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Esterified podophyllum derivative with antitumor activity and preparation method and usage of esterified podophyllum derivative

A technology of anti-tumor activity and derivatives, applied in the direction of anti-tumor drugs, organic active ingredients, medical preparations containing active ingredients, etc., can solve the problems of low anti-tumor activity and limited use

Inactive Publication Date: 2013-01-16
HUBEI UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, podophyllotoxin and 4′-desmethyl epipodophyllotoxin have defects such as low anti-tumor activity in varying degrees, which limits their clinical use

Method used

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  • Esterified podophyllum derivative with antitumor activity and preparation method and usage of esterified podophyllum derivative
  • Esterified podophyllum derivative with antitumor activity and preparation method and usage of esterified podophyllum derivative
  • Esterified podophyllum derivative with antitumor activity and preparation method and usage of esterified podophyllum derivative

Examples

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Effect test

Embodiment 1

[0036] Example 1 Synthesis and purification of 4-O-(adamantanecarboxylic acid-1)-4-deoxy-4'-desmethyl epipodophyllotoxin (compound (1))

[0037] (1) Synthesis of 4-O-(adamantanecarboxylic acid-1)-4-deoxy-4'-desmethyl epipodophyllotoxin: Weigh 207mg of 4'-desmethyl epipodophyllotoxin and 270mg of adamantanecarboxylic acid respectively In a plate, vacuum-dry at 45°C for 2 hours; under the protection of nitrogen, add the dried 4'-desmethyl epipodophyllotoxin and adamantanecarboxylic acid and 1236 mg of dicyclohexylcarbodiimide into a four-necked bottle, and then add 10ml of dried dichloromethane, stirred and reacted for 30min, then added 10mg of 4-dimethylaminopyridine to the reaction system, and reacted at room temperature 25°C for 24 hours; after the reaction was completed, filter the reaction solution with filter paper to remove insoluble matter, add 100ml of deionized water, keep the organic phase, repeat twice, then back-extract the aqueous phase obtained in the previous ste...

Embodiment 2

[0042] Example 2 Synthesis and purification of 4-O-(adamantanecarboxylic acid-1)-4-deoxypodophyllotoxin (compound (2))

[0043] (1) Synthesis of 4-O-(adamantanecarboxylic acid-1)-4-deoxypodophyllotoxin: Weigh 207mg of podophyllotoxin and 510mg of adamantanecarboxylic acid respectively in a plate, dry in vacuum at 45°C for 2 hours; , add the dried podophyllotoxin, adamantanecarboxylic acid and 1236mg of dicyclohexylcarbodiimide into a four-necked flask, then add 10ml of dried dichloromethane, stir for 30min, and then add 10mg of 4-dichloromethane to the reaction system Methylaminopyridine, react at 20°C for 48 hours; after the reaction is completed, filter the reaction solution with filter paper to remove insoluble matter, add 100ml deionized water, keep the organic phase, repeat twice, and then use dichloromethane to dilute the obtained solution in the previous step. The aqueous phase was back-extracted, the organic layers were combined, dried overnight with anhydrous sodium s...

Embodiment 3

[0049] Example 3 Synthesis and purification of 4-O-(4-(pyrimidinethio)acetic acid-1)-4-deoxy-4'-desmethyl epipodophyllotoxin (compound (3))

[0050] (1) Synthesis of 4-O-(4-(pyrimidinethio)acetic acid-1)-4-deoxy-4′-desmethyl epipodophyllotoxin: Weigh 200mg of 4′-desmethyl epipodophyllotoxin respectively and 504mg of 4-(pyrimidinylthio)acetic acid in a plate, and vacuum-dry at 45°C for 2 hours; In the four-neck flask, add 2ml of dried dichloromethane and 1.6ml of triethylamine to react for 30min, add 5mg of 4-dimethylaminopyridine to the reaction system, and react at 25°C for 24 hours. After completion of the reaction, filter the reaction solution with filter paper to remove insoluble matter, add 100ml of deionized water, keep the organic phase, repeat twice, then use dichloromethane to back-extract the aqueous phase obtained in the previous step, combine the organic layers, and use Dry overnight with anhydrous sodium sulfate, spin dry to obtain the crude product of 4-O-(4-(py...

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Abstract

The invention discloses an esterified podophyllum derivative with antitumor activity and a preparation method and the usage of the esterified podophyllum derivative. The esterified podophyllum derivative with antitumor activity and shown as a formula (V) is obtained by means of esterification reaction of adamantine formic acid, orotic acid, 4-(pyrimidine sulfo) phenylacetic acid, cyclohexane carboxylic acid, 3,4-dimethoxy benzoic acid, 2-butoxycarbonyl-3-phenylalanine or 4-methoxy phenylacetic acid with podophyllotoxin or 4'-demethyl-epipodophyllotoxin. The esterified podophyllum derivative has multi-way multi-target actions on tumor cells to achieve better antitumor curative effects. According to in-vitro cell viability inhibition tests, the esterified podophyllum derivative has excellent antitumor activity and low toxic and side effects and can be prepared into antitumor drugs to be applied to antitumor treatment.

Description

technical field [0001] The present invention relates to podophyllin derivatives, in particular to esterified podophyllin derivatives with anti-tumor activity obtained by substituting the 4-position of C ring of podophyllotoxin or 4'-desmethyl epipodophyllotoxin and preparation thereof The method, the present invention also relates to the use of the esterified podophyllum derivatives in the preparation of antitumor drugs, which belongs to the field of preparation and application of podophyllum derivatives. Background technique [0002] Podophyllotoxin and 4′-Demethylepipodophyllotoxin (4′-Demethylepipodophyllotoxin) are extracted from podophyllum plants (for example: Berberidaceae plant Taoerqi, mountain lotus leaf, star anise lotus, etc.) The obtained natural active lead compound with unique antitumor activity. However, podophyllotoxin and 4'-desmethylepipodophyllotoxin have defects such as low antitumor activity to varying degrees, which limits their clinical use. Conten...

Claims

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Application Information

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IPC IPC(8): C07D493/04A61K31/365A61K31/443A61K31/513A61P35/00
Inventor 汤亚杰肖黎
Owner HUBEI UNIV OF TECH
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