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Advisor(s)
Abstract(s)
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 lM for the most promising compounds.
Altogether, these findings point to an antiangiogenic effect in HUVECs.
Description
Keywords
Thienopyridinethioether 1,3-diarylureas VEGFR-2 tyrosine kinase inhibitors Enzymatic assays Molecular docking HUVECs Antiangiogenesis assays Western blotting
Citation
Machado, Vera A.; Peixoto, Daniela; Costa, Raquel T.; Froufe, Hugo J.C.; Calhelha, Ricardo C.; Abreu, Rui M.V.; Ferreira, Isabel C.F.R.; Soares, Raquel; Queiroz, Maria João R.P. (2015). Synthesis, antiangiogenesis evaluation and molecular docking studies of 1-aryl-3-[(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas: Discovery of a new substitution pattern for type II VEGFR-2 Tyr kinase inhibitors. Bioorganic & Medicinal Chemistry. ISSN 0968-0896. 23:19, p. 6497-6509