CN114437128B - Choline phosphate modified taxol medicine and preparation method and application thereof - Google Patents

Choline phosphate modified taxol medicine and preparation method and application thereof Download PDF

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CN114437128B
CN114437128B CN202210107371.4A CN202210107371A CN114437128B CN 114437128 B CN114437128 B CN 114437128B CN 202210107371 A CN202210107371 A CN 202210107371A CN 114437128 B CN114437128 B CN 114437128B
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choline
taxol
choline phosphate
paclitaxel
drug
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CN114437128A (en
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于喜飞
李晟冉
刘三荣
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Changchun Institute of Applied Chemistry of CAS
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    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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Abstract

The invention provides a choline phosphate modified taxol drug which has a structure shown in a formula I. The choline phosphate group of the choline phosphate taxol has extremely strong hydrophilicity, can obviously improve the water solubility of taxol medicaments and realizes the injection administration of the taxol medicaments; meanwhile, the choline phosphate group has stronger protein adsorptivity, and can enhance the circulation time of taxol in vivo; the linking group, such as glycine, forms an ester bond with paclitaxel, which can be cleaved by esterase in the tumor area environment, so that the drug property of paclitaxel is recovered, and the aim of targeted elimination of cancer cells is fulfilled.

Description

Choline phosphate modified taxol medicine and preparation method and application thereof
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a choline phosphate modified paclitaxel drug and a preparation method and application thereof.
Background
Paclitaxel (PTX) is a natural product extracted from bark of Taxus brevifolia, and can also be obtained by semisynthetic method. Paclitaxel binds to cell tubulin, promotes tubulin aggregation and inhibits dissociation thereof, and cells cannot divide normally, causing cell cycle arrest and apoptosis. Paclitaxel is a broad-spectrum antitumor drug for treating breast cancer, ovarian cancer, non-small cell lung cancer and the like, and has remarkable curative effect. However, taxol is almost insoluble in water, and taxol injection as a clinical common preparation uses a mixed solution of polyoxyethylated castor oil and absolute ethyl alcohol as a solvent, and the use of the nonaqueous solvent can cause serious anaphylactic reaction; in order to reduce the generation of anaphylactic reaction, the patients need to be subjected to desensitization pretreatment by medicaments such as dexamethasone, diphenhydramine and the like before injecting paclitaxel, so that the burden of the patients and medical staff is increased; in addition, paclitaxel lacks targeting, and is extremely prone to cause systemic adverse reactions such as neutropenia and neurological diseases. Therefore, from the clinical application of paclitaxel, structural modification, reformation and formulation reformation of paclitaxel have been paid attention to at home and abroad.
The structural modification of taxol mainly uses different chemical groups to synthesize taxol structural analogues with different substituents; the modification of the dosage form mainly refers to physical coating of paclitaxel by using amphoteric high molecular polymer to form nano micelle, nano capsule or nano particle. The structural modification of taxol mainly refers to that small molecules or macromolecular compounds are connected on the radical of taxol through chemical bonds to generate conjugates, and the conjugates are hydrolyzed in vivo to release taxol again, so that the antitumor effect of taxol proto-drugs is exerted. Currently, there are still numerous structural modifications of paclitaxel in preclinical or clinical trials. The functions of the modification groups and the structural composition of the connecting fragments influence the release of the paclitaxel and the uptake of tumor cells, so that the development of a novel paclitaxel medicament with high efficiency, low toxicity and targeting effect is urgently needed in clinical tumor treatment.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a choline phosphate modified paclitaxel drug, a preparation method and an application thereof, wherein the prepared choline phosphate modified paclitaxel drug has high water solubility, in vivo circulation time and tumor targeting capability.
The invention provides a choline phosphate modified taxol drug which has a structure shown in a formula I:
wherein R is selected from substituted or unsubstituted C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C3-C8 epoxy, C2-C8 azido, C1-C8 amino, residue left after any hydroxyl is removed from polyalcohol substances or selected protecting groups;
m isOr O;
when M isWhen L is selected from amino acid residues;
when M is O, L is selected from the residues of carboxylic acids and derivatives thereof.
In the present invention, the carboxylic acid and its derivative have at least two carboxyl groups.
