標題: Synthesis and Preclinical Evaluations of 2-(2-Fluorophenyl)-6,7-methylenedioxyquinolin-4-one Monosodium Phosphate (CHM-1-P-Na) as a Potent Antitumor Agent
作者: Chou, Li-Chen
Chen, Chien-Ting
Lee, Jang-Chang
Way, Tzong-Der
Huang, Chi-Hung
Huang, Shih-Ming
Teng, Che-Ming
Yamori, Takao
Wu, Tian-Shung
Sun, Chung-Ming
Chien, Du-Shieng
Qian, Keduo
Morris-Natschke, Susan L.
Lee, Kuo-Hsiung
Huang, Li-Jiau
Kuo, Sheng-Chu
應用化學系
Department of Applied Chemistry
公開日期: 25-Feb-2010
摘要: CHM-1 [2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one] (1) has a unique antitumor mechanism of action. However, because 1 has relatively low hydrophilicity, it was evaluated only via ip administration, which is not clinically acceptable. In this study, we synthesized the monosodium phosphate salt (CHM-1-P-Na, 4) of 1 as a hydrophilic prodrug. Compound 4 was rapidly converted into 1 following iv and po administration and also possessed excellent antitumor activity in a SKOV-3 xenograft nude mice model. Compound 4 also had clear-cut pharmacological effects oil enzymes related with tumor cells. Neither 4 not 1 significantly affected normal biological function in a safety pharmacology profiling study. Compound 1 caused apoptotic effects in breast carcinoma cells via accumulation of cyclin B1, and importantly, the endogenous levels of the mitotic spindle checkpoint proteins BubR1 directly correlated with cellular response to microtubule disruption. With excellent antitumor activity profiles, 4 is highly promising for development as all anticancer clinical trials candidate.
URI: http://dx.doi.org/10.1021/jm901292j
http://hdl.handle.net/11536/5822
ISSN: 0022-2623
DOI: 10.1021/jm901292j
期刊: JOURNAL OF MEDICINAL CHEMISTRY
Volume: 53
Issue: 4
起始頁: 1616
結束頁: 1626
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