Synthesis And Bioactivity Of [1,4]dioxino[2,3-f] Quinazoline Derivatives As Dual Inhibitors Of C-Met And VEGFR-2

Vascular endothelial growth factor receptor（VEGFR）,VEGFR-2 mediates VEGF-regulated cell signal transduction pathway,which stimulates proliferation of vascular endothelial cells and leads to blood vessel growth.VEGFR-2 is highly expressed in a variety of malignancies,ovarian and thyroid cancer,melanoma and medulloblastoma.Hepatocyte growth factor receptor（c-Met）is a kind of tyrosine kinase receptor,and its abnormal activation plays an important role in the occurrence and development of various malignant tumors including lung cancer.Both c-Met and VEGFR-2 are 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 are designed and synthesized.All target compounds are confirmed by ¹H NMR,¹³C NMR,and HRMS.The enzyme assay demonstrated that most target compounds have inhibition potency on both c-Met and VEGFR-2 with IC₅₀ values in nanomolar range especially compounds N-（3-Fluoro-4-（（5-（2-methoxyethoxy）-2,3-dihydro-[1,4]dioxine[2,3 f]quinazole porphyrin-10-yl）oxy）phenyl）-N-（4-fluorophenyl）cyclopropane-1,1-dimethylformamide（7m）and N-4（-fluorophenyl）-N-（4-（（5-methoxy-2,3-dihydro-[1,4]dioxine[2,3f]quinazoline）-10-yl）oxy）phenyl)cyclopropan e-1,1-dimethylformamide（7k）.We dock the compound 7m with c-Met and VEGFR-2 kinases,and interpret the SAR of these analogues.Base on further cell proliferation assay in vitro,compound 7k shows significantly anti-tumor activity in vivo on a hepatocellular carcinoma（MHCC97H cells）xenograft mouse model.All results indicate that the target compounds are dual inhibitors of c-Met and VEGFR-2 kinases that hold promising potential in cancer therapy.