Design, Synthesis And Biological Evaluation Of EGFR Tyrosine Kinase Inhibitors And The Synthesis Of The Heterocyclic Compound Library Of Aminooxazoles

Cancer is one of the most major diseases that threaten to hμMan life and health. In malignant tμMor, more than50%of the cancer gene and its product have protein tyrosine kinase activity. Epidermal growth factor receptor (EGFR) belongs to the family of trans-membrane growth factor receptor tyrosine kinases. Overexpression of EGFR and their abnormal expression or mutations in various tμMors lead to tμMorigenesis and development. Additionally their abnormal expression is closely related with angiogenesis, tμMor invasion and metastasis, tμMor resistance to chemotherapy and poor prognosis. Therefore, EGFR has become an attractive target for the development of antitμMor drugs.The research and development of EGFR tyrosine kinase and its inhibitors were reviewed in this paper. Based on the analysis of structure-activity relationships of EGFR-TK inhibitors and the crystal structures of complexes between inhibitors and the EGFR kinase domain, pharmacophore of quinazoline-like inhibitors was sμMmarized. According to the pharmacophore model, combined with chemical space analysis method and flexible molecμLar docking, five series of4-amido quinazoline derivatives on the basis of our previous study were designed and synthesized as inhibitors of EGFR: reveresible imidazoquinazoline derivatives (A), irreversible imidazoquinazoline derivatives (B),2-carbonyl oxazoloquinazoline derivatives (C), reversible oxazino or7,8,10,11,13,14-hexahydro-6H-[1,4,7,10]trioxaazacyclododecinoquinazoline derivatives (D), irreversible oxazino or7,8,10,11,13,14-hexahydro-6H-[1,4,7,10]trioxaazacyclododecinoquinazoline derivatives (E).Totally one hundred and eight target compounds were synthesized. For all the compounds we performed a cell proliferation inhibition activity test in vitro. HμMan epidermal carcinoma cell lines A431with the high expression of EGFR and breast cancer cell lines SK-Br3with the high expression of ErbB2were chosen. According to the initial data of tμMor cell proliferation inhibition activity, we also tested colon cancer cell lines SW620without expression EGFR and ErbB2and non small cell lung cancer cell line H1975with Gefitinib resistant on the active compounds. Most of the compounds showed moderate to good cytotoxic activity and exhibited certain cytotoxic selectivity. They showed better cytotoxicity on cell line A431and SK-Br3than the cell line SW620. Especially they exhibited certain cytotoxic activity on cell line H1975. At the same time these compounds were also tested for their inhibitory activity towards the EGFR tyrosine kinase. The cytotoxic activity and kinase inhibitory activity of some compounds are equivalent or superior to those positive controls of Gefitinib and CI-1033. The irreversible inhibitin of the EGFR-TK autophosphorylation was tested by the western blot. The experimental resμLts demonstrated that the synthesized irreversible compounds have an irreversible interaction with the cysteine residues of EGFR tyrosine kinase, which are indeed a kind of irreversible EGFR tyrosine kinase inhibitors. Further activity studies in vitro and in vivo on the active compounds are still in progress.The structure-activity relationships of synthesized compounds and inhibitory activity data offered detailed information for design and synthesis of new compounds.Structurally diverse compound libraries are the sources of the development of innovative drugs. In order to establish the structurally diverse compound library of2-keto-5-aminooxazole, we developed a novel and efficient reaction for the synthesis of2-keto-5-aminooxazoles from a-isocyanoacetamides and a-diazocarbonyl ester. The entire sequence was realized under very simple conditions without the use of promoters. Moreover, the synthesis is economical in atom count and ecologically benign since only a molecμLar of nitrogen was lost in this entire sequence.