Destgn,Synthesis And Biological Activity Of Small Molecule Inhibitora Of EGFR/VEGFR-2 Dual Target

Based on the preliminary research work in the laboratory,this research has designed and synthesized new dioxino[2,3-f]quinazoline compounds and their derivatives,and used HPLC,~1H NMR,¹³C NMR and HRMS for purity analysis and structural identification,and their biological activity determination to determine and screen out EGFR/VEGFR-2 dual target inhibitors with good inhibitory activity and selectivity.In this project,15 new dioxino[2,3-f]quinazoline compounds were synthesized as EGFR/VEGFR-2 dual target small molecule tyrosine kinase inhibitors and the interaction between the compound and the kinase was predicted by the method of molecular docking.The synthesis of the target compound is achieved step by step.First,the intermediate X series compounds are synthesized through esterification,nitration,reduction,cyclization and other reactions,and then the intermediate Y series compounds are synthesized through esterification and oxidation reactions.The X intermediate and Y intermediate generate the target product through a nucleophilic substitution reaction.The biological activity research mainly includes the kinase inhibitory activity test at the molecular level,the cell anti-proliferation test and the cytotoxicity test at the cellular level.Experimental data shows that most of the compounds synthesized in this subject have good inhibitory activities on EGFR and VEGFR,and 7 of them（W1,W5,W6,W9,W10,W12,W15）on EGFR and VEGFR-2 kinase and cell levels The IC₅₀values have reached below 50n M.Among them,W12 has an IC₅₀value of 10 n M for EGFR kinase,an IC₅₀value of15 n M for VEGFR-2 kinase,an IC₅₀value of 10 n M for A549 cells,and an IC₅₀value of 11 n M for HUVEC cells.The IC₅₀value for Hela cell is greater than 800n M,showing good selectivity.In this project,a series of novel dioxaquinazoline compounds have been designed and synthesized,their structures have been characterized,and their biological activities have been evaluated at the molecular and cellular levels.The results show that most of the compounds have good biological activity and selectivity.The research on compounds of this type has enriched the types of quinazoline small molecule kinase inhibitors,and has potential value for the development of multi-target small molecule inhibitors.Since drug development still requires research in pharmacokinetics,pharmacokinetics,and animal experiments,there is still a lot of work to be done.