CN102030807B - Theasapogenol derivative with anti-HIV (Human Immunodeficiency Virus) activity, preparation method and application thereof - Google Patents
Theasapogenol derivative with anti-HIV (Human Immunodeficiency Virus) activity, preparation method and application thereof Download PDFInfo
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- CN102030807B CN102030807B CN 201010515917 CN201010515917A CN102030807B CN 102030807 B CN102030807 B CN 102030807B CN 201010515917 CN201010515917 CN 201010515917 CN 201010515917 A CN201010515917 A CN 201010515917A CN 102030807 B CN102030807 B CN 102030807B
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- 0 CC(C)(CC([C@@]1([C@]2*)C(O)=O)C3=CCC(C(C)(CC4)C(CC5)C(C)(C)[C@@]4OC(C)=O)C5(C)[C@]3(C)C[C@]1OC(C)=O)C2OC(C)=O Chemical compound CC(C)(CC([C@@]1([C@]2*)C(O)=O)C3=CCC(C(C)(CC4)C(CC5)C(C)(C)[C@@]4OC(C)=O)C5(C)[C@]3(C)C[C@]1OC(C)=O)C2OC(C)=O 0.000 description 3
Abstract
The invention discloses a theasapogenol derivative with anti-HIV (Human Immunodeficiency Virus) activity, a preparation method and application thereof. The theasapogenol derivative with anti-HIV activity has a structure disclosed as a formula I. The preparation method comprises the following steps of: (1) reacting the 4-dimethylaminopyridine with trityl chloride to obtain a compound a1, wherein theasapogenol as a raw material, and 4-dimethylaminopyridine is used as a catalyst in a pyridine solvent; (2) reacting the a1 with acetic anhydride by using the dimethylaminopyridine as the catalyst in an anhydrous pyridine solvent and adding sulfanilic acid pyridinium into a solution for reaction to obtain a compound a2; (3) oxidizing the a2 by using pyridinum chlorochromate salt to obtain a compound a3; (4) oxidizing the a3 by using NaClO2 and NaH2PO4 to obtain a4; and (5) hydrolyzing the a4 by using an aqueous solution of methanol and sodium hydroxide to obtain the theasapogenol derivative with anti-HIV activity disclosed as the formula I. The theasapogenol derivative has the advantages of high anti-HIV activity, simple preparation technology, high product purity, easy control of reaction conditions and industrial production.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to have the theasapogenol verivate and preparation method thereof and application of HIV-resistant activity.
Background technology
AIDS is since 1981 come to light in clinical, and velocity of propagation is exceedingly fast, and has every year 2100000 people to die from AIDS approximately, and newly-increased 2,500,000 HIV-positives.Yet up to now, AIDS remains the mortality communicable disease that can't cure, how to find a kind of medicine of effective inhibition virus of AIDS, has become the maximum problem that the medicine worker of the world today faces.
Traditional anti-AIDS drug is hiv protease, intergrase and RTI, but their bioavailabilities are low, and toxic side effect is strong, and is prone to produce resistance.From natural product, seek the important directions that the anti-AIDS active compound becomes anti-AIDS research.
In natural compounds, triterpene compound has shown excellent HIV-resistant activity.Peng Zhenhua etc. (the anti-HIV progress of triterpene compound, research and development of natural products, 2009,21,258-262) discuss pentacyclic triterpene saponins such as Oleanolic Acid, ursolic acid, Crategolic acid and had anti-preferably HIV effect.Therefore be the basis with the pentacyclic triterpene compound, the lead compound of synthetic a series of high-efficiency low-toxicities is that the discovery of anti-HIV new medicament provides bigger possibility.
Tea saponin is to be present in a kind of staple in tea seed or the tea seed, and it is made up of sapogenin, sugared body and organic acid three parts, is one type of oleanane type pentacyclic triterpene saponin compound, extensively is present in root, the stem of plant of theaceae: among leaf, flower, the fruit.It has antibiotic, anti-inflammatory, multiple biological activity such as antitumor, anti-oxidant.China is the country of high-yield tea-oil, and the content of saponin accounts for 12% in the tea seed, has bigger exploitation and is worth.
