期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 53, 期 4, 页码 1616-1626出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm901292j
关键词
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资金
- National Science Council of the Republic of China [NSC 96-2323-B-039-001, NSC 97-2323-B-039-001]
- [CA17625]
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.
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