CN114437128A - Choline phosphate modified paclitaxel medicine and preparation method and application thereof - Google Patents

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

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CN114437128A
CN114437128A CN202210107371.4A CN202210107371A CN114437128A CN 114437128 A CN114437128 A CN 114437128A CN 202210107371 A CN202210107371 A CN 202210107371A CN 114437128 A CN114437128 A CN 114437128A
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phosphocholine
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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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Abstract

The invention provides a choline phosphate modified paclitaxel drug which has a structure shown in a formula I. The choline phosphate group of the paclitaxel provided by the invention has extremely strong hydrophilicity, so that the water solubility of the paclitaxel medicament can be obviously improved, and the injection administration of the paclitaxel medicament is realized; meanwhile, the choline phosphate group has stronger anti-protein adsorption and can enhance the circulation time of the paclitaxel in vivo; the ester bond formed by the connecting group such as glycine and the paclitaxel can be cracked by esterase in the tumor area environment, so that the property of the paclitaxel is recovered, and the aim of targeting and eliminating cancer cells is fulfilled.

Description

Choline phosphate modified paclitaxel medicine and preparation method and application thereof
Technical Field
The invention relates to the technical field of medicinal preparations, in particular to a choline phosphate modified paclitaxel medicament and a preparation method and application thereof.
Background
Paclitaxel (PTX) is a natural product extracted from the bark of Taxus brevifolia, and can also be obtained by semi-synthesis. Paclitaxel binds to tubulin of cells, promotes tubulin aggregation and inhibits dissociation thereof, and the cells cannot normally divide, 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, paclitaxel is hardly dissolved in water, and the paclitaxel injection as a common clinical preparation uses a mixed solution of polyoxyethylene castor oil and absolute ethyl alcohol as a solvent, and the use of the non-aqueous solvent can cause severe anaphylactic reaction; in order to reduce the generation of anaphylactic reaction, the patient needs to be given dexamethasone, diphenhydramine and other medicaments for desensitization pretreatment before injecting paclitaxel, so that the burden of the patient and medical personnel is increased; in addition, paclitaxel lacks targeting property, and is very easy to cause systemic adverse reactions such as neutropenia, neurogenic diseases and the like. Therefore, from the clinical application of paclitaxel, structural modification, modification and dosage form modification of paclitaxel have been regarded as important at home and abroad.
The structural modification of the paclitaxel mainly uses different chemical groups to synthesize paclitaxel structural analogues with different substituents; the modification of the dosage form mainly means that the amphiprotic high molecular polymer is used for physically coating the paclitaxel to form nano micelles, nano capsules or nano particles. The structural modification of paclitaxel mainly means that a small molecule or a macromolecular compound is connected on a group of paclitaxel through a chemical bond to generate a conjugate, and the conjugate is hydrolyzed in vivo to release paclitaxel again, so that the antitumor effect of the paclitaxel proto-type drug is exerted. Currently, there are still numerous modifications of paclitaxel structure in preclinical or clinical trials. The function of the modifying group and the structural composition of the connecting segment can influence the release of the paclitaxel and the uptake of tumor cells, so that the research and development of a novel paclitaxel medicament with high efficiency, low toxicity and targeting effect are urgently needed in the clinical treatment of tumors.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a phosphocholine-modified paclitaxel drug, and a preparation method and an application thereof, wherein the prepared phosphocholine-modified paclitaxel drug has high water solubility, in vivo circulation time and tumor targeting ability.
The invention provides a choline phosphate modified paclitaxel drug, which has a structure shown in a formula I:
Figure BDA0003493851840000021
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, residual residue left after removing any hydroxyl in polyalcohol substances or selective protecting group;
m is
Figure BDA0003493851840000022
Or O;
when M is
Figure BDA0003493851840000023
When L is selected from amino acid residues;
when M is O, L is selected from the group consisting of residues of carboxylic acids and derivatives thereof.
In the present invention, the carboxylic acid and the derivative thereof have at least two carboxyl groups.
In the present invention, R is a group capable of further modifying the phosphocholine terminus, and is preferably a substituted or unsubstituted alkyl group having C1-C8, an alkenyl group having C3-C8, an alkynyl group having C3-C8, an epoxy group having C3-C8, an azido group having C2-C8, an amino group having C1-C8, a residue remaining after removing any hydroxyl group from a polyol, or a selective protecting group.
