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Antineoplastic drug Combretastatin water-soluble derivative and method for making same

An anti-tumor drug, the technology of compretidine, which is applied in the field of medicine and chemical industry, can solve the problems of poor fat solubility and achieve the effects of stable quality, strong selectivity and easy operation

Inactive Publication Date: 2008-04-09
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although CA-4P improves the water solubility of compretidine A-4, its fat solubility is poor, and it is difficult to enter cells to exert its drug effect

Method used

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  • Antineoplastic drug Combretastatin water-soluble derivative and method for making same
  • Antineoplastic drug Combretastatin water-soluble derivative and method for making same
  • Antineoplastic drug Combretastatin water-soluble derivative and method for making same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Preparation of (Z)-3'-O-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}-compretidine A-4.

[0058] 3,4,5-trimethoxyphenylacetic acid (2.0g, 8.56mmol) and isovanillin (2.61g, 17.2mmol) were added in the reaction flask, triethylamine (2.5ml) and acetic anhydride (5ml) were added, Under the protection of nitrogen, stir to dissolve, heat to 140°C and reflux for 2 hours. Stop the reaction, cool to room temperature, add concentrated ammonia water (7ml) to adjust the pH of the reaction solution to 8, stir at 45°C for 1 hour, cool to room temperature, add concentrated hydrochloric acid (6ml) to adjust the pH to 2, and a large amount of light yellow precipitates are precipitated. Stir overnight. Collect the precipitate by filtration and recrystallize in absolute ethanol to obtain (E)-3-(3'-hydroxy-4'-methoxyphenyl)-2-(3", 4", 5" as light yellow fine needle crystals -Trimethoxyphenyl)prop-2-enoic acid (1.90 g, 5.27 mmol), yield 61.4%.

[0059] Gained crystals (0.50g, 1.39mmol) were disso...

Embodiment 2

[0066] (Z)&(E)-3'-O-{2-[2-(2-{2-[2-(2-methoxyethoxy)-ethoxy]ethoxy}ethoxy )-ethoxyl] ethyl}-compretin A-4.

[0067] Referring to Example 1, with 3,4,5-trimethoxyphenylacetic acid and isovanillin as starting materials, acetic anhydride was changed to propionic anhydride, the reaction temperature was changed to 150° C., the reaction conditions were changed to 3 hours, and other conditions were not changed. change, to obtain light yellow fine needle crystals (E)-3-(3'-hydroxy-4'-methoxyphenyl)-2-(3", 4", 5"-trimethoxyphenyl) propane- 2-enoic acid.

[0068] Referring to the conditions of Example 1, it was reacted with monomethyl polyethylene glycol p-toluenesulfonate (monomethyl polyethylene glycol molecular weight: 296 Daltons) (1.56 g, 3.47 mmol) to obtain a brown viscous liquid. Purified by silica gel column chromatography (eluted with ethyl acetate:methanol=50:1) to obtain (E)-3-(3'-{2-[2-(2-{2-[2-(2 -methoxyethoxy)-ethoxy]ethoxy}ethoxy)-ethoxy]ethoxy}-4'-methoxyphenyl)-2-(...

Embodiment 3

[0075] (Z)&(E)-3'-O-(1,3-bis{2-[2-(2-methoxyethoxy)ethoxy]ethyl}propanediol-2-yl)-con Puritin A-4.

[0076] Referring to Example 1, with 3,4,5-trimethoxyphenylacetic acid and isovanillin as starting materials, acetic anhydride was changed to butyric anhydride, the reaction temperature was changed to 170°C, the reaction time was changed to 4 hours, and other conditions were not changed. change, to obtain light yellow fine needle crystals (E)-3-(3'-hydroxy-4'-methoxyphenyl)-2-(3", 4", 5"-trimethoxyphenyl) propane- 2-enoic acid.

[0077] Referring to the conditions of Example 1, it was reacted with monomethyl polyethylene glycol p-toluenesulfonate (multi-arm monomethyl polyethylene glycol molecular weight 400 Daltons) (2.25 g, 4.17 mmol) to obtain a light yellow solid. Purified by silica gel column chromatography (dichloromethane:methanol=100:1 elution) to obtain (E)-3-{3'-[1,3-bis(3,6,9-trioxodecane) as a white solid Base) glycerol-2-yl]-4'-methoxyphenyl}-2-(3", 4", 5"-trimet...

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Abstract

The invention discloses water-solubility derivate of the antineoplastic medicine Combretastatin and the corresponding preparing method, and belongs to the technical field of medical and chemical industry. The compound of the invention takes substituted phenylacetic acid and isovanillin or the substitutional isovanillin as the initial material, and by condensation obtains (E)-substituted styrene acid; after that decorates a target group by amphotericity multi-polymer micromolecule with ether linkage, and finally, obtains water-solubility antineoplastic medicine Combretastatin derivate decorated by amphotericity multi-polymer micromolecule through decarboxylation or further decorating alkene linkage. The water-solubility is remarkably improved compared with the Combretastatin and the derivates before decoration, and basically maintains the intrinsic lipid solubility. Apart from easy material obtaining, the invention has the advantages of short synthesis line, simple operation and high yield as well as possessing strong selectivity to the cis-product with activity.

Description

technical field [0001] The invention relates to a derivative in the technical field of medicine and chemical engineering and a preparation method thereof, in particular to a water-soluble derivative of compretidine, an antitumor drug modified by an amphiphilic polymer small molecule, and a preparation method thereof. Background technique [0002] Combretastatins is an active ingredient isolated from the tropical tree Combretum Caffrum in South Africa. It has a similar chemical structure to the anti-mitotic drug colchicine and has a higher affinity to the colchicine-binding site on tubulin. Studies have found that by utilizing the physiological differences between tumor tissue and normal tissue endothelial cells, compretin can selectively inhibit the binding of tumor tubulin, change the skeleton structure and morphology of endothelial cells, enhance its vascular permeability, disrupt Blood flow, thereby causing apoptosis of tumor vascular endothelial cells, resulting in seco...

Claims

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Application Information

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IPC IPC(8): C07C43/215C07C41/09A61K47/48A61K31/09A61P35/00A61K47/60
Inventor 傅磊顾中怡陈尧邹燕张健存
Owner SHANGHAI JIAO TONG UNIV
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