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Taxane medicinal precursor

A technology of taxanes and drugs, applied in the direction of peptides, etc., can solve the problem that drug targeting cannot be effectively improved, and achieve good market prospects, good safety, and mild preparation conditions

Active Publication Date: 2014-05-21
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these current technologies can only improve the water solubility of taxane drugs, and the problem of drug targeting cannot be effectively improved.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1 Preparation of Paclitaxel Prodrug Coupled with Liver Cancer Targeting Peptide SP94 via Ester Bond

[0042] Taxane prodrugs were prepared by coupling paclitaxel with liver cancer targeting peptide SP94, and the synthetic route was as follows figure 1 shown, including the following steps:

[0043] (1) Synthesis of paclitaxel C’-2 derivative 2

[0044]Add paclitaxel 1 (300mg, 0.35mmol) to the dry reaction bottle, and dissolve it with anhydrous pyridine 2ml; add succinic anhydride (105mg, 1.05mmol) and 4-dimethylaminopyridine DMAP (4.3mg, 0.035 mmol). Stir at room temperature for 2 hours, TLC showed that the reaction was terminated after the end of the reaction, and the pyridine was removed by rotary evaporation under reduced pressure; normal phase silica gel column (dichloromethane: methanol = 20:1) separated to obtain a white solid, and the product yield was 91%. use 1 H-NMR ( figure 2 ) to confirm the target product 2.

[0045] (2) Synthesis of paclitaxe...

Embodiment 2

[0049] Example 2 Preparation of docetaxel conjugated prodrug with liver cancer targeting polypeptide SP94 through carbonate bond and disulfide bond

[0050] Taxane prodrugs were prepared by coupling docetaxel with liver cancer targeting peptide SP94, and the synthetic route was as follows Figure 5 shown, including the following steps:

[0051] (1) Synthesis of compound 9

[0052] Compound 9 was synthesized according to the literature (E.A.Dubikovskaya et al., Overcoming multidrug resistance of small-molecule therapeutics through conjugation with releasable octaarginine transporters, Proceedings of the National Academy of Sciences, 2008, 105(34):12128-12133.).

[0053] (2) Synthesis of docetaxel derivative 11

[0054] Dissolve docetaxel 10 (40 mg, 49.5 μmol) in 2 ml of anhydrous DCM, add compound 9 (22 mg, 59.4 μmol) and DMAP (7.3 mg, 59.4 μmol) to the reaction solution; stir at room temperature for 4 hours, TLC shows that the reaction is complete Then terminate the reactio...

Embodiment 3

[0057] Example 3 Evaluation of Antitumor Drug Efficacy

[0058] In order to evaluate the killing ability of the target product 4 (SP94-PTX) obtained in Example 1 on tumor cells, taking the liver cancer cell line 7721 as an example, the drug efficacy was evaluated by MTT method, and paclitaxel was used as a control. Cytotoxicity results of SP94-PTX4 on liver cancer 7721 see Figure 8 . Depend on Figure 8 It can be seen that after 72 hours of co-culture of water-soluble SP94-PTX and cells, its anti-hepatoma effect in vitro shows that SP94-PTX has the same cytotoxicity as PTX.

[0059]

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Abstract

The invention discloses a taxane medicinal precursor, which is a conjugate formed by bonding a hydroxyl group at C-2' or C-7 position of a taxane compound and water-soluble targeting peptide through a conjugation bridge, wherein the conjugation bridge contains at least one of an ester bond, a carbonic ester bond, a urea bond and a disulfide bond. Compared with the taxane compound, the medicinal precursor has the advantages that the medicinal precursor has extremely high water solubility capable of reaching 2mg / ml, so that the problem that the taxane compound can only be dissolved by using an unsafe substance such as an organic solvent and tween 80 in the prior art is solved; due to the adoption of a covalent coupling mode, the taxane medicinal precursor is ensured to have high stability when being stored in vitro, and the taxane compound can be rapidly released to achieve medicinal effects after the taxane medicinal precursor enters cells; the taxane compound can be carried to a specific tumor cell through the targeting peptide to reduce killing ability to normal cells; a decomposed product of the targeting peptide in the cells is amino acid, so that high biocompatibility is ensured.

Description

technical field [0001] The invention relates to a taxane drug prodrug, in particular to a taxane drug prodrug. Background technique [0002] Taxane drugs mainly include paclitaxel and docetaxel, which are currently one of the most effective clinical antitumor drugs. Paclitaxel is a tetracyclic diterpenoid isolated from the bark of Pacific yew with the molecular formula C 47 h 51 o 14 N, the molecular weight is 853.9, insoluble in water. Approved by the US FDA in 1992, its mechanism of action is to bind to cellular tubulin and promote tubulin polymerization to resist depolymerization and block mitosis, thereby inhibiting tumor growth and inducing tumor cell apoptosis. Clinical studies have confirmed that paclitaxel has a significant effect in the treatment of various solid tumors, including breast cancer, advanced ovarian cancer, lung cancer, brain and neck tumors, and acute leukemia. Docetaxel is semi-synthesized from the non-cytotoxic precursor compound 10-deacylated b...

Claims

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Application Information

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IPC IPC(8): C07K7/08
Inventor 徐骁王杭祥魏绪勇谢海洋周琳郑树森
Owner ZHEJIANG UNIV
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