Design, synthesis and biological evaluation of pyrimidine-based derivatives as VEGFR-2 tyrosine kinase inhibitors

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in tumor angiogenesis, and inhibition of the VEGFR-2 signaling pathway has already become an attractive approach for cancer therapy. In this study, a novel pyrimidine-based derivative 7j was designed as lead compound, and three series of potent VEGFR-2 inhibitors were synthesized and biologically evaluated against A549 and HepG2 cell lines. Compounds 7d, 9s and 13n exhibited superior inhibitory activities against A549 cell with IC50 ranged from 9.19 to 13.17 mu M and HepG2 cell with IC50 ranged from 11.94 to 18.21 mu M compared to those of Pazopanib (IC50 = 21.18 and 36.66 mu M). In addition, molecular docking study was performed to investigate the binding capacity and binding mode between target compounds and VEGFR-2.