Computer Based Design and Synthesis of Certain Quinazoline Derivatives as Tyrosine Kinase Inhibitors with Potential Anticancer Activity

Abstract

In this thesis a series of novel 4-substituted quinazoline derivatives was rationally designed, synthesized and biologically evaluated for their anticancer activity. The sixteen synthesized compounds IVa-f, Va-d, VIa-d and VIIa,b were evaluated for their antitumor activity against certain breast and hepatic cell lines at National Cancer Institute (NCI, Egypt). Eight of these compounds IVc, IVf, Vc, VIa-d, VIIb were selected due to their promising activity against the cell lines to be tested in vitro against VEGFR2 inhibition in KINEXUS cooperation, Canada. Compound VIa show marked activity against VEGFR2. The obtained results were clarified using molecular modeling study. The presented thesis comprises the following chapters: 1- Introduction: It contains a survey covering the definition of cancer, its causes, and how it is formed, also through this section cancer therapy strategies are fully explained with examples, especially kinases, where their structures, types and inhibitors are fully explained. 2- Rationale and design: In this section quinazoline derivatives have been synthesized hoping to act as VEGFR-2 inhibitors. The design depends on exploration of the previous revealed SAR studies, identification of the key interactions with the binding site and bioisosteric modifications of the reference compound. Synthesis of target compounds was carried out adopting the chemical pathway outlined in schemes (1-2). 3- Results and Discussions: This part contains the theoretical discussions for the obtained results.