Design,Synthesis And Biological Evaluation Of EGFR Inhibitors And Researh On The Synthesis Of Pyrrole Compounds

Nowadays,lung cancer remains the most common cancer worldwide;the two major forms of this cancer are non-small cell lung cancer(NSCLC)and small-cell lung cancer,and NSCLC accounts for almost 85%of all lung cancers.Overexpression or abnormal activation of epidermal growth factor receptor(EGFR)is associated with varieties of human cancers,especially NSCLC.So EGFR has become a well-established critical target for the treatment of NSCLC.The drugs targeting on EGFR are mainly divided into two categories,one is monoclonal antibody drugs,and the other is small molecular kinase inhibitors.So far,many small molecular kinase inhibitors have been listed for clinical treatment.The two approved reversible EGFR tyrosine kinase inhibitors(TKIs)gefitinib and erlotinib showed very potent inhibition profiles for NSCLC.Though such TKIs have good inhibitory potency for the treatment of NSCLC,the acquired resistance mutation EGFRT790M develops after months of treatment,accounting for about 50%of cases.Covalent irreversible EGFR inhibitors showed promising potential for treating Gefitinib-resistant tumors.Based on the studies of the X-ray structure of the third generation EGFR inhibitors and EGFR,we designed and synthesized 5 series derivatives,totally 53 compounds.There are two design ideas:one is based on the structure of the third generation inhibitors to synthesize a series of compounds with modification of the acrylamide,such as compounds 12,17 and 21;the other one is to designe new skeletal structure compounds with the acrylamide,such as compouds 32 and 43.All of these compounds were evaluated by MTT method against human epidermal carcinoma cell A431(with EGFRWT overexpression)and Gefitinib-resistant NSCLC cell H1975(bearing EGFRL858R/T790M).The compouds which incorporated chloro or fluoro on the a-position of acrylamide showed good potency against both two cancer cell.Then,those compounds were evaluated by kinase assay(EGFRWT and EGFR L858R/T790M).The results showed the potency of chlorides were better than the fluorides against both two kinases.However,the further in vivo antitumor efficacy study showed chloride 121 and fluoride 12j could not inhibit the tumor growth.Moreover,liver S9 metabolism assay indicated that the chlorides had low metabolic stability.This results could support the poor potency of compound 121 in vivo.Compund 38c and 43a were selected from compouds 38 and 43 as lead compouds.They showed good potency against H1975 and A431 cell.The IC50 values against H1975 and A431 of 38c and 43a were similar with the third EGFR TKIs C01686 and WZ4002.Further research is continuing on.A multi-component synthesis of N-substituted 2-amino-3-cyano pyrroles from nitroepoxides,amines and malononitrile has been demonstrated.The reaction proceeded well for a wide range of nitroepoxides and amines in a mild condition without transition metal catalysis following with three new bonds formation.