title: Synthesis and biological evaluation of 6-fluoro-3-phenyl-7-piperazinyl quinolone derivatives as potential topoisomerase I inhibitors.
abstract: The design and synthesis of a new series of 6-fluoro-3-phenyl-7-piperazinyl quinolone derivatives, built on the structure of 1-ethyl-3-(6-nitrobenzoxazol-2-yl)-6,8-difluoro-7-(3-methylpiperazin-1-yl)-4(1H)-quinolone, are described. These compounds provide new scaffold for the discovery of Topoisomerase I (Top I) inhibitors and target based assay showed that they can obviously inhibited Top I at 100 μM. The in vitro anti-proliferative activity of these new compounds was evaluated against A549, Hela, BGC-823, and HepG2 cell lines. Compounds 18a-g showed potent inhibitory activity against the growth of those cancer cell lines. The most positive compounds 18f and 18g demonstrated as potent as camptothecin in Top I inhibition assay and MTT assay. Compounds 18f and 18g led to an obvious increase in the percentage of S phase of the cells in 24 h. The in vivo data showed that 18f and 18g inhibited tumor growth with the inhibitory rate of 29.25% and 42.75% at 20 mg/kg, respectively. The data suggested the therapeutic potential for further development.
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China.
authors.forename: Raoling
authors.initials: R
authors.lastname: Ge
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China.
authors.forename: Zhouling
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China.
authors.forename: Qinglong
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China. Electronic address: zhiyuli@cpu.edu.cn.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China. Electronic address: zhaoli@cpu.edu.cn.
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004247:DNA / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D010879:Piperazines / Q000737:chemistry*; D011487:Protein Conformation; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D010879:Piperazines; D015363:Quinolones; D059004:Topoisomerase I Inhibitors; D004247:DNA; D004264:DNA Topoisomerases, Type I
keywords: Anti-proliferative activity; Quinolone derivatives; Synthesis; Top I inhibitors