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

Li Chen Chou, Chien Ting Chen, Jang Chang Lee, Tzong Der Way, Chi Hung Huang, Shih Ming Huang, Che Ming Teng, Takao Yamori, Tian Shung Wu, Chung Ming Sun, Du Shieng Chien, Keduo Qian, Susan L. Morris-Natschke, Kuo Hsiung Lee, Li Jiau Huang, Sheng Chu Kuo

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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 Bl, and importantly, the endogenous levels of the mitotic spindle checkpoint, proteins BubRl 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.

Original languageEnglish
Pages (from-to)1616-1626
Number of pages11
JournalJournal of Medicinal Chemistry
Volume53
Issue number4
DOIs
Publication statusPublished - 2010 Feb 25

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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    Chou, L. C., Chen, C. T., Lee, J. C., Way, T. D., Huang, C. H., Huang, S. M., Teng, C. M., Yamori, T., Wu, T. S., Sun, C. M., Chien, D. S., Qian, K., Morris-Natschke, S. L., Lee, K. H., Huang, L. J., & Kuo, S. C. (2010). Synthesis and preclinical evaluations of 2-(2-fluorophenyl)-6,7- methylenedioxyquinolln-4-one monosodium phosphate (CHM-I-P-Na) as a potent antitumor agent. Journal of Medicinal Chemistry, 53(4), 1616-1626. https://doi.org/10.1021/jm901292j