The substituent is preferably a fluorine-substituted C1-C8 alkyl group, C3-C8 alkenyl group, C3-C8 alkynyl group, C3-C8 epoxy group, C3-C8 azido group, C3-C8 amino group or fluorine-substituted polyol.
More preferably, R is selected from C1-C5 alkyl, C3-C5 alkenyl, C3-C5 alkynyl, C3-C5 epoxy, C2-C5 azido, C1-C5 amino and C3-C5 alcohol, and residues remained after removing any hydroxyl.
Further preferably, R is selected from methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, tert-butyl, allyl, alkenylbutyl, propargyl, N-butyl, and N-butyl3-(CH2)2-、N3-(CH2)3-、N3-(CH2)4-、NH2CH2-、NH2(CH2)2-、NH2(CH2)3-、NH2(CH2)4-、BOC-NH(CH2)2-、BOC-NH(CH2)3-、BOC-NH(CH2)4、HO-(CH2)2-、HO-(CH2)3-、HO-(CH2)4-、HO-(CH2)5-、HO-(CH2)2-O-(CH2)2-。
In the present invention, L is a group linking phosphocholine to paclitaxel, one end of L reacts with a hydroxyl group of paclitaxel, and the other end reacts with a phosphocholine group. And M is a modification group of the choline phosphate, can react with amino or carboxyl, and is used as a reaction group to enable the choline phosphate to react with L and further be connected with the paclitaxel.
When M is
Figure BDA0003493851840000031
When L is preferably a residue of glycine, alanine, serine, threonine, aspartic acid, glutamic acid, lysine or arginine; the above residue refers to a residue remaining after an amino group of an amino acid has lost one hydrogen atom and a carboxyl group has lost one OH group. In the above M, the ester group terminal is linked to the phosphocholine terminal, the ethyl group terminal is linked to the amino group of the amino acid residue, and the carbonyl group terminal of the amino acid residue is linked to the oxygen atom of paclitaxel.
When M is O, L is preferably the residue of succinic acid, glutaric acid, adipic acid, 3 ' -dithiodiacetic acid, 3 ' -dithiodipropionic acid, 3 ' -dithiodibutanoic acid, diglycolic acid, triglycolic acid or tetraglycolic acid; the residues refer to the residues left after two carboxyl groups of carboxylic acid and derivatives thereof respectively lose OH.
Specifically, when M is
Figure BDA0003493851840000032
When, L is selected from any of the following structures:
Figure BDA0003493851840000041
when M is O, L is selected from any of the following structures:
Figure BDA0003493851840000042
Figure BDA0003493851840000051
in some embodiments of the invention, the phosphocholine-modified paclitaxel drug has any of the following structures:
Figure BDA0003493851840000052
the invention provides a preparation method of a choline phosphate modified paclitaxel medicament, which comprises the following steps:
reacting acryloyl oxyethyl choline ethyl phosphate, paclitaxel and amino acid to obtain the choline phosphate modified paclitaxel medicament.
The structural formula of the acryloyloxyethyl choline ethyl phosphate is as follows:
Figure BDA0003493851840000053
the invention provides a preparation method of a choline phosphate modified paclitaxel medicament, which comprises the following steps:
the hydroxyethyl choline ethyl phosphocholine, the paclitaxel and the carboxylic acid or the derivatives thereof react to obtain the choline phosphate modified paclitaxel medicament.
The structural formula of the hydroxyethyl choline ethyl phosphate is as follows:
Figure BDA0003493851840000061
in the above preparation process, the reaction of paclitaxel with linking group L and acryloyloxyethyl choline ethyl phosphate can be carried out by one-step method. The hydroxyl group at the C-2' site of paclitaxel undergoes an esterification reaction with the carboxyl group on the linker L, while the amino group on the linker L undergoes a Michael addition reaction with the acrylate double bond on the phosphocholine. According to 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 can be obtained by column chromatography after the reaction is finished. Similarly, the reaction of paclitaxel with linker L and hydroxyethyl phosphocholine ethyl ester can be performed in a single step, preferably using DMAP, DIC as catalyst, preferably at room temperature, preferably for 24 hours, preferably by precipitating the product in tetrahydrofuran and drying after the reaction is completed.
