Design,Synthesis And Bioactivity Study Of Antitumor Drugs Gefitinib Derivatives

Malignant tumor has always been one of the difficult diseases that the medical community has not been able to conquer.In recent years,with the rise of targeted drugs,progression-free survival in cancer patients has been effectively treated.Gefitinib is a star drug for the targeted treatment of non-small cell lung cancer.It is a class of epidermal growth factor receptor tyrosine kinase inhibitors?EGFR-TKIs?that can target cancer cells.Based on this,the similar anti-tumor drugs erlotinib,icotinib and other race to market,marking the arrival of a new era of"targeted therapy".However,the use of small-molecule targeted anti-tumor drugs is inevitably accompanied by acquired drug resistance,which poses new challenges for researchers in drug development.In this paper,the epidermal growth factor receptor tyrosine kinase?EGFR?was used as the target,and the 6-acetyl-7-methoxy-quinazoline-4-ketone was used as the raw material through chlorination,amination,hydrolysis,amidation and alkylation.21 derivatives of 4-aromatic amino-quinazoline which have not been reported in the literature were designed and synthesized in order to obtain lead compounds with good activity and to solve the problem of gefitinib resistance.The structures of all the target compounds and their intermediates were confirmed by IR and ¹H-NMR,and the crystal structure of compound 5az was characterized and analyzed by X-ray single crystal diffraction.MTT method was used to test the inhibitory activity of the target compounds on MKN45,H1975,K562 and A549 tumor cells,with gefitinib as the positive control drug.The results showed that some compounds of N-oxygen-heterocyclic substituted amides?x series?had certain inhibitory activities against MKN45 and K562.N-dimethyl-substituted amides?y series?had better inhibitory activity on MKN45 tumor(5dy IC₅₀=2.360?M,5ey IC₅₀=2.012?M).In N-diethyl-substituted amides?z series?compounds,5az(IC₅₀=2.872?M),5ez(IC₅₀=3.616?M)and 5gz(IC₅₀=2.822?M)had good inhibitory activities against MKN45.Compound 5gz(IC₅₀=5.179?M)had better inhibitory activities against drug-resistant cell line H1975.