RESUMEN

A series of oxazolopyrimidine-based ureas and amides were designed, synthesized, and biologically evaluated for their antiproliferative and antiangiogenic activities. These compounds were identified to exhibit inhibitory activities against human umbilical vein endothelial cells (HUVEC) in vitro. Among these compounds, compound 22 effectively inhibited the migration and capillary-like tube formation of human umbilical vein endothelial cells. It also exhibited a concentration-dependent inhibition on capillary sprouting from the rat aorta rings. Preliminary mechanistic studies revealed that compound 22 suppressed protein kinases activation, by decreasing PI3K and ERK 1/2 phosphorylation. These results support the further investigation of this class of compounds as potential anticancer agents.

Asunto(s)

Amidas/farmacología , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/farmacología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Oxazoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Pirimidinas/farmacología , Urea/farmacología , Amidas/síntesis química , Amidas/química , Inhibidores de la Angiogénesis/síntesis química , Animales , Aorta/efectos de los fármacos , Capilares/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Oxazoles/química , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Ratas , Relación Estructura-Actividad , Urea/análogos & derivados , Urea/química

RESUMEN

Tumor angiogenesis is mediated by vascular endothelial growth factor receptor (VEGFR) and other protein kinases. Inhibition of these kinases presents an attractive approach for developing anticancer therapeutics. In this work, a series of 2,5,7-trisubstituted oxazolo[5,4-d]pyrimidines were synthesized, and their inhibitory activities were investigated against VEGFR-2 and human umbilical vein endothelial cells (HUVEC) in vitro. Compound 9n exhibited the most potent inhibitory activity with IC50 values of 0.33 and 0.29 µM for VEGFR-2 kinase and HUVEC, respectively. A further kinase selectivity assay revealed that these compounds exhibit good VEGFR and moderate EGFR inhibitory activities. Docking analysis suggested a common mode of interaction at the ATP-binding site of VEGFR-2.

Asunto(s)

Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Adenosina Trifosfato/metabolismo , Sitios de Unión , Proliferación Celular/efectos de los fármacos , Técnicas de Química Sintética , Evaluación Preclínica de Medicamentos/métodos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Pirimidinas/química , Relación Estructura-Actividad , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo