1-Aryl-3-[4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]ureas as VEGFR2 tyrosine kinase inhibitors: synthesis, docking studies, enzymatic and cellular assays
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resumo
A number of thienopyrimidines derivatives have shown potent vascular endothelial growth factor receptor 2 (VEGFR2) inhibition activity.
Here, we present the synthesis of new 1-aryl-3-[4-(thieno[3,2-d)
pyrimidin-4-yloxy)phenyl]ureas by promoting t he regioselective attack of the hydroxy group of the 4-aminophenol in the chlorine nucleophilic displacement on two 4-chlorinated thieno[3,2-d]pyrimidines, obtaining compounds la and 1b which were reacted with arylisocyanates to give t he corresponding 1,3-diarylureas 2a-f (see scheme).
These compounds were evaluated for inhibition of VEGFR2 tyrosine kinase activity using enzymatic assays, and 2a- c showed good inhibition ability with IC50 values in the range of hundreds of nanomolar.
The rationale for the inhibition activity is also discussed
using docking. To examine the activity of 2a- c in endothelial cells,
human umbilical vein endothelial cells (HUVECs) were cultured in
the presence or absence of each compound in different concentrations.
A decrease in the proliferation of HUVECs was observed by
the incorporation of BrdU quantified by ELISA assay. Given the established
role of VEGFR2 in proliferation and migration of endothelial
cells, these molecules are promising antiangiogenic agents that can
be used for therapeutic purposes in pathological conditions where
angiogenesis is exacerbated, such as cancer.
