Synthesis And Antiproliferative Activity Of Benzo[d]Azepinyl(Phenoxy) Quinazoline Derivatives

Receptor tyrosine kinases（RTKs）,such as epidermal growth factor receptor（EGFR）,have been implicated in multiple human tumors.Therefore,receptor tyrosine kinases have been an attractive target for various antitumor strategies.Two classes of tyrosine kinases antagonists are now in clinical use,monoclonal antibodies and small-molecule tyrosine kinase inhibitors.A well-studied class of small-molecule inhibitors are represented by 4-anilinoquinazolines,examplified by Gefitinib and Erlotinib,as mono-targeted EGFR inhibitors,which have been approved for the treatment of non-small-cell lung cancers（NSCLC）.Mono-targeted medicine may result in drug resistance and the innovation of multi-targeted drugs has become an active field.Three series of thirty-seven quinazolines were designed and synthesized.Antiproliferative activities and docking studies of our new quinazoline-based compounds were carried out.Experiments mainly included the following aspects:1)Twenty 4-substituted amidoquinazoline derivatives were synthesized from substituted benzoic acid methyl ester and benzo[d]azepine（a series of compoundsⅠ）.On the other hand,seventeen4-phenoxyquinazolines as potential EGFR/COX-2 inhibiters were obtained by reacting 2-aminobenzoic acid methyl ester with4-trifluoromethyl-salicylic acid or diflunisal（series of compoundsⅡandⅢ）,respectively.The structures of these thirty-seven new compounds were analyzed and identified.2)The antitumor activities of these compounds in vitro were evaluated against the growth of Huh7 by MTT method.The results showed several compounds exhibited antitumor activity.The IC₅₀ value of the compound possessing the best activity against Huh7 is 18.61μM.3)Our docking study was carried out for the target compounds into existing EGFR crystal structure.The crystal structure of EGFR with lapatinib（PDB code 1XKK）was obtained from protein data bank PDB.The docking results showed that the active compounds may act on the same enzyme target where EGFR inhibitor of lapatinib acts.The target compounds were postulated to represent a novel approach to EGFR-TK inhibitors.The target compounds exhibited antitumor activity which set a solid foundation for the optimization of lead compounds.