CN1310898C - Taxinol water soluble derivative - Google Patents
Taxinol water soluble derivative Download PDFInfo
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- CN1310898C CN1310898C CNB2004100027227A CN200410002722A CN1310898C CN 1310898 C CN1310898 C CN 1310898C CN B2004100027227 A CNB2004100027227 A CN B2004100027227A CN 200410002722 A CN200410002722 A CN 200410002722A CN 1310898 C CN1310898 C CN 1310898C
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Abstract
The present invention relates to a water-solubility taxol derivative containing galactosyl or agmatine groups or heparin and a kind of taxol dimer connected by amino polyethyleneglycol. The derivatives have improved water-solubility, and simultaneously have definite tissue targeting performance. The present invention can be used as an effective antitumor medicine.
Description
Technical Field
The invention relates to a Taxol (Taxol) water-soluble derivative with anti-tumor activity and a preparation method thereof.
Background
Paclitaxel is a novel anticancer drug containing taxane extracted from Taxus plant. The unique anticancer mechanism makes it a hot spot for research on anticancer drugs in the world. The detection of national cancer research institute proves that the compound is the first stable anticancer drug with unique effect in the world. However, the water solubility of the taxol is poor, the solubility of the taxol in water is less than 0.004mg/ml, although the water solubility of the taxol can be improved by the aid of the cosolvent, the cosolvent has toxic and side effects of different degrees, and the severe anaphylactic reaction is often caused by the mixed use of the cosolvent and the taxol, so that the novel taxol derivative which is easily soluble in water, high in anticancer activity and low in toxic and side effects is obtained by modifying and modifying the chemical structure, and has important significance.
Disclosure of Invention
The invention relates to water-soluble taxol derivatives, including galactosylated taxol, agmatine-based taxol, heparin-modified taxol and taxol dimers.
Another aspect of the present invention relates to the preparation method of the above water-soluble paclitaxel derivative, which comprises reacting paclitaxel with corresponding acid anhydride and dicarboxylic acid halide to generate carboxylic acid paclitaxel, and then amidating with galactosylation agent or agmatine, respectively, or amidating with diamine and then reacting with heparin to generate corresponding water-soluble paclitaxel derivative, respectively. The taxol dimeris formed by the amide reaction of carboxylic acid acyl taxol and amino polyethylene glycol. The water solubility of paclitaxel is considerably improved by the above modification. And the taxol molecule is grafted with galactosyl, guanidine butylamino or heparin, has certain tissue targeting property, and can directionally act on target tissues through blood circulation after administration, so that the local medicine concentration is greatly improved, and the toxic and side effects of the taxol on other organs of the body are greatly reduced.
According to the invention, the water-soluble galactosylated taxol of the invention has the following general formula (I)
Wherein R is selected from: -CO- (CH)y)m-CO-NH-(CH2)n-NH-M，
or-CO- (CH)y)m-CO-NH-M', wherein
m＝1-6，
y is 1-2, y is not 1 only when m is 1,
n＝2-6，
m is
M' is
Wherein Ac ═ acetyl and Bz ═ benzoyl.
According to the present invention, preferred galactosylated paclitaxel has the above formula (I) wherein y is 2, m is 2, n is 2, more preferably y is 2, m is 2 and n is 3.
The water-soluble agmatine-based paclitaxel of the present invention has the following general formula (II):
wherein R1 and R3 are selected from-CO- (CH)y)m-CO-M and H,
r2 is selected from-CO- (CH)y)m-CO-M and Ac, wherein
m＝1-6，
y is 1-2, y is not 1 only when m is 1,
m is agmatine group
Only one of R1, R2 and R3 is-CO- (CH)y)m-CO-M。
According to the present invention, the preferred agmatinyl paclitaxel has formula (II) above, wherein y is 2 and m is 2.
According to the present invention, the heparin-modified paclitaxel has the following general formula (II):
wherein R1 and R3 are selected from-CO- (CH)y)m-CO-NH-(CH2)n-NH-M and H,
r2 is selected from-CO- (CH)y)m-CO-NH-(CH2)n-NH-M and Ac wherein
m＝1-6，
y is 1-2, y is not 1 only when m is 1,
n＝2-6，
m is heparin with a molecular weight range of 2000-30000,
only one of R1, R2 and R3 is-CO- (CH)y)m-CO-NH-(CH2)n-NH-M。
According to the present invention, preferred heparin-modified paclitaxel has formula (II) above, wherein y is 2, m is 2, n is 2, more preferably y is 2, m is 2, and n is 3.
