Design and Synthesis of 2-(3-Benzo[b]thienyl)-6,7-methylenedioxyquinolin-4-one Analogues as Potent Antitumor Agents that Inhibit Tubulin Assembly

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• 作者：Yu-Hsun Chang ; Mei-Hua Hsu ; Sheng-Hung Wang ; Li-Jiau Huang ; Keduo Qian ; Susan L. Morris-Natschke ; Ernest Hamel ; Sheng-Chu Kuo ; Kuo-Hsiung Lee
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：August 13, 2009
• 年：2009
• 卷：52
• 期：15
• 页码：4883-4891
• 全文大小：892K
• 年卷期：v.52,no.15(August 13, 2009)
• ISSN：1520-4804

文摘

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 μM. Results from mechanism of action studies revealed that these new quinolone derivatives function as antitubulin agents.