Design, Synthesis And Biological Evaluation Of EGFR Inhibitors And The Construction Of Drug-Like Libraries

Nowadays, Cancer has been a frequently-occurring disease which threats to human health. Research shows that overexpression or aberrant activation of EGFR receptors occurs in many solid tumors. As EGFR signaling pathway plays a crucial role in human cancers, EGFR and its family members have been emerged as attractive targets for the development of antitumor drugs. The first generation of EGFR inhibitors such as Gefitinib and Erlotinib have been approved by the US Food and Drug Administration (FDA) in patients with NSCLC. The FDA recently granted approval for the use of afatinib in patients with EGFR-mutated NSCLC.The growth and development of cancer involve in more than one receptors and signal pathways. Multi-targeted drugs could be much more efficient than drugs directed at a single target or combined drugs. They can also avoid the drug interactions and reduce the side effects in the combined drug therapy. The development of multi-targeted tyrosine kinase inhibitors is of great significance for anti-cancer therapy. Lapatinib is a reversible and dual inhibitor of EGFR and HER2 tyrosine kinases, it has already been approved by the US Food and Drug Administration as a treatment for HER2-positive metastatic breast cancer.Iron (Fe) is fundamental for many important cellular processes, It is an essential component of many proteins and enzymes that are involved in cell growth and replication. Tumor cells are far more sensitive than normal cells to Fe depletion, probably because of their increased Fe requirements. It is clear that Fe chelators are effective antitumor agents. Based on the S AR studies of a series of EGFR inhibitors in the trials and ligand binding model in the literatures, we designed and synthesized 2 series of 4-anilinoquinazoline derivative by incorporating an 3-Hydroxy-4-pyridinone motif at the position 6 or 7 of the conventional quinazoline scaffolds. The general preparation for the 72 compounds was described in this thesis and all of them wereidentified by 1H NMR, HPLC-HRMS and melt point.Most of the synthesized compounds potently inhibited the proliferation of the human epidermal carcinoma cell A431 (with EGFR overexpression), and have a moderate inhibition in Gefitinib-resistant NSCLC cell HI975 (bearing EGFR [L858R/T790M]).Some of the compounds were selected to test their potency to inhibit the kinase including EGFRWT, EGFRT790M, and EGFRL858R, and the result turns out well. In addition most of the synthesized compounds potently inhibited the proliferation of HeLa cells. Importantly, some compounds displayed weaker inhibitory on the EGFR-negative cell SW620. The result of GSH-conjugate reaction and Western Blotting revealed these 3-Hydroxy-4-pyridinone-containing quinazoline derivatives do not own the ability to covalently bind to Cysteine. Further extensive evaluation is undergoing and will be reported in due course.The construction of huge compound libraries plays a key role in the development of new drugs. Nitrogen-containing heterocyclic account for a large proportion of marketed drugs, so it is important to construct a huge amount of nitrogen-containing heterocyclic compound libraries for the discovery of lead compounds. During the Ph.D. Program,8 structurally diverse libraries with 655 compounds were developed. Among them, sorafenib related library and thiazole related library have been evaluated in the corresponding tumor cells in vitro, and leading compounds have been selected for the further biological assay. We have developed convenient methods for the synthesis of polyfunctionalized anilines and 2-aminoimidazoles from vinyl azides. Iron chelator related library has been evaluated in in vitro model to determine their affinity to iron ions as well as their ability to across the blood-brain barrier. Further extensive biological evaluation is undergoing and will be reported in due course.