1-aryl-3-[4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]ureas as VEGFR-2 tyrosine kinase inhibitors: synthesis, biological evaluation, and molecular modelling studies.
The vascular endothelial growth factor receptor-2 (VEGFR-2) is a tyrosine kinase receptor involved in the growth and differentiation of endothelial cells that are implicated in tumor-associated angiogenesis. In this study, novel 1-aryl-3-[4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]ureas were synthesized and evaluated for the VEGFR-2 tyrosine kinase inhibition. Three of these compounds showed good VEGFR-2 inhibition presenting low IC50 values (150-199 nM) in enzymatic assays, showing also a significant proliferation inhibition of VEGF-stimulated human umbilical vein endothelial cells (HUVECs) at low concentrations (0.5-1 µM), using the Bromodeoxyuridine (BrdU) assay, not affecting cell viability. The determination of the total and phosphorylated (active) VEGFR-2 was performed by western blot, and it was possible to conclude that the compounds significantly inhibit the phosphorylation of the receptor at 1 µM pointing to their antiproliferative mechanism of action in HUVECs. The molecular rationale for inhibiting the tyrosine kinase domain of VEGFR-2 was also performed and discussed using molecular docking studies.
Centro de Química, Escola de Ciências, Universidade do Minho, Braga, Portugal.
Pedro
P
Soares
Raquel
R
Costa
Hugo J C
HJ
Froufe
Ricardo C
RC
Calhelha
Daniela
D
Peixoto
Isabel C F R
IC
Ferreira
Rui M V
RM
Abreu
Raquel
R
Soares
Maria-João R P
MJ
Queiroz
D001665:Binding Sites; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics*; D010671:Phenylurea Compounds / Q000138:chemical synthesis*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D040301:Vascular Endothelial Growth Factor Receptor-2