The water-soluble taxol dimer has the following general formulas (III) to (V), and is characterized in that the dimer is formed by connecting taxol at the 2' position, the 7 position or the 10 position through a connecting arm:
wherein R is-CO- (CH)y)m-CO-, M is an aminated PEG.
Wherein m is 1-6,
y is 1-2, and y is not 1 only when m is 1.
A preferred paclitaxel dimer is one wherein M is PEG hydrazide
The water-soluble taxol derivative of the invention takes taxol as a raw material, and the taxol derivative is reacted with corresponding acid anhydride (such as succinic anhydride, glutaric anhydride and the like) or corresponding dicarboxylic acid halide (such as succinyl chloride, glutaryl chloride and the like) to generate the carboxylic acid acyl taxol. Then the carboxylic acid acyl taxol and galactosyl reagent or agmatine are subjected to amidation reaction to obtain corresponding galactosyl taxol and agmatine taxol; or, the carboxylic acid acyl paclitaxel is amidated with diamine and then reacts with sulfonic group in heparin to obtain heparin-modified paclitaxel; or amidation reaction between carboxylic acyl taxol and amino polyglycol to obtain taxol dimer.
According to the invention, galactosylated paclitaxel can be prepared as follows:
protecting 7-hydroxy of taxol with triethyl chlorosilane, reacting with corresponding acid anhydride or dicarboxylic acid halide to produce 2 '-carboxylic acid acyl taxol, reacting with prepared galactosylation reagent, and debenzylating to obtain 2' -galactosylation taxol.
In order to improve the activity of the galactosylation reagent when being connected with the carboxylic acyl taxol, the method introduces-NH2The synthetic route of (1). Galactosylating agents may introduce active-NH by lactonic lactone ring opening2Is obtained by reacting a derivative of lactose with a carboxamide, or by preparing a derivative of lactose and acidifying to form RNH2And obtaining the compound.
Agmatine-based paclitaxel can be prepared as follows:
2' -agmatine-based paclitaxel: the 7-hydroxyl of the taxol is protected by triethylchlorosilane, then the 7-hydroxyl is reacted with corresponding acid anhydride or dicarboxylic acid halide to generate 2 '-carboxylic acid acyl taxol, and the 2' -carboxylic acid acyl taxol is reacted with agmatine and then debenzylated to obtain the 7-agmatine taxol.
7-agmatine-based paclitaxel: firstly, triethylchlorosilane is used for protecting the hydroxyl at the 2' position of paclitaxel, then the triethylchlorosilane is reacted with corresponding acid anhydride or dicarboxylic acid halide to generate 7-carboxylic acid acyl paclitaxel, and the 7-guanidine butylamine-based paclitaxel can be obtained by debenzylation after the reaction with guanidine butylamine.
10-agmatine-based paclitaxel: firstly removing acetyl at 10-position of paclitaxel, respectively protecting hydroxyl at 2' -position and 7-position with triethylchlorosilane, then reacting with corresponding acid anhydride or dicarboxylic acid halide to generate 10-carboxylic acid acyl paclitaxel, reacting with agmatine, and removing benzyl to obtain 10-agmatine-based paclitaxel.
Heparin-modified paclitaxel can be prepared as follows:
2' -heparin-modified paclitaxel: the 7-hydroxyl of the paclitaxel is protected by triethylchlorosilane, then reacts with corresponding acid anhydride or dicarboxylic acid halide to generate 2 '-carboxylic acid acyl paclitaxel, then reacts with diamine, and finally reacts with heparin to remove benzyl to obtain the 2' -heparin modifiedpaclitaxel.
7-heparin-modified paclitaxel: firstly, triethylchlorosilane is used for protecting 2' -hydroxyl of paclitaxel, then the triethylchlorosilane is reacted with corresponding acid anhydride or dicarboxylic acid halide to generate 7-carboxylic acid acyl paclitaxel, then the 7-carboxylic acid acyl paclitaxel is reacted with diamine, and finally the 7-heparin modified paclitaxel can be obtained by debenzylation after the reaction with heparin.