In the present invention, R is a group whose choline phosphate terminal can be further modified, preferably a substituted or unsubstituted C1-C8 alkyl group, a C3-C8 alkenyl group, a C3-C8 alkynyl group, a C3-C8 epoxy group, a C2-C8 azide group, a C1-C8 amino group, a residue remaining after any hydroxyl group is removed from a polyhydric alcohol substance, or a protecting group is selected.
The above substituent group is preferably a fluorine-substituted C1-C8 alkyl group, a C3-C8 alkenyl group, a C3-C8 alkynyl group, a C3-C8 epoxy group, a C3-C8 azide group, a C3-C8 amino group or a fluorine-substituted polyol.
More preferably, R is selected from the group consisting of C1-C5 alkyl, C3-C5 alkenyl, C3-C5 alkynyl, C3-C5 epoxy, C2-C5 azide, C1-C5 amino, and C3-C5 alcohol, the residue remaining after any hydroxy group has been removed.
Further preferably, R is selected from the group consisting of methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, tert-butyl, allyl, propargyl, N 3 -(CH 2 ) 2 -、N 3 -(CH 2 ) 3 -、N 3 -(CH 2 ) 4 -、NH 2 CH 2 -、NH 2 (CH 2 ) 2 -、NH 2 (CH 2 ) 3 -、NH 2 (CH 2 ) 4 -、BOC-NH(CH 2 ) 2 -、BOC-NH(CH 2 ) 3 -、BOC-NH(CH 2 ) 4 、HO-(CH 2 ) 2 -、HO-(CH 2 ) 3 -、HO-(CH 2 ) 4 -、HO-(CH 2 ) 5 -、HO-(CH 2 ) 2 -O-(CH 2 ) 2 -。
In the invention, L is a group connecting choline phosphate with paclitaxel, one end of L reacts with the hydroxyl of paclitaxel, and the other end reacts with choline phosphate group. And M is a modified group of choline phosphate, and can react with amino or carboxyl, and the choline phosphate is reacted with L as a reactive group so as to be connected with taxol.
When M isWhen L is preferably a glycine, alanine, serine, threonine, aspartic acid, glutamic acid, lysine or arginine residue; the above residue refers to the residue left after the amino group of the amino acid loses one hydrogen atom and the carboxyl group loses one OH. The ester end and the choline phosphate end in the M are connected, the ethyl end is connected with the amino group of the amino acid residue, and the carbonyl end of the amino acid residue is connected with the oxygen atom of the taxol.
When M is O, L is preferably the residue of succinic acid, glutaric acid, adipic acid, 3' -dithiodiacetic acid, 3' -dithiodipropionic acid, 3' -dithiodibutyric acid, diglycolic acid, triglycolic acid or tetraglycol acid; the above residue refers to the residue left after the two carboxyl groups of the carboxylic acid and its derivative, respectively, lose OH.
Specifically, when M isWhen L is selected from any one of the following structures:
when M is O, L is selected from any one of the following structures:
in some embodiments of the invention, the choline phosphate modified paclitaxel drug has any one of the following structures:
the invention provides a preparation method of a choline phosphate modified taxol medicament, which comprises the following steps:
reacting the acryloyloxyethyl choline ethyl phosphate, the taxol and the amino acid to obtain the choline phosphate modified taxol medicine.
The structural formula of the acryloyloxyethyl choline ethyl phosphate is as follows:
the invention provides a preparation method of a choline phosphate modified taxol medicament, which comprises the following steps:
and (3) reacting hydroxyethyl choline ethyl phosphate, taxol and carboxylic acid or derivatives thereof to obtain the choline phosphate modified taxol medicament.
The structural formula of the hydroxyethyl choline ethyl phosphate is as follows:
in the preparation process, the reaction of taxol and the connecting group L and the acryloyloxyethyl choline ethyl phosphate can be prepared by a one-step method. The hydroxyl on the C-2' locus of the taxol and the carboxyl on the connecting group L are subjected to esterification reaction, and simultaneously, the amino on the connecting group L and the acrylic ester double bond on the choline phosphoric acid are subjected to Michael addition reaction. In the invention, DMAP and DIC are preferably used as catalysts, the reaction is carried out for 48 hours at room temperature under the protection of nitrogen, and the final product is obtained through column chromatography after the reaction is finished. Similarly, the reaction of paclitaxel with the linking group L and hydroxyethyl choline ethyl phosphate can also be carried out in a single step, preferably with DMAP, DIC as catalyst, preferably at room temperature, preferably for 24 hours, preferably by precipitating the product in tetrahydrofuran after the end of the reaction and drying.
