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

• Autor(a) principal: Soares, Pedro
• Data de Publicação: 2013
• Outros Autores: 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.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10198/8554
• topic: Thienopyrimidine ether ureas; VEGFR-2 inhibitors; HUVECs; Western-blot; Molecular modelling

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.