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

• Type: Article in International Scientific Journal
• Date: 2015

Authors

Machado, VA (Author) Other; Peixoto, D (Author) Other; Costa, R (Author) Other; Froufe, HJC (Author) Other; Calhelha, RC (Author) Other; Abreu, RMV (Author) Other; Ferreira, ICFR (Author) Other; soares, r (Author) FMUP; Queiroz, MJRP (Author) Other

Journal

Title: Bioorganic and Medicinal Chemistry

Vol. 23

Pages: 6497-6509

ISSN: 0968-0896

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 68 Citations

Scopus - 72 Citations

Other information

Authenticus ID: P-00G-NR4

DOI: 10.1016/j.bmc.2015.08.010

Abstract (EN): 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 mu M for the most promising compounds. Altogether, these findings point to an antiangiogenic effect in HUVECs.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 13