title: Design and synthesis of 2-(3-benzo[b]thienyl)-6,7-methylenedioxyquinolin-4-one analogues as potent antitumor agents that inhibit tubulin assembly.
abstract: As part of our continuing investigation of azo-flavonoid derivatives as potential anticancer drug candidates, a series of 2-aryl-6,7-methylenedioxyquinolin-4-one analogues was designed and synthesized. The design combined structural features of 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one (CHM-1), a previously discovered compound with potent in vivo antitumor activity, and 2-arylquinolin-4-ones, identified by CoMFA models. The newly synthesized analogues were evaluated for cytotoxicity against seven human cancer cell lines, and structure-activity relationship (SAR) correlations were established. Analogues 1, 37, and 39 showed potent cytotoxicity against different cancer cell lines. Compound 1 demonstrated selective cytotoxicity against Hep 3B (hepatoma) cells. Compound 37 was cytotoxic against HL-60 (leukemia), HCT-116 (colon cancer), Hep 3B (hepatoma), and SK-MEL-5 (melanoma) cells. Compound 39 exhibited broad cytotoxicity against all seven cancer cell lines, with IC50 values between 0.07 and 0.19 microM. Results from mechanism of action studies revealed that these new quinolone derivatives function as antitubulin agents.
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan.
authors.forename: Yu-Hsun
authors.initials: YH
authors.lastname: Chang
authors.forename: Mei-Hua
authors.initials: MH
authors.lastname: Hsu
authors.forename: Sheng-Hung
authors.initials: SH
authors.lastname: Wang
authors.forename: Li-Jiau
authors.initials: LJ
authors.lastname: Huang
authors.forename: Keduo
authors.initials: K
authors.lastname: Qian
authors.forename: Susan L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.forename: Sheng-Chu
authors.initials: SC
authors.lastname: Kuo
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D004149:Dioxoles / Q000494:pharmacology; D015195:Drug Design; D018922:HL-60 Cells; D006801:Humans; D051379:Mice; D015363:Quinolones / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C525063:2'-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone; D000970:Antineoplastic Agents; D004149:Dioxoles; D015363:Quinolones; D050257:Tubulin Modulators