Discovery of Dioxino[2,3-f]quinazoline derivative VEGFR-2 inhibitors exerting significant antipro-liferative activity in HUVECs and mice

Abstract Twelve 2,3-dihydro-[ 1 , 4 ]-dioxino[ 2 , 3-f ]quinazoline derivatives were designed and evaluated as vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitors. The most half-maximal inhibitory concentration (IC 50 ) values of them were less than 10 nM. Among these compounds, 13d displayed highly effective inhibitory activity against VEGFR-2 (IC 50  = 2.4 nM) and excellent antiproliferative activities against human umbilical vein endothelial cells (HUVECs) (IC 50  = 1.2 nM). When anti-tumor animal experiments were carried out in mice, the tumor almost disappeared (TGI = 133.0%) after six days of administration of 13d . Therefore, 13d was a potential and effective anticancer agent. The binding conformations were respectively compared between VEGFR-2 with 13d and leading compound lenvatinib, and shows that they have similar binding modes.