Esterified podophyllum derivative with antineoplastic activity and preparation method and application thereof

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 large toxic and side effects, limited use, poor bioavailability, etc., and achieve anti-tumor Increased activity and good anti-tumor efficacy

Inactive Publication Date: 2013-10-16
HUBEI UNIV OF TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, 4'-desmethyl epipodophyllotoxins have defects such as large toxic and side effects and poor bioavailability to varying degrees, which seriously limit their clinical use. Therefore, for 4'-desmethyl epipodophyllotoxins Modification of the structure of phyllotoxin to obtain podophyllin derivatives with improved anti-tumor activity or reduced side effects will be of great significance for the clinical treatment of tumors

Method used

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  • Esterified podophyllum derivative with antineoplastic activity and preparation method and application thereof
  • Esterified podophyllum derivative with antineoplastic activity and preparation method and application thereof
  • Esterified podophyllum derivative with antineoplastic activity and preparation method and application thereof

Examples

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Embodiment 1

[0036] Example 1 Synthesis and purification of 4-O-(2-pyrazinecarboxylic acid-1)-4-deoxy-4'-desmethyl epipodophyllotoxin (compound 1)

[0037] (1) Synthesis of 4-O-(2-pyrazinecarboxylic acid-1)-4-deoxy-4'-desmethyl epipodophyllotoxin: Weigh 400mg4'-desmethyl epipodophyllotoxin and 124mg2 -Pyrazinecarboxylic acid in a plate, vacuum-dried at 45°C for 2h; under the protection of nitrogen, add the dried 4'-desmethyl epipodophyllotoxin, 2-pyrazinecarboxylic acid and 208mg of dicyclohexylcarbodiimide Add 10 mL of dried dichloromethane to the four-neck flask, stir for 6 minutes, then add 40 mg of 4-dimethylaminopyridine to the reaction system, and react at room temperature for 24 hours at 25°C; after the reaction, filter the reaction solution with filter paper , remove the insoluble matter, add 100mL deionized water, keep the organic phase, repeat twice, then back-extract the aqueous phase obtained in the previous step with dichloromethane, combine the organic layers, dry overnight w...

Embodiment 2

[0043] Example 2 Synthesis and purification of 4-O-(5-methyl 2-pyrazinecarboxylic acid-1)-4-deoxy-4'-desmethyl epipodophyllotoxin (compound 2)

[0044] (1) Synthesis of 4-O-(5-methyl-2-pyrazinecarboxylic acid-1)-4-deoxy-4'-desmethyl epipodophyllotoxin: Weigh 400mg of 4'-desmethyl epipodophyllotoxin Podophyllotoxin and 138mg of 5-methyl-2-pyrazinecarboxylic acid were placed in a plate, and vacuum-dried at 45°C for 2h; -Pyrazinecarboxylic acid and 208mg of dicyclohexylcarbodiimide were added to a four-neck flask, then 10mL of dry dichloromethane was added, and the reaction was stirred for 6min, then 40mg of 4-dimethylaminopyridine was added to the reaction system, and the mixture was heated at 25°C React for 24 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, then back-extract the aqueous phase obtained in the previous step with dichloromethane, and ...

Embodiment 3

[0050] Example 3 Synthesis and purification of 4-O-(theophylline acetate-1)-4-deoxy-4'-desmethyl epipodophyllotoxin (compound 3)

[0051] (1) Synthesis of 4-O-(theophylline acetic acid-1)-4-deoxy-4'-desmethyl epipodophyllotoxin: Weigh 400mg 4'-desmethyl epipodophyllotoxin and 238mg theophylline acetic acid respectively In a plate, vacuum-dry at 45°C for 2 hours; under the protection of nitrogen, add the dried 4'-desmethyl epipodophyllotoxin, theophylline acetic acid and 208 mg of dicyclohexylcarbodiimide into a four-necked bottle, and then add 5 mL Dried dichloromethane was stirred and reacted for 6 minutes, 40 mg of 4-dimethylaminopyridine was added to the reaction system, and reacted at 25° C. for 24 hours. After the reaction is completed, 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, and co...

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Abstract

The invention discloses an esterified podophyllum derivative with antineoplastic activity and a preparation method and application thereof. According to the invention, 2-pyrazine pyrazine, 5-methyl-2-pyrazine pyrazine, theophylline acetic acid, fluoroquinolone acid and 2-quinoline carboxylic acid are subjected to esterification reaction with 4'-demethylepipodophyllotoxin, so that the esterified podophyllum derivative with the antineoplastic activity, expressed by the formula (V), can be obtained. The esterified podophyllum derivative acts on cancer cells by means of multiple ways and multiple target points, and thus has better antineoplastic efficacy. As indicated by the in vitro cell activity inhibition test, the esterified podophyllum derivative disclosed by the invention has excellent antineoplastic activity and low toxic and side effects, and can be made into antineoplastic drugs for clinic antineoplastic treatment.

Description

technical field [0001] The present invention relates to podophyllotoxin derivatives, in particular to esterified podophyllotoxin derivatives with anti-tumor activity obtained by substituting the 4-position of the C ring of 4'-desmethyl epipodophyllotoxin and a preparation method thereof. It also relates to the use of the esterified podophyllotoxin derivatives in the preparation of antitumor drugs, belonging to the field of preparation and application of podophyllotoxin derivatives. Background technique [0002] Podophyllum plants belong to the Berberidaceae family, including the genus Anise, Podophyllum, and Heliconia. These plants have significant biological activity and have a long history of medicinal use. 4'-Demethylepipodophyllotoxin (4'-Demethylepipodophyllotoxin) is a natural active lead compound extracted from podophyllum plants with unique anti-tumor activity. However, 4'-desmethyl epipodophyllotoxins have defects such as large toxic and side effects and poor bioav...

Claims

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Application Information

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IPC IPC(8): C07D493/04C07D519/00A61K31/497A61K31/522A61K31/4709A61P35/00
CPCY02P20/582
Inventor 汤亚杰陈露赵巍
Owner HUBEI UNIV OF TECH
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