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Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in cancer angiogenesis. In this study, a series of novel furo[2,3- d ]pyrimidine and thieno[2,3- d ]pyrimidine based-derivatives were designed and synthesized as VEGFR-2 inhibitors, in accordance to the structure activity relationship (SAR) studies of known type II VEGFR-2 inhibitors. The synthesized compounds were evaluated for their ability to  in vitro  inhibit VEGFR-2 kinase enzyme. Seven compounds  (15b, 16c, 16e, 21a, 21b, 21c  and  21e)  demonstrated highly potent dose-related VEGFR-2 inhibition with IC 50  values in nanomolar range, of which the thieno[2,3- d ]pyrimidine based-derivatives  (21b, 21c  and  21e)  exhibited IC  50   values of 33.4, 47.0 and 21 nM respectively. Moreover, furo[2,3- d ]pyrimidine-based derivative  (15b)  showed the strongest inhibition of human umbilical vein endothelial cells (HUVEC) proliferation with 99.5% inhibition at 10 μM concentration. Consistent with our  in vitro  findings, compounds ( 21b  and  21e)  orally administered at 5 and 10 mg/kg/day for 8 consecutive days demonstrated potent anticancer activity in Erhlich ascites carcinoma (EAC) solid tumor murine model. Such compounds blunted angiogenesis in EAC as evidenced by reduced percent microvessel via decreasing VEGFR-2 phosphorylation with subsequent induction of apoptotic machinery. Furthermore, Miles vascular permeability assay confirmed their antiangiogenic effects  in vivo . Intriguingly, such compounds showed no obvious toxicity.

Discovery of Potent VEGFR-2 Inhibitors based on Furopyrimidine and Thienopyrimidne Scaffolds as Cancer Targeting Agents