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, Ferreira, Isabel C. F. R., Abreu, Rui M. V., 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: https://hdl.handle.net/1822/63796
• topic: Binding Sites; Human Umbilical Vein Endothelial Cells; Humans; Models, Molecular; Molecular Docking Simulation; Neoplasms; Neovascularization, Pathologic; Phenylurea Compounds; Protein Binding; Protein Kinase Inhibitors; Pyrimidines; Vascular Endothelial Growth Factor Receptor-2; Science & Technology

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.