الفهرس 
ContentsOnly 14 pages are availabe for public view
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Abstract
Background : The thesis is divided into five parts, in addition to the Arabic summary. Part 1 : Introduction : deals with the anticancer drugs classification based on their mechanism of action. In addition, this section highlights various recently reported fused thiophene derivatives with promising antitumor activity. Part 2 : Research Objectives: explains the vision and the aims of this study that direct the theoretical and experimental work. Part 3 : Theoretical discussion of the experimental work: illustrates several possible conditions for the synthesis of the target compounds. It also discusses the results of the in vitro and in vivo antitumor evaluation, cellular and mechanistic study and molecular modeling for the most promising derivatives. Forty-eight final compounds were evaluated as antitumor agents against A549 human adenocarcinoma cell line using the CellTiter 96 AQueous One Solution Cell Proliferation assay (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS assay). Moreover, twelve compounds were investigated for their antitumor activity against SH-SY5Y human neuroblastoma cell line adopting MTS assay. Compounds 79, 82, 90, 98, 100, 102, 106, 114, 122–124 and 127 are the most promising derivatives towards A549 cell line with GI50 values range from 1.60–17.02 µM. Benzylamine derivatives with acetamide linker 122–124 are the most promising towards SH-SY5Y cell lines (GI50 varies from 5.68 to 18.22 μM). In addition, the National Cancer Institute (NCI) selected twenty-four final compounds for single dose testing (10 µM) against 60 cancer cell lines, and the most promising compounds 106 and 114 were selected for further five dose testing mode. The benzylureido derivatives 106 and 114 were identified as potent and broad-spectrum antiproliferative agent with GI50 values in sub-micromolar range (0.201–0.98 µM) towards most of the tested cell lines. A549 cells cycle analysis was performed for compounds 106 and 114, and the data pointed out that both compounds trigger cell cycle arrest after G2/M accumulation. Moreover, apoptosis was detected in the same cell line treated with these compounds by flow cytometry and caspase 3, 8 and 9 activation were confirmed as well. Targeting tubulin polymerization may explain the mechanism of the antiproliferative activity of compounds 106 and 114 based on cell cycle analysis, detected apoptosis, and in vitro inhibition of tubulin polymerization. Furthermore, polymeric nanoparticles (NPs) of compound 106 was formulated as a delivery system to be tested in vivo using a CT-26 murine tumor model. Compound 106, the nanoparticle formulation of compound 106 and compound 114 displayed promising in vivo antitumor activity in the CT-26 murine tumor model. Both free form of compounds 106 and 114 administrated in tween 80 significantly decreased tumor growth in mice treated with them in comparison to untreated group. Moreover, the nanoparticles of 106 displayed superior results to its free form in terms of tumor growth inhibition and mice survival. Part 4 Experimental work : discusses the synthetic procedures, structural characterization of the designed compounds and the adopted procedure of the in vitro antitumor evaluation, cellular and mechanistic study, the in vivo antitumor assessment and molecular modeling. Part 5 : List of references cited in this thesis.