammarane-3 β, 12 β, 20,25-tetrol-3 β, 12 β-maleic acid monoesters embodiment 16: preparation dammarane-3 β, 12 β, 20,25-tetrol-12 β-single a-chloracetate and dammarane-3 β, 12 β, 20, the two a-chloracetates of 25-tetrol
0.3g dammarane-3 β, 12 β, 20, the 25-tetrol is dissolved in the anhydrous tetrahydrofuran solution, adds the 0.3g chloroacetyl chloride, drips the tetrahydrofuran solution of 0.3g triethylamine, generates white mist, and reaction solution is separated out white solid.At room temperature react complete to raw material.White solid is separated out in filtration.Removal of solvent under reduced pressure gets yellow liquid.The crude product silica gel column chromatography is used the chloroform wash-out, gets dammarane-3 β, 12 β, 20,25-tetrol-12 β-single a-chlorine capronate and dammarane-3 β, 12 β, 20, the two a-chloracetates (50.9%) of 25-tetrol.
Embodiment 17: preparation dammarane-3 β, and 12 β, 20,25-tetrol-20-is rare-12 β-a-(amantadine) acetic ester
0.3g dammarane-3 β, 12 β, 20,25-tetrol-12 β-a-chloracetate, the 0.15g Symmetrel, the 0.03g Tetrabutyl amonium bromide adds 5ml toluene, and 0.5g potassium hydroxide adds successively, and 60 ℃ of reactions 7 hours, placement was spent the night.Reactant adds 20ml toluene, and 20ml water is transferred PH=2, tells toluene layer, washes three times.Methylbenzene extraction thing evaporated under reduced pressure, the crude product silica gel column chromatography is used the chloroform wash-out, dammarane-3 β, 12 β, 20,25-tetrol-20-is rare-12 β-a-acetic ester (70.4%).
Embodiment 18: preparation dammarane-3 β, and 12 β, 20,25-tetrol-20-is rare-12 β-a-(endoxan) acetic ester
1.4g endoxan adds the dissolving of 15ml anhydrous tetrahydro furan, adds 0.12g sodium Metal 99.5 sheet and makes its whole dissolvings, adds 0.3g dammarane-3 β, 12 β, 20,25-tetrol-12 β-a-chloracetate, under agitation back flow reaction is 12 hours, filters and separates out solid, filtrate solvent evaporated, the crude product silica gel column chromatography, use the chloroform wash-out, get dammarane-3 β, 12 β, 20,25-tetrol-20-is rare-12 β-a-(endoxan) acetic ester (79.9%)
Embodiment 19: preparation dammarane-3 β, and 12 β, 20,25-tetrol-20-is rare-12 β-a-(5 FU 5 fluorouracil) acetic ester
0.35g 5 FU 5 fluorouracil adds the dissolving of 15ml dimethyl formamide, adds sodium hydride (60%), treat sodium hydride complete molten after, add 0.3g dammarane-3 β, 12 β, 20,25-tetrol-12 β-a-chloracetate dimethyl formamide solution was 60-70 ℃ of reaction 5 hours.Be cooled to room temperature, add water 20ml, use chloroform extraction, extracting solution washing secondary, anhydrous magnesium sulfate drying, removal of solvent under reduced pressure, the residue silica gel column chromatography gets dammarane-3 β, 12 β, 20,25-tetrol-20-is rare-12 β-a-(endoxan) acetic ester (60.9%).
Embodiment 20 dammarane-3 β, 12 β, 20, the test of 25-tetraalcohol derivative antitumour activity
To we synthetic dammarane-3 β, 12 β, 20,25-tetraalcohol derivative and part control compound are used existing 6 kinds of tumor cell line human leukemia cell line HL-60, Human Prostate Cancer Cells strain Du145, human colon cancer cell Colon205, the human lung cancer cell A549, human breast cancer cell MCF-7, human liver cancer cell HepG2 adopts classical mtt assay to carry out the anti-tumor activity test.
