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Anti-tumor prodrug with P-glycoprotein inhibition function and preparation method

An anti-tumor drug, glycoprotein technology, applied in the direction of anti-tumor drugs, pharmaceutical formulations, medical preparations with non-active ingredients, etc., can solve the problems of slow release of active drugs, reduced efficacy of chemotherapy drugs, etc. The effect of long circulation, increasing drug solubility

Active Publication Date: 2018-07-06
HUAZHONG UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The invention solves the technical problems in the prior art that the chemical bond between the antineoplastic drug and the polymer is difficult to break, resulting in slow release of the active drug, and the curative effect of the antineoplastic drug is reduced due to drug resistance

Method used

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  • Anti-tumor prodrug with P-glycoprotein inhibition function and preparation method
  • Anti-tumor prodrug with P-glycoprotein inhibition function and preparation method
  • Anti-tumor prodrug with P-glycoprotein inhibition function and preparation method

Examples

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Embodiment 1

[0052] This embodiment provides a paclitaxel prodrug with both P-glycoprotein inhibitory function and redox dual response characteristics, which is synthesized by the following steps:

[0053] (1) Synthesis of 2,2'-thiodiacetic anhydride: Weigh 3.0g of 2,2'-thiodiacetic acid into a 50mL round bottom flask, add 15mL of acetic anhydride. After reflux reaction at 65°C for 4 hours, acetic anhydride, acetic acid, etc. were distilled off under reduced pressure; an appropriate amount of ether was added, and rotary evaporation was repeated 2-3 times to obtain a white solid powder, which was dried under vacuum at 40°C overnight to obtain 2,2'- Thiodiacetic anhydride, the yield is 98.7%.

[0054] (2) Synthesis of TPGS-S-COOH: Weigh 1.5g TPGS into a 25mL round bottom flask, add 10mL N,N-dimethylformamide to dissolve, then add 0.122g 4-dimethylaminopyridine (DMAP ) and 0.225g 2,2'-thiodiacetic anhydride at 60°C for 12-16h. After the reaction, the reaction solution was placed in a dialys...

Embodiment 2

[0065] This embodiment provides a paclitaxel prodrug with both P-glycoprotein inhibitory function and redox dual response characteristics, which is synthesized by the following steps:

[0066] (1) Synthesis of (ethylenedithio)diacetic anhydride: Weigh 2.0 g of (ethylenedithio)diacetic acid into a 50 mL round bottom flask, and add 20 mL of anhydrous acetyl chloride. After reflux reaction at 65°C for 4 hours, acetyl chloride, acetic acid, etc. were distilled off under reduced pressure; an appropriate amount of ether was added, and the rotary evaporation was repeated 2-3 times to obtain a white solid powder, which was dried in vacuum at 40°C overnight, namely (ethylene di Thio) diacetic anhydride, the yield is 95.6%.

[0067] (2) Synthesis of TPGS-SCCS-COOH: Weigh 1.7g TPGS, 0.122g 4-dimethylaminopyridine and 0.31g (ethylenedithio) diacetic anhydride in a 50mL round bottom flask, add 20mL pyridine After dissolving, react at 60°C for 16h. After the reaction was completed, the py...

Embodiment 3

[0078] This embodiment provides a paclitaxel prodrug with both P-glycoprotein inhibitory function and redox dual response characteristics, which is synthesized by the following steps:

[0079] (1) Synthesis of TPGS-pNC: Weigh 3.0g TPGS into a 50mL round-bottomed flask, dry it in vacuum at 60°C for 4h, then add 10mL anhydrous dichloromethane, anhydrous tetrahydrofuran, anhydrous N,N-dimethylformaldehyde After the amide, anhydrous acetone or anhydrous dimethylsulfoxide are dissolved, add 0.45 mL of anhydrous triethylamine (TEA). Weigh 0.61g of 4-nitrophenyl chloroformate (pNC), 10mL of anhydrous dichloromethane, anhydrous tetrahydrofuran, anhydrous N,N-dimethylformamide, anhydrous acetone or anhydrous dimethylmethylene After the maple was dissolved, it was added dropwise to the TPGS dichloromethane solution under ice cooling. After the dropwise addition, the reaction was continued for 12 h at room temperature. After the reaction, dichloromethane was removed by rotary evaporati...

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Abstract

The invention discloses an anti-tumor prodrug with a P-glycoprotein inhibition function and a preparation method. The prodrug comprises a part formed by covalently connecting an anti-tumor drug and polyethylene glycol vitamin E succinate through a connecting arm, wherein the connecting arm comprises a sensitive bond; the sensitive bond is a chemical bond which is broken in an oxidization or reduction environment. The free polyethylene glycol vitamin E succinate and the active anti-tumor drug are dissociated; the polyethylene glycol vitamin E succinate is combined with P-glycoprotein; the expression of a P-glycoprotein efflux pump is inhibited, the activity of the P-glycoprotein is inhibited, the excretion of the anti-tumor drug is reduced and the intracellular concentration of the drug isimproved, so that the multi-drug drug resisting property of tumor cells is inhibited, the intracellular concentration of the active anti-tumor drug is greatly improved and a remarkable anti-tumor effect is obtained. The released active drug can be combined with a specific target spot in the cells and the growth of the tumor cells is inhibited.

Description

technical field [0001] The invention belongs to the technical field of chemical medicines, and in particular relates to an antitumor prodrug with P-glycoprotein inhibitory function and redox dual response characteristics. Background technique [0002] Cancer is one of the leading causes of death in modern society. According to the statistics of the Ministry of Health in 2016, the incidence of cancer in my country is close to the world level, but the mortality rate is higher than the world level, and the death toll accounts for a quarter of the global cancer patients. Currently, chemotherapy is one of the main means of treating cancer. However, during long-term chemotherapy, cancer patients often develop resistance to chemotherapeutic drugs, and also develop cross-resistance to other chemotherapeutic drugs with different chemical structures and different mechanisms of action. The multidrug resistance (MDR) of this chemotherapy drug greatly reduces the curative effect, which...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/60A61K47/54A61K9/107A61K45/00A61K31/337A61K31/4745A61K31/704A61P35/00
CPCA61K9/1075A61K31/337A61K31/4745A61K31/704A61K45/00
Inventor 张志平徐晨枫
Owner HUAZHONG UNIV OF SCI & TECH
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