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

• Tipo: Artigo em Revista Científica Internacional
• Data: 2013

Autores

soares, p (Autor) Outra; costa, r (Autor) Outra; froufe, hjc (Autor) Outra; calhelha, rc (Autor) Outra; peixoto, d (Autor) Outra; ferreira, icfr (Autor) Outra; abreu, rmv (Autor) Outra; soares, r (Autor) FCNAUP; queiroz, mjrp (Autor) Outra

Revista

Título: BioMed Research International

Vol. 2013

Páginas: 1-9

ISSN: 2314-6133

Editora: Hindawi

Indexação

ISI Web of Knowledge - 9 Citações

Scopus - 6 Citações

Outras Informações

ID Authenticus: P-006-G5A

DOI: 10.1155/2013/154856

Abstract (EN): 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 mu M), 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 mu M 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.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 9