Design,Synthesis And Biological Activity Evaluation Of Novel Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

Epidermal growth factor receptor (EGFR, ErbB) belongs to type I receptor tyrosine kinase family. Upon binding to corresponding ligands. the EGFR forms homo-or heterodimers and activate downstream signal transduction pathways. The high expression of EGFR can promote the proliferation, angiogenesis. adhesion, invasion and metastasis of tumor cells. The research of EGFR drugs had always been the hot piont. Until now. including two monoclonal antibodies and five small molecular compounds, there were seven EGFR drugs on market.The initial research of small molecule EGFR inhibitors was natural products, the first reported products were natural flavones and isoflavones. such as quercetin and genistein. After that, by the introduction of high throughput screening (HTS) technology and molecular biology, more active compounds were found.In2002. the cocrystal model of small molecular drug OSI-744(gifitinib) with EGFR was determined, which had a better interpretation of drugs action pocket and binding sites of EGFR and had made a very important significance to the research of the small molecule EGFR inhibitors.4-anilinoquinazoline is a usual scaffold in small molecule kinase inhibitors. Benzothiazole compounds are a class of potent selective antitumor agents with a wide range of biological activity, such as inhibitors of topoisomerase Ⅱ and tyrosine kinase as well as an antioxidant. Aniline was substituted by aminobenzothiazole. a series of4-(6-aminobenzothiazole)quinazoline derivatives were designed and synthesized by employing hybrid approach. On the other hand, we focused on the caused of drug-fast of gifitinib-mutation on amino acid residue790and858(EGFRT790M,EGFR1.858R), using WZ4002as lead compound, we designed some compounds which used quinazoline or pyrimidine as scaffold.In this thesis, we designed and synthesized30compounds, and tested EGFR inhibitory activity on the enzyme levels,6derivatives showed moderate inhibitory activities against EGFR (IC50<10μM).2derivatives with potent inhibitory activities against EGFR(IC50<1μM). The compounds3-65has a weak inhibitor against wild EGFR. but against the EGFRT790M/EHFR1.858R. its inhibition ratio can reach74.2%. further studies are in progress.