Theasaponin can obtain theasapogenol after hydrolysis, their structure is the pentacyclic triterpene chemicals, and basic framework is similar with Oleanolic Acid, is not used for the anti HIV experiment report but still there is it at present.
Summary of the invention
The shortcoming that primary and foremost purpose of the present invention is to overcome prior art is with not enough; Theasapogenol is carried out structural modification; It is water-soluble to improve it; Introduce the HIV-resistant activity group, a kind of theasapogenol verivate with HIV-resistant activity of high-efficiency low-toxicity is provided, for the development inverase provides potential lead compound.
Another object of the present invention is to provide above-mentioned preparation method with theasapogenol verivate of HIV-resistant activity.
A purpose more of the present invention is to provide above-mentioned application with theasapogenol verivate of HIV-resistant activity.
The object of the invention is realized through following technical proposals:
Theasapogenol verivate with HIV-resistant activity, its structure is suc as formula shown in the I:
(formula I)
Wherein: to be
R ' be-OH, amino acid chain NHR to R "; R " be that
n is 7.
Theasapogenol verivate with HIV-resistant activity comprises compound shown in the formula I and pharmaceutically acceptable acid or the formed additive salt of alkali.
Above-mentioned preparation method with theasapogenol verivate of HIV-resistant activity may further comprise the steps:
(1) being raw material with the theasapogenol, is that catalyzer and Tr-Cl (trityl chloride) reaction obtains compound a 1 with 4-Dimethylamino pyridine (DMAP) in pyridine solvent;
(2) a1 is catalyzer and acetic anhydride generation acetylization reaction with the Dimethylamino pyridine in the anhydrous pyridine solvent, in solution, adds PPTS (p-methyl benzenesulfonic acid pyridinium salt) again, and reaction obtains compound a 2;
(3) obtain compound a 3 with PCC (PCC drone salt) oxidation a2;
(4) use NaClO again
2And NaH
2PO
4Oxidation a3 obtains a4;
(5) use methyl alcohol, aqueous sodium hydroxide solution hydrolysis a4 obtains suc as formula the theasapogenol verivate with HIV-resistant activity shown in the I.
Sapogenol-A before the preferred tea of the described theasapogenol of step (1).
Step (5) can also be, a4 in ethylene dichloride (EDC)/1-hydroxy benzo triazole (HOBT) solvent with the reaction of L-leucine methyl esters, obtain compound b 1, b1 obtains suc as formula the theasapogenol verivate with HIV-resistant activity shown in the I 20～30 ℃ of following hydrolysis.
Step (5) can also be; A4 reacts with 4S-(the amino decoylamide of 8-)-3R-hydroxy-6-methylheptanoic acid benzene methyl in ethylene dichloride (EDC)/1-hydroxy benzo triazole (HOBT) solvent; Obtain compound c 1; C1 reacts with sodium hydroxide in methyl alcohol/tetrahydrofuran solvent, obtains suc as formula the theasapogenol verivate with HIV-resistant activity shown in the I.
Above-mentioned application with theasapogenol verivate of HIV-resistant activity is characterized in that: the theasapogenol verivate can combine to process the pharmaceutical prepn of anti-HIV with pharmaceutically acceptable carrier or pharmaceutical excipient.
The pharmaceutical prepn of said anti-HIV can be any of oral or injecting drug use formulation.
The pharmaceutical prepn of said anti-HIV can be the folk prescription or the compound preparation of theasapogenol verivate.
The present invention has following advantage and effect with respect to prior art:
(1) the present invention is raw material with the theasapogenol, and through after the derivatization treatment, the target compound HIV-resistant activity of acquisition is high.
(2) preparation technology of the present invention is simple, and reaction conditions is easy to control, and product purity is high, can be used for suitability for industrialized production.
Embodiment
Below in conjunction with embodiment the present invention is described in further detail, but embodiment of the present invention is not limited thereto.