Main agents and major equipment: RMPI RPMI-1640 (available from Gibco); The high sugared nutrient solution (available from Gibco) of DMEM; DMEM low sugar nutrient solution (available from Gibco); Calf serum (available from Hyclone); Foetal calf serum (TBD company); Tetramethyl-azo azoles salt (MTT) U.S. Sigma (St.Louis, MO); Trypsin Biosharp); DMSO (Shenyang chemical reagent factory); NaCl (Shenyang chemical reagent factory); KCl (Shenyang chemical reagent factory); KH2PO3 (Shenyang chemical reagent factory); Na2HPO3 (Shenyang chemical reagent factory); NaHCO3 (Shenyang chemical reagent factory); Microplate reader (Austrian TECAN); 96 porocyte culture plates (Costar company).
Experimental technique: HL-60 cell strain, the Du145 cell strain, the culture condition of Colon205 cell strain is the RMPI RPMI-1640,10% foetal calf serum, the culture condition of MCF-7 cell strain is low sugar DMEM nutrient solution 10% foetal calf serum, the culture condition of HepG2 cell strain is high sugared DMEM nutrient solution 10% foetal calf serum, and the culture condition of A549 cell strain is the RMPI RPMI-1640,10% calf serum.Above cell strain all is incubated at 5%CO2, in 37 ℃ the incubator.Meal and paste are arranged in the natural product, and wherein, meal uses the DMSO dissolving, and paste uses anhydrous alcohol solution.Be made into the mother liquor that concentration is 50mmol/L, be stored in-20 ℃.
The RMPI RPMI-1640 of cell strain use serum-free is diluted to 1000umol/L with the mother liquor of medicine, 500umol/L, and 100umol/L, 10umol/L, every hole adds 10uL, makes that the final concentration of medicine is 100umol/L, 50umol/L, 10umol/L, 1umol/L.
Table 1 experimental compound is to the influence (%) of human breast cancer cell MCF-7 surviving rate (M ± SE)
The influence (%) of table 2 pair human liver cancer cell HepG2 cell survival rate (M ± SE)
The influence (%) of table 3 pair human prostate cell Du145 cell survival rate (M ± SE)
The influence (%) of table 4 pair human colon cancer cell Colon205 cell survival rate (M ± SE)
The table 5 first series natural product is to the influence (%) of human lung cancer cell A549's cell survival rate (M ± SE)
The influence (%) of table 6 pair human leukemia cell HL-60 cell survival rate (M ± SE)
Experimental result shows, anti tumor activity in vitro and dammarane-3 β of the derivative 1-3 for preparing by this patent method, and 12 β, 20, the 25-tetrol is compared remarkable enhancing.
Claims (8)
1, a kind of 20 (S) or 20 (R)-dammarane-3 β, 12 β, 20, the 25-tetraalcohol derivative is characterized in that: have following structure:
Wherein, R
1, R
2, R
3And R
4For alkyl, alkylene, fatty acyl group, aromaticacyl radical, assorted aromaticacyl radical, substituted aroma acyl group, di-carboxylic acid monoacyl M1OOC-M2-CO-, inorganic acidic group or-CO-(CH2) nR.
2, according to described 20 (S) of claim 1 or 20 (R)-dammarane-3 β, 12 β, 20, the 25-tetraalcohol derivative is characterized in that: the M2 among the described M1OOC-M2-CO-is alkylidene group, aromatic base, substituted aromatic base, heterocyclic radical, substituted heterocyclic radical or alkylene; M1 is H or alkali metal; The integer of n=1-20 among-CO-(CH2) nR, R are halogen or pharmaceutically acceptable anti-tumor activity group.
3, according to described 20 (S) of claim 1 or 20 (R)-dammarane-3 β, 12 β, 20,25 tetraalcohol derivatives is characterized in that:
Described alkyl is the alkyl with 1-20 carbon atom;
Described alkylene is the alkylene with 2-20 carbon atom;
Described fatty acyl group is the fatty acyl group with 1-20 carbon atom;
Described aromaticacyl radical is the aromaticacyl radical with 6 carbon atoms;
Described assorted aromaticacyl radical is the aromaticacyl radical with pyridine ring;
Described substituted aroma acyl group is to have the substituted aroma acyl group that has different substituents on the phenyl ring of aromaticacyl radical of 6 carbon atoms;
M2 among the described di-carboxylic acid monoacyl M1OOC-M2-CO-is the alkyl of C1-5 carbon atom or the alkylene that C2-5 carbon atom arranged;
Described inorganic acidic group is phosphate or sulfonic group;
Among described-CO-(CH2) nR, R is: mustargen, endoxan, 5 FU 5 fluorouracil, Rimantadine, purinethol, acyclovir, didanosine, fixed, the lamifudin of the many furans of department.
