Design, Synthesis And Biological Evaluation Of Quinazolines Containing Aziridine Component As Irreversible EGFR Inhibitors And The Construction Of Drug-Like Libraries

Cancer has been a common and frequently-occurring disease which threats to human health. The resistance of cancer cells produced during the treatment is one of the important reasons that make cancers difficult to cure. The family of EGFR (Epidermal Growth Factor Receptor) 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. Due to their multidimensional role in the progression of cancer, EGFR and its family members have emerged as attractive targets for anti-cancer therapy. However, the first generation of EGFR inhibitors such as Gefitinib and Erlotinib also encountered the resistance over time. Clinical studies have demonstrated that the T790M mutation is an important cause of the treatment resistance. The second generations of EGFR inhibitors are represented as Afatinib. The most attractive characteristic of them is that they can covalently bind to the target protein, and showed promising potential for the treatment of Gefitinib-resistant tumors.Based on the SAR studies of a series of EGFR inhibitors in the trials and ligand binding model in the literatures, we designed and synthesized4series of4-anilinoquinazoline derivatives, totally66compounds, by incorporating an aziridine motif at the position6of the conventional quinazoline scaffolds. All the preparation procedures for the66compounds were described in this thesis and all of them were identified by1HNMR、HPLC-HRMS and melt point. Most of the synthesized compounds potently inhibited the proliferation of selected cancer cell lines, including the human epidermal carcinoma cell A431(with EGFR overexpression) and Gefitinib-resistant NSCLC cell H1975(bearing EGFR(L85SR/T790MI) The assay on the kinase including EGFRWT, EGFRT79OM, and EGFRL858R also perform well. Some of the compounds displayed equal potencies to the reference drugs Afatinib or Canatinib in the in vitro biological assay. Importantly, some compounds displayed weaker inhibitory on the EGFR-negative cell SW620and SKBr. The result of GSH-conjugate reaction and Western Blotting also revealed these aziridine-containing quinazoline derivatives own the ability to covalently bind to Cysteine though display partial irreversible binding compared to Afatinib. The above results implied that the designed compounds may have a reduced likelihood of targeting on other protein. Further extensive draggability is undergoing and will be reported in due course.The discovery of leading compounds plays a key role in the development of new drugs, especially at the original stage. The construction of huge compound libraries accelerates the drug discovery and the modification of lead compounds. During the Ph.D. Program,6structurally diverse libraries with800compounds were developed via novel methodologies. Among them, the analgesic effects of the Morphine related library have been evaluated in vivo and in vitro model, and3compounds were selected as leading compounds for the further biological assay. The anti-tumor effects of other compound libraries were also discussed in the thesis. Further extensive biological evaluation is undergoing and will be reported in due course.