Experimental results show that the taxol modified by the choline phosphate has good water solubility and biocompatibility, and the L group can be broken under the slightly acidic condition of a tumor area and an enzyme environment, so that the cytotoxicity of the taxol is recovered, and the targeted killing of tumor cells is realized.
The invention provides application of the choline phosphate modified taxol medicament or the choline phosphate modified taxol medicament prepared by the preparation method in preparation of anticancer medicaments. More preferably in the preparation of targeted anticancer drugs.
Preferably, the anticancer drug is a drug for resisting breast cancer and ovarian cancer.
Compared with the prior art, the invention provides a choline phosphate modified taxol medicament with a structure shown in a formula I. The choline phosphate group of the choline phosphate taxol has extremely strong hydrophilicity, can obviously improve the water solubility of taxol medicaments and realizes the injection administration of the taxol medicaments; meanwhile, the choline phosphate group has stronger protein adsorptivity, and can enhance the circulation time of taxol in vivo; the linking group, such as glycine, forms an ester bond with paclitaxel, which can be cleaved by esterase in the tumor area environment, so that the drug property of paclitaxel is recovered, and the aim of targeted elimination of cancer cells is fulfilled.
Drawings
FIG. 1 nuclear magnetic resonance hydrogen and phosphorus spectra of choline phosphotaxol with glycine as the linking group;
FIG. 2 mass spectrum of choline phosphotaxol with glycine as the linking group;
FIG. 3 nuclear magnetic resonance hydrogen and phosphorus spectra of phosphocholine paclitaxel with lysine as the linking group;
FIG. 4 mass spectrum of phosphocholine paclitaxel with lysine as the linking group;
FIG. 5 nuclear magnetic resonance hydrogen and phosphorus spectra of choline phosphotaxol with succinic acid as the linking group;
FIG. 6 mass spectrum of phosphocholine paclitaxel with succinic acid as the linking group;
FIG. 7 results of cytotoxicity test of paclitaxel choline phosphate on mouse fibroblasts (NIH-3T 3) and mouse breast cancer cells (4T 1);
FIG. 8 results of a hemolysis test of paclitaxel choline phosphate;
FIG. 9 results of biopsied test of phosphocholine paclitaxel on mouse fibroblasts (NIH-3T 3) and mouse breast cancer cells (4T 1).
Detailed Description
In order to further illustrate the present invention, the following describes in detail the choline phosphate modified paclitaxel drug provided by the present invention, and the preparation method and application thereof.
EXAMPLE 1 preparation of Choline Phosphoxepixel drug with amino acid as linking group
Triethylamine (51 g,0.51 mol) and absolute ethyl alcohol (22 g,0.5 mol) are added into a branched flask filled with 300mL of absolute tetrahydrofuran, magnetic stirring is carried out under the protection of nitrogen, after the mixture is cooled in an ice water bath for 30 minutes, 2-chloro-2-oxo-dioxaphospholane (71 g,0.5 mol) is added dropwise from a constant pressure dropping funnel, a large amount of white precipitate is generated in the reaction system during the dropwise adding process, the mixture is slowly warmed to room temperature after the ice water bath is kept for 2 hours after the dropwise adding process is completed within 1 hour, the reaction is continued for 2 hours, the filtration and the absolute tetrahydrofuran washing filter cake are carried out twice, the filtrate is combined and collected, the solvent is removed under reduced pressure, and crude products are obtained, and the crude products are distilled through a short neck, thus obtaining pure 2-oxyethyl-2-oxo-dioxaphospholane (COP) with the yield of 65 percent. The product structure is as follows:
1 H-NMR(500MHz,CDCl 3 ):4.44-4.35(m,-OCH 2 CH 2 O-)，4.15(m,-OCH 2 CH 3 )，1.41(t,-OCH 2 CH 3 )； 31 P-NMR(500MHz,CDCl 3 ):δ(ppm)17.60(s).
