Please use this identifier to cite or link to this item: http://hdl.handle.net/1822/63796

Title1-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
Author(s)Soares, Pedro
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.
KeywordsBinding 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
Issue date2013
PublisherHindawi Limited
JournalBiomed 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.
TypeArticle
URIhttp://hdl.handle.net/1822/63796
DOI10.1155/2013/154856
ISSN2314-6133
Publisher versionhttps://www.hindawi.com/journals/bmri/2013/154856/
Peer-Reviewedyes
AccessOpen access
Appears in Collections:DBio - Artigos/Papers

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