Novel Antitumor Indolizino[6,7-b]indoles with Multiple Modes of Action: DNA Cross-Linking and Topoisomerase I and II Inhibition

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• 作者：Ravi Chaniyara ; Satishkumar Tala ; Chi-Wei Chen ; Xiuguo Zang ; Rajesh Kakadiya ; Li-Fang Lin ; Ching-Huang Chen ; Shin-I Chien ; Ting-Chao Chou ; Tung-Hu Tsai ; Te-Chang Lee ; Anamik Shah ; Tsann-Long Su
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：February 28, 2013
• 年：2013
• 卷：56
• 期：4
• 页码：1544-1563
• 全文大小：746K
• 年卷期：v.56,no.4(February 28, 2013)
• ISSN：1520-4804

文摘

A series of bis(hydroxymethyl)indolizino[6,7-b]indoles and their bis(alkylcarbamates) were synthesized for antitumor studies. These agents were designed as hybrid molecules of 尾-carboline (topoisomerase inhibition moiety) and bis(hydroxymethyl)pyrrole (DNA cross-linking moiety). The preliminary antitumor studies indicated that these agents exhibited significant cytotoxicity against a variety of human tumor cells in vitro. Treatment of human breast carcinoma MX-1 xenograft-bearing nude mice with compounds 18b and 28c achieved more than 99% tumor remission. We also observed that 18a displayed potent therapeutic efficacy against human lung adenocarcinoma A549 and colon cancer HT-29 xenografts. These results revealed that compound 18a was more potent than irinotecan against HT-29 cells and was as potent as irinotecan against A549 cells in xenograft models. Furthermore, we demonstrated that these derivatives possess multiple modes of action, such as induction of DNA cross-linking, inhibition of topoisomerase I and II, and cell-cycle arrest at the S-phase.