Disulfide bond-containing polymerizable taxol monomer and synthetic method thereof

A paclitaxel and disulfide bond technology, applied in the field of drug synthesis, can solve the problems of unstable micellar system, increased drug toxicity and side effects, weak interaction force, etc., and achieves reduction of drug burst release, wide application range and simple method. Effect

Inactive Publication Date: 2015-02-04
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the weak interaction between the carrier and the drug and the reversible binding process of the non-covalent drug-loading system, most of the micellar systems are unstable, and they are prone to burst release after entering the body, which increases the toxicity of the drug. side effect

Method used

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  • Disulfide bond-containing polymerizable taxol monomer and synthetic method thereof
  • Disulfide bond-containing polymerizable taxol monomer and synthetic method thereof
  • Disulfide bond-containing polymerizable taxol monomer and synthetic method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] 4.4g 3,3'-dithiodipropionic acid (DTPA), 0.6mL hydroxyethyl methacrylate (HEMA) and 0.05g 4-dimethylaminopyridine ( DMAP) was dissolved in 50mL tetrahydrofuran (THF), then 0.5mL N,N'-diisopropylcarbodiimide (DIC) was added dropwise to the solution, stirred at room temperature overnight, and the crude product was washed with n-hexane:ethyl acetate=1 DTPA-HEMA (1) was obtained after silica gel column chromatography at :1.

[0019] Add 1g of paclitaxel (PTX), 0.024g of DMAP, 0.78g of DTPA-HEMA into 70mL of dichloromethane (DCM), then dropwise add 23μLDIC, stir the solution at room temperature overnight, and use a silica gel column layer of n-hexane:ethyl acetate=1:1 The crude product was analyzed to obtain PTX-DTPA-HEMA (PTX-linker, 2).

[0020] synthetic route:

[0021]

Embodiment 2

[0023] According to the synthetic route, 6.7g of 3,3'-dithiodipropionic acid, 0.9mL of hydroxypropyl methacrylate and 0.09g of 4-dimethylaminopyridine were dissolved in 100mL of toluene, and then 1.0mL of N,N'-diisopropylcarbodiimide, stirred overnight at room temperature. The crude product was subjected to silica gel column chromatography with n-hexane:ethyl acetate=1:1 to obtain the intermediate product (1).

[0024] Add 1 g of docetaxel, 0.024 g of DMAP, and 0.78 g of intermediate product (1) into 70 mL of dichloromethane, followed by dropwise addition of 23 μL of DIC, and stir the solution overnight at room temperature. The crude product was also treated with silica gel column chromatography with n-hexane: ethyl acetate = 1:1 to obtain disulfide bond-containing polymerizable docetaxel monomer (2).

Embodiment 3

[0026] According to the synthetic route, 7.4g of 3,3'-dithiodibenzoic acid, 1.1mL of 2-hydroxypropyl acrylate and 0.09g of 4-dimethylaminopyridine were dissolved in 100mL of tetrahydrofuran, and then 1.0 mLN,N'-diisopropylcarbodiimide, stirred overnight at room temperature. The crude product was subjected to silica gel column chromatography with n-hexane: ethyl acetate = 1:1 to obtain the intermediate product (1);

[0027] Add 1 g of paclitaxel, 0.024 g of DMAP, and 0.78 g of the intermediate product (1) into 70 mL of dichloromethane, then add 23 μL of DIC dropwise, and stir the solution overnight at room temperature. The crude product was also treated with silica gel column chromatography with n-hexane: ethyl acetate = 1:1 to obtain disulfide bond-containing polymerizable paclitaxel monomer (2).

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Abstract

The invention belongs to the technical field of drug synthesis, relates to modified synthesis of drug molecules, and specifically relates to a novel disulfide bond-containing polymerizable taxol monomer and a synthetic method thereof. by virtue of esterification or amidation reactions, the disulfide bond-containing polymerizable taxol monomer can be obtained by reacting carboxyl groups at one end of a dithio-dicarboxylic acid compound with acrylic acid monomer containing carboxyl groups or amino groups, and reacting carboxyl groups at the other end to esterification with hydroxyl groups on taxol chemotherapeutic drug. The method provided by the invention is simple; raw materials are cheap; the disulfide bonds in the monomer allow the monomer having reducing and responsive drug controlled release properties, and the polymerizable acyclic acid structure makes the monomer generate polymerization easily or prepare a drug controlled release system by copolymerization with other monomers.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, relates to the modification and synthesis of medicine molecules, in particular to a novel disulfide bond-containing polymerizable paclitaxel monomer and a synthesis method thereof. Background technique [0002] The prior art discloses that chemotherapy is an indispensable and important means in the comprehensive treatment of cancer, but most chemotherapy drugs have the problem of relatively large toxic and side effects in the process of practical application. The report discloses that paclitaxel has special cytotoxicity to ovarian cancer, lung cancer, breast cancer, etc., and is a new type of anti-tumor drug. Non-small cell lung cancer. However, clinical practice shows that the solubility of paclitaxel in water is very low, which greatly limits the clinical application of paclitaxel. Most of the commercially available paclitaxel injections are polyhydroxyethyl castor oil (Cremopher E...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D305/14A61K47/48A61P35/00
CPCA61K47/58C07D305/14
Inventor 胡建华杨东丁艺陈武炼
Owner FUDAN UNIV
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