COP (5.41 g,30 mmol), ethyl 2- (dimethylamino) methacrylate (5.2 g,33 mmol) and 100mg polymerization inhibitor BHT were added to a 100 mL flask containing 50mL of anhydrous acetonitrile, heated to 70 ℃ for reaction for 56 hours, after the reaction was completed, the solution was precipitated three times in 500mL of tetrahydrofuran solution, and finally tetrahydrofuran was removed to obtain 5.6g of ethyl choline ethyl acryloyloxyphosphate product, yield 63%, product structure was as follows:
1 H-NMR(500MHz,D 2 O):6.43 and 6.21(d and m,-OCCH＝CH 2 )，6.03(d,-OCCH＝CH 2 )，4.64(t,-CH 2 O-CO-)，4.29(t,-CH 2 OP)，3.86(m,-CH 2 N(CH 3 ) 2 -CH 2 -)，3.74(d,P-OCH 2 -CH 2 -)，3.25(s,-N-(CH 3 ) 2 )，1.25(t,P-OCH 2 -CH 3 )； 31 P-NMR(500MHz,D 2 O):δ(ppm)0.06(s).
paclitaxel (2.0 g,2.34 mmol), acryloyloxyethyl choline ethyl phosphate (0.7 g,2.34 mmol) and glycine (0.18 g,2.34 mmol) were added to a 100 mL flask containing 30mL of anhydrous acetonitrile, reacted at room temperature for 48 hours, after the reaction was completed, the solution was precipitated three times in 500mL of tetrahydrofuran solution, and finally tetrahydrofuran was removed to obtain 1.73g of choline phosphotaxol with glycine as a linking group, yield 60%, product structure was as follows:
1 H-NMR(500MHz,CDCl 3 ):7.3-8.2(d,m,-C 6 H 5 -),6.25(d,-NH-CH-CH-),5.8(d,-NH-CH-CH-),5.7(d,-C＝C-CH-O-),5.0(s,-C-CH 2 -O-),4.64(t,-CH 2 O-CO-),4.29(t,-CH 2 OP),4.4(t,-O-CH-C-),4.0(d,C-CH-O-),3.86(m,-CH 2 N(CH 3 ) 2 -CH 2 -),3.8(-C-CH-OH-),3.74(d,P-OCH 2 -CH 2 -),3.25(s,-N-(CH 3 ) 2 ),1.25(t,P-OCH 2 -CH 3 ),2.4(s,-C-CH 3 ),2.3(t,-CH-CH 2 -C-OH),2.2(s,-OOC-CH 3 ),1.75(s,-OOCCH 3 ),1.7(s,-C＝C-CH 3 ),1.6(m,-CH-CH 2 -CH-),1.25(s,-CO-C-CH 3 ),1.24(s,-C＝C-C-CH 3 )； 31 P-NMR(500MHz,CDCl 3 ):δ(ppm)-1.9(s).
the nuclear magnetic resonance hydrogen spectrum and the phosphorus spectrum of the choline phosphotaxol with glycine as the connecting group are shown in figure 1, and the mass spectrum is shown in figure 2.
Paclitaxel (2.0 g,2.34 mmol), acryloyloxyethyl choline ethyl phosphate (0.7 g,2.34 mmol) and lysine (0.34 g,2.34 mmol) were added to a 100 mL flask containing 30mL of anhydrous acetonitrile, reacted at room temperature for 48 hours, after the reaction was completed, the solution was precipitated three times in 500mL of tetrahydrofuran solution, and finally tetrahydrofuran was removed to obtain 1.73g of choline phosphotaxol with lysine as a linking group, yield 60%, product structure as follows:
1 H-NMR(500MHz,CDCl 3 ):7.3-8.2(d,m,-C 6 H 5 -),6.25(d,-NH-CH-CH-),5.8(d,-NH-CH-CH-),5.7(d,-C＝C-CH-O-),5.0(s,-C-CH 2 -O-),4.64(t,-CH 2 O-CO-),4.29(t,-CH 2 OP),4.4(t,-O-CH-C-),4.0(d,C-CH-O-),3.86(m,-CH 2 N(CH 3 ) 2 -CH 2 -),3.8(-C-CH-OH-),3.74(d,P-OCH 2 -CH 2 -),3.25(s,-N-(CH 3 ) 2 ),1.25(t,P-OCH 2 -CH 3 ),2.4(s,-C-CH 3 ),2.3(t,-CH-CH 2 -C-OH),2.2(s,-OOC-CH 3 ),1.75(s,-OOCCH 3 ),1.7(s,-C＝C-CH 3 ),1.6(m,-CH-CH 2 -CH-),1.25(s,-CO-C-CH 3 ),1.24(t,-NH-(CH 2 ) 4 -CH-)； 31 P-NMR(500MHz,CDCl 3 ):δ(ppm)-1.9(s).
the nuclear magnetic resonance hydrogen spectrum and the phosphorus spectrum of the choline phosphotaxol with lysine as the connecting group are shown in figure 3, and the mass spectrum is shown in figure 4.
