Design,Synthesis And Evaluation Of Azaacridine Derivatives As Dual-target EGFR And Src Kinase Inhibitors

Due to patients'resistance and complicated network of signaling pathways,dual-targets in anticancer treatment has more advantages than single-target,which has been a research hotspot.Working synergistically with Src,researches showed EGFR plays an indispensable role in cancer cell proliferation and invasion.The combination of EGFR inhibitors and Src inhibitors could effectively overcome the resistance of EGFR inhibitor to treat certain cancers.It is of therapeutic advantage for cancer treatment to develope multiple-target compounds against EGFR and Src.However,there is no report on the dual-target EGFR and Src molecules.Based on our prevous studies,we rationally designed a new series of azaacridine derivatives as potent EGFR and Src dual inhibitors to treat tumors.The first part of this thesis is to design and synthesize the azaacridine derivatives,which were charactered by NMR and HRMS.In addition,the synthesis method of the key intermediate 4 was screened,including the solvent,reaction temperature,reaction time,oxygen content and molar ratio of reacta nts.The optimized reaction condition of compound 4was obtained,which was 160°C,6 h,formamide as solvent in the air.The second part of this thesis is to study the biological activity and mechanism of the azaacridine derivatives.MTT assay was performe d and found that the synthesized compounds displayed moderate to good antiproliferative activty against K562 and A549 cells,especially compound 13b,the IC₅₀ values of whichwere 0.22 nM and 0.25 nM against K562 and A549 cells,respectively.The structure-activity relationship was studied.Kinase inhibition assay indicated the 18 compounds played good inhibition rates at 10?M.Compound 13b had inhibition rate at 72.12%against Src at 1?M and 13f had inhibition rate at 33.53%against EGFR at 10?M.As 13b displayed good antiproliferative activity and inhibition activity of EGFR and Src,it was selected to study the mechanism.The results indicated 13b played good inhibition rate of A549 cell invasion.13b could efficiently induce K562 cells apoptosis through inhibition of EGFR and Src in the western blot assay and apoptosis assay.Therefore,our study suggested that compound 13b maybe acted as a lead compound targed EGFR and Src.