ABSTRACT
A series of oxazolopyrimidine-based ureas and amides were designed, synthesized, and biologically evaluated for their antiproliferative and antiangiogenic activities. These compounds were identified to exhibit inhibitory activities against human umbilical vein endothelial cells (HUVEC) in vitro. Among these compounds, compound 22 effectively inhibited the migration and capillary-like tube formation of human umbilical vein endothelial cells. It also exhibited a concentration-dependent inhibition on capillary sprouting from the rat aorta rings. Preliminary mechanistic studies revealed that compound 22 suppressed protein kinases activation, by decreasing PI3K and ERK 1/2 phosphorylation. These results support the further investigation of this class of compounds as potential anticancer agents.
Subject(s)
Amides/pharmacology , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Human Umbilical Vein Endothelial Cells/drug effects , Oxazoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein Kinases/metabolism , Pyrimidines/pharmacology , Urea/pharmacology , Amides/chemical synthesis , Amides/chemistry , Angiogenesis Inhibitors/chemical synthesis , Animals , Aorta/drug effects , Capillaries/drug effects , Cell Movement/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Humans , Molecular Structure , Oxazoles/chemistry , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Rats , Structure-Activity Relationship , Urea/analogs & derivatives , Urea/chemistryABSTRACT
Tumor angiogenesis is mediated by vascular endothelial growth factor receptor (VEGFR) and other protein kinases. Inhibition of these kinases presents an attractive approach for developing anticancer therapeutics. In this work, a series of 2,5,7-trisubstituted oxazolo[5,4-d]pyrimidines were synthesized, and their inhibitory activities were investigated against VEGFR-2 and human umbilical vein endothelial cells (HUVEC) in vitro. Compound 9n exhibited the most potent inhibitory activity with IC50 values of 0.33 and 0.29â µM for VEGFR-2â kinase and HUVEC, respectively. A further kinase selectivity assay revealed that these compounds exhibit good VEGFR and moderate EGFR inhibitory activities. Docking analysis suggested a common mode of interaction at the ATP-binding site of VEGFR-2.