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Heterocyclic aromatic acid ester type podophyllotoxin derivatives with anti-tumor activity as well as preparation method and application

A technology of anti-tumor activity and podophyllotoxin, applied in the direction of anti-tumor drugs, organic chemistry, drug combination, etc., can solve the problems of high toxicity and side effects, easy to produce drug resistance, etc., and achieve a strong inhibitory effect

Inactive Publication Date: 2016-10-12
ZUNYI MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, novel podophyllotoxin antineoplastic drugs such as etoposide and teniposide still have relatively large toxic and side effects and are prone to drug resistance, so people's research on podophyllotoxin has not stopped

Method used

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  • Heterocyclic aromatic acid ester type podophyllotoxin derivatives with anti-tumor activity as well as preparation method and application
  • Heterocyclic aromatic acid ester type podophyllotoxin derivatives with anti-tumor activity as well as preparation method and application
  • Heterocyclic aromatic acid ester type podophyllotoxin derivatives with anti-tumor activity as well as preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1: Preparation of 4α-(thiazole-4-yl)-4-deoxy-podophyllotoxin (1)

[0026] Add podophyllotoxin (0.29 mmol), 4-dimethylaminopyridine (0.46 mmol) and 4-thiazole formic acid (0.29 mmol), then add N,N-dimethylformamide (5 mL), stir at 25°C for 10 minutes, then add 1-(3-dimethylaminopropyl)-3-ethyl carbon in batches Diimine hydrochloride (0.58 mmol). Under the protection of nitrogen, the reaction solution was stirred and reacted at 25°C 4 Hour. The reaction solution was poured into water, stirred to precipitate a solid, filtered with suction, washed with water, and dried in vacuo to obtain a crude product. The crude product was purified by column chromatography to obtain a white solid product 4α-(thiazole-4-yl)-4-deoxy-podophyllotoxin (1), yield 72%.

[0027] Mp: 251~253℃; 1 H NMR (400 MHz, CDCl 3 ) δ 8.89 (d, J = 1.6 Hz, 1H), 8.27 (d, J = 1.6 Hz, 1H), 6.88 (s, 1H), 6.57 (s, 1H), 6.44 (s, 2H), 6.14 (d ,J = 8.4 Hz, 1H), 5.97 (s, 2H), 4.64 (d, J = 2.4 Hz, 1H)...

Embodiment 2

[0028] Example 2: Preparation of 4α-(1-methylpyrazole-4-yl)-4-deoxy-podophyllotoxin (2)

[0029] Add podophyllotoxin (0.29 mmol), 4-dimethylaminopyridine (0.46 mmol) and 1-Methyl Pyrazole-4-carboxylic acid (0.29 mmol), then add N,N-dimethylformamide (5 mL), stir at 25°C for 10 minutes, then add 1-(3-dimethylaminopropyl)-3-ethyl carbon in batches Diimine hydrochloride (0.58 mmol). Under the protection of nitrogen, the reaction solution was stirred and reacted at 25°C 6 Hour. The reaction solution was poured into water, stirred to precipitate a solid, filtered with suction, washed with water, and dried in vacuo to obtain a crude product. The crude product was purified by column chromatography to obtain a white solid product 4α-(1-methylpyrazole-4-yl)-4-deoxy-podophyllotoxin Su (2), yield 70%.

[0030] Mp: 126~128℃; 1 H NMR (400 MHz, CDCl 3) δ 7.88 (d, J = 11.6 Hz, 2H), 6.82 (s, 1H), 6.55 (s, 1H), 6.41 (s, 2H), 6.02 (d, J = 8.4 Hz, 1H), 5.97 (d ,J = 8.0 Hz, 2H), 4.6...

Embodiment 3

[0031] Example 3: Preparation of 4α-(1-methylimidazol-4-yl)-4-deoxy-podophyllotoxin (3)

[0032] Add podophyllotoxin (0.29 mmol), 4-dimethylaminopyridine (0.46 mmol) and 1-Methyl imidazole-4-carboxylic acid (0.32 mmol), Then N,N-dimethylformamide (5 mL) was added, Stir for 5 minutes at 30°C Then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.58 mmol) was added in batches. Under nitrogen protection, Reaction solution in Stir the reaction at 30°C for 4 hours . The reaction solution was poured into water, stirred to precipitate a solid, filtered with suction, washed with water, and dried in vacuo to obtain a crude product. The crude product was purified by column chromatography to obtain a white solid product 4α-(1-Methylimidazol-4-yl)-4-deoxy-podophyllotoxin (3), yield 57%.

[0033] Mp: 143~145℃; 1 H NMR (400 MHz, CDCl 3 ) δ 7.58 (s, 1H), 7.50 (s, 1H),6.85 (s, 1H), 6.52 (s, 1H), 6.43 (s, 2H), 6.06 (d, J = 7.2 Hz, 1H), 5.94 (s,2H), 4.60 (s, 1H), ...

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Abstract

The invention discloses an aromatic heterocyclic ester podophyllotoxin derivative represented by formula (I), its preparation method and its use in the preparation of antitumor drugs. The present invention combines podophyllotoxin with 4-thiazole formic acid, 1-methylpyrazole-4-formic acid, 1-methylimidazole-4-formic acid, isoquinoline-1-formic acid, 2-quinoxaline formic acid, 1- Esterification with cyclopropyl-1,4-dihydro-4-oxo-6-fluoro-7-chloroquinoline-3-carboxylic acid, 1-methylindazole-3-carboxylic acid or thioindene-2-carboxylic acid , to obtain the aromatic heterocyclic ester podophyllotoxin derivatives represented by the formula (I) with antitumor activity. In vitro cell activity experiments prove that the aromatic heterocyclic ester podophyllotoxin derivatives of the present invention can inhibit the proliferation of tumor cells, have significant antitumor activity, and are expected to be prepared as podophyllotoxin antitumor drugs.

Description

technical field [0001] The invention relates to a class of aromatic heterocyclic acid ester podophyllotoxin derivatives, a preparation method thereof, and an application thereof in the field of antitumor. Background technique [0002] Podophyllotoxin is a lignan natural product isolated from podophyllum plants with significant antitumor activity. However, the clinical use of podophyllotoxin is largely limited due to its relatively large toxic and side effects and poor bioavailability. Therefore, in order to improve the activity and reduce the side effects, the structural modification and transformation of podophyllotoxin as the lead compound has attracted widespread attention, and people have successfully obtained clinical antitumor drugs such as etoposide and teniposide. However, novel podophyllotoxin-like antitumor drugs such as etoposide and teniposide still have relatively large toxic and side effects and are prone to drug resistance, so people's research on podophyllot...

Claims

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Application Information

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IPC IPC(8): C07D493/04A61P35/00A61P35/02
CPCC07D493/04
Inventor 张磊王京陈永正
Owner ZUNYI MEDICAL UNIVERSITY
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