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

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.

Design,synthesis and activity evaluation of novel 2-indolone derivatives as the c-Met kinase inhibitors / 国际药学研究杂志

Objective To design and synthesize novel 2-indolone derivatives as the c-Met kinase inhibitors. Methods With c-Met kinase inhibitor SU11274 as lead compound,a series of 2-indolone derivatives were designed according to the concept of bioiso-sterism. Then the target compounds(10a-10r)were synthesized from 2-indolone through 5-chlorosulfonation with chlorosulfonic acid, sulfonamidation with intermediate 3,condensation with 6a-6h,7a-7h and 4a-4b,respectively. Their inhibitory activity against c-Met and proliferation of MCF-7 cells were evaluated. Results and Conclusion The designed compounds were successfully prepared and their structures were confirmed by 1H NMR and ESI-MS. Some compounds had certain inhibitory activity against c-Met and prolif-eration of MCF-7 cells. An initial structure-activity relationship analysis of these compounds was performed to provide useful informa-tion for further optimization of their structures.