Experimental results show that the taxol modified by the choline phosphate shows good water solubility and biocompatibility, and the L group can be broken under the slightly acidic condition and the enzyme environment of a tumor area, so that the cytotoxicity of the taxol is recovered, and the targeted killing of tumor cells is realized.
The invention provides the application of the choline phosphate modified paclitaxel medicine or the choline phosphate modified paclitaxel medicine prepared by the preparation method in preparing anti-cancer medicines. More preferably in the preparation of targeted anticancer drugs.
In the invention, preferably, the anti-cancer drug is a drug for resisting breast cancer and ovarian cancer.
Compared with the prior art, the invention provides a choline phosphate modified paclitaxel medicament which has a structure shown in a formula I. The choline phosphate group of the paclitaxel provided by the invention has extremely strong hydrophilicity, so that the water solubility of the paclitaxel medicament can be obviously improved, and the injection administration of the paclitaxel medicament is realized; meanwhile, the choline phosphate group has stronger anti-protein adsorption and can enhance the circulation time of the paclitaxel in vivo; the ester bond formed by the connecting group such as glycine and the paclitaxel can be cracked by esterase in the tumor area environment, so that the property of the paclitaxel is recovered, and the aim of targeting and eliminating cancer cells is fulfilled.
Drawings
FIG. 1 NMR hydrogen and phosphorus spectra of paclitaxel choline phosphate with glycine as the linking group;
FIG. 2 is a mass spectrum of paclitaxel choline phosphate with glycine as the linking group;
FIG. 3 NMR hydrogen and phosphorus spectra of choline phosphopaclitaxel with lysine as the linking group;
FIG. 4 is a mass spectrum of paclitaxel choline phosphate with lysine as the linking group;
FIG. 5 nuclear magnetic resonance hydrogen and phosphorus spectra of paclitaxel choline phosphate with succinic acid as the linker group;
FIG. 6 is a mass spectrum of paclitaxel phosphocholine with succinic acid as the linker;
FIG. 7 cytotoxicity test results of Phosphataxel on mouse fibroblast (NIH-3T3) and mouse breast cancer cell (4T 1);
FIG. 8 results of hemolysis test of Phosphataxel;
FIG. 9 the results of the dying and alive tests of the choline phosphotaxol on mouse fibroblasts (NIH-3T3) and mouse breast cancer cells (4T 1).
Detailed Description
In order to further illustrate the present invention, the choline phosphate modified paclitaxel drug and the preparation method and application thereof provided by the present invention are described in detail below with reference to the examples.
EXAMPLE 1 preparation of Choline Phosphotaxel drugs with amino acids as the linking group
Adding triethylamine (51g,0.51mol) and absolute ethyl alcohol (22g,0.5mol) into a flask with a branch mouth containing 300mL of anhydrous tetrahydrofuran, magnetically stirring under the protection of nitrogen, cooling in an ice-water bath for 30 minutes, dropwise adding 2-chloro-2-oxo-dioxolane (71g,0.5mol) from a constant-pressure dropping funnel, wherein a large amount of white precipitates are generated in a reaction system in the dropwise adding process, after dropwise adding is finished within 1 hour, keeping the ice-water bath reaction for 2 hours, slowly raising the temperature to room temperature, continuing to react for 2 hours, filtering, washing a filter cake twice with the anhydrous tetrahydrofuran, combining and collecting filtrates, removing a solvent under reduced pressure to obtain a crude product, and distilling the crude product with a short neck to obtain a pure product of 49.4g of 2-oxyethyl-2-oxo-dioxolane (COP) with the yield of 65%. The product structure is as follows:
Figure BDA0003493851840000071
1H-NMR(500MHz,CDCl3):4.44-4.35(m,-OCH2CH2O-)，4.15(m,-OCH2CH3)，1.41(t,-OCH2CH3)；31P-NMR(500MHz,CDCl3):δ(ppm)17.60(s).
