Synthesis and preclinical evaluations of 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one monosodium phosphate (CHM-1-P-Na) as a potent antitumor agent.
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.
Chou
Li-Chen
LC
Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan.
Chen
Chien-Ting
CT
Lee
Jang-Chang
JC
Way
Tzong-Der
TD
Huang
Chi-Hung
CH
Huang
Shih-Ming
SM
Teng
Che-Ming
CM
Yamori
Takao
T
Wu
Tian-Shung
TS
Sun
Chung-Ming
CM
Chien
Du-Shieng
DS
Qian
Keduo
K
Morris-Natschke
Susan L
SL
Lee
Kuo-Hsiung
KH
Huang
Li-Jiau
LJ
Kuo
Sheng-Chu
SC
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
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