الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Cancer is continuing to be a major problem that endangers human health worldwide. For the past years, cancer treatment has been a major endeavor of research and development in both academia and pharmaceutical industry. Although chemotherapy represents the main core for cancer treatment, the available anticancer therapeutics suffer from various drawbacks such as: lack of selectivity, systemic toxicity and multidrug resistance developed in the cancerous cells. Hence, there is an imperative need for design and development of new effective and selective anticancer agents with minimal side effects.
On the other hand, pyrazine derivatives are acknowledged as attractive bioactive scaffolds in the area of medicinal chemistry, owing to its wide spectrum of biological activities including anticancer activity. Moreover, several pyrazine derivatives have been recently reported as promising protein kinase inhibitors. Consequently, the present study was directed towards the design and synthesis of some new hybrid molecules comprising pyrazine scaffold attached to various substituted bioactive heterocycles such as: pyridine, thieno and furopyridines at position-2 as potential anticancer agents. All target compounds were selected and screened for their in vitro anticancer activity against a panel of approximately 60 cancer cell lines at a single dose of 10 μM at NCI, USA. Among them, compound 14a was selected for evaluation in five-dose screening assay.Furthermore, all compounds were evaluated for their in vitro anti-proliferative activity against human liver (HUH-7) and lung cancer (A549) cell lines, in addition to their cytotoxic activity against normal lung cell line (WI-38) to predict their safety profiles. In addition, the most active compounds were then selected for further in vitro evaluation for their inhibitory activity against FAK kinase. Moreover, cell cycle analysis and the apoptotic mechanism of the most active compounds (17c and 18f) through caspase-3 activation were investigated.