Synthesis And Evaluate The Antitumor Activity In Vitro Of The Novel EGFR Inhibtors 4-aminoquinazolin Derivatives

Cancer is the leading cause of death in the world.The overexpression of epidermal growth factor receptor(EGFR)has been observed in many cancers such as NSCLC,head cancer,skin carcinama.EFGR is related closely to the abnormal activation of signal transduction pathways in cells and plays a vital role in cell proliferation,differentiation,metabolism and apoptosis.For its significant impact,EGFR has been viewed as one of the most improtant therapeutic targets of anti-cancer therapy.Nine 4-aminoquinazolin derivatives bearing 2-thiophenemethanamine were designed and synthesised in this study,named them as 5a,5b,5c,5d,5e,5f,5g,5h,5i and five compounds(5d,5e,5f,5g,5h,5i)were firstly reported.We evaluated their activities on both A431 cells over expressing EGFR and A549 cells wild type EGFR firstly.We further evaluated the compounds on A431 cells later.The experiments in vitro included MTT assay,microscopic observation,wound healing assay,flow cytometry and Western Blot detecting the expression of p-EGFR(Tyr1086)in A431 cells.Results showed that the compounds named as 5e,5f,5h,5i had remarkable inhibitory effects on the proliferation of A431 cells while 9 compounds almostly had no effects on A549 cells.Particularly,the antiproliferative roles of compound 5e(IC50 =3.4?M)approached Erlotinib.Compound 5e inhibited A431 cells growth in a dose-dependent manner and changed cells morphous by the results of observing A431 cells under microscope and Wound healing assay.Compound 5e induced the apoptosis of A431 cells and restrained A431 cells in G1/G0 phase.In addition,the dates of Western Blot showed that compound 5e inhibited autophosphorylation of EGFR in A431 cells significantly at the concentration of 4.0 ?mol/L(P<0.05)and at the concentration of 20.0 ?mol/L approached Erlotinib(P<0.01).Nine 4-aminoquinazolin derivatives bearing 2-thiophenemethanamine were designed and synthesised and five compounds were firstly reported in our study.Compound 5e was the best one to inhibit the proliferation of A431 cells among nine compounds,and it induced the apoptosis of A431 cells and restrained A431 cells in G1/G0 phase,what's more,inhibited autophosphorylation of EGFR in A431 cells significantly.