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Polyglycol modified antitumor compound and its preparing method

A polyethylene glycol, anti-tumor technology, applied in the field of medicine, can solve problems such as poor water solubility

Inactive Publication Date: 2006-11-08
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The present invention aims at the characteristics of poor water solubility of Combretastatin and its derivatives, and provides a polyethylene glycol-modified anti-tumor compound and a preparation method thereof. The obtained polyethylene glycol-modified anti-tumor compound has good water solubility and Anti-tumor activity, which solves some key problems in the clinical application of Combretastatin and its derivatives

Method used

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  • Polyglycol modified antitumor compound and its preparing method
  • Polyglycol modified antitumor compound and its preparing method
  • Polyglycol modified antitumor compound and its preparing method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] In a 50mL three-necked flask equipped with magnetic stirring, add mPEG (2700) (0.54g, 0.2mmol), succinic anhydride (0.05g, 0.24mmol), DMAP (0.0246g, 0.2mmol), triethylamine (0.028mL , 0.2mmol) and 20mL of dioxane, stirred until completely dissolved, then stirred and reacted at room temperature for 24 hours. Filter, remove the solvent dioxane by rotary evaporation, then dissolve in a small amount of dichloromethane to form a thick shape, slowly drop the thick solution into ice anhydrous ether under vigorous stirring, fully analyze the precipitate, filter , to obtain 0.51 g of white solid, which was stored dry.

[0034] In a 100mL three-neck flask equipped with magnetic stirring, add the above white solid (0.135g, 0.05mmol) and 30mL of dichloromethane. -3-Hydroxy-4,3',4',5'-tetramethoxystilbene (0.0316g, 0.1mmol), DIPC (16μL, 0.1mmol) and DMAP (0.0246g, 0.2mmol), stirred All of them were dissolved, slowly raised to room temperature, and continued stirring for 24 hours. ...

Embodiment 2

[0038] In a 100mL three-neck flask equipped with magnetic stirring, add mPEG-COOH (5000+5000) (0.5g, 0.05mmol), (Z)-3-hydroxy-4,3',4',5'-tetramethoxy Diphenylethylene (0.0316g, 0.1mmol), triethylamine (0.042mL, 0.3mmol) and 30mL of dry tetrahydrofuran were reacted at room temperature for 4 hours, and then refluxed for 72 hours. After cooling, filter, remove most of the solvent by rotary evaporation, slowly drop the concentrated mPEG conjugated tetrahydrofuran solution into ice anhydrous ether under vigorous stirring, so that the mPEG-Combretastatin A-4 conjugate is fully precipitated, filtered, 0.46 g of white solid was obtained, which was stored dry. The chemical structure is shown in Formula 2, 1H NMR (CDCl3): δ 3.65 (s, 1483H, CH2), 3.49 (d, 2.1H, OMe), and the calculated connection rate is about 35%. Silica gel column separation, ethanol:dichloromethane ratio of 1:90. Compared with water solubility, it is 560 times higher.

[0039]

[0040] F...

Embodiment 3

[0042]In a 100mL three-neck flask equipped with magnetic stirring, add mPEG-COOH (5000+5000) (0.5g, 0.05mmol), (Z)-3-amino-4,3',4',5'-tetramethoxy Diphenylethylene (0.0315g, 0.1mmol), triethylamine (0.042mL, 0.3mmol) and 30mL of dry tetrahydrofuran were reacted at room temperature for 4 hours, and then refluxed for 72 hours. After cooling, filter, remove most of the solvent by rotary evaporation, slowly drop the concentrated mPEG conjugate solution in tetrahydrofuran into ice anhydrous ether under vigorous stirring, so that the mPEG-Combretastatin conjugate is fully precipitated, and filter to obtain a white solid 0.41g, dry storage. The chemical structure is shown in Formula 3, 1H NMR (CDCl3): δ 3.65 (s, 1483H, CH2), 3.49 (d, 2.1H, OMe), and the calculated connection rate is about 35%. Silica gel column separation, ethanol:dichloromethane ratio of 1:90. Compared with water solubility, it is 270 times higher.

[0043]

[0044] Formula 3

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Abstract

The present invention discloses a kind of polyglycol modified antitumor compound and its preparation process. The polyglycol modified antitumor compound has Combretastatin and its derivative as matrix and linear chain polyglycol and dendritic polyglycol for modifying to improve water solubility. It has water solubility 200-2500 times that of Combretastatin and its derivative before modification. The present invention solves the difficult problem of applying Combretastatin and its derivative clinically.

Description

technical field [0001] The invention relates to a compound in the technical field of medicine and a preparation method thereof, in particular to a polyethylene glycol-modified antitumor compound and a preparation method thereof. Background technique [0002] Combretastatin is isolated from the South African tropical plant Combretum Caffrum. It can quickly combine with tubulin, has a good selective anti-mitosis effect, destroys tumor blood vessels, causes tumor vascular endothelial cell apoptosis, and leads to the death of secondary tumor cells. Tumor activity, has a huge clinical application prospect. However, the water solubility of combretastatin and its derivatives is extremely poor, which largely limits the clinical application of combretastatin and its derivatives, and the design and preparation of water-soluble prodrugs is a research hotspot. The studies on water-soluble prodrugs of combretastatin and its derivatives reported in domestic and foreign literatures are l...

Claims

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Application Information

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IPC IPC(8): A61K31/045A61K31/085A61K31/10A61K31/12A61K31/136A61K31/215A61K31/41A61K47/60A61P35/00
Inventor 张健存章丽辉倪娜周亮张璇崔大军
Owner SHANGHAI JIAO TONG UNIV
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