Design and Synthesis of Quinazoline Based Compounds as Tyrosine kinase Inhibitors with Anticipated Anti-Proliferative Activity

Abstract

This study includes an overview about cancer and the role played by tyrosine kinase in cancer progression. A new series of 4-anilinoquinazolines with C-6 ureido and thioureido side chains and various substituents at the C-4 anilino moiety was designed, synthesized and evaluated as wild type (WT) and mutant EGFR inhibitors. Most of the compounds inhibited EGFR kinase wild type (EGFR WT) with IC50 values in the low nanomolar range (<0.495-9.05 nM) and displayed more potent cytotoxic effect in BaF/3 cell linesexpressing EGFR WT than reference compound gefitinib. The anti-proliferative effect of all synthesized compounds against gefitinib insensitive double mutant cell lines Ba/F3 expressing Del19/T790M and Ba/F3 expressing L858R/T790M were assayed. Compounds XII, XIVb, XVb showed significant inhibition (IC50= 1.76-2.38 μM) in these mutant lines and significant HER2 enzyme inhibition (IC50= 19.2-40.6 nM) compared to lapatinib (60.1 nM) as well as cytotoxic effect against BT-474 cells of high HER2 expression. The Binding mode of compounds VIIId, XIVb, IXb, IXc and Xb were demonstrated. Furthermore, growth inhibition against gefitinib insensitive cell lines PC9-GR4 (Del19/T790M) were tested, compounds XIVb and XVb showed about eight and three folds respectively greater potency than gefitinib. Our structure-activity relationships (SAR) studies suggested that presence of ethyl piperidino urea/thiourea at 6-position and bulky group of (3-chloro-4-(3-fluorobenzyloxy)phenyl)amino at 4-position of quinazoline may serve as promising scaffold for developing inhibitors against wild type and mutant EGFR. The thesis is divided into different parts: 1. Introduction: This part includes a brief survey about cancer, causes of cancer and several approaches for treatment of cancer in addition to targeted cancer therapy with special focus on epidermal growth factor kinases (EGFR). 2. Rational and design: It describes the scientific basis upon which the targeted quinazoline based compounds were designed, Compounds were designed to target gefitinib resistant cell lines without cytotoxicity of covalent inhibitors. Design is based on two main strategies; first strategy was Abstract xvi based on targeting of EGFR double mutants L858R/T790M and Del19/T790M by adding additional hydrogen bond acceptor at C6 position of quinazoline. Second strategy was based on dual inhibition of EGFR/HER2 to target compensatory pathway of acquired resistance of EGFR inhibition. In addition, a molecular docking study was performed to support the design of the proposed compounds.