Synthesis and bioevaluation and doking study of 1 H -pyrrolo[2,3- b ]pyridine derivatives bearing aromatic hydrazone moiety as c-Met inhibitors

摘要

Abstract Two series of aromatic hydrazone derivatives bearing 1 H -pyrrolo[2,3- b ]pyridine moiety ( 7a – r , 8a – i , 12a – b , 13a – c , 16a – d and 17a – e ) were designed, synthesized and evaluated for the IC 50 values against four cancer cell lines (A549, HepG2, MCF-7and PC-3). Two selected compounds ( 7c and 17e ) were further evaluated for the activity against c-Met, Flt-3, VEGFR-2 and EGFR kinases. The data indicated that targets compounds were selective for c-Met kinase. And the most promising compound 7c was further studied in terms of dose-dependent, time-dependent and cell apoptosis. Most of the compounds showed excellent cytotoxicity activity, especially the most promising compound 7c with the IC 50 values of 0.82?±?0.08?μM, 1.00?±?0.11?μM, 0.93?±?0.28?μM and 0.92?±?0.17?μM against A549, HepG2, MCF-7 and PC-3?cell lines and 0.506?μM against c-Met kinase. Structure–activity relationships (SARs) and docking studies indicated that the activities of the phenyl hydrazone derivatives ( 7a – r and 8a – i ) were superior to that of the heterocyclic hydrazone series ( 12a – b , 13a – c , 16a – d and 17a – e ). What's more, the further studies indicated that the target compounds can induce apoptosis of A549?cells and arrest efficiently the cell cycle progression in G2/M phase of A549?cells. Graphical abstract Two series of aromatic hydrazone derivatives bearing 1 H -pyrrolo[2,3- b ]pyridine moiety ( 7a – r , 8a – i , 12a – b , 13a – c , 16a – d and 17a – e ) were designed. What's more, enzyme-based selectivity, cell cycle, cell apoptosis and molecules docking study were also carried out in this paper. Display Omitted Highlights ? Two series of 1 H -pyrrolo[2,3- b ]pyridine derivatives bearing aromatic hydrazone moiety were designed and synthesized. ? Most of the synthesized compounds showed moderate to significant antitumor activity. ? 7c arrest efficiently the cell cycle progression in G2/M phase of A549?cells. ? Docking study was investigated to explore the binding modes of compounds with c-Met.