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Abstract An introductory part describing the chemistry of quinazoline, different approaches for its synthesis and tyrosine kinase inhibitors as targeted chemotherapeutic agents such as gefitinib, erlotinib, lapatinib and caneratinib. An introductory part describing the ATP-binding pocket of TK domain of EGFR. Chapter II (Research Objectives): The aim of this research is to synthesize structural analogues of gefitinib (Iressa®) and its congeners: erlotinib (Tarceva®), lapatinib (Tykerb®) and caneratinib (CI 1033®). Our strategy is directed toward the design of a variety of ligands by attaching new moieties at C-6 of the quinazoline ring of substituted 4- anilinoquinazoline derivatives and/or by varying the aniline substitution pattern in the hope of discovering more active ATP site inhibitors. Chapter III (Theoretical Discussion): A theoretical discussion of synthetic pathways that have been followed to obtain final new compounds and their mechanisms and spectral data. Eight cell lines were used to measure cytotoxic sensitivity of the proposed quinazoline derivatives. Most of tested compounds showed good activity against breast cancer (MCF-7) with IC50 range of 5.52-34.91 µg/ml. Molecular docking was performed into EGFR-TK active site and some compounds showed comparable binding mode to lapatinib. Molecular docking studies supported the strong inhibitory activity of our newly synthesized compounds and help to design novel potent inhibitors. 5 Chapter IV (Experimental): The starting materials, quinazolin-4(3H)-one (I) was prepared according to Niementowski reaction. The reaction involved the condensation of anthranilic acid with formamide at 120 °C. Scheme 1 involved the chlorination of quinazolin-4(3H)-one (I), with phosphorus oxychloride (POCl3). The next step involved a nucleophilic attack of p-pheneylene diamine on the carbon atom at the position-4 of the quinazoline ring to produce 4-(4-aminoanilino)quinazoline (III). Scheme 2 involved the reaction of 4-(4-aminoanilino)quinazoline (III) with phenyl isocyanate, phenyl isothiocyanate, glyoxalic acid, acrylic acid and succinic anhydride to produce 1-phenyl-3-(4-(quinazolin-4-ylamino) phenyl)- urea (IV), 1-phenyl-3-(4-(quinazolin-4-ylamino) phenyl)thiourea (V), 2-(4- (quinazolin-4-ylamino)phenylimino)acetic acid (VI), 3-(4-(quinazolin-4- ylamino)phenylamino)propanoic acid (VII) and 4-oxo-4-(4-(quinazolin-4- ylamino)phenylamino)butanoic acid (VIII) respectively. Scheme 3 involved the chlorosulfonation of quinazolin-4(3H)-one (I) at position-6 followed by a nucleophilic attack of a variety of substituted piperazines, piperdine and cyclohexyl amine on the sulfur atom to produce compounds (Xa-g). Compounds (Xa-g) were treated with phosphorus oxychloride (POCl3) to afford the desired derivatives (XIa-g). Scheme 4 and 5, compounds (XIa-g) were undergone a nucleophilic substitution reaction in the prescence of substituted aniline derivatives to give the final products (XIIb,c,d,g & XIIIa-g). The structures of the newly synthesized compounds were confirmed by both analytical and spectral data (IR, 1H-NMR, MS). The present investigation involves the synthesis of the following intermediates:- 1] Quinazolin-4(3H)-one (I). 2] 4-Chloroquinazoline (II). 3] 4-(4-Aminoanilino)quinazoline (III). 6 4] 6-Chlorosulfonylquinazolin-4(3H)-one (IX). 5] N-Cyclohexyl-4-oxo-3,4-dihydroquinazoline-6-sulfonamide (Xa). 6] 6-(Piperidin-1-ylsulfonyl)quinazolin-4(3H)-one (Xb). 7] 6-(Piperazin-1-ylsulfonyl)quinazolin-4(3H)-one (Xc). 8] 6-(4-Methylpiperazin-1-ylsulfonyl)quinazolin-4(3H)-one (Xd). 9] 6-(4-Ethylpiperazin-1-ylsulfonyl)quinazolin-4(3H)-one (Xe). 10] 6-(4-Phenylpiperazin-1-ylsulfonyl)quinazolin-4(3H)-one (Xf). 11] 6-(4-Benzylpiperazin-1-ylsulfonyl)quinazolin-4(3H)-one (Xg). 12] 4-Chloro-N-cyclohexylquinazoline-6-sulfonamide (XIa). 13] 4-Chloro-6-(piperidin-1-ylsulfonyl)quinazoline (XIb). 14] 4-Chloro-6-(piperazin-1-ylsulfonyl)quinazoline (XIc). 15] 4-Chloro-6-(4-methylpiperazin-1-ylsulfonyl)quinazoline (XId). 16] 4-Chloro-6-(4-ethylpiperazin-1-ylsulfonyl)quinazoline (XIe). 17] 4-Chloro-6-(4-phenylpiperazin-1-ylsulfonyl)quinazoline (XIf). 18] 6-(4-Benzylpiperazin-1-ylsulfonyl)-4-chloro-quinazoline (XIg). In addition to, the synthesis of the following final new compounds: 1] 1-Phenyl-3-(4-(quinazolin-4-ylamino)phenyl)urea (IV). 2] 1-Phenyl-3-(4-(quinazolin-4-ylamino)phenyl)thiourea (V). 3] 2-(4-(Quinazolin-4-ylamino)phenylimino)acetic acid (VI). 4] 3-(4-(Quinazolin-4-ylamino)phenylamino)propanoic acid (VII). 5] 4-Oxo-4-(4-(quinazolin-4-ylamino)phenylamino)butanoic acid (VIII). 6] 4-(4-Bromoanilino)-6-(piperidin-1-ylsulfonyl)quinazoline (XIIb). 7] 4-(4-Bromoanilino)-6-(piperazin-1-ylsulfonyl)quinazoline (XIIc). 8] 4-(4-Bromoanilino)-6-(4-methylpiperazin-1-ylsulfonyl)quinazoline (XIId). 9] 6-(4-Benzylpiperazin-1-ylsulfonyl)-4-(4-bromoanilino)quinazoline (XIIg). 7 10] N-Cyclohexyl-4-(phenylamino)quinazoline-6-sulfonamide (XIIIa). 11] 4-Anilino-6-(piperidin-1-ylsulfonyl)quinazoline (XIIIb). 12] 4-Anilino-6-(piperazin-1-ylsulfonyl)quinazoline (XIIIc). 13] 4-Anilino-6-(4-methylpiperazin-1-ylsulfonyl)quinazoline (XIIId). 14] 4-Anilino-6-(4-ethylpiperazin-1-ylsulfonyl)quinazoline (XIIIe). 15] 4-Anilino-6-(4-phenylpiperazin-1-ylsulfonyl)quinazoline (XIIIf). 16] 4-Anilino-6-(4-benzylpiperazin-1-ylsulfonyl)quinazoline (XIIIg). Lead compounds were evaluated for their ability to inhibit the growth of human breast carcinoma (MCF-7) in which tyrosine kinase activity is over expressed. Docking study for the most active compounds was carried out on the crystal structure of EGFR- lapatinib complex (PDB code: 2J5F). Chapter V (Conclusion): A summary of the present study, conclusions and the future work. Chapter VI (References): A list of references which were used and their arrangement according to their order in the thesis. |