Design, Synthesis,Anti-tumor Evaluation Of Quinazolines As Irreversible Inhibitors Of EGFR; Construction Heterocycle Library

Cancer is still one of the most serious diseases of humans. At present, statistics show that:approximately12million new cancer patients are treated globally,7.6million people died from cancer. In addition, the incidence of cancer is sequentially rising, and it is estimated that new cancer patients worldwide would reach15million in2020. Cancer has attracted the whole world’s attention including government, society, universities and companies, who put great deal of efforts on cancer research.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 pathway plays a crucial role in the apoptosis, proliferation, differentiation, migration and cell cycle of cancer cells. On the basis of deep understanding of the EGFR pathway, it should be possible to artificially interfere with certain targets to block its signal transmission. Thus, it is a good strategy that design anti-cancer drug by inhibiting the EGFR pathway. However, a new challenge, drug resistance, is coming to us along with the pharmacotherapy of some commercialized anti-cancer drug targeting EGFR (e.g., Gefitinib, Tarceva).On the basis of our early stages of research, we now focus on the studies of irreversible inhibitors of EGFR. We have synthesized two different series of irreversible inhibitors, totally32compounds. Then we performed in vitro cancer cell inhibitory activity test of all the compounds; and the best ones among them were also performed inhibitory activity towards EGFR/HER2/EGFR[T790M] tyrosine kinase, a cell inhibitory activity test on human lung cancer cell line H1975, which has Gefitinib resistance. The cell inhibitory activity tests revealed that most compounds had good inhibitory activity with excellent selectivity; furthermore, some of them were equivalent or superior to the two positive controls, i.e. Gefitinib and CI-1033. On the basis of in vitro cell inhibitory activity tests, we carried a Wash/No Wash inhibitory experiment on cancer cell line A431using Western Blotting to clarify the irreversible inhibitory activity on the EGFR-TK autophosphorylation of series I; we also carried pharmacodynamics studies on human lung cancer cell NCI-H1975xenograft BALB/c mouse model of series II, revealing its strong inhibitory activity on xenograft BALB/c mouse model. With the result we had, we analyzed the structure-activity relationship to offer detailed information for further design and synthesis of novel irreversible inhibitors of EGFR.Discovery of leading compounds plays a key role in the period of new drug discovery and development, especially during the original stage. Construction a large scale of compounds library accelerates the development of drug discovery and the modification of lead compounds. Considering this, we synthetized a336-compounds library of Spiro-compounds.In addition, eco-friendly and facile synthetic methods have meaningful contribution to Organic Synthesis and Pharmaceutical Synthesis. Herein, we developed a novel, facile approach to provide polyfunctionalized2-aminopyrroles using vinyl azides and a-cyano derivatives. The reaction was performed in water/ethanol co-solvent system without catalyst and the workup was simple. We synthetized23compounds of2-aminopyrroles, which would provide an attractive strategy for pharmaceutical building blocks and medicinal chemistry applications.