الفهرس 
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Abstract
The present study deals with the design and synthesis of novel hybrid molecules combining xanthine derivatives and oximes as nitric oxide (NO)-releasing moiety in one compact structure and evaluating of their anti-inflammatory, ulcerogenic liability and anticancer activities.The thesis includes four main parts; introduction, scope of investigation, results & discussion and the experimental one.1- Introduction The introductory chapter consists of three parts; the first one gave presented an overview about xanthine derivatives, their synthesis and their biological activities involves antitumor, anti-inflammatory, antidiabetic, anti-hyperlipidemic, antimicrobial, anti-asthmatic and antioxidant. The second part includes a literature survey about the NO biosynthesis and physiological activity, focusing on its important role in protecting the gastrointestinal system leading to the development of a new class of non-steroidal anti-inflammatory drugs (NSAIDs), NO-NSAIDs as well as its potential role as anticancer agent resulting in emerging a novel agents that produce NO which have the ability to overcome the resistance to chemotherapy and refractoriness to conventional therapeutics which is one of the major challenges in the treatment of cancer. The third part involves a literature survey about some of NO donor hybrids and their ability to release NO2- Scope of investigation This section outlines the main goals and the rational of this work, including the synthesis of target compounds and biological evaluation of novel xanthine NO-donating prodrugs, indicating the idea of combining xanthine derivatives with oxime as hybrid for the purpose of synergistic effect and/or decreasing anti-inflammatory and anticancer activity. 3- Results and discussion This chapter deals with discussion of the results obtained and it is subdivided into three main categories: A- The first part:Chemistry section, which includes description of the methods employed in the synthesis of ketone intermediates (6-7 and 12-19) and their corresponding xanthine NO-donating oxime hybrids 20-29. Structural characterization of the newly synthesized compounds is based on different spectral methods including (1H-NMR and 13C-NMR) as well as elemental analysis.B- The second part: Biology which is subdivided into six parts:1- Screening of anti-inflammatory activity: The synthesized twenty compounds (6-7 and 12-29) were evaluated for their anti-inflammatory activity, compared with indomethacin as a reference drug, using carrageenan-induced paw edema in rats described by Winter et al [1]. The results revealed that most of synthesized 2-((1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio)-N-(4-(1-hydroxyimino)ethyl)phenyl)acetamide induced significant anti-inflammatory activity compared to indomethacin.2- Screening of ulcerogenicity: Evaluation of the ulcerogenicity after oral administration of the synthesized compounds or indomethacin. The results revealed that the synthesized compounds exhibit safer ulcerogenic liability relative to indomethacin.3- Histopathological investigation:Histopathological investigation of the ulcerative regions of the synthesized compounds in order to assess the ulcerogenicity of the synthesized compounds on the gastric mucosa. Stomach sections of the ulcers for the control and the treated groups were stained by standard hematoxylin and eosin stain. The produced slides were subjected to microscopical examination and pictures were picked for these slides. A very low incidence or absence of gastric ulceration was induced by the tested compounds where a continuous mucosal layer was observed with the absence of capillary inflammatory cells and the ulcerative damage of the gastric mucosa was markedly decreased which was proved by the very low UI of 1.4- Screening of COX inhibition:Compounds 16, 20, 22, 23 and 28, were evaluated for their ability to inhibit COX-1 and COX-2 enzymatic activity. The IC50 values of test compounds was determined and compared to that of reference molecules indomethacin and celecoxib. The in vitro COX-1/COX-2 inhibition studies showed that the most potent COX inhibitors in this series were 20 and 28 . 