الفهرس 
Treatment of cancerOnly 14 pages are availabe for public view
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Abstract
In recent years, 4-anilinoquinazolines have emerged as a versatile template for inhibition of a diverse range of receptor tyrosine kinases. Epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors are the most widely studied compounds among all tyrosine kinases. In this work, we present a new sub-family of compounds containing 4-anilinoquinazoline, core as promising potent and selective EGFR inhibitors. Our strategy is directed toward designing a variety of ligands with bulky substituents at the anilino moiety, mimicking that of Lapatinib which is recently launched as potent inhibitor for both EGFR and erbB2.
Three series of new 6,7-dimethoxy-4-substituted-anilino-quinazolines (Xa-i, XIa-g, XII) were designed and synthesized from 4,5-dimethoxyanthranilic acid. EGFR inhibitory activity of the final compounds was assessed. Moreover, the in vitro activities of the most active hits were assessed on human breast carcinoma cell line (MCF-7) where the EGFR is highly expressed. Fortunately, compound XIb and XIg displayed highest activity for cell line test. Finally, the active hits and some of the inactive ones were docked to the active site pocket of the EGFR-TK enzyme for investigation of their binding mode to the receptor active site.
This thesis comprises the synthesis of the following unavailable unreported starting materials and intermediates:-
1) m-(3-Methylbenzyloxy)acetanilide (VId)
2) m-(2-(Morpholin-4-yl)ethoxy)acetanilide (VIf)
3) m-(3-Fluorobenzyloxy)acetanilide (VIg)
4) 4-(3-Carboxyanilino)-2-chloro-6,7-dimethoxyquinazoline (VIII).
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In addition the study comprises the synthesis of the following new compounds:-
1) 2-Chloro-6,7-dimethoxy-4-(3-(morpholin-4-ylcarbonyl) anilino)quinazoline (Xa)
2) 2-Chloro-4-(3-(cyclohexylaminocarbonyl)anilino)-6,7-di methoxyquinazoline (Xb)
3) 4-(3-(Benzylaminocarbonyl)anilino)-2-chloro-6,7-dimeth oxyquinazoline (Xc)
4) 2-Chloro-6,7-dimethoxy-4-(3-((ethyl piperazin-1-ylcarbox-ylate)-4-ylcarbonyl)anilino)quinazoline (Xd)
5) 2-Chloro-6,7-dimethoxy-4-(3-(piperidin-1-ylcarbonyl)ani-lino)quinazoline (Xe)
6) 2-Chloro-6,7-dimethoxy-4-((3-(2-phenylethyl)aminocarbon-yl)anilino)quinazoline (Xf)
7) 2-Chloro-6,7-dimethoxy-4-(3-(isopropylaminocarbonyl)an-ilino)quinazoline (Xg)
8) 2-Chloro-6,7-dimethoxy-4-(3-(t-butylaminocarbonyl)anil-ino)quinazoline (Xh)
9) 2-Chloro-6,7-dimethoxy-4-(3-((1-phenylpiperazin)-4-ylcarb-onyl)anilino)quinazoline (Xi)
10) 4-(3-(Benzyloxy)anilino)-2-chloro-6