10-heparin-modified paclitaxel: firstly removing acetyl at 10-position of paclitaxel, respectively protecting hydroxyl at 2' -position and 7-position with triethylchlorosilane, then reacting with corresponding acid anhydride or dicarboxylic acid halide to generate 10-carboxylic acid acyl paclitaxel, reacting with diamine, finally reacting with heparin, and removing benzyl to obtain 10-heparin modified paclitaxel.
The paclitaxel dimer can be prepared as follows:
2' -paclitaxel dimer: protecting 7-hydroxy of taxol with triethyl chlorosilane, reacting with corresponding acid anhydride or dicarboxylic acid halide to produce 2 '-carboxylic acid acyl taxol, reacting with aminated PEG, and debenzylating to obtain 2' -taxol dimer.
7-paclitaxel dimer: firstly, triethyl chloromethylsilane is used for protecting 2 '-hydroxyl of paclitaxel, then the 2' -hydroxyl is reacted with corresponding acid anhydride or dicarboxylic acid halide to generate 7-carboxylic acid acyl paclitaxel, and then the 7-paclitaxel dimer is obtained after the 7-carboxylic acid acyl paclitaxel reacts with amination PEG and debenzylation.
10-paclitaxel dimer: firstly removing acetyl at 10-position of paclitaxel, respectively protecting hydroxyl at 2' -position and 7-position with triethylchlorosilane, then reacting with corresponding acid anhydride or dicarboxylic acid halide to generate 10-carboxylic acid acyl paclitaxel, reacting with aminated PEG, and removing benzyl to obtain 10-paclitaxel dimer.
The invention also relates to a method for the electrolytic oxidation of sugars. In the preparation of the galactosylating agent, lactose is first oxidized to sodium lactobionate. The commonly adopted halogen oxidation method has the defects of low efficiency, long reaction time, high side reaction degree, more fed oxidant, more complex product purification and the like. Based on a halogen oxidation method, direct current is used for oxidizing halogen ions into halogen atoms on an anode of an electrolytic cell, nascent halogen atoms can be disproportionated in a weak alkaline environment to generate halogen ions and hypohalite ions, the hypohalite ions can oxidize hemiacetal hydroxyl of lactose to generate lactobionic acid and halogen ions, and the lactobionic acid finally exists in a sodium salt form. The reaction process is as follows:
anode:
cathode:
disproportionation:
and (3) oxidation: l + XO-＝HLA+X-
Salifying:
and (3) total reaction:
wherein X represents halogen, L represents sugar, and HLA represents sugar acid.
In this reaction, the halide salt is recycled by merely acting as a catalyst for the electron transfer agent, and the driving force for oxidation of lactose is the electrolysis current. The requirement for the halogen salt dosage in the reaction is not high, as long as the requirement for the cyclic utilization of electron transfer can be met. And the electrolytic oxidation method has low requirement on reaction temperature, does not need heating, has mild reaction conditions and few side reactions, and is beneficial to product purification.
Drawings
FIG. 1, FIG. 2, FIG. 3 and FIG. 4 are infrared spectra of products obtained in examples 3, 5, 6 and 7, respectively.
Detailed Description
Example 1
Synthesis of sodium lactobionate
1.8g (5mmol) of lactose and 0.4g (10mmol) of NaOH were put into a reaction flask, and a little water was added until the solid was completely dissolved. 0.8g (256. mu.L, 5mmol) of concentrated bromine water was added dropwise with stirring at 40 ℃. Reacting at 40 ℃ for 48 h. Excess Br2 was extracted with chloroform until the aqueous phase was colorless. The aqueous phase is adjusted to neutral or slightly alkaline with solid NaOH. The solution volume was reduced to around 20mL on a rotary evaporator. Adding Ag dropwise into the solution2SO4The solution was saturated hot until no AgBr precipitate was formed. Concentrated hydrochloric acid is dripped to remove excessive Ag+. The precipitate is removed by filtration or centrifugation. Placing the clear liquid in a rotating wayEvaporated to dryness on an evaporator to obtain 1.7g of a product with the yield of 89%.
Example 2
Synthesis of delta-lactobionicacid lactone
Adopts a glacial acetic acid co-heating reflux method. The lactobionate crude product 1.9g was dissolved in 10 times the mass of glacial acetic acid and heated to slight boiling while stirring on a glycerol bath. And reacting for 3 h. The reaction solution was cooled, precipitated with benzene and the product was washed. The precipitate was dried by suction to give 1.5g of the crude product of delta-lactonic lactone in 88% yield.