COP (5.41g,30mmol), ethyl 2- (dimethylamino) methacrylate (5.2g,33mmol) and 100mg of BHT inhibitor were added to a 100 mL flask containing 50mL of anhydrous acetonitrile, heated to 70 ℃ for 56 hours, after the reaction was completed, the solution was precipitated three times in 500mL of tetrahydrofuran solution, and finally the tetrahydrofuran was removed to give 5.6g of acryloyloxyethyl choline ethyl phosphate, in 63% yield, having the following structure:
Figure BDA0003493851840000081
1H-NMR(500MHz,D2O):6.43 and 6.21(d and m,-OCCH＝CH2)，6.03(d,-OCCH＝CH2)，4.64(t,-CH2O-CO-)，4.29(t,-CH2OP)，3.86(m,-CH2N(CH3)2-CH2-)，3.74(d,P-OCH2-CH2-)，3.25(s,-N-(CH3)2)，1.25(t,P-OCH2-CH3)；31P-NMR(500MHz,D2O):δ(ppm)0.06(s).
paclitaxel (2.0g,2.34mmol), acryloyloxyethyl phosphocholine ethyl ester (0.7g,2.34mmol) and glycine (0.18g,2.34mmol) 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-phosphocholine with glycine as a linker in 60% yield, the product structure was as follows:
Figure BDA0003493851840000082
1H-NMR(500MHz,CDCl3):7.3-8.2(d,m,-C6H5-),6.25(d,-NH-CH-CH-),5.8(d,-NH-CH-CH-),5.7(d,-C＝C-CH-O-),5.0(s,-C-CH2-O-),4.64(t,-CH2O-CO-),4.29(t,-CH2OP),4.4(t,-O-CH-C-),4.0(d,C-CH-O-),3.86(m,-CH2N(CH3)2-CH2-),3.8(-C-CH-OH-),3.74(d,P-OCH2-CH2-),3.25(s,-N-(CH3)2),1.25(t,P-OCH2-CH3),2.4(s,-C-CH3),2.3(t,-CH-CH2-C-OH),2.2(s,-OOC-CH3),1.75(s,-OOCCH3),1.7(s,-C＝C-CH3),1.6(m,-CH-CH2-CH-),1.25(s,-CO-C-CH3),1.24(s,-C＝C-C-CH3)；31P-NMR(500MHz,CDCl3):δ(ppm)-1.9(s).
the NMR spectrum and the NMR 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 (2.0g,2.34mmol), acryloyloxyethyl phosphocholine ethyl ester (0.7g,2.34mmol) and lysine (0.34g,2.34mmol) 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 phosphocholine with lysine as a linker in a yield of 60%, and the product structure was as follows:
Figure BDA0003493851840000091
1H-NMR(500MHz,CDCl3):7.3-8.2(d,m,-C6H5-),6.25(d,-NH-CH-CH-),5.8(d,-NH-CH-CH-),5.7(d,-C＝C-CH-O-),5.0(s,-C-CH2-O-),4.64(t,-CH2O-CO-),4.29(t,-CH2OP),4.4(t,-O-CH-C-),4.0(d,C-CH-O-),3.86(m,-CH2N(CH3)2-CH2-),3.8(-C-CH-OH-),3.74(d,P-OCH2-CH2-),3.25(s,-N-(CH3)2),1.25(t,P-OCH2-CH3),2.4(s,-C-CH3),2.3(t,-CH-CH2-C-OH),2.2(s,-OOC-CH3),1.75(s,-OOCCH3),1.7(s,-C＝C-CH3),1.6(m,-CH-CH2-CH-),1.25(s,-CO-C-CH3),1.24(t,-NH-(CH2)4-CH-)；31P-NMR(500MHz,CDCl3):δ(ppm)-1.9(s).
the NMR spectrum and the NMR spectrum of the choline phosphotaxol with lysine as the connecting group are shown in FIG. 3, and the mass spectrum is shown in FIG. 4.
EXAMPLE 2 preparation of Choline Phosphotaxel drugs with succinic acid as the linker group
The procedure for the preparation of 2-oxyethyl-2-oxo-phospholane (COP) was the same as in example 1.