Embodiment 1: synthetic suc as formula the compound shown in the II
(1) gets preceding sapogenol-A (5g, about 8.9mmol) of tea and 50mlDMF (N) and mix stirring and dissolving; Under argon shield, add TrCl (trityl chloride 18mmol) reaction, slowly add DMAP (the about 10mmol of 1.2g) catalyzed reaction again, 60 ℃ were reacted 2 hours.Reaction finishes, and the mixed solution dilute with water adds ETHYLE ACETATE again and extracts.Organic phase is used anhydrous magnesium sulfate drying, filters, and underpressure distillation gets thick product a1, and transformation efficiency is 98%.Crude product need not to purify and is used for next step reaction.
(2) get the dissolving of a1 (the about 8.7mmol of 7.3g) and anhydrous pyridine (50ml), add acetic anhydride 10ml again, slowly add DMAP (the about 10mmol of 1.2g), mixture at room temperature stirring reaction spends the night.Be refrigerated to 0 ℃ then, add 1N HCl (25ml).With ethyl acetate extraction 3 times (each 30ml), combining extraction liquid with saturated sodium bicarbonate solution and brine wash, is used anhydrous sodium sulfate drying, removes by filter SODIUM SULPHATE ANHYDROUS 99PCT, and vacuum concentration gets thick product, and need not to purify is used for next step reaction.
This crude product is dissolved in absolute ethyl alcohol (50ml), add then PPTS (7mg, 28mmol), mixture was 70 ℃ of stirring reactions 8 hours; Be cooled to room temperature, reduction vaporization falls solvent, in residue, adds cold water (50ml); With ethyl acetate extraction 3 times (each 50ml), combining extraction liquid is with saturated sodium bicarbonate solution and brine wash; Use anhydrous sodium sulfate drying, remove by filter SODIUM SULPHATE ANHYDROUS 99PCT, vacuum concentration gets crude product.Crude product is further purified by chromatography column (sherwood oil: ETHYLE ACETATE, 15: 1), gets white powder solid a2, and transformation efficiency is 80%.
(3) a2 (the about 6.8mmol of 4.98g) is dissolved in CH
2Cl
2(50ml), slowly add PCC (2.9g13.6mmol).Stir 40min under the reactant room temperature, in mixture, add silica gel, reduction vaporization falls solvent to doing, and residue is directly used purification by silica gel column chromatography (sherwood oil: ETHYLE ACETATE, 19: 1), obtains the aldehyde compound a3 of the preceding sapogenol-A of tea, and transformation efficiency is 92%.
(4) a3 (the about 6.1mmol of 4.5g) is dissolved in the solution of t-BuOH (50ml), THF (10ml) and 2-methyl-2-ethene (15ml), and pours this solution into NaH that 30ml has just prepared
2PO
4/ NaClO
2(1.5g/1.5g) in the aqueous solution, 0 ℃ keeps 15min, is placed on room temperature then, stirs 1 hour.Pour mixture in the ammonium chloride saturated solution (50ml).Use dichloromethane extraction, combining extraction liquid is with saturated sodium bicarbonate solution and brine wash; Use anhydrous sodium sulfate drying, remove by filter SODIUM SULPHATE ANHYDROUS 99PCT, concentrating under reduced pressure; Residue obtains white solid a4 through purification by silica gel column chromatography (sherwood oil: ETHYLE ACETATE, 12: 1), and transformation efficiency is 86%.
(5) with a4 (the about 5.2mmol of 3.9g) with 50ml MeOH dissolving, dropwise add 10ml4mol/L NaOH solution then, mixture was 40 ℃ of following stirring reactions 2 hours, mixture is used CH then
2Cl
2Extraction, the back is with 10%HCl and brine wash.Organic layer solution is used anhydrous sodium sulfate drying, removes by filter SODIUM SULPHATE ANHYDROUS 99PCT, and underpressure distillation gets crude product, gets white powder (compound shown in the formula II) through column chromatography (sherwood oil: ETHYLE ACETATE, 4: 1) purifying, and productive rate is 96%.
The Spectrum Analysis of product shows that MS:m/z 504, molecular formula: C
30H
48O
6,
13C NMR (DMSO) shows and has carboxyl carbon (d180.3) in its structure, and other displacement is identical with theasapogenol, and its structure is suc as formula shown in the II.
