Structure-activity relationship in the antitumor activity of 6-, 8- or 6,8-substituted 3-benzylamino-尾-carboline derivatives

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• 作者：Reiko Ikeda^a ; ^b ; Takanori Kimura^a ; Tatsuya Tsutsumi^a ; Syunsuke Tamura^a ; Norio Sakai^a ; Takeo Konakahara^a ; ^b ; ^{konaka@rs.noda.tus.ac.jp}
• 关键词：尾-Carboline ; Antitumor drug ; Apoptosis ; Cell cycle in the G2/M phase ; Structure&ndash ; activity relationship
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 May, 2012
• 卷：22
• 期：10
• 页码：3506-3515
• 文件大小：5222 K

摘要

We synthesized 47 kinds of 3-amino- or 3-benzylamino-尾-carboline derivatives with a substituent on the 6-, 8-, or 6,8-carbon atoms and evaluated their antitumor activities for Hela S-3 and Sarcoma 180 cell lines using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Consequently, we succeeded to develop 3-benzylamino-8-methylamino-尾-carboline (17a) and 8-methylamino-3-(3-phenoxybenzyl)amino-尾-carboline (17c) with antitumor activity with IC₅₀ values of 0.046, 0.032 渭M, respectively, against HeLa S-3 cell line, which are higher than that of previously reported 3-(3-phenoxybenzyl)amino-尾-carboline (10e) of 0.074 渭M. Furthermore, effects of Cl group at 6-carbon atom on the type of cell death was evaluated using 3-benzylamino-6-chloro-尾-carboline (10b), 3-benzylamino-尾-carboline (10d), N-(3-benzylamino)-6-chloro-9H-尾-carbolin-8-yl)benzamide (14g), and N-(3-benzylamino-9H-尾-carbolin-8-yl)benzamide (17b) to show no effect. Hoechst 33342 staining and DNA fragmentation assay suggested that these compounds induced cell death by apoptosis. In addition, using flow cytometry analysis, we established that the cell death pathway was through the arrest of the cell cycle in the G₂/M phase.