Design, Synthesis and Antitumor Activities of c-Met Inhibitors Possessing Thiazolinone Scaffolds / 中国药学杂志

ABSTRACT

OBJECTIVE: To design and synthesize 4-phenoxy-6,7-disubstituted quinolines possessing thiazolinone scaffolds and investigate their in vitro antitumor activities. METHODS: Taking the c-Met kinase inhibitor cabozantinib as lead compound and based on the obtained SARs, combination principles and local modification, target compounds were prepared by nucleophilic substitution, nitration, reduction and condensation, etc. The c-Met inhibition and in vitro antitumor activities were evaluated by HTRF and MTT methods, respectively. The cytotoxicity against cancer cells was evaluated by real-time dynamic living cell imaging. RESULTS: Seventeen novel compounds were obtained, and their structures were confirmed by 1H-NMR, 13C-NMR and HRMS. In vitro bioassay indicated that all the compounds showed inhibitory activities against A549, HepG2 and MDA-MB-231 cell lines as well as c-Met kinase. Compound m2 exhibited potent cytotoxicity with IC50 values of 2.45, 4.01, and 1.05 μmol·L-1, respectively. CONCLUSION: The series of compounds show preferable antitumor activities, which are worthy of further study.