الفهرس 
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Abstract
Cancer is a life-threatening disease and the leading cause of death worldwide so in the last few years, cancer attracted great attention and noticeable progress has been made in the discovery and development of modern anticancer drugs. Discovering newer and safer anticancer agents continues to be a challenge.
The present investigation aimed to find novel chemical compounds that may serve as innovative antitumor agents and assess the biochemical effects of these novel chemical compounds on various human cancer cell lines.
The experiment was carried out on two types of cancer cell lines MCF7 (breast cancer) and Hpg2 (liver cancer) which were treated with seven novel thienopyramidine derivatives (3a, 3b, 3c, 3d, 3e, 3f, and 3g), and several studies were made as follows:
1) Determination of the cytotoxic activity.
2) Analysis of cellular DNA content using propiium iodide.
3) The quantitative assessment of apoptosis was determined by Annexin V-FITC/PI staining by flow cytometry.
4) Gene expressions of Bcl-2, Bax, Caspes3 and Caspes9.
5) Oxidant\antioxidant status in cells culture by measurement of (MAD) and (GR).
6) Molecular Docking.
The results included 12 tables and 28 figures. The obtained data were subjected to statistical analysis and revealed the following:
• Novel chalcone-pyridothienopyrimidinone derivatives were synthesized by the reaction of chalcones with different pyridothienopyrimidine under reflux conditions.
• It is interesting to observe that the IC50 of the two compounds 3b and 3g showed a higher cytotoxicity than 5-FU against HepG2 and MCF-7 cell lines.
• The seven tested compounds (3a- 3e and 3g) succeeded remarkably in arresting the proliferation of HepG2 and MCF-7 cell lines at different phases. Interestingly, our results revealed that treatment of HepG2 and MCF-7 cell with the newly synthesized tested compound elicited apoptotic effect comparable to that of 5-FU.
• The tested compounds induced significant increase of the MDA levels together with marked reduction of GR activity in HepG2 and MCF-7 cell lines compared to control cells.
• The results of the molecular docking study of the new compounds 3a-g into binding groove of the anti-apoptotic protein Bcl-2, revealed relatively moderate binding free energies compared to the selective Bcl-2 inhibitor, DRO. Among the new compounds, 3g showed the highest binding free energy toward Bcl-2. Analysis of the binding interactions of 3a-g revealed multiple hydrophobic interactions besides the hydrogen bonds, and electrostatic interactions with amino acids in the active site of Bcl-2.
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This suggested that the newly synthesized chalcone-thienopyrimidines derivatives had the ability to induce anticancer activity via inducing oxidative stress that were involved in induction of apoptosis in MCF-7 and HepG2 cells through intrinsic pathway. Anticancer compounds act mechanistically by arresting the cell cycle and by oxidative-dependent apoptosis. Therefore, regulation of the cell cycle and apoptosis are suggested to be active therapeutic strategies for the development of novel therapies in oncology. The tested compounds have the potential to be taken up for further modern clinical trials after more in vivo investigations particularly against liver and breast cancer.