Design, Synthesis And SAR Of Novel Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors

The protein tyrosine kinase (PTK) plays critical roles in many of the signal transduction processes that control cell growth, differentiation, mitosis, and apoptosis. Epidermal growth factor receptor (EGFR) belongs to the family of trans-membrane growth factor receptor PTKs. It can transfer the γ-phosphate of ATP to specific tyrosine residue on functional proteins and then trigger signal-transmitting process that regulate a wide variety of cellular processes. The EGFR and its ligands (EGF, TGFα) have been implicated in various tumors of epithelial origin (e.g. aquamous cell carcinoma; breast, ovarian, and NSC lung cancer). Thus, inhibitors of the EGFR have emerged as promising anticancer agents and two main approaches, humanized monoclonal antibodies and tyrosine kinase inhibitors, have been developed.Small molecule tyrosine kinase inhibitors are one class of promising new anticancer drugs and several chemical series such as 4-anilinoquinazolines, 4-anilinopyrazolo[3,4-d] pyrimidines, 4-anilinopyrazolo- and 4-anilinopyrroloquinazolines, have been reported as EGFR tyrosine kinase inhibitors. Some compounds in the quinazoline series have been launched (Iressa^? and Taceva^?) or in clinical trials.Based on the analysis of structure-activity relationships of quinazoline-like EGFR inhibitors and the binding model of inhibitor with EGFR, pharmacophore of quinazoline-like inhibitors was summarized. According to the pharmacophore model, a series of acryioylamino-salicylanilides were synthesized as inhibitors of EGFR tyrosine kinase. Pseudo six-membered ring of salicylanilides, formed by the intramolecular hydrogen bond between OH and O=C, was used to mimic the pyrimidine ring of quinazoline EGFR inhibitors. Acrylamido moiety was incorporated to target the Cys-773 of EGFR specifically as Michael acceptor. And three other series of target compounds were also designed and synthesized as inhibitors of EGFR: triazines, pyrimidines and purines.Totally ninety-six target compounds were synthesized, among which seventy-six were substituted salicylanilides. All of them were identified by ¹HNMR(300 MHz, 400MHz) and MS(EI, FAB, or ESI), sixty-one of which were identified by high revolution MS(EI,FAB).The synthesized target compounds were tested for their inhibitory activity towards the EGFR tyrosine kinase. Salicylanilides exhibited good activity as EGFR inhibitors. It could...