Design,Synthesis And Bioactivity Of EGFR Inhibitors With 6-substituted Purine Structure

This paper describes the physiological effect of EGFR in vivo.By binding with corresponding ligands,EGFR can produce dimer,then phosphorylate,further activate EGFR,conduct the downstream Ras RAF MAPK pathway or PI3 K PKC IKK pathway,and finally generate cell proliferation process through RNA transcription.Through the study of this mechanism,scientists invented two main EGFR inhibitors,monoclonal antibody EGFR inhibitors and EGFR small molecule inhibitors.In this project,we developed a series of new EGFR small molecule compounds for the treatment of nonsmall cell lung cancer.This paper summarizes the first generation of EGFR small molecule inhibitors,including gefitinib,erlotinib,exetinib,etc.,and finds that they all have aromatic pyrimidine ring structure,which can form hydrogen bond with met769 or met793 residues of EGFR receptor,so this part of structure is preserved as the structure of target compounds.The second generation of EGFR small molecule inhibitors,including afatinib,daptinib,lenatinib,carnetinib,and pelletinib,were summarized.It was found that they have not only aromatic pyrimidine ring structure,but also unsaturated amide bond.This kind of unsaturated amide structure can react with sulfhydryl group in cys797 residue of EGFR receptor by Michael addition and form irreversible binding with the receptor This structure is also retained as the structure of the target compound.The third generation of EGFR small molecule inhibitors,including wz-4002,co-1686 and azd-9291,were also summarized.It was found that they all have pyrimidine ring structure,which can form hydrogen bond with met769 or met793 residues of EGFR receptor.Therefore,this part of structure was preserved as the structure of target compound.Finally,the principle of bioelectronic isoarrangement and superposition are used,and the feasibility of synthesis and the source of raw materials are considered.A novel small molecule EGFR inhibitor with purine as the mother nucleus,9-unsaturated amide side chains,6-substituted p-aminophenol structure and a new mother nucleus structure was designed.In order to have a better effect,reduce drug resistance and side effects.This paper summarizes the characteristics of the first generation of EGFR small molecule inhibitors,the second generation of EGFR small molecule inhibitors and the third generation of EGFR small molecule inhibitors,and also summarizes the structure-activity relationship between their main parent nuclei,quinozoline and pyrimidine.Based on the principle of bioelectronic isoexclusion and considering the feasibility of synthesis and the source of raw materials,we designed a purine as the parent nucleus,9-unsaturated amide side chain,6-position with the structure of substituted paminophenol new mother nucleus EGFR small molecule inhibitorsare expected to have better effect,reduce drug resistance and side effects.In this project,the target compound was analyzed by reverse synthesis,and a reasonable synthesis route was designed,4-dichloro-5-fluoropyrimidine is used as the starting material,amino side chain is introduced by substitution at position 4,and then amino phenol structure is introduced by substitution at position 2 to form the key intermediate 2-n-substituted-4-n-substituted-5-fluoropyrimidine.After the amidation reaction of 6-chloropine and acryloyl chloride,a new intermediate 1-(6-chloro-9hpurine-9-yl)propan-2-ene-1-one is formed,and then the two intermediates are carried out with each other Substitution forms the final target compound.According to this route,19 target compounds were synthesized.The structures of the target compounds were confirmed by 1H-NMR and MS,and they are all new compounds which have not been reported in literature.In this study,A549 cell line was selected and gefitinib was used as the positive control drug.The inhibitory activity of 19 target compounds on A549 cell line was measured by MTT method at the concentration of 100?M/L,and the inhibitory rates of 19 target compounds were compared:M7 > M10 > M13 > M2 > M14 > M15 > M8 > M9 > M3 > M11> M6 > M4 > M16 > M12 > M18 > M1 > gefitinib > M19 > M5 > M17.From the comparison of the above inhibition rates,it can be found that in addition to M19,M5 and M17,the other 16 compounds have better inhibition effect than the control drug gefitinib in vitro,which is in line with our design and expectation for the target compounds.