title: Discovery of a novel series of quinolone and naphthyridine derivatives as potential topoisomerase I inhibitors by scaffold modification.
abstract: A novel series of topoisomerase I (Top I) inhibitors were designed on the basis of camptothecin using scaffold modification strategy. Thirty-one new compounds were synthesized and evaluated for anticell proliferation activity. The most potent compound 26 presented a significant inhibitory effect on Top I, leading to Top I-mediated cleavage and influences on Top I expression at the cellular level. Moreover, 26 was proved to induce cell death via apoptosis and accelerated DNA strand breaks without significant alteration in cell cycle populations. All of the experimental results herein indicated that 26 could interact with DNA-Top I complex and induce cancer cell apoptosis to produce antitumor effects. The in vivo evaluation of 26 on the growth of HT-29 tumor xenografts in nude mice suggested its therapeutic potential for further development.
authors.affiliation: School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. youqidong@gmail.com
authors.forename: Qi-Dong
authors.initials: QD
authors.lastname: You
authors.forename: Zhi-Yu
authors.initials: ZY
authors.lastname: Li
authors.forename: Chiung-Hua
authors.initials: CH
authors.lastname: Huang
authors.forename: Qian
authors.initials: Q
authors.lastname: Yang
authors.forename: Xiao-Jian
authors.initials: XJ
authors.lastname: Wang
authors.forename: Qing-Long
authors.initials: QL
authors.lastname: Guo
authors.forename: Xiao-Guang
authors.initials: XG
authors.lastname: Chen
authors.forename: Xun-Gui
authors.initials: XG
authors.lastname: He
authors.forename: Tsai-Kun
authors.initials: TK
authors.lastname: Li
authors.forename: Ji-Wang
authors.initials: JW
authors.lastname: Chern
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D008968:Molecular Conformation; D009287:Naphthyridines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D015363:Quinolones / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D059004:Topoisomerase I Inhibitors; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009287:Naphthyridines; D015363:Quinolones; D059004:Topoisomerase I Inhibitors; D004247:DNA