Design, synthesis, and preclinical evaluation of new 5,6- (or 6,7-) disubstituted-2-(fluorophenyl)quinolin-4-one derivatives as potent antitumor agents.
Our previous exploration of 2-phenylquinolin-4-ones (2-PQs) has led to an anticancer drug candidate 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one monosodium phosphate (CHM-1-P-Na). In order to develop additional new drug candidates, novel 2-PQs were designed, synthesized, and evaluated for cytotoxic activity. Most analogues, including 1b, 2a,b, 3a,b, 4a,b, and 5a,b, exhibited significant inhibitory activity (IC(50) of 0.03-8.2 μM) against all tested tumor cell lines. As one of the most potent analogue, 2-(3-fluorophenyl)-5-hydroxy-6-methoxyquinolin-4-one (3b) selectively inhibited 14 out of 60 cancer cell lines in a National Cancer Institute (NCI) evaluation. Preliminary mechanism of action study suggested that 3b had a significant effect on the tyrosine autophosphorylation of insulin-like growth factor-1 receptor (IGF-1R). Safety pharmacology profiling of 3b showed no significant effect on normal biological functions of most enzymes tested. Furthermore, sodium 2-(3-fluorophenyl)-6-methoxy-4-oxo-1,4-dihydroquinolin-5-yl phosphate (15), the monophosphate of 3b, exceeded the activity of doxorubicin and was comparable to CHM-1-P-Na in a Hep3B xenograft nude mice model. In summary, 15 is a promising clinical candidate and is currently under preclinical study.
Chou
Li-Chen
LC
Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan.
Tsai
Meng-Tung
MT
Hsu
Mei-Hua
MH
Wang
Sheng-Hung
SH
Way
Tzong-Der
TD
Huang
Chi-Hung
CH
Lin
Hui-Yi
HY
Qian
Keduo
K
Dong
Yizhou
Y
Lee
Kuo-Hsiung
KH
Huang
Li-Jiau
LJ
Kuo
Sheng-Chu
SC
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D010755:Organophosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
C554509:2-(3-fluorophenyl)-6-methoxy-4-oxo-1,4-dihydroquinolin-5-yl phosphate; D000970:Antineoplastic Agents; D018970:Insulin-Like Growth Factor Binding Protein 1; D010755:Organophosphates; D015363:Quinolones