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|Title:||1-aryl-3-[4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]ureas as VEGFR-2 tyrosine kinase inhibitors: synthesis, biological evaluation, and molecular modelling studies|
Froufe, Hugo J C
Calhelha, Ricardo C
Ferreira, Isabel C. F. R.
Abreu, Rui M V
Queiroz, Maria João R. P.
Human Umbilical Vein Endothelial Cells
Molecular Docking Simulation
Protein Kinase Inhibitors
Vascular Endothelial Growth Factor Receptor-2
|Journal:||Biomed Research International|
|Abstract(s):||The vascular endothelial growth factor receptor-2 (VEGFR-2) is a tyrosine kinase receptor involved in the growth and differentiation of endothelial cells that are implicated in tumor-associated angiogenesis. In this study, novel 1-aryl-3-[4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]ureas were synthesized and evaluated for the VEGFR-2 tyrosine kinase inhibition. Three of these compounds showed good VEGFR-2 inhibition presenting low IC50 values (150-199 nM) in enzymatic assays, showing also a significant proliferation inhibition of VEGF-stimulated human umbilical vein endothelial cells (HUVECs) at low concentrations (0.5-1 µM), using the Bromodeoxyuridine (BrdU) assay, not affecting cell viability. The determination of the total and phosphorylated (active) VEGFR-2 was performed by western blot, and it was possible to conclude that the compounds significantly inhibit the phosphorylation of the receptor at 1 µM pointing to their antiproliferative mechanism of action in HUVECs. The molecular rationale for inhibiting the tyrosine kinase domain of VEGFR-2 was also performed and discussed using molecular docking studies.|
|Appears in Collections:||DBio - Artigos/Papers|