EXAMPLE 2 preparation of Choline Phosphoxepixel drug with succinic acid as the linking group
The procedure for the preparation of 2-oxyethyl-2-oxo-dioxaphospholane (COP) was as in example 1.
COP (5.41 g,30 mmol) and dimethylaminoethanol (2.94 g,33 mmol) were added to a 100 mL flask containing 50mL anhydrous acetonitrile, heated to 70℃for 56 hours, after completion of the reaction the solution was precipitated three times in 500mL tetrahydrofuran solution and finally tetrahydrofuran was removed to give 5.6g of the product hydroxyethyl choline ethyl phosphate in 63% yield, the product structure was as follows:
1 H-NMR(500MHz,D 2 O):4.64(t,-CH 2 O-CO-)，4.29(t,-CH 2 OP)，3.86(m,-CH 2 N(CH 3 ) 2 -CH 2 -)，3.74(d,P-OCH 2 -CH 2 -)，3.25(s,-N-(CH 3 ) 2 )，1.25(t,P-OCH 2 -CH 3 )； 31 P-NMR(500MHz,D 2 O):δ(ppm)0.06(s).
paclitaxel (2.0 g,2.34 mmol), hydroxyethyl choline ethyl phosphate (0.62 g,2.34 mmol) and succinic acid (0.28 g,2.34 mmol) were added to a 100 mL flask containing 30mL of anhydrous acetonitrile, reacted at room temperature for 48 hours, after the reaction was completed, the solution was precipitated three times in 500mL of tetrahydrofuran solution, and finally tetrahydrofuran was removed to obtain 1.73g of paclitaxel choline phosphate with succinic acid as a linking group, the yield was 60%, the product structure was as follows:
1 H-NMR(500MHz,CDCl 3 ):7.3-8.2(d,m,-C 6 H 5 -),6.25(d,-NH-CH-CH-),5.8(d,-NH-CH-CH-),5.7(d,-C＝C-CH-O-),5.0(s,-C-CH 2 -O-),4.64(t,-CH 2 O-CO-),4.29(t,-CH 2 OP),4.4(t,-O-CH-C-),4.0(d,C-CH-O-),3.86(m,-CH 2 N(CH 3 ) 2 -CH 2 -),3.8(-C-CH-OH-),3.74(d,P-OCH 2 -CH 2 -),3.25(s,-N-(CH 3 ) 2 ),2.8(t,-OOC-(CH 2 ) 2 -COO-),2.4(s,-C-CH 3 ),2.3(t,-CH-CH 2 -C-OH),2.2(s,-OOC-CH 3 ),1.75(s,-OOCCH 3 ),1.7(s,-C＝C-CH 3 ),1.6(m,-CH-CH 2 -CH-),1.25(s,-CO-C-CH 3 ),1.25(t,P-OCH 2 -CH 3 ),1.24(s,-C＝C-C-CH 3 )； 31 P-NMR(500MHz,CDCl 3 ):δ(ppm)-1.9(s).
the nuclear magnetic resonance hydrogen spectrum and the phosphorus spectrum of the choline phosphotaxol with the succinic acid as the connecting group are shown in figure 5, and the mass spectrum is shown in figure 6.
EXAMPLE 3 use of Choline phosphotaxol as an anticancer drug
Testing the water solubility of choline phosphotaxol: taking a certain amount of the choline phosphotaxol medicaments prepared in the examples 1 and 2, dissolving the medicaments in a certain amount of distilled water, continuously stirring the distilled water until the distilled water is clear, and continuously adding the medicaments until the medicaments are not dissolved any more, wherein the ratio of the adding amount of the medicaments to the using amount of the water is the maximum solubility of the choline phosphotaxol in the water. This solubility is one of the important indicators for guiding the amount of drug administered.
The result shows that the maximum solubility of the choline phosphotaxol drug taking glycine as a connecting group in water is 10mg/mL; the maximum solubility of the choline phosphotaxol drug taking lysine as a connecting group in water is 10.5mg/mL; the maximum solubility of the choline phosphotaxol drug taking succinic acid as a connecting group in water is 8.5mg/mL.