Example 3
Synthesis of ethylenediamine-tailed lactamide
Dissolving 1.7g delta-lactonic acid lactone crude product in a proper amount of anhydrous dimethyl sulfoxide, adding 30 times of ethylenediamine into the solution in N2The reaction is refluxed for 2h at 70 ℃ under protection. The liquid phase of the reaction liquid was transferred to another vessel, and chloroform was added dropwise to precipitate the product. The precipitate was collected by filtration and washed thoroughly with chloroform and drained. After washing with benzene and absolute ethyl alcohol several times, the mixture was evaporated to dryness. After the product is dissolved in water, the solution is passed through an acidic ion exchange resin. Most of the impurities such as pigment in the column were washed off with pure water. The sugar amine was eluted with 0.5mol/L ammonia water. The product solution was decompressed at 50 deg.CAnd (5) drying by distillation. Re-dissolving the product in water, decolorizing with active carbon, and filtering to obtain filtrate. The filtrate was evaporated to dryness at 50 ℃ under reduced pressure to give 1.62g of product in 81% yield.
TLC detection showed that the product spots developed color with both the sugar and amino color developers, indicating that the galactosylating agent had been primary aminated.
mp.112-116℃，
1H NMR(D2O)：3.03(2H，t，NH2-CH2-)，3.27(2H，t，CONH-CH2-), 3.48 to 4.18(12H, m, saccharide-H), 4.53(1H, d, 1-H).
The infrared identification result is shown in figure 1.
Example 4
Synthesis of 2' -succinyl monoester taxol
Into the reaction flask were charged 1.176g of paclitaxel and 151mg of succinic anhydride, and 6mL of anhydrous pyridine was added. Placing on a magnetic stirrer, stirring at room temperature, reacting, and sealing. Sampling is carried out at intervals of 30min from the beginning of the reaction for TLC detection, the sampling interval time of the intermediate reaction stage can be prolonged to 12h, and the sampling interval time is shortened near the end point. After the reaction was completed, pyridine was removed under reduced pressure at room temperature. The product was dissolved in 6mL of chloroform, and a suitable amount of a dilute hydrochloric acid solution of pH3.0 was added, and the mixture was washed a few times. The aqueous layer was removed and chloroform was removed under reduced pressure at room temperature to give 1.12g of the product in 85% yield.
1H NMR(CDCl3)：1.13(3H，s，17-Me)，1.22(3H，s，16-Me)，1.67(3H，s，19-Me)，1.78(3H，s，18-Me)，1.89(1H，m，6-H)，2.22(3H，s，-OAc)，2.40(3H，s，-OAc)，2.60(1H，m，6-αH)，3.79(1H，d，3-H)，4.21(1H，d，20-H)，4.31(1H，d，20-αH)，4.43(1H，dd，7α-H)，4.96(1H，d，5-αH)，5.53(1H，d，2-H)，5.68(1H，d，3’-H)，5.99(1H，dd，2’-H)，6.24(1H，d，13-H)，6.29(1H，s，10-H)，7.09(1H，d，3’-NH)，7.25～7.79(13H，m，brt，Ar-H)，8.12(2H，d，Ar-H)。
Example 5
Synthesis of ethylenediamine-tailed lactose amidated paclitaxel
50mg of 2' -succinyl paclitaxel was dissolved in 1mL of anhydrous DMSO, and 5. mu.L of ethyl chloroformate and 15. mu.L of triethylamine were added. And (3) sealing and stirring at room temperature for reaction for 10-60 min. 25mg of ethylenediamine-tailed lactamide was dissolved in several drops of DMSO in a cold water bath and added to the reaction system. After completion of the TLC detection reaction, pure water was added and the reaction system was frozen. Freeze drying and pumping out the solvent. The product was dissolved in methanol and separated by TLC on large plates using methanol as the chromatographic medium. After scraping off the corresponding silica gel layer, the adsorbed product was eluted with methanol. Adding pure water into the eluent until the eluent is slightly turbid, placing the eluent on a water bath at 55 ℃ for clarification, and then adding water until the eluent is slightly turbid. Placing in a fume hood for natural cooling, volatilizing methanol, and separating out recrystallization. The product crystals were recovered by suction filtration to give 58.1mg, 83% yield.
