Design, synthesis and biological evaluation of 4-phenoxy-pyridine/pyrimidine derivatives as dual VEGFR-2/c-Met inhibitors

Abstract

A class of 4-phenoxy-pyridine/pyrimidine derivatives (23a–23p and 24a–24h) were designed, synthesized and evaluated as potent dual VEGFR-2/c-Met inhibitors. The in vitro anti-cancer cell proliferative activity of the compounds indicated that compound 23k was regarded as a promising derivative. Compared to the lead compounds Foretinib and Sorafenib, 23k showed excellent inhibitory activity against the A549, MCF-7, HepG2 and Ovcar-3 cell lines with IC₅₀ values of 2.16 ± 0.19 μM, 9.13 ± 0.65 μM, 20.15 ± 2.64 and 9.65 ± 0.51 μM, respectively. In addition, 23k exhibited low toxicity to human normal cells (LO2 cells) with IC₅₀ values above 100 μM. In kinase assays, the most promising compound 23k showed excellent kinase inhibitory activity and selectivity against VEGFR-2 and c-Met with IC₅₀ values of 1.05 and 1.43 μM, respectively. Further activity studies demonstrated that 23k not only induced apoptosis in A549, but also blocked the A549 cell lines in the G0/G1 phase in a dose-dependent manner. Moreover, molecular docking and molecular dynamics simulation studies revealed the binding modes of 23k to VEGFR-2 and c-Met. The binding modes and structure–activity relationship (SAR) investigations of synthetic pyridine/pyrimidine derivatives, as well as a brief mechanism of their anti-VEGFR-2 and c-Met kinase activities, are presented in this paper.