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.
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.
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.
Vera A
VA
Machado
Departamento/Centro de Química, Escola de Ciências, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
Daniela
D
Peixoto
Departamento de Bioquímica, Faculdade de Medicina, Universidade do Porto, 4200-319 Porto, Portugal; I3S-Instituto de Investigação e Inovação em Saúde, Porto, Portugal.
Raquel
R
Costa
CIMO-ESA, Instituto Politécnico de Bragança, Campus de Sta. Apolónia, Apartado 1172, 5301-855 Bragança, Portugal.
Hugo J C
HJ
Froufe
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.
Ricardo C
RC
Calhelha
CIMO-ESA, Instituto Politécnico de Bragança, Campus de Sta. Apolónia, Apartado 1172, 5301-855 Bragança, Portugal.
Rui M V
RM
Abreu
CIMO-ESA, Instituto Politécnico de Bragança, Campus de Sta. Apolónia, Apartado 1172, 5301-855 Bragança, Portugal.
Isabel C F R
IC
Ferreira
Departamento de Bioquímica, Faculdade de Medicina, Universidade do Porto, 4200-319 Porto, Portugal; I3S-Instituto de Investigação e Inovação em Saúde, Porto, Portugal.
Raquel
R
Soares
Departamento/Centro de Química, Escola de Ciências, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal. Electronic address: mjrpq@quimica.uminho.pt.
Maria-João R P
MJ
Queiroz
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D062105:Molecular Docking Simulation; D018919:Neovascularization, Physiologic / Q000187:drug effects; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D014508:Urea; D040301:Vascular Endothelial Growth Factor Receptor-2
Antiangiogenesis assays; Enzymatic assays; HUVECs; Molecular docking; Thienopyridinethioether 1,3-diarylureas; VEGFR-2 tyrosine kinase inhibitors; Western blotting