title: Discovery of novel polycyclic spiro-fused carbocyclicoxindole-based anticancer agents.
abstract: A series of novel polycyclic spiro-fused carbocyclicoxindoles were synthesized and investigated for their in vitro antiproliferative activities against nine human cancer cell lines. Five compounds (10i, 10l, 10n, 10p, and 10r) demonstrated anticancer activities against A2780s cells with IC50values of less than 30 μM. In particular, compound 10i showed anticancer activities against seven cancer cell lines and stronger activities than cisplatin in A2780s, A2780T, CT26, and HCT116 cells. Further studies illustrated that compound 10i arrested cell cycle in G1 phase and induced apoptosis of HCT116 cells. This compound also effectively increased the protein levels of cleaved caspase-3, p53, and MDM2. Molecular docking results revealed that compound 10i could bind well to the p53-binding site on MDM2, indicating that it might work by blocking the MDM2-p53 interactions.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Lidan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Ren
authors.affiliation: Analytical & Testing Center, Sichuan University, Chengdu 610064, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Jiaying
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China. Electronic address: liujie2011@scu.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Chengdu University, Sichuan Industrial Institute of Antibiotics, Chengdu 610052, China. Electronic address: lifengzhao@scu.edu.cn.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China. Electronic address: zhang-xia@scu.edu.cn.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D000078183:Oxindoles; D011487:Protein Conformation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D000078183:Oxindoles; D013141:Spiro Compounds; D016159:Tumor Suppressor Protein p53; C022960:2-oxindole; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Antiproliferative activity; MDM2; Polycyclic spiro-fused carbocyclicoxindoles; p53 inducer