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*

*Autor correspondente para este trabalho

Resultado de pesquisarevisão de pares

111 Citações (Scopus)

Resumo

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.

Idioma originalEnglish
Número do artigo12514
Páginas (de-até)6497-6509
Número de páginas13
RevistaBioorganic and Medicinal Chemistry
Volume23
Número de emissão19
DOIs
Estado da publicaçãoPublicado - 1 out. 2015
Publicado externamenteSim

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