1H NMR(DMSO6)：1.12(3H，s，17-Me)，1.23(3H，s，16-Me)，1.49(3H，s，19-Me)，1.75(3H，s，18-Me)，1.79(1H，m，6-H)，2.11(3H，s，-OAc)，2.51(3H，s，-OAc)，2.65(1H，m，6-αH)，3.13(2H，t，NH2-CH2-)，3.59(2H，t，CONH-CH2-), 2.86 to 4.15(12H, m, saccharide-H), 3.60(1H, d, 3-H), 4.09(1H, d, 20-H), 4.57(1H, d, 20- α H), 4.63(1H, dd,7 α -H), 4.92(1H, d, 5- α H), 5.26(1H, d, saccharide-1-H), 5.34(1H, d, 2-H), 5.42(1H, d, 3 ' -H), 5.83(1H, dd, 2 ' -H), 6.28(1H, s, 10-H), 6.35(1H, d, 13-H), 7.17(1H, d, 3 ' -NH), 7.35 to 7.93(13H, m, brt, Ar-H), 8.00(2H,d，Ar-H)。
the infrared identification result is shown in figure 2.
Example 6
Synthesis of 1-lactosamine
36g of α -D-lactose (0.1mol) was taken with 250mL of saturated NH4HCO3Mixing the solutions, and standingThe reaction was carried out in a mouth vessel at 40 ℃. TLC detection tracking reaction is carried out every day, and NH is supplemented timely4HCO3Solid to maintain the saturation state of the solution. Reducing the volume of the solution at 40 ℃ under reduced pressure after TLC shows that the reaction is complete, adding distilled water for dilution, reducing the volume of the solution at 40 ℃ under reduced pressure, and repeating the steps for multiple times. And (4) putting the concentrated solution on a strong acid type ion exchange column. Washing residual sugar in the column by using pure water at 0-5 ℃. The sugar amine was eluted with 0.5mol/L ammonia water. Evaporated to dryness at 40 ℃ under reduced pressure. Re-dissolving the product in water, decolorizing with active carbon, and filtering to obtain filtrate. Adding isopropanol into the filtrate to precipitate the glucosamine, centrifuging at 3000rpm for 10min, and discarding the supernatant. The product was freeze dried to yield 31.3g of a tan solid in 87% yield.
The infrared identification result is shown in figure 3.
Example 7
Synthesis of 1-lactamic paclitaxel
Approximately 510mg of prepared 2' -succinylpaclitaxel was dissolved in 5mL of anhydrous DMSO in a 25mL round bottom flask and adjusted to pH 8-9 with TEMED. 174mg of 1-lactosamine and 146mg of EDC were added and the reaction was stirred at room temperature for 1 h. The reaction solution was transferred to a small beaker containing 2g of silica H. Mixing the reaction solution with silica gel, freezing at-20 deg.C, freeze drying overnight to remove solvent. And (3) performing pressurized column chromatography on the silica gel filler adsorbed with the product, wherein a column chromatography supporter is silica gel H, and an eluent is methanol. The eluates collected in the separate tubes were combined and methanol was removed under reduced pressure at 36 ℃ to give 556.7mg of a product with a yield of 80%.
1H NMR(DMSO6) 1.08(3H, s, 17-Me), 1.24(3H, s, 16-Me), 1.51(3H, s, 19-Me), 1.75(3H, s, 18-Me), 1.86(1H, m, 6-H), 2.11(3H, s, -OAc), 2.54(3H, s, -OAc), 2.66(1H, m, 6- α H), 2.98-4.14 (12H, m, saccharide-H), 3.62(1H, d, 3-H), 4.03(1H, d, 20-H), 4.56(1H, d, 20- α H), 4.83(1H, dd, 7 α -H), 4.92(1H, d, 5- α H), 5.33(1H, d, 2-H), 5.44(1H, d '-3-Me), 5.58H' -5H (1H, 2-H), 5.58-ddH, 1H, 5-32-ddH, 1H, 5-32-H, 1-ddl, 1H, 5.58-H, 1-H, 2-H, 5-H, 1-H, 5-HH)，6.37(1H，s，10-H)，7.19(1H，d，3’-NH)，7.38～7.92(13H，m，brt，Ar-H)，8.00(2H，d，Ar-H)。
The infrared identification result is shown in figure 4.
