title: Synthesis and pharmacological evaluation of novel bisindole derivatives bearing oximes moiety: identification of novel proapoptotic agents.
abstract: 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.
authors.affiliation: State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, PR China.
authors.forename: Hong-En
authors.initials: HE
authors.lastname: Qu
authors.affiliation: State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, PR China.
authors.forename: Ri-Zhen
authors.initials: RZ
authors.lastname: Huang
authors.affiliation: Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.
authors.forename: Gui-Yang
authors.initials: GY
authors.lastname: Yao
authors.affiliation: State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, PR China.
authors.forename: Jiu-Ling
authors.initials: JL
authors.lastname: Li
authors.affiliation: State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, PR China.
authors.forename: Man-Yi
authors.initials: MY
authors.lastname: Ye
authors.affiliation: State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, PR China. Electronic address: whengshan@163.com.
authors.forename: Heng-Shan
authors.initials: HS
authors.lastname: Wang
authors.affiliation: Department of Chemistry and Chemical Engineering, Gannan Normal University, Ganzhou, Jiangxi 341000, PR China. Electronic address: lxliu@xmu.edu.cn.
authors.forename: Liangxian
authors.initials: L
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D010091:Oximes; D017382:Reactive Oxygen Species; D053148:Caspase 3; D053453:Caspase 9
keywords: Anti-cancer; Apoptosis; Bisindole; Cell cycle arrest; Oxime