Design and synthesis of 2-(3-benzo[b]thienyl)-6,7-methylenedioxyquinolin-4-one analogues as potent antitumor agents that inhibit tubulin assembly.
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.
Chang
Yu-Hsun
YH
Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan.
Hsu
Mei-Hua
MH
Wang
Sheng-Hung
SH
Huang
Li-Jiau
LJ
Qian
Keduo
K
Morris-Natschke
Susan L
SL
Hamel
Ernest
E
Kuo
Sheng-Chu
SC
Lee
Kuo-Hsiung
KH
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
C525063:2'-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone; D000970:Antineoplastic Agents; D004149:Dioxoles; D015363:Quinolones; D050257:Tubulin Modulators