Example 8
Synthesis of paclitaxel dimer (2' position)
Approximately 450mg of prepared 2' -succinyl paclitaxel was dissolved in 5mL of anhydrous DMSO in a 25mL round bottom flask and adjusted to pH 8-9 with TEMED. 0.25mol of PEG hydrazide and 300mg of EDC were added and the reaction was stirred at room temperature for 1 h. The reaction solution was transferred to a small beaker containing 2g of silica H. Mixing the reaction solution with silica gel, freezing at-20 deg.C, freeze drying overnight to remove solvent. The silica gel filler adsorbed with the product is carried out pressurized column chromatography with the carrier being silica gel H and the eluent being methanol. The eluates collected in the separate tubes were combined and methanol was removed under reduced pressure at 36 ℃.
Example 9
Electrolytic oxidation method for synthesizing sodium lactobionate
Saturated NaHCO at 100mL3Adding 2g NaBr and 3.6g α -D-lactose monohydrate into the solution, feeding 12V direct current at room temperature, stirring and electrolyzing, performing electrolysis reaction for about 18h, and evaporating Br under reduced pressure at 40 DEG C2Then, the water was distilled off under reduced pressure at 60 ℃ until the volume of the solution became 20mL75 ℃ and the insoluble impurities were removed by filtration while it was hot. The filtrate was recrystallized twice from absolute ethanol to yield 3.6g of crude sodium lactobionate in 94% yield.
Claims (3)
1. A water-soluble derivative of paclitaxel represented by the following general formula (I):
wherein R is selected from: -CO- (CH)y)m-CO-NH-(CH2)n-NH-M，
or-CO- (CH)y)m-CO-NH-M', wherein
m＝1-6，
y＝2，
n＝2-6，
M is
M' is
Wherein Ac ═ acetyl and Bz ═ benzoyl.
2. The water-soluble derivative of paclitaxel according to claim 1, wherein m is 2 and n is 2 or 3.
3. A water-soluble derivative of paclitaxel according to claim 1 or 2, which is:
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| CN102552930B (en) * | 2011-10-28 | 2013-09-04 | 苏州大学 | Water-soluble paclitaxel derivative with cell targeting effect and preparation thereof |
| CN102731442B (en) * | 2012-07-18 | 2014-06-11 | 中国医学科学院生物医学工程研究所 | Preparation method and application of water-soluble docetaxel compounds |
| DK2924053T3 (en) | 2012-11-22 | 2020-12-14 | Glytech Inc | GLYCOSYLATED LINKS, CONNECTIONS CONTAINING GLYCOSYLED LINKS PART AND PHYSIOLOGICAL ACTIVE SUBSTANCE PART OR SALTS THEREOF, AND METHODS FOR THE PREPARATION OF THE CONNECTION OR |
| CN103641925B (en) * | 2012-11-27 | 2016-08-17 | 王晖 | Water solublity polysaccharide and the covalency polyacetylene compound of bearing taxanes, its preparation method and medical usage |
| CN106349193B (en) * | 2016-08-25 | 2019-01-25 | 中国科学院长春应用化学研究所 | Taxanes dimer, preparation method and its preparation |
| CN108409810A (en) * | 2018-03-30 | 2018-08-17 | 广州中医药大学(广州中医药研究院) | Bearing taxanes glycosylated derivative and its preparation method and application |
| EP3812376A4 (en) * | 2018-06-20 | 2022-08-17 | Santolecan Pharmaceuticals LLC | Paclitaxel-lipid-polysaccharide dual-type conjugate, preparation method therefor and use thereof |
| CN112250647A (en) * | 2020-06-30 | 2021-01-22 | 浙江大学 | Taxane prodrug, preparation method and application |
| CN115385875B (en) * | 2022-07-18 | 2023-06-13 | 中国药科大学 | Paclitaxel derivatives, and preparation method and application thereof |
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| CN1283619A (en) * | 2000-04-20 | 2001-02-14 | 复旦大学 | Water-soluble polyhydroxyl derivative of taxusol and its preparing process |
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| US6465625B1 (en) * | 1995-09-11 | 2002-10-15 | Albany Molecular Research, Inc. | Taxol derivatives |
| CN1288890A (en) * | 1999-09-17 | 2001-03-28 | 漆又毛 | Water soluble taxad alcohol derivative |
| CN1283619A (en) * | 2000-04-20 | 2001-02-14 | 复旦大学 | Water-soluble polyhydroxyl derivative of taxusol and its preparing process |
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