COP (5.41g,30mmol), dimethylaminoethanol (2.94g,33mmol) was added to a 100 mL flask containing 50mL of anhydrous acetonitrile and heated to 70 ℃ for 56 hours, after the reaction was completed, the solution was precipitated three times in 500mL of tetrahydrofuran solution and finally the tetrahydrofuran was removed to give 5.6g of hydroxyethyl choline ethyl phosphate, the yield being 63%, the product having the structure:
Figure BDA0003493851840000101
1H-NMR(500MHz,D2O):4.64(t,-CH2O-CO-)，4.29(t,-CH2OP)，3.86(m,-CH2N(CH3)2-CH2-)，3.74(d,P-OCH2-CH2-)，3.25(s,-N-(CH3)2)，1.25(t,P-OCH2-CH3)；31P-NMR(500MHz,D2O):δ(ppm)0.06(s).
paclitaxel (2.0g,2.34mmol), hydroxyethyl choline phosphoethyl ester (0.62g,2.34mmol) and succinic acid (0.28g,2.34mmol) 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 phospho with succinic acid as a linker in 60% yield, the product structure was as follows:
Figure BDA0003493851840000102
1H-NMR(500MHz,CDCl3):7.3-8.2(d,m,-C6H5-),6.25(d,-NH-CH-CH-),5.8(d,-NH-CH-CH-),5.7(d,-C＝C-CH-O-),5.0(s,-C-CH2-O-),4.64(t,-CH2O-CO-),4.29(t,-CH2OP),4.4(t,-O-CH-C-),4.0(d,C-CH-O-),3.86(m,-CH2N(CH3)2-CH2-),3.8(-C-CH-OH-),3.74(d,P-OCH2-CH2-),3.25(s,-N-(CH3)2),2.8(t,-OOC-(CH2)2-COO-),2.4(s,-C-CH3),2.3(t,-CH-CH2-C-OH),2.2(s,-OOC-CH3),1.75(s,-OOCCH3),1.7(s,-C＝C-CH3),1.6(m,-CH-CH2-CH-),1.25(s,-CO-C-CH3),1.25(t,P-OCH2-CH3),1.24(s,-C＝C-C-CH3)；31P-NMR(500MHz,CDCl3):δ(ppm)-1.9(s).
the NMR and NMR spectra of the above-mentioned Choline Phosphotaxel with succinic acid as the linking group are shown in FIG. 5, and the mass spectrum is shown in FIG. 6.
EXAMPLE 3 application of Phosphataxols as anticancer drugs
Testing of aqueous solubility of paclitaxel phosphocholine: a certain amount of the paclitaxel choline phosphate drugs prepared in examples 1 and 2 are dissolved in a certain amount of distilled water, the mixture is continuously stirred until the drugs are clear, and the drugs are continuously added until the drugs are not dissolved, wherein the ratio of the added amount of the drugs to the amount of the water is the maximum solubility of the paclitaxel choline phosphate in the water. The solubility is one of important indicators for guiding the dose.
The result shows that the maximum solubility of the choline phosphotaxol medicament taking the glycine as the connecting group in water is 10 mg/mL; the maximum solubility of the choline phosphotaxol medicament taking lysine as a connecting group in water is 10.5 mg/mL; the maximum solubility of the paclitaxel choline phosphate drug with succinic acid as the connecting group in water is 8.5 mg/mL.
Testing of the cytotoxicity of the cholinephosphortaxel drug: mouse fibroblasts (NIH-3T3) and mouse breast cancer cells (4T1) were plated at 1X 10 in 96-well plates4Is incubated at the density of (1). After 12 hours of incubation, cells were incubated with media containing 2-12. mu.M concentration of the paclitaxel choline phosphate drug prepared in examples 1 and 2, respectively, for 24 hours, and then 10. mu.L of Celltiter-Blue reagent was added to each well. After a further 4 hours of incubation, cell viability was determined by means of a microplate reader (. lamda. ex. 560nm,. lamda. em. 590 nm). Cell viability was calculated by the following formula:
cell viability (%) - (sample fluorescence intensity/control fluorescence intensity) × 100%
The cytotoxicity test results of Phosphataxel on mouse fibroblast (NIH-3T3) and mouse breast cancer cell (4T1) are shown in FIG. 7.
