Synthesis And Bioactivity Of Gefitinib Analogs

Gefitinib is a EGFR tyrosine kinase inhibitor.It is a first-line oral drug for the treatment of non-small cell lung cancer.Compared with conventional treatment regimens,gefitinib has a great advantage.Because of the drug resistance of gefitinib in non-small cell lung cancer patients,the limitation of the second-generation EGFR inhibitor,the third generation of EGFR inhibitors is still in the clinical stage.It is important to make some structural modifications to enhance the biological activity of gefitinib.In this paper nine pyrrolidine analogs have been synthesized by the substitution reaction of 4-(3-chloro-4-fluoroanilino)-6-hydroxy-7-methoxyquinazoline,which was prepared from 2-amino-4,5-dimethoxybenzoic acid through the reactions of cyclization,,selective demethylation,acetyl protection,chlorination,substitution with 3-chloro-4-fluoro benzenamine and deprotection respectively.And then introducing a long chain of pyrrolidine groups,it is desired to improve the bioactivity of gefitinib.All the target compounds were confirmed by 1H NMR,13C NMR,HRMS.The results of ELISA and SRB assay showed that nine kinds of gefitinib analogs of pyrrolidine part of the inhibitory activity of kinase and cancer cells were all better than gefitinib in vitro.In addition,B5 and B8 showed that the inhibition of EGFR kinase and A431,MDA-MB-231 and A549 cell lines vitro the highest activity.IC50 of B5 and B8 against EGFR kinase were 33.1 nM,17.7 nM.IC50 of against A431,MDA-MB-231 and A549 cancer cell lines were 0.35?M,11.1?M,2.9?M and 0.19?M,25.8?M,2.6?M.It is possible to improve the inhibitory activity of gefitinib by introducing a fluorine-and alkyloxy-containing pyrrolidine group.