title: Discovery, synthesis and biological evaluation of cycloprotoberberine derivatives as potential antitumor agents.
abstract: A series of new 1,13-cycloprotoberberine derivatives defined through variations at the 9-position were designed, synthesized and evaluated for their cytotoxicities in human HepG2 (hepatoma), HT1080 (fibrosarcoma) and HCT116 (colon cancer) cells. The preliminary structure-activity relationship (SAR) revealed that the replacement of 9-methoxyl with an ester moiety might significantly enhance the antiproliferative activity in vitro. Notably, compound 7f demonstrated equipotent cytotoxicity activity against breast cancer MCF-7 (parent) and doxorubicin (DOX)-resistant MCF-7 (MCF-7/ADrR) cells, indicating a mode of action different from that of DOX. Further mechanism study showed that 7f significantly inhibited activity of DNA topoisomerase I (Top I) and Top II. G2/M phase arrest and tumor cell growth reduction was observed thereafter. Thus, we consider cycloprotoberberine analogues to be a new family of promising antitumor agents with an advantage of inhibiting drug-resistant cancer cells.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China.
authors.forename: Yang-Biao
authors.initials: YB
authors.lastname: Li
authors.forename: Wu-Li
authors.initials: WL
authors.lastname: Zhao
authors.forename: Yan-Xiang
authors.initials: YX
authors.lastname: Wang
authors.forename: Cai-Xia
authors.initials: CX
authors.lastname: Zhang
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Jiang
authors.forename: Chong-Wen
authors.initials: CW
authors.lastname: Bi
authors.forename: Sheng
authors.initials: S
authors.lastname: Tang
authors.forename: Ru-Xian
authors.initials: RX
authors.lastname: Chen
authors.forename: Rong-Guang
authors.initials: RG
authors.lastname: Shao
authors.forename: Dan-Qing
authors.initials: DQ
authors.lastname: Song
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001600:Berberine Alkaloids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D003500:Cyclization; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D008954:Models, Biological; D062105:Molecular Docking Simulation; D015394:Molecular Structure
chemical_list: D000970:Antineoplastic Agents; D001600:Berberine Alkaloids; C009090:protoberberine
keywords: Antiproliferative; Cycloprotoberberine; Drug resistance; Structure−activity relationship; Topoisomerase