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

Vera A. Machado, Daniela Peixoto, Raquel Costa, Hugo J.C. Froufe, Ricardo C. Calhelha, Rui M.V. Abreu, Isabel C.F.R. Ferreira, Raquel Soares, Maria João R.P. Queiroz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

82 Citations (Scopus)

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.

Original languageEnglish
Article number12514
Pages (from-to)6497-6509
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number19
DOIs
Publication statusPublished - 1 Oct 2015
Externally publishedYes

Keywords

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

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