Design,Synthesis,and Bioactivity Studies Of Novel EGFR Inhibitors

Non-small cell lung cancer is currently the most common cancer,according to 2016 statistics,the incidence in China is about 5%.Traditional treatment has not achieved good results,the current targeted therapy for non-small cell lung cancer is the most effective means.Common targets are C-met,ALK and EGFR.Studies have shown that in patients with non-small cell lung cancer,there are a large number of EGFR overexpression,so EGFR in cell physiological processes play an important regulatory role.Through the study of EGFR,analysis of its structure,mechanism of action,protein activity pocket characteristics,and the combination of inhibitors for the study of new EGFR inhibitors is very important.Currently EGFR inhibitors are divided into four generations.Due to the resistance problem of the first generation of inhibitors,subsequent inhibitors are used to design the inhibitor structure against resistance gene mutations.Major resistance mutations are L858R/T790M double mutations and C797S.The latest fourth-generation inhibitor,EAI045,is currently undergoing breakthroughs in combination with monoclonal antibodies.The research work of this thesis is to design the EGFR inhibitors by means of computer aided drug molecular design simulation and virtual screening technology,and synthesize the designed compounds by synthetic means.A total of two batches of molecules were designed,the first batch was 2,4-dichloro-R-pyrimidine as the nucleus,the second was based on cyanuric chloride as the nucleus,and the structure of the compound was determined by nuclear magnetic resonance,through data for further optimization.H2a and H3a have some inhibitory activity against ALK,and the design of ALK inhibitors can be used later.The structure of these two compounds can be referred to for the design of ALK inhibitors.Through the analysis of the activity data,the inhibition rate of the compound with 2,4-dichloro-R-pyrimidine as the parent nucleus,we think that the longer the carbon chain is in the R3 position,the inhibition rate of the wild type EGFR and the double mutation EGFR The higher the inhibitory activity,the better.In the R3 adjacent position is a fluorine atom rather than methyl,EGFR double mutation inhibition rate is higher,the better the inhibitory activity.We also conclude that the target protein for flexible molecules,the space is large enough,flexible molecules are not easy to bind to the target.When the compound is a rigid molecule,the compound has a good inhibitory activity against the target protein,so it is possible to design the rigid molecule as much as possible in the design of the molecule,and the inhibitory activity can be improved.