The concrete reaction scheme of present embodiment is following:
Embodiment 2: synthetic compound shown in formula III
(1) with a4 (the about 2mmol of 1.5g) and anhydrous CH
2Cl
2(20ml) mix, stirring and dissolving adds EDC (3mmol) and HOBT (3mmol), in this solution, adds L-leucine methyl esters (2.5mmol) then, stirred overnight, and solution is used CH
2Cl
2(50ml) extraction, CH
2Cl
2Layer water (50ml) given a baby a bath on the third day after its birth inferior, uses anhydrous MgSO
4Drying removes by filter SODIUM SULPHATE ANHYDROUS 99PCT, and concentrating under reduced pressure gets crude product, through purification by silica gel column chromatography, uses ETHYLE ACETATE and normal butane crystallization at last, gets b1, and productive rate is 96%.
(2) with b1 (the about 1mmol of 1.2g), MeOH (4ml) and THF (4ml) dissolving, in this solution, add 4N NaOH (2ml), wait reaction to finish after, mixture use hcl acidifying to pH be 4, with chloroform extraction three times (3 * 50ml), use anhydrous MgSO
4Drying removes by filter SODIUM SULPHATE ANHYDROUS 99PCT, and concentrating under reduced pressure gets crude product, through purification by silica gel column chromatography, uses ETHYLE ACETATE and normal butane crystallization at last, gets the compound shown in the formula III, and productive rate is 88%.
The Spectrum Analysis of product shows that MS:m/z 617, molecular formula: C
36H
59NO
7,
13C NMR (DMSO) shows existence 2 carbonyl carbon (d174.7,175.8) in its structure, and other displacement is identical with theasapogenol, and its structure is shown in formula III.
The concrete reaction scheme of present embodiment is:
Embodiment 3: synthetic suc as formula the compound shown in the IV
(1) with a4 (the about 2mmol of 1.5g) and anhydrous CH
2Cl
2(20ml) mix, stirring and dissolving adds EDC (3mmol) and HOBT (3mmol), in this solution, adds 4S-(the amino decoylamide of 8-)-3R-hydroxy-6-methylheptanoic acid benzene methyl (1.6mmol) then, stirred overnight, and solution is used CH
2Cl
2(50ml) extraction, CH
2Cl
2Layer water (50ml) given a baby a bath on the third day after its birth inferior, uses anhydrous MgSO
4Drying removes by filter SODIUM SULPHATE ANHYDROUS 99PCT, and concentrating under reduced pressure gets crude product, through purification by silica gel column chromatography, uses ETHYLE ACETATE and normal butane crystallization at last, gets c1, and productive rate is 96%.
(2) with c1 (the about 1mmol of 0.5g), MeOH (4ml) and THF (4ml) dissolving, in this solution, add 4N NaOH (2ml), wait reaction to finish after, mixture use hcl acidifying to pH be 4, with chloroform extraction three times (3 * 50ml), use anhydrous MgSO
4Drying removes by filter SODIUM SULPHATE ANHYDROUS 99PCT, and concentrating under reduced pressure gets crude product, through purification by silica gel column chromatography, uses ETHYLE ACETATE and normal butane crystallization at last, gets the compound shown in the formula IV, and productive rate is 88%.
The Spectrum Analysis of product shows that MS:m/z 802, molecular formula: C
46H
78N
2O
9,
13C NMR (DMSO) shows existence 3 carbonyl carbon (d173.8,175.8,176.2) in its structure, and other displacement is identical with theasapogenol, and its structure is suc as formula shown in the IV.
The concrete reaction scheme of present embodiment is:
Embodiment 4
(1) the theasapogenol verivate is to HIV cells infected toxicity test
Method: human T clone C8166, H9, chronic infection H IV-1
IIIBT clone H9/H IV-1
IIIB(from MRC A IDS Regent Project, UK).Above-mentioned cell in the RPM of 10% calf serum I-1640 substratum, 5%CO
2, cultivate under 37 ℃ of conditions.H IV-1 is by the H9/H IV-1 that cultivates
IIIBThe clone supernatant obtains ,-70 ℃ of preservations.Virus TC ID
50(tissue culture infective dose) measured with the Reed2Muench method.Initial virus titer is 9 * 10
5TC ID
50/ mL.
