Novel combretastatin analogues effective against murine solid tumors: Design and structure-activity relationships

被引：274

作者：

Ohsumi, K ^{[1
]}

Nakagawa, R ^{[1
]}

Fukuda, Y ^{[1
]}

Hatanaka, T ^{[1
]}

Morinaga, Y ^{[1
]}

Nihei, Y ^{[1
]}

Ohishi, K ^{[1
]}

Suga, Y ^{[1
]}

Akiyama, Y ^{[1
]}

Tsuji, T ^{[1
]}

机构：

[1] Ajinomoto Co Inc, Cent Res Labs, Kawasaki Ku, Kawasaki, Kanagawa 210, Japan

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1998年 / 41卷 / 16期

关键词：

D O I：

10.1021/jm980101w

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of combretastatin A-4 (CA-4) analogues were synthesized, and their cytotoxic effects against murine Colon 26 adenocarcinoma and inhibitory activity on tubulin polymerization were evaluated. Since CA-4 has limited aqueous solubility, the target compounds were designed to improve solubility by introduction of a nitrogen-containing group. Among the compounds synthesized, those with an amino moiety in place of the phenolic OH of CA-4 showed potent antitubulin activity and cytotoxicity against murine Colon 26 adenocarcinoma in vitro. Some of the compounds which were potent in vitro were evaluated in the murine tumor model Colon 26 in vivo. Among these, 13bHCl, 21aHCl, and 21bHCl showed significant antitumor activity in the animal model, while CA-4 was ineffective. 13bHCl and 21aHCl were further evaluated in two murine tumor models (Colon 38 and 3LL) and human xenografts HCT-15. These compounds showed potent antitumor activity comparable or superior to that of CDDP. The structure-activity relationships of this series of compounds are also discussed.

引用

页码：3022 / 3032

页数：11

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