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

• Type: Article in International Scientific Journal
• Date: 2013

Authors

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

Journal

Title: BioMed Research International

Vol. 2013

Pages: 1-9

ISSN: 2314-6133

Publisher: Hindawi

Indexing

ISI Web of Knowledge - 9 Citations

Scopus - 6 Citations

Other information

Authenticus ID: 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 9