Theasapogenol verivate formula II, formula III and formula IV that embodiment 1～3 prepares with the DMSO dissolving, are made into the 10mg/mL working fluid before using, and are diluted to 100,20 with substratum, 4 μ g/mL and 4 concentration of 0.8 μ g/mL.The theasapogenol verivate adopts the MTT colorimetric method for determining to the cytotoxicity of C8166 clone.(cell density is 4 * 10 with 100 μ LC8166 cells
5/ mL) be inoculated in the 96 hole well plates, add 100 μ L different concns and tried the theasapogenol verivate, establish the blank that does not contain compound.5%CO
2, cultivate 72h under 37 ℃ of conditions, discard 100 μ L supernatants; Add 25 μ L MTT reagent (5mg/mL; PH 7.14PBS lysate) cultivates 4h, add 100 μ L50%DMF-10%SDS again, fully after the dissolving; Under 595nm and 630nm wavelength, measure A595/A630, the compound concentration CC when calculating cell survival rate and half cell survival through enzyme mark determinator
50(to half culturing cell toxigenicity time compound concentration).
The result sees table 1, and theasapogenol verivate formula II, formula III and formula IV all have cytotoxic effect to the human T cell of chronic infection HIV.
(2) the active inhibition of the anti-H IV of theasapogenol verivate tests
Method: (cell density is 4 * 10 with 50 μ LC8166
5/ mL) cell inoculation adds 100 μ L different concns theasapogenol verivate formula II, formula III and formula IV in 96 hole well plates, adds 50 μ L HIV-1 diluents (200TC ID50) again, mixes 5%CO
2, cultivate 72h under 37 ℃ of conditions, inverted microscope (100 *) detects the syncytial cell number down.Each concentration repeats 3 times, establishes the blank that does not contain the theasapogenol verivate, the positive medicine contrast of AZT.The inhibiting rate that syncytial cell forms calculates EC50 value (syncytial cell forms the compound concentration that half suppresses) with theasapogenol verivate formula II, formula III and formula IV substratum syncytial cell number of handling and the ratio value representation that infects control group syncytial cell number.
The result sees table 1, and theasapogenol verivate formula II, formula III and formula IV all have HIV-resistant activity, and be stronger with formula III and formula IV compound, and it is active suitable with AZT.
The cytotoxicity and the HIV-resistant activity of table 1 theasapogenol verivate
Embodiment 5
Get each 2g of theasapogenol verivate of embodiment 1-3, mix by 7: 2: 1 mixture 6g, 1% Magnesium Stearates with starch, lactose, crystalline cellulose respectively, process 3 kinds of theasapogenol verivate tablets through tabletting machine.Each tablet (1g) contains theasapogenol verivate 220mg, but 6～9 theasapogenol verivates of patient's solar eclipse tablet.
Embodiment 6
Get each 2g of theasapogenol verivate that embodiment 1-3 makes, add medical starch 6g respectively, mix, wet granulation is regulated with ethanol, makes loose particles and crosses 20 mesh sieves, dries.Drying is filled capsules afterwards, promptly gets the capsule of 3 kinds of theasapogenol verivates.Each capsule (1g) contains theasapogenol verivate 250mg, but 6～9 theasapogenol verivates of patient's solar eclipse capsule.
Embodiment 7
Get each 2g of theasapogenol verivate of embodiment 1-3, with after the Spheron MD 30/70 1000mL dissolving, pour into bottle respectively, process injection.Each injection (1ml) contains theasapogenol verivate 2mg, and the patient should inject 2～3ml theasapogenol verivate injection every day.
The foregoing description is a preferred implementation of the present invention; But embodiment of the present invention is not restricted to the described embodiments; Other any do not deviate from change, the modification done under spirit of the present invention and the principle, substitutes, combination, simplify; All should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (6)
1. have the theasapogenol verivate of HIV-resistant activity, it is characterized in that: said theasapogenol verivate has suc as formula the structure shown in the I:
(formula I)
Wherein, said R is that
said R ' is-OH or amino acid chain NHR "; Said R " be that
n is 7.
