1-Aryl-3-[4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]ureas as VEGFR-2 tyrosine ki...

• Author(s): Soares, Pedro ; Costa, Raquel ; Froufe, Hugo J.C. ; Calhelha, Ricardo C. ; Peixoto, Daniela ; Abreu, Rui M.V. ; Ferreira, Isabel C.F.R. ; Soares, Raquel ; Queiroz, Maria João R.P.
• Date: 2013
• Persistent ID: http://hdl.handle.net/10198/8554
• Origin: Biblioteca Digital do IPB
• Subject(s): Thienopyrimidine ether ureas; VEGFR-2 inhibitors; HUVECs; Western-blot; Molecular modelling
• Document Type: Article
• Language: English

Description

The Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) is a tyrosine kinase receptor involved in the growth and differentiation of endothelial cells that is 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. The latter promoted also significant inhibition of cell proliferation at low concentrations (0.5-1 µM), not affecting cell viability, of VEGF-stimulated Human Umbilical Vein Endothelial Cells (HUVECs) using the BrdU assay. 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 done and discussed using molecular docking studies.