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Abstract Summary In a search for new candidates for the treatment of breast cancer and encouraged by the critical role of PI3K enzyme inhibitors as potentiators of the antitumor activity of DNA-damaging drugs and ionizing radiation and as single agents drugs in breast cancer, in addition to the marked cytotoxic activity exhibited by some quinazoline derivatives through adapting different mechanism of actions, it seemed of interest to synthesize and investigate the anticancer and PI3K inhibition activities of different series of (pyridin-4-yl)quinazolin-4(3H)-one derivatives. The thesis consists of the following parts: I) Introduction This This part includes a brief literature review on cancer, principles of chemotherapy, a brief survey on PI3K and its inhibitors as well as the anticancer activity of different quinazoline derivatives regarding their mechanism of action. In addition, different chemical methods adopted for the synthesis of different quinazoline derivatives are discussed. II) Results and Discussion This section deals with the explanations of the chemical reactions involved in the synthesis of the known compound and the variable new compounds besides the different analytical methods applied for the characterization and verification of the structures of the obtained derivatives. Schemes (1-4) illustrate the preparation of the target quinazolines. Summary vii Section A: Synthesis of Ethyl 4-(4-oxo-2-(pyridin-4-yl)quinazolin-3(4H)- yl)benzoate (2) , 4-(4-oxo-2-(pyridin-4-yl)quinazolin-3(4H)-yl)benzohydrazide(3) and (4-hydroxy-3-methoxybenzylidene)-4-(4-oxo-2-(pyridin-4-yl)quinazolin- 3(4H)-yl)benzohydrazide(8). Scheme1. Reagents and conditions: (A) ethyl-4-aminobenzoate, gl.AcOH, CH3COONa, Reflux 8h;(B) H2N-NH2, abs.EtOH, Reflux4h;(C) diethyl malonate, AcOH, Reflux 8h;(D) maleic anhydride , AcOH, Reflux 8h;(E) CS2, abs.EtOH, KOH, Reflux 12h;(F) ethoxymethylene malononitrile , abs.EtOH, Reflux 2-4h;(G) vanillin aldehyde , abs.EtOH, reflux 6h;(H) thio salicylic acid , benzene, reflux 8h;(I) thioglycolic acid , benzene, reflux 8h;(j) acetyl chloride, triethyl amine, dioxane, stirring 24h;(K) chloro acetylchloride, dioxane, triethyl amine, stirring 6h. Summary viii Section B: Synthesis of 1-(4-oxo-2-(pyridin-4-yl)quinazolin-3(4H)- yl)thiourea(13a) and 1-(4-oxo-2-(pyridin-4-yl)quinazolin-3(4H)-yl)-3- phenylthiourea(13b). Scheme 2. Reagents and conditions: (A) thiosemicarbazide and /or phenylthiosemicarbazide, abs.EtOH, reflux 2-4h;(B) 3-chloro-2,4-pentadione, CH3COONa, abs.EtOH, reflux 10-14h;(C) Ethyl 2- bromo propanoate, abs.EtOH, CH3COONa, reflux 6-10h.(D) Phenacyl bromide, abs.EtOH, CH3COONa, reflux 4-6h;(E) ClCH2COOH, gl.AcOH, CH3COONa, reflux 8-11h;(F) vanillin aldehyde and /or 3,4,5 tri methoxybenzaldehyde , gl.AcOH, CH3COONa, reflux 6-10h. Summary ix Section C: Synthesis of 4-(4-oxo-2-(pyridin-4-yl)quinazolin-3(4H)-yl)benzene sulfa derivatives(19a-f) and 3-(4-aminophenyl)-2-(pyridin-4-yl)quinazolin- 4(3H)-one(21). Scheme3. Reagents and conditions: (A) appropriate sulfa drug namely, sulfamethazine, sulfa guanidine, sulfamethoxazole, sulfanilamide, sulfa pyridine and sulfadiazine, gl.AcOH, CH3COONa, reflux 15h. (B) Ethyl isothiocyanate, cyclohexyl isothiocyanate and /or phenyl isocyanate, Acetone, anhydrous K2CO3, reflux 1.5h. (C) p-phenylenediamine, pyridine, reflux, 6h. (D) D-mannose and /or D-arabinose, ethanol, drops of gl.AcOH, reflux 6h. (E) Thiosalicylic acid, benzene, reflux 16h. (F) Carbon disulphide, DMF, hydrazine hydrate, stirring 1h. (G) Acetyl acetone, heating 9h. (H) Ethyl acetoacetate, heating 8h. Summary x Section D: Synthesis of (Substituted)-2-mercapto-quinazolin-4-ones(27a,b) and it is derivatives. Scheme4. Reagents and conditions: (A) Cyclohexyl isothiocyanate and /or O-tolyl isothiocyanate, acetone, Reflux for 6h (B) acetyl /benzoyl chloride, pyridine, refluxed for 6h (C) Chloroacetic acid, NaOH, stirring for 15 min, (D) ethyl chloroacetate, NaOH, methanol, stirring for 2h. (E) 4-chloroaniline, ethanol, refluxed for 2h (F) thiosemicarbazide, DMF, refluxed for 6h. Summary xi III) Experimental This part describes the practical procedures and conditions adopted for the synthesis of the desired compounds, in addition to the different physical, spectral and micro-analytical analyses applied for the identification of the new compounds. IV) Biological evaluation and Molecular Modeling Study The synthesized compounds were evaluated for their anticancer activity against breast adenocarcinoma cell line (MCF-7) besides studying the enzyme inhibitory activity against PI3K enzyme. After in vitro evaluation, it was thought worthy to study the interaction of synthesized compounds with PI3K using MOE 2008.10 program. The coordinates of PI3K structure were obtained from the crystal structure of PI3K with its inhibitor (PDB ID: 2WXG). The data of docking scores and interactive amino acid residues with the screened compounds is depicted. V) References: This part comprises 137 references stated in the thesis and most of them are recent. VI) Arabic Summary |