Synthesis and investigation of biological effects of new quinoline/quinazoline derivatives

Cancer is considered to be one of the most important health problems today because of the increase in the incidence and mortality rate, which depends on increasing in the average life expectancy. Lung cancer, which is the most rapidly progressing and difficult to diagnose among cancer types, has a higher mortality rate than other types. With the development of the first-generation EGFR inhibitors, erlotinib and gefitinib, interest in EGFR inhibitors developed for the treatment of lung cancer have increased since 2004. This thesis, it is aimed to obtain new molecules that are more selective for cancer cells, which can be an alternative to current drugs which are not useful anymore because of drug resistance. For this purpose, eleven new hypotheses were developed using two different methods based on the existing EGFR inhibitors and the literature knowledge, and then scanning the in-house database, the hit molecules were determined. Then, based on these hit molecules, the synthesis and analysis of four different series (three quinazolines and one quinoline series) were carried out and their anticancer activity was investigated. Finally, by using molecular docking and dynamic simulation methods, binding mode and structure-activity relationship were examined. Among the quinazoline-4-(3H)-one derivatives, those containing halogen atom were found to be potentially effective, while the best EGFR inhibition and apoptosis induction were displayed by compounds containing N-aminotriazole moiety. Obtaining an nM concentration of activity for EGFR inhibition shows that the thesis has achieved its purpose.