title: Structure-activity relationship in the antitumor activity of 6-, 8- or 6,8-substituted 3-benzylamino-β-carboline derivatives.
abstract: We synthesized 47 kinds of 3-amino- or 3-benzylamino-β-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-β-carboline (17a) and 8-methylamino-3-(3-phenoxybenzyl)amino-β-carboline (17c) with antitumor activity with IC(50) values of 0.046, 0.032 μM, respectively, against HeLa S-3 cell line, which are higher than that of previously reported 3-(3-phenoxybenzyl)amino-β-carboline (10e) of 0.074 μM. Furthermore, effects of Cl group at 6-carbon atom on the type of cell death was evaluated using 3-benzylamino-6-chloro-β-carboline (10b), 3-benzylamino-β-carboline (10d), N-(3-benzylamino)-6-chloro-9H-β-carbolin-8-yl)benzamide (14g), and N-(3-benzylamino-9H-β-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 G(2)/M phase.
authors.affiliation: Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI), Noda, Chiba, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Ikeda
authors.forename: Takanori
authors.initials: T
authors.lastname: Kimura
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Tsutsumi
authors.forename: Syunsuke
authors.initials: S
authors.lastname: Tamura
authors.forename: Norio
authors.initials: N
authors.lastname: Sakai
authors.forename: Takeo
authors.initials: T
authors.lastname: Konakahara
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002243:Carbolines / Q000737:chemistry* / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D013329:Structure-Activity Relationship
chemical_list: C558522:3-benzylamino-beta-carboline; D000970:Antineoplastic Agents; D002243:Carbolines