Design,Synthesis And Activity Study Of Quinazoline Derivatives Targeted VEGFR-2

The morbidity and mortality of cancer are showing a rapid increase.It is the"first killer"of human and poses a serious threat to human health.Studies have shown that the occurrence and metastasis of cancer is often accompanied by angiogenesis.Therefore,anti-cancer drugs targeting vascular endothelial growth factor and its receptor family have become hot research topics.This thesis focuses on the target of vascular endothelial growth factor receptor 2（VEGFR-2）,and elaborates on the work of drug molecule design,target compound synthesis method and biological activity measurement.Through structural analysis of VEGFR-2 tyrosine kinase inhibitors,it was found that the urea chain is the main structural unit of small molecule inhibitors such as lenvatinib.Previous studies in our laboratory have shown that dioxo-quinazoline derivatives have a significant inhibitory effect on EGFR.Therefore,232,3-dihydro-[1,4]-dioxane[2,3-f]quinazolin urea derivatives were designed and synthesized as novel VEGFR-2 tyrosine kinase inhibitors.The docking predicted the interaction of such compounds with the VEGFR-2 kinase domain.Through reviewing a large number of literatures,the synthesis method of the dioxane quinazoline nucleus explored in the laboratory was modified to simplify the synthesis route of the mother nucleus.The urea chain was synthesized by the triphosgene method or phenyl chloroformate.The structure of the target compound was determined by ¹H NMR,¹³C NMR,HRMS or MS.Biological level tests include kinase levels,cell levels,and animal level tests.Kinase level studies showed that most compounds have significant inhibitory activity against VEGFR-2 kinase,and 11 compounds have a half-inhibitory concentration(IC₅₀)of less than 5 n M against VEGFR-2.Cell level studies showed that the 9compounds tested had significant antiproliferative activity against human umbilical vein endothelial cells（HUVECs）,in which 5 compounds（N13-3,N13-4,N13-6,N13-9,N13-12）had slightly better inhibitory activity against HUVECs than the control drug lenvatinib.In addition,most of the compounds showed IC₅₀values greater than 1000 nm for both LO2 cells and HEK293 cells,showing good selectivity.Animal-level anti-tumor studies conducted in mice showed that after 6 days of administration（N13-4）,the tumors of the mice almost disappeared（TGI=133.0%）,and the tumor volume did not increase significantly after 3 days of drug withdrawal（TGI=117.6%）.Therefore,the designed compounds have potential anti-tumor application prospects and are potentially effective anticancer drugs,which need further study.