Design, Synthesis, and Preclinical Evaluation of New 5,6- (or 6,7-) Disubstituted-2-(fluorophenyl)quinolin-4-one Derivatives as Potent Antitumor Agents

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• 作者：Li-Chen Chou ; Meng-Tung Tsai ; Mei-Hua Hsu ; Sheng-Hung Wang ; Tzong-Der Way ; Chi-Hung Huang ; Hui-Yi Lin ; Keduo Qian ; Yizhou Dong ; Kuo-Hsiung Lee ; Li-Jiau Huang ; Sheng-Chu Kuo
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：November 25, 2010
• 年：2010
• 卷：53
• 期：22
• 页码：8047-8058
• 全文大小：1156K
• 年卷期：v.53,no.22(November 25, 2010)
• ISSN：1520-4804

文摘

Our previous exploration of 2-phenylquinolin-4-ones (2-PQs) has led to an anticancer drug candidate 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one monosodium phosphate (CHM-1−P-Na). In order to develop additional new drug candidates, novel 2-PQs were designed, synthesized, and evaluated for cytotoxic activity. Most analogues, including 1b, 2a,b, 3a,b, 4a,b, and 5a,b, exhibited significant inhibitory activity (IC₅₀ of 0.03−8.2 μM) against all tested tumor cell lines. As one of the most potent analogue, 2-(3-fluorophenyl)-5-hydroxy-6-methoxyquinolin-4-one (3b) selectively inhibited 14 out of 60 cancer cell lines in a National Cancer Institute (NCI) evaluation. Preliminary mechanism of action study suggested that 3b had a significant effect on the tyrosine autophosphorylation of insulin-like growth factor-1 receptor (IGF-1R). Safety pharmacology profiling of 3b showed no significant effect on normal biological functions of most enzymes tested. Furthermore, sodium 2-(3-fluorophenyl)-6-methoxy-4-oxo-1,4-dihydroquinolin-5-yl phosphate (15), the monophosphate of 3b, exceeded the activity of doxorubicin and was comparable to CHM-1−P-Na in a Hep3B xenograft nude mice model. In summary, 15 is a promising clinical candidate and is currently under preclinical study.