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Paclitaxel (PTX) derivative, its preparation method and its use

A technology of paclitaxel derivatives and surfactants, which is applied in pharmaceutical formulations, drug combinations, and medical preparations containing active ingredients, etc., can solve problems such as acute allergic reactions, low drug concentrations, and reduced concentrations, so as to avoid allergic reactions, The effect of multidrug resistance inhibition and drug concentration enhancement

Active Publication Date: 2012-11-14
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The preparation has the following problems: ①Cremophor EL can cause severe acute allergic reaction and hypotension in the body; ②Cremophor EL can cause the plasticizer in the PVC packaging to dissolve, further increasing the toxicity; ③Dilution before clinical use can easily crystallize paclitaxel Precipitation; ④ Paclitaxel is prone to non-specific binding with the surface of glass or plastic in the solution, resulting in a decrease in concentration
An important reason for this problem is that it is difficult for anti-tumor drugs to enter tumor cells, or the concentration of drugs in tumor cells is low, and tumor cells develop drug resistance under the stimulation of long-term low-dose drugs

Method used

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  • Paclitaxel (PTX) derivative, its preparation method and its use
  • Paclitaxel (PTX) derivative, its preparation method and its use
  • Paclitaxel (PTX) derivative, its preparation method and its use

Examples

Experimental program
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Effect test

Embodiment 1～8

[0016] The preparation method is: according to the dosage shown in Table 1, mix different types of Pluronic and 3-3'-dithiodipropionic acid, add dimethylaminopyridine and 1-ethyl-(3-dimethylaminopropyl ) carbodiimide hydrochloride, dissolved in dichloromethane, kept in a water bath at 25°C for 48 hours, added PTX and kept warm for 24 hours, after vacuum drying, the sample was dissolved in absolute ethanol, added water for injection and ultrasonically placed in Dialyze in a dialysis bag of 3500 Daltons to obtain paclitaxel derivatives of the present invention (ie substances with a molecular weight greater than 3500 Daltons).

[0017] Table 1 prepares the raw material consumption of various paclitaxel derivatives

[0018]

[0019]

Embodiment 1

[0021] Paclitaxel derivatives prepared in Example 1: δ1.17ppm is CH in Pluronic 2 CH(CH 3 ) The methyl characteristic peak of O, δ3.3-3.7ppm is CH in Pluronic 2 CH(CH 3 )O and CH 2 CH 2 The characteristic peak of the methylene group of O; δ7.2-7.8ppm is the characteristic peak of the benzene ring in paclitaxel, and δ2.2ppm is the -OOC-CH in paclitaxel 3 The characteristic peak of methyl group; δ2.4ppm, δ2.8ppm belongs to -OOCCH 2 CH 2 SSCH 2 CH 2 The characteristic peak of methylene in COO-. From 1 There are both paclitaxel and Pluronic peaks and disulfide bond peaks on H-NMR, which proves the formation of paclitaxel derivatives.

Embodiment 2

[0022] Paclitaxel derivatives prepared in Example 2: δ1.18ppm is CH in Pluronic 2 CH(CH 3 ) The methyl characteristic peak of O, δ3.3-3.7ppm is CH in Pluronic 2 CH(CH 3 )O and CH 2 CH 2 The characteristic peak of the methylene group of O; δ7.2-7.8ppm is the characteristic peak of the benzene ring in paclitaxel, and δ2.2ppm is the -OOC-CH in paclitaxel 3 The characteristic peak of methyl group; δ2.4ppm, δ2.8ppm belongs to -OOCCH 2 CH 2 SSCH 2 CH 2 The characteristic peak of methylene in COO-.

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Abstract

The invention provides a PTX derivative which can inhibit the multidrug resistances of tumor cells, its preparation method, and its use in the inhibition of the multidrug resistances of the tumor cells. The molecular formula of the PTX derivative is Pluronic-(S-S-PTX)2, wherein Pluronic represents a surfactant Pluronic having a structural general formula being (HO-[CH2CH2O]X-[CH2CH(CH3)O]Y-[CH2CH2O]X-H, x and y are numbers of groups, x is an integer between 2 and 100, and y is an integer between 30 and 70; PTX is an antitumor drug paclitaxel; S-S- is a disulfide bond; and two PTX molecules are connected with one Pluronic molecule through the disulfide bond.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to derivatives of antineoplastic drug paclitaxel, a preparation method thereof and an application in inhibiting multidrug resistance of tumor cells. Background technique [0002] Paclitaxel (PTX) is a natural anticancer drug developed by Bristol-Myers Squibb at the end of the 20th century. It is a cytostatic drug with a unique mechanism of action. It can promote the assembly of tubulin into microtubules, inhibit the depolymerization of microtubules, stabilize the microtubules, lead to abnormal arrangement of microtubules, and cause the spindle to lose its normal function and lead to cell death. It has an outstanding curative effect on breast cancer and ovarian cancer. , It also has a certain effect on liver cancer, lung cancer, esophageal cancer, head and neck cancer, and prostate cancer. [0003] Paclitaxel is used as an injectable chemotherapy drug. The main obstacl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/00A61K31/795A61P35/00
Inventor 肖计生陈伶俐顾王文张志文高瑜李亚平
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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