Synthesis and preclinical evaluations of 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one monosodium phosphate (CHM-1-P-Na) as a potent antitumor agent

Journal of Medicinal Chemistry
Li-Chen ChouSheng-Chu Kuo

Abstract

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 on enzymes related with tumor cells. Neither 4 nor 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 an anticancer clinical trials candidate.

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Citations

Mar 30, 2011·Beilstein Journal of Organic Chemistry·Wentao GaoYang Li
Nov 12, 2013·Antioxidants & Redox Signaling·Pablo RíosRafael Pulido
Mar 15, 2014·Expert Opinion on Investigational Drugs·Elizabeth R SharlowJohn S Lazo
Sep 12, 2015·Medicinal Research Reviews·Zhiyan XiaoKuo-Hsiung Lee
Sep 13, 2011·European Journal of Pharmacology·Jang-Chang LeeSheng-Chu Kuo
Jul 17, 2019·Bioorganic & Medicinal Chemistry Letters·Nikhil R TaskerPeter Wipf

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