Design,Synthesis And Anti-tumor Activities Of Purine-Containing EGFR^L858R/T790M Kinase Inhibitors And Palladium-Catalyzed Allene Methodological Study

Epidermal growth factor receptor(EGFR)has been intensively studied due to its strong influence on the formulation and deterioration of carcinoma.Meanwhile,the EGFR signaling pathway plays a crucial role in the apoptosis,proliferation,differentiation,migration and cell cycle of cancer cells.There are a lot of small molecules inhibitors targeting the EGFR on the market and they have been put into clinical use.But at the same time,the problem emerged that these drugs can lead to drug resistance in the process of treatment.Third-generation EGFR inhibitors provide new therapeutic ideas for overcoming the T790M mutation,which is one of the main causes for acquired drug resistance.In this thesis,three series of 41 compounds containing N,9-diphenyl-9H-purin-2-amine were designed and synthesized based on the conformational constraints and combination principle with AZD9291 as the lead compound.The structures of all the target compounds were confirmed by MS and 1H-NMR and some were further confirmed by IR and 13C-NMR.All target compounds were evaluated for antiproliferative activities against 3 cancer cell lines included the HT-29(human colon cancer),A549(human lung adenocarcinoma),and H1975(Gefitinib-resistant human lung cancer line)using the standard MTT assay in vitro,with AZD9291 as the positive control.The activity results showed that most of the compounds showed moderate to significant anti-tumor activity.Among them,the activity and selectivity of compound C2 was the best.It’s IC50 values against the three cell lines A549,HT-29 and H1975 were 6.08 μM,8.7μM and 0.038 μM,respectively.To further investigate the mechanism of compounds,compound C2 was evaluated for the kinase activity assay,apoptosis assay and binding mode analysis in the paper.The results elucidatetd that:1)C2(EGFRwt IC50=22.3 nM,EGFRL858R/T790M IC50=2.7 nM)was a selective inhibitor between EGFRwt and EGFRL858R/T790M mutant kinases;2)C2 can obstruct the process of mitosis by inducing apoptosis of Hela cells obviously;3)A variety of interactions between C2 and the receptor,such as H-bond,π-lkyl,π-Sigma,and π-Sulfur interactions,contributed to the stabilization of the lowest energy conformation of ligand-receptor complex.The author also describes the construction of potential imidazolidine and imidazoline derivatives based on Pd-catalyzed cascade reactions in this paper.In the synthesis of imidazolidine derivatives,2,3-allenyl amines was used as a raw material which reacted with aryl iodides and imines in one step using by zero-valent palladium catalysis.Imidazolidine derivatives were obtained by high diastereoselectivity,and the stereo-configuration of compound 4an was confrimed by X-ray single crystal diffraction.The optimal reaction conditions and the substrate suitability were obtained through a large number of experiments with the yield of 43%～81%.This synthetic strategy of imidazolidines has more significant advantages than traditional stepwise synthetic methods,which indicated that the reaction should have potential application value.The new imidazoline derivatives were obtained by the cyclization reaction of oxime acetates and aryl iodide under zero-valent palladium catalyzed.It was found that the reaction can be successfully extended to various substituted iodobenzenes and oxime acetates,and the target compound can be obtained in a yield of 53%to 85%.The author proposes a possible reaction mechanism and provides new ideas for the study of heterocyclic chemistry.In summary,the novel EGFR inhibitors and diastereoselectivity methods for the synthesis of imidazolidine and imidazoline were studied in this article.In the research of innovative drugs,the anti-tumor activity and structure-activity relationship of compounds were summarized,which will provide some guidance for the future research on EGFR inhibitors.By the study of palladium-catalyzed functionalization of allenes to synthesize imidazolidine and imidazoline,the application of allenes in organic synthesis was deeply understood,which provided a new idea for the development of heterocyclic chemistry.