Testing cytotoxicity of the phosphocholine paclitaxel drug: mouse fibroblasts (NIH-3T 3) and mouse breast cancer cells (4T 1) were plated in 96-well plates at 1X 10 4 Is used for the density incubation of the culture medium. After 12 hours of incubation, the cells were incubated with medium containing 2-12. Mu.M of the phosphocholine paclitaxel drug prepared in examples 1, 2, respectively, for 24 hours, and then 10. Mu.L of Celltiter-Blue reagent was added to each well. After an additional 4 hours of incubation, the vessel was openedCell viability was measured by a microplate reader (λex=560 nm, λem=590 nm). Cell viability was calculated by the following formula:
cell viability (%) = (sample fluorescence intensity/control fluorescence intensity) ×100%
The cytotoxicity test results of paclitaxel choline phosphate on mouse fibroblasts (NIH-3T 3) and mouse breast cancer cells (4T 1) are shown in FIG. 7.
Testing the haemolysis rate of the phosphocholine paclitaxel drug: fresh mouse blood was collected from the heart and Red Blood Cells (RBCs) were washed 3 times with PBS. Thereafter, RBCs were diluted and suspended with 10mL PBS. First, 0.3mL of RBCs suspension was mixed with 1.2mL of PBS as a negative control group and with 1.2mL of water as a positive control group. Different concentrations of drug dissolved in 1.2mL PBS were added to RBCs suspension (0.3 mL) and then incubated for 2 hours at 37 ℃. Finally, the sample was centrifuged at 12000r/min for 10 minutes, the supernatant was collected, and absorbance at 541nm was measured with a microplate spectrophotometer. Percent hemolysis was calculated according to the following equation:
percent of hemolysis (%) = (absorbance of sample)/(absorbance of positive control) ×100%
The results of the hemolysis test are shown in FIG. 8.
Lived and dead staining test on mouse fibroblasts (NIH-3T 3) and mouse breast cancer cells (4T 1): NIH-3T3 cells and 4T1 cells were cultured in 24-well plates at a density of 1X 10 5 Individual cells. After 24 hours of incubation, the medium was replaced with fresh medium containing 10 μg/mL of the phosphocholine paclitaxel drug. The cells were cultured for an additional 24 hours. Then, the old medium was removed, the cells were washed twice with PBS, 0.25mL of a mixture of Calcein methyl acetoacetate (Calcein AM, ex/Em=494/517 nm) and propidium iodide (PI, ex/Em=535/617 nm), and incubated in the dark for 40 minutes, and finally the prepared samples were imaged under a laser scanning confocal microscope, the results of which are shown in FIG. 9.
The results show that the choline phosphotaxol medicament has excellent water solubility, can target and eliminate cancer cells, can not damage normal cells, and has the potential of serving as a targeted anticancer medicament.
The above description of the embodiments is only for aiding in the understanding of the method of the present invention and its core ideas. It should be noted that it will be apparent to those skilled in the art that various modifications and adaptations of the invention can be made without departing from the principles of the invention and these modifications and adaptations are intended to be within the scope of the invention as defined in the following claims.

Claims (6)

1. A choline phosphate modified paclitaxel drug having a structure represented by formula i:
wherein R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; m isWhen L is selected from any one of the following structures:
when M is O, L is selected from any one of the following structures:
2. the choline phosphate modified paclitaxel drug according to claim 1, which has any one of the following structures:
3. a method of preparing the choline phosphate modified paclitaxel drug of claim 1 or 2, comprising the steps of:
reacting the acryloyloxyethyl choline ethyl phosphate, the taxol and the amino acid to obtain the choline phosphate modified taxol medicine.
4. A method of preparing the choline phosphate modified paclitaxel drug of claim 1 or 2, comprising the steps of:
and (3) reacting hydroxyethyl choline ethyl phosphate, taxol and carboxylic acid to obtain the choline phosphate modified taxol medicine.
5. Use of the choline phosphate modified paclitaxel drug according to any one of claims 1 to 2 or the choline phosphate modified paclitaxel drug prepared by the preparation method according to any one of claims 3 to 4 in the preparation of anticancer drugs.
6. The use according to claim 5, wherein the anticancer drug is an anti-breast or ovarian cancer drug.
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