5- Docking studies: Molecular model studies were performed on COX-1 and COX-2 active site for compounds 16, 20, 22, 23 and 28 using MOE software program. Docking studies in COX-1 showed that compound 20 with IC50 of 0.3 µM has the highest number of interaction with COX-1 active site and hence explain the high anti-inflammatory activity of this compound. Also, compound 28 show four hydrogen bond interactions with amino acid residues (Glu524, Val523, Tyr385 and Arg513) present in pocket of COX-2 active site. So, these bindings explain the observed activity of this compound on COX-2 active site (IC50= 0.15 µM).6- Screening of anticancer activity: National Cancer Institute (NCI) selected synthesized compounds 20, 22, 23, 24 and 25 according to the protocol of the Drug Evaluation Branch of the National Cancer Institute, USA, for in vitro anticancer screening. The human tumor cell lines were derived from nine different cancer types. Results for each compound were reported as the growth percent of the treated cells, which are evaluated spectrophotometrically and compared to that of the untreated control cells. Most of the tested compounds exhibited mild antiproliferative activity against most of the cell lines.Compound 25 was selected for advanced five-dose testing against the full panel of 60 human tumor cell lines. All the 60 cell lines representing nine tumor subpanels were incubated at five different concentrations (0.01, 0.1, 1, 10 and 100 µM).C- Experimental part The fourth part is the experimental part, and it is divided into two sections; 1- Chemistry section:It describes different procedures employed in synthesis of the intermediates, with the following IUPAC nomenclature:1,3-Dimethyl- 6-aminouracil (1a)3-Methyl-6-aminouracil (1b)1,3-Dimethyl- 6-amino-5-nitrosouracil (2a)3-Methyl-6-amino-5-nitrosouracil (2b)1,3-Dimethyl- 5,6-diaminouracil (3a)3-Methyl-5,6-diaminouracil (3b)1,3-Dimethyl-8-thioxo-3,7,8,9-tetrahydro-1H-purine-2,6-dione (4a)3-Methyl-8-thioxo-3,7,8,9-tetrahydro-1H-purine-2,6-dione (4b)N-(4-Acetylphenyl)-2-bromoacetamide (5)N-(4-Acetylphenyl)-2-((1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio)acetamide (6)N-(4-Acetylphenyl)-2-((1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio)
acetamide (7)1,3-Dimethyl-8-((2-oxo-2-phenylethyl)thio)-3,7-dihydro-1H-purine-2,6-dione (12)8-((2-(4-Methoxyphenyl)-2-oxoethyl)thio)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (13)8-((2-(4-Chlorophenyl)-2-oxoethyl)thio)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (14)8-((2-(4-Bromophenyl)-2-oxoethyl)thio)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (15)3-Methyl-8-((2-oxo-2-phenylethyl)thio)-3,7-dihydro-1H-purine-2,6-dione (16)8-((2-(4-Methoxyphenyl)-2-oxoethyl)thio)-3-methyl-3,7-dihydro-1H-purine-2,6-dione (17)8-((2-(4-Chlorophenyl)-2-oxoethyl)thio)-3-methyl-3,7-dihydro-1H-purine-2,6-dione (18)8-((2-(4-Bromophenyl)-2-oxoethyl)thio)-3-methyl-3,7-dihydro-1H-purine-2,6-dione (19)N-(4-Acetylphenyl)-2-((1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio)-N’-hydroxyacetimidamide (20)N-(4-Acetylphenyl)-N’-hydroxy-2-((1-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio)acetimidamide (21)8-((2-(Hydroxyimino)-2-phenylethyl)thio)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (22) 8-((2-(Hydroxyimino)-2-phenylethyl)thio)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (23)8-((2-(4-Chlorophenyl)-2-(hydroxyimino)ethyl)thio)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (24)8-((2-(4-Bromophenyl)-2-(hydroxyimino)ethyl)thio)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (25)8-((2-(Hydroxyimino)-2-phenylethyl)thio)-3-methyl-3,7-dihydro-1H-purine-2,6-dione (26)8-((2-(Hydroxyimino)-2-(4-methoxyphenyl)ethyl)thio)-3-methyl-3,7-dihydro-1H-purine-2,6-dione (27)8-((2-(4-Chlorophenyl)-2-(hydroxyimino)ethyl)thio)-3-methyl-3,7-dihydro-1H-purine-2,6-dione (28)8-((2-(4-Bromophenyl)-2-(hydroxyimino)ethyl)thio)-3-methyl-3,7-dihydro-1H-purine-2,6-dione (29)2. The measurement of NO release from the targeted NO donor compounds 20, 25 and 28 in phosphate buffer of pH 7.4 using modified Griess colorimetric method.3. The biological evaluation: it is subdivided into six sections:i-Screening of the anti-inflammatory activity of the synthesized compounds using carrageenan-induced paw edema in rats using indomethacin as a reference drug.ii-Screening of the ulcerogenicity of the synthesized compounds after oral administration of the synthesized compounds or indomethacin. iii-Histopathological investigation of the ulcerative regions of the synthesized compounds in order to assess the ulcerogenicity of the synthesized compounds on the gastric mucosa.iv-Cyclooxygenase inhibitory assay for compounds 6-7 and 12-29.v-Docking studies of compound 16, 20, 22, 23 and 28 into the active site of COX-1 and COX-2 enzymes by using MOE software program. vi-Evaluation of the anticancer activity of compounds 20, 22, 23, 24 and 25 that were selected by National Cancer Institute (NCI) according to the protocol of the Drug Evaluation Branch of the National Cancer Institute, USA.