Please use this identifier to cite or link to this item: http://hdl.handle.net/1822/39853

TitleSynthesis, 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
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.
KeywordsThienopyridinethioether 1,3-diarylureas
VEGFR-2 tyrosine kinase inhibitors
Enzymatic assays
Molecular Docking
HUVECs
Antiangiogenesis assays
Western blotting
Issue date2015
PublisherElsevier
JournalBioorganic & Medicinal Chemistry
Citation53. Machado, V. A., Peixoto, D., Costa, R., Froufe, H. J. C., Calhelha, R. C., Abreu, R. M. V., . . . Queiroz, M. J. 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 and Medicinal Chemistry, 23(19), 6497-6509. doi: 10.1016/j.bmc.2015.08.010
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 microM for the most promising compounds. Altogether, these findings point to an antiangiogenic effect in HUVECs.
TypeArticle
URIhttp://hdl.handle.net/1822/39853
DOI10.1016/j.bmc.2015.08.010
ISSN0968-0896
Publisher versionhttp://dx.doi.org/10.1016/j.bmc.2015.08.010
Peer-Reviewedyes
AccessOpen access
Appears in Collections:CDQuim - Artigos (Papers)

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