Synthesis and pharmacological evaluation of novel bisindole derivatives bearing oximes moiety: Identification of novel proapoptotic agents

• Published in: European journal of medicinal chemistry Vol. 95; pp. 400 - 415
• Main Authors: Qu, Hong-En, Huang, Ri-Zhen, Yao, Gui-Yang, Li, Jiu-Ling, Ye, Man-Yi, Wang, Heng-Shan, Liu, Liangxian
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.05.2015; Elsevier
• Subjects: Anti-cancer; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Bisindole; Caspase 3 - metabolism; Caspase 9 - metabolism; Cell Cycle - drug effects; Cell cycle arrest; Cell Line, Tumor; Chemistry Techniques, Synthetic; Chemistry, Medicinal; Drug Screening Assays, Antitumor; Humans; Indoles - chemistry; Intracellular Space - drug effects; Intracellular Space - metabolism; Life Sciences & Biomedicine; Membrane Potential, Mitochondrial - drug effects; Oxime; Oximes - chemical synthesis; Oximes - chemistry; Oximes - pharmacology; Pharmacology & Pharmacy; Reactive Oxygen Species - metabolism; Science & Technology; Cell cycle arrest; Oxime; Bisindole; Anti-cancer; Apoptosis; CANCER-CELLS; SURVIVAL; INDUCTION; ANTITUMOR-ACTIVITY; IN-VITRO; POTENT; INDOLE-3-CARBINOL; INDOLE ALKALOIDS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.03.058

In an effort to develop potent anti-cancer chemopreventive agents, a novel series of bisindole derivatives bearing oxime moiety were synthesized. Structures of all compounds were characterized by NMR and HRMS. Anti-proliferative activities for all of these compounds were investigated by the method of MTT assay on 7 human cancer lines and the normal cell lines (HUVEC). Most of them showed a noteworthy anti-cancer activity in vitro, the half maximal inhibitory concentration (IC50) value is 4.31 μM of 4e against T24. The results from Hoechst 33258 and acridine orange/propidium iodide staining as well as annexinV-FITC assays provided evidence for an apoptotic cell death. The further mechanisms of compound 4e-induced apoptosis in T24 cells demonstrated that compound 4e induced the productions of ROS, and altered anti- and pro-apoptotic proteins, leading to mitochondrial dysfunction and activations of caspase-9 and caspase-3 for causing cell apoptosis. Moreover, the cell cycle analysis and western-blot analysis indicated that compound 4e effectively arrested T24 cells in G1 stage and possibly has an effect on cell cycle regulatory proteins particularly cyclin D1. A series of bisindole derivatives bearing oxime moiety were synthesized. Representative compound 4e may induce apoptosis through a mitochondrion-dependent pathway and possibly has an effect on cell cycle regulatory proteins. [Display omitted] •A novel series of bisindole derivatives bearing oxime moiety were synthesized.•Some of compounds showed good anti-proliferative activities against tumor cells than the commercial anticancer drug 5-Fu.•Representative compounds 4e may induce apoptosis through a mitochondrion-dependent pathway.•4e effectively arrested T24 cells in G1 stage and possibly has an effect on cell cycle regulatory proteins.