2. the said preparation method with theasapogenol verivate of HIV-resistant activity of claim 1 is characterized in that may further comprise the steps:
(1) being raw material with the theasapogenol, is that the reaction of catalyzer and trityl chloride obtains compound a 1 with the 4-Dimethylamino pyridine in pyridine solvent;
(2) a1 is catalyzer and acetic anhydride generation acetylization reaction with the Dimethylamino pyridine in the anhydrous pyridine solvent, in solution, adds the p-methyl benzenesulfonic acid pyridinium salt again, and reaction obtains compound a 2;
(3) obtain compound a 3 with PCC drone salt oxidation a2;
(4) use NaClO again
2And NaH
2PO
4Oxidation a3 obtains a4;
(5) use methyl alcohol, aqueous sodium hydroxide solution hydrolysis a4 obtains suc as formula the theasapogenol verivate with HIV-resistant activity shown in the I; Perhaps, a4 reacts with L-leucine methyl esters in ethylene dichloride/1-hydroxy benzo triazole solvent, obtains compound b 1, and b1 obtains suc as formula the theasapogenol verivate with HIV-resistant activity shown in the I 20～30 ℃ of following hydrolysis; Again perhaps; React with 4S-(the amino decoylamide of 8-)-3R-hydroxy-6-methylheptanoic acid benzene methyl in ethylene dichloride/1-hydroxy benzo triazole solvent with a4; Obtain compound c 1; C1 reacts with sodium hydroxide in methyl alcohol/tetrahydrofuran solvent, obtains suc as formula the theasapogenol verivate with HIV-resistant activity shown in the I;
Described theasapogenol is to have suc as formula sapogenol-A before the tea of structure shown in the V,
(formula V);
The structure of said compound a 1, compound a 2, compound a 3, compound a 4, compound b 1 and compound c 1 is as follows:
In the structure of said compound a 1, compound a 2, compound a 3, compound a 4, compound b 1 and compound c 1, Tr is a trityl.
3. according to the said preparation method of claim 2, it is characterized in that with theasapogenol verivate of HIV-resistant activity:
Said a3 and NaClO
2Be to participate in reaction with 3: 1 mass ratio;
Said a3 and NaH
2PO
4Be to participate in reaction with 3: 1 mass ratio.
4. the said application with theasapogenol verivate of HIV-resistant activity of claim 1 is characterized in that: said theasapogenol verivate and pharmaceutically acceptable carrier or pharmaceutical excipient combine to process the pharmaceutical prepn of anti-HIV.
5. according to the said application with theasapogenol verivate of HIV-resistant activity of claim 4, it is characterized in that: said pharmaceutical prepn is oral or injecting drug use formulation any.
6. according to the said application with theasapogenol verivate of HIV-resistant activity of claim 4, it is characterized in that: said pharmaceutical prepn is the folk prescription or the compound preparation of theasapogenol verivate.
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| CN114874281B (en) * | 2022-01-27 | 2023-09-26 | 贵州医科大学 | Oleanolic acid derivative and preparation method and application thereof |
| CN114950480B (en) * | 2022-07-06 | 2023-06-27 | 西北大学 | Carbon-based solid acid catalyst and method for preparing tea sapogenin by catalyzing tea saponin by using carbon-based solid acid catalyst |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101747403A (en) * | 2009-12-31 | 2010-06-23 | 江南大学 | Method for extracting tea saponin from camellia seed meal |
| CN101747401A (en) * | 2009-12-23 | 2010-06-23 | 中华全国供销合作总社杭州茶叶研究所 | Novel method for preparing high-purity tea saponin |
| CN101863949A (en) * | 2010-05-25 | 2010-10-20 | 青田中野天然植物科技有限公司 | Structural modification type cameclia oleifera saponin and preparation method and application thereof |
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| CN101747401A (en) * | 2009-12-23 | 2010-06-23 | 中华全国供销合作总社杭州茶叶研究所 | Novel method for preparing high-purity tea saponin |
| CN101747403A (en) * | 2009-12-31 | 2010-06-23 | 江南大学 | Method for extracting tea saponin from camellia seed meal |
| CN101863949A (en) * | 2010-05-25 | 2010-10-20 | 青田中野天然植物科技有限公司 | Structural modification type cameclia oleifera saponin and preparation method and application thereof |
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