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
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.
To the Foundation for Science and Technology (FCT–Portugal)
for financial support through the NMR Portuguese network (Bruker
400 Avance III-Univ Minho). FCT and FEDER (European Fund for
Regional Development)-COMPETE/QREN/EU for financial support
through the research unities PEst-C/QUI/UI686/2013-2014, PEst-
OE/SAU/UI0038/2013 and 2014 and PEst-OE/AGR/UI0690/2013
and 2014, the research project PTDC/QUI-QUI/111060/2009, the
PhD grant attributed to V.M. (SFRH/BD/77373/2011) and the
post-Doctoral grant attributed to R.C.C. (SFRH/BPD/68344/2010),
also financed by the POPH and FSE.