Testing of the hemolysis rate of a Choline Phosphotaxel 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 and 1.2mL of water as a positive control. Various concentrations of drug dissolved in 1.2mL PBS were added to RBCs suspensions (0.3mL) and incubated at 37 ℃ for 2 hours. Finally, the sample was centrifuged at 12000r/min for 10 minutes, the supernatant was collected, and the absorbance at 541nm was measured with a microplate spectrophotometer. Percent hemolysis was calculated according to the following equation:
percent hemolysis (%) - (absorbance of sample)/(absorbance of positive control) × 100%
The results of the hemolysis test are shown in FIG. 8.
Live and dead staining test for mouse fibroblasts (NIH-3T3) and mouse breast cancer cells (4T 1): NIH-3T3 cells and 4T1 cells were cultured in 24-well plates at a density of 1X 105And (4) cells. After 24 hours of incubation, the medium was changed to fresh medium containing 10. mu.g/mL of the paclitaxel-choline phosphate drug. The cells were cultured for 24 hours. Then, the old medium was removed, the cells were washed twice with a mixture of PBS, 0.25mL of Calcein acetoxymethyl ester (Calcein AM, Ex/Em ═ 494/517nm) and propidium iodide (PI, Ex/Em ═ 535/617nm) and added to each well, and incubated for 40 minutes in the dark, and finally the prepared samples were imaged under a laser scanning confocal microscope, and the results are shown in fig. 9.
The results show that the phosphocholine taxol medicaments have excellent water solubility, can eliminate cancer cells in a targeted manner, do not damage normal cells, and have the potential of serving as targeted anticancer medicaments.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.

Claims (9)

1. A cholinophosphoric acid modified paclitaxel drug has a structure shown in formula I:
Figure FDA0003493851830000011
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, residual residue left after removing any hydroxyl in polyalcohol substances or selective protecting group;
m is
Figure FDA0003493851830000012
Or O;
when M is
Figure FDA0003493851830000013
When L is selected from amino acid residues;
when M is O, L is selected from the group consisting of residues of carboxylic acids and derivatives thereof.
2. The phosphocholine-modified paclitaxel drug according to claim 1, wherein R is selected from the group consisting of methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, tert-butyl, allyl, alkene butyl, propargyl, alkyne butyl, N3-(CH2)2-、N3-(CH2)3-、N3-(CH2)4-、NH2CH2-、NH2(CH2)2-、NH2(CH2)3-、NH2(CH2)4-、BOC-NH(CH2)2-、BOC-NH(CH2)3-、BOC-NH(CH2)4-、HO-(CH2)2-、HO-(CH2)3-、HO-(CH2)4-、HO-(CH2)5-、HO-(CH2)2-O-(CH2)2-。
3. The phosphocholine-modified paclitaxel drug according to claim 1, wherein when M is
Figure FDA0003493851830000021
When L is selected from the group consisting of glycine, alanine, serine, threonine, aspartic acid, glutamic acid, lysine or arginine residues;
when M is O, L is selected from the group consisting of succinic, glutaric, adipic, 3 ' -dithiodiacetic, 3 ' -dithiodipropionic, 3 ' -dithiodibutanoic, diglycolic, triglycollic or tetraglycolic residues.
4. The phosphocholine-modified paclitaxel drug according to claim 1, wherein when M is
Figure FDA0003493851830000022
When, L is selected from any of the following structures:
Figure FDA0003493851830000023
when M is O, L is selected from any of the following structures:
Figure FDA0003493851830000024
Figure FDA0003493851830000031
5. the phosphocholine-modified paclitaxel drug according to claim 1, having any of the following structures:
Figure FDA0003493851830000032
6. a method for preparing a cholinophosphoric acid modified paclitaxel medicament comprises the following steps:
reacting acryloyl oxyethyl choline ethyl phosphate, paclitaxel and amino acid to obtain the choline phosphate modified paclitaxel medicament.
7. A method for preparing a cholinophosphoric acid modified paclitaxel medicament comprises the following steps:
the hydroxyethyl choline ethyl phosphocholine, the paclitaxel and the carboxylic acid or the derivatives thereof react to obtain the choline phosphate modified paclitaxel medicament.
8. Use of a phosphocholine-modified paclitaxel drug according to any of claims 1-5 or a phosphocholine-modified paclitaxel drug prepared by the preparation method according to any of claims 6-7 for the preparation of an anticancer drug.
9. The use of claim 8, wherein the anti-cancer drug is an anti-breast or ovarian cancer drug.
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