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Both c-Met and VEGFR-2 were important targets for cancer therapies. In order to develop reversible and non-covalent c-Met and VEGFR-2 dual inhibitors, a series of [1,4]dioxino[2,3-f]quinazoline derivatives were designed and synthesized. The enzyme assay demonstrated that most target compounds had inhibition potency on both c-Met and VEGFR-2 with IC50 values in nanomolar range especially compounds 7m and 7k. Based on further cell proliferation assay in vitro, compound 7k showed significantly anti-tumor activity in vivo on a hepatocellular carcinoma (MHCC97H cells) xenograft mouse model. We docked the compound 7m with c-Met and VEGFR-2 kinases, and interpreted the SAR of these analogues. All results indicated that the target compounds were dual inhibitors of c-Met and VEGFR-2 kinases that held promising potential in cancer therapy.

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 (IC50) values of them were less than 10 nM. Among these compounds, 13d displayed highly effective inhibitory activity against VEGFR-2 (IC50 = 2.4 nM) and excellent antiproliferative activities against human umbilical vein endothelial cells (HUVECs) (IC50 = 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.