title: Synthesis and preclinical evaluations of 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one monosodium phosphate (CHM-1-P-Na) as a potent antitumor agent.
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.
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan.
authors.forename: Li-Chen
authors.initials: LC
authors.lastname: Chou
authors.forename: Chien-Ting
authors.initials: CT
authors.lastname: Chen
authors.forename: Jang-Chang
authors.initials: JC
authors.lastname: Lee
authors.forename: Tzong-Der
authors.initials: TD
authors.lastname: Way
authors.forename: Chi-Hung
authors.initials: CH
authors.lastname: Huang
authors.forename: Shih-Ming
authors.initials: SM
authors.lastname: Huang
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Teng
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
authors.forename: Tian-Shung
authors.initials: TS
authors.lastname: Wu
authors.forename: Chung-Ming
authors.initials: CM
authors.lastname: Sun
authors.forename: Du-Shieng
authors.initials: DS
authors.lastname: Chien
authors.forename: Keduo
authors.initials: K
authors.lastname: Qian
authors.forename: Susan L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
authors.forename: Li-Jiau
authors.initials: LJ
authors.lastname: Huang
authors.forename: Sheng-Chu
authors.initials: SC
authors.lastname: Kuo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D056744:Cyclin B1 / Q000096:biosynthesis; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis; D009368:Neoplasm Transplantation; D010755:Organophosphates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011804:Quinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D014183:Transplantation, Heterologous
chemical_list: C547950:2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one phosphate; D000970:Antineoplastic Agents; C584278:Bub1b protein, mouse; D018797:Cell Cycle Proteins; D056744:Cyclin B1; D010755:Organophosphates; D011355:Prodrugs; D011804:Quinolines; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases