الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
Due to the importance and versatility of thalidomide as multi-target drug and several clinical studies of thalidomide for the treatment of multiple myeloma, colon cancer, prostate cancer, and other cancer diseases are ongoing in the literature. Over the years, thalidomide has been used in the treatment of a variety of inflammatory and autoimmune diseases. Thalidomide consists of two moieties. One of these moieties is the phthalimide molecule, a class of cyclic imides, and the second is the piperdin2,6-dione molecule. Phthalimide moiety is one of the thalidomide metabolites and might be the effective part of thalidomide toward many diseases. Moreover, considerable interest has been focused on dithiocarbamates which are known to be active as anticancer agents. Also, 1,3,4-oxadiazole derivatives have attracted significant attention in the field of drug discovery because of their wide array of pharmacological activities, especially anticancer activities. Therefore, a combination and merging of thalidomide with a moiety of dithiocarbamate as well as dithioate containing two sulfur atoms, phthalimide attached to the same dithiocarbamate as well as dithioate moieties and design thalidomide and phthalimide oxadiazole sulfur bridged derivatives had attracted the attention in order to design new high bioactive molecules. Thus, a novel synthesis of new thalidomide and phthalimide dithiocarbamate and dithioate analogs and new thalidomide and phthalimide oxadiazole sulfur bridged derivatives were presented. To fulfill this aim the following investigation were performed: 1- Antitumor activity. 2- Antiangiogenic activity. 3- Anti-inflammatory effect. 4- Immunomodulatory effect. Therefore, N-Chloromethylthalidomide 272, N-chloromethylphthalimide 264 and N-(2-bromoethyl) phthalimide 265 were reacted with different amines 268a-j and hydrazides 266a-d in the presence of carbonyl sulfide stirring in CH3CN or DMF for 48 h at room temperature to afford thalidomide dithiocarbamate and dithioate analogs 273a-c and phthalimide dithiocarbamate and dithioate analogs 267a-c, 269a-j, 270a-e and 270g-j respectively in good to excellent. Moreover, N-Chloromethylthalidomide 272 and N-chloromethylphthalimide 264 were reacted with different hydrazides 266a-d in the presence of carbonyl sulfide and potassium hydroxide in DMF for stirring overnight at room temperature to afford thalidomide oxadiazole sulfur bridged derivatives 274a-d and phthalimide oxadiazole sulfur bridged derivatives 271a-d in good to excellent. The chemical structure for all the prepared compounds was confirmed through the correct IR, 1H NMR, 13C NMR and FAB Mass. All the synthesized compounds were screened for in vitro antitumor against different human cancer cell lines as well as their effect on the different immune cells. Moreover, the estimation of all the synthesized compounds toward Tumor Necrosis Factor (TNF-α) and Nitric oxide (NO) was evaluated. Also, the investigation for all the synthesized compounds toward the binding affinity to Vascular Endothelial Growth Factor (VEGF), its receptor Vascular Endothelial Growth Factor receptor (VEGFR) and Histone Deacetylase (HDAC) was discussed. Meanwhile, the genotoxic effect of some compounds were tested and compared to cyclophosphamide as a known mutagen. Moreover, the establishment of the appropriate structure activity relationship was clarified using molecular docking study for some synthesized compounds in the investigation of Vascular Endothelial Growth Factor (VEGF). The results were tabulated and summarized as follow: Phthalimide derivatives 270e and 270i were the best cytotoxic compound against MCF7 and HepG2 cells among other cancer cells. Both derivatives 270e and 270i inhibited NO, TNF-α, and cellular VEGF and possessed potent direct binding to its receptor VEGFR and showed binding mode to the lead compound with high docking score values. Both derivatives 270e and 270i possessed a higher potential to induce genotoxic activity than thalidomide. On the other hand, thalidomide derivative 274a has potent antiangiogenic effect and thalidomide derivative 273b has potent anti-inflammatory effect.