Author(s):
Machado, Vera A. ; Peixoto, D. ; Costa, R. ; Froufe, H. J. C. ; Calhelha, Ricardo C. ; Abreu, R. M. V ; Ferreira, Isabel C. F. R. ; Soares, R. ; Queiroz, Maria João R. P.
Date: 2015
Persistent ID: https://hdl.handle.net/1822/39853
Origin: RepositóriUM - Universidade do Minho
Subject(s): Thienopyridinethioether 1,3-diarylureas; VEGFR-2 tyrosine kinase inhibitors; Enzymatic assays; Molecular Docking; HUVECs; Antiangiogenesis assays; Western blotting; Ciências Médicas::Outras Ciências Médicas; Ciências Naturais::Ciências Químicas
Description
The synthesis and biological evaluation of novel 1-aryl-3-[2-, 3- or 4-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas 3, 4 and 5 as VEGFR-2 tyrosine kinase inhibitors, are reported. The 1-aryl-3-[3-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas 4a-4h, with the arylurea in the meta position to the thioether, showed the lowest IC50 values in enzymatic assays (10-206 nM), the most potent compounds 4d-4h (IC50 10-28 nM) bearing hydrophobic groups (Me, F, CF3 and Cl) in the terminal phenyl ring. A convincing rationalization was achieved for the highest potent compounds 4 as type II VEGFR-2 inhibitors, based on the simultaneous presence of: (1) the thioether linker and (2) the arylurea moiety in the meta position. For compounds 4, significant inhibition of Human Umbilical Vein Endothelial Cells (HUVECs) proliferation (BrdU assay), migration (wound-healing assay) and tube formation were observed at low concentrations. These compounds have also shown to increase apoptosis using the TUNEL assay. Immunostaining for total and phosphorylated (active) VEGFR-2 was performed by Western blotting. The phosphorylation of the receptor was significantly inhibited at 1.0 and 2.5 microM for the most promising compounds. Altogether, these findings point to an antiangiogenic effect in HUVECs.