4, according to described 20 (S) of claim 3 or 20 (R)-dammarane-3 β, 12 β, 20,25 tetraalcohol derivatives is characterized in that: the substituting group in the described substituted aroma acyl group is hydroxyl, methoxyl group, amino or halogen; Substituent position is 2,3,4,5 of a phenyl ring, and single replacement of 6, two replacement or three replace.
5, according to claim 1 or 3 described 20 (S) or 20 (R)-dammarane-3 β, 12 β, 20, the 25-tetraalcohol derivative is characterized in that:
Described alkyl is methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl;
Described fatty acyl group is ethanoyl, propionyl, butyryl radicals, pentanoyl, caproyl, oenanthyl, capryloyl, nonanoyl, decanoyl, palmitoyl, unsaturated fatty acyl group; Described aromaticacyl radical is benzoyl, phenylacetyl, phenylpropenoyl;
Described substituted aroma acyl group is benzoyl, to methoxybenzoyl base, cinnamoyl, asafoetide acyl group;
Described assorted aromaticacyl radical is 2-pyridine formyl radical, 3-pyridine formyl radical, 4-pyridine formyl radical;
Described di-carboxylic acid monoacyl M1OOC-M2-CO-is Succinic Acid monoacyl, maleic acid monoacyl or phthalic acid monoacyl;
Among described-CO-(CH2) nR ,-(CH2) n is ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, ethanoyl, positive propionyl, propionyl, positive butyryl radicals.
6, a kind of 20 (S) or 20 (R)-dammarane-3 β, 12 β, 20, the salt of 25-tetraalcohol derivative is characterized in that: it is 20 (S) or 20 (R)-dammarane-3 β, 12 β, 20, the sylvite of 25-tetraalcohol derivative, sodium salt, ammonium salt, magnesium salts or calcium salt.
7,20 (S) or 20 (R)-dammarane-3 β, 12 β, 20, the pharmaceutical composition of 25-tetraalcohol derivative and salt thereof, it is characterized in that: said composition is with 20 (S) or 20 (R)-dammarane-3 β, 12 β, 20,25-tetraalcohol derivative and salt thereof are main component, and contain pharmaceutically acceptable carrier.
8,20 (S) or 20 (R)-dammarane-3 β, 12 β, 20, the application in preparation cancer therapy drug, antiviral of 25-tetraalcohol derivative and salt thereof.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102558270A (en) * | 2012-03-09 | 2012-07-11 | 辽宁新中现代医药有限公司 | 20(S) and 20(R)-dammarane-3beta,12beta,20,25-tetrol derivative and preparation method and application thereof |
| CN108314698A (en) * | 2017-01-17 | 2018-07-24 | 刘珂 | Protopanoxadiol sodium phosphate and its preparation and its independent or multiple medicine combine the application in treating nephrotic syndrome |
| CN110903340A (en) * | 2019-12-09 | 2020-03-24 | 沈阳药科大学 | Tetracyclic triterpene derivative, and pharmaceutical composition and application thereof |
| CN111690033A (en) * | 2020-07-05 | 2020-09-22 | 沈阳药科大学 | Dammarane sapogenin derivative, preparation method and application |
-
2008
- 2008-04-15 CN CNA2008100110311A patent/CN101250212A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102558270A (en) * | 2012-03-09 | 2012-07-11 | 辽宁新中现代医药有限公司 | 20(S) and 20(R)-dammarane-3beta,12beta,20,25-tetrol derivative and preparation method and application thereof |
| CN108314698A (en) * | 2017-01-17 | 2018-07-24 | 刘珂 | Protopanoxadiol sodium phosphate and its preparation and its independent or multiple medicine combine the application in treating nephrotic syndrome |
| CN110903340A (en) * | 2019-12-09 | 2020-03-24 | 沈阳药科大学 | Tetracyclic triterpene derivative, and pharmaceutical composition and application thereof |
| CN110903340B (en) * | 2019-12-09 | 2022-03-01 | 沈阳药科大学 | Tetracyclic triterpene derivative, and pharmaceutical composition and application thereof |
| CN111690033A (en) * | 2020-07-05 | 2020-09-22 | 沈阳药科大学 | Dammarane sapogenin derivative, preparation method and application |
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