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Bioorg Med Chem. 2015 Oct 1;23(19):6497-509. doi: 10.1016/j.bmc.2015.08.010. Epub 2015 Aug 18.

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.

Author information

1
Departamento/Centro de Química, Escola de Ciências, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal; Departamento de Bioquímica, Faculdade de Medicina, Universidade do Porto, 4200-319 Porto, Portugal; I3S-Instituto de Investigação e Inovação em Saúde, Porto, Portugal.
2
Departamento/Centro de Química, Escola de Ciências, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
3
Departamento de Bioquímica, Faculdade de Medicina, Universidade do Porto, 4200-319 Porto, Portugal; I3S-Instituto de Investigação e Inovação em Saúde, Porto, Portugal.
4
CIMO-ESA, Instituto Politécnico de Bragança, Campus de Sta. Apolónia, Apartado 1172, 5301-855 Bragança, Portugal.
5
Departamento/Centro de Química, Escola de Ciências, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal; CIMO-ESA, Instituto Politécnico de Bragança, Campus de Sta. Apolónia, Apartado 1172, 5301-855 Bragança, Portugal.
6
Departamento/Centro de Química, Escola de Ciências, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal. Electronic address: mjrpq@quimica.uminho.pt.

Abstract

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 μM for the most promising compounds. Altogether, these findings point to an antiangiogenic effect in HUVECs.

KEYWORDS:

Antiangiogenesis assays; Enzymatic assays; HUVECs; Molecular docking; Thienopyridinethioether 1,3-diarylureas; VEGFR-2 tyrosine kinase inhibitors; Western blotting

PMID:
26344591
DOI:
10.1016/j.bmc.2015.08.010
[Indexed for MEDLINE]

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