The Synthesis And Biological Evaluation Of Novel Anti-Tumor Quinazoline Derivatives

A series of novel 4-anilinoquinazoline derivatives with macrocyclic polyamine moiety was designed,synthesized and evaluated for biological activities both in vitro and in vivo.Based on the structure of gefitinib,we got 30 final compouds named 13a-o,15a-o.Most compounds exhibited highly anti-proliferative activities against A431 and A549 tumor cell lines.Especially,compound 13f presented strong anti-proliferative activities against the tested two tumor cell lines(IC50 of 0.9 and 2.35 μM,respectively),which were much better than Gefitinib(IC50 of 3.49 and 11.08 μM,respectively)and lapatinib(IC50 of 2.66 and 3.64 μM,respectively).In addition,the structure-function relationship was discussed in this study.Further investigation revealed that compound 13f could induce the apoptosis of A549 cell lines.In cell cytotoxicity test,compound 13f possessed moderate cytotoxicity against the EGFR independent cancer cell line L929 compared with gefitinib.Then eight compounds which showed remarkable potency in anti-proliferative experiment were selected to evaluate their inhibitory activity agains three kinds of kinases,in which compound 13f showed potent inhibitory activity against EGFRwt(IC50 of 6.4 nM)and HER2(IC50 of 2.1 nM),which were similar to gefitinib.Furthermore,compound 13f was exhibit obvious antitumor activity in A549 tumor xenografts model in vivo and the TGI of compound 13f was 44.23%.Finally,molecular docking analysis was performed for compound 13f inside the active site of EGFR.This work could be very useful starting point for developing a new series of tyrosine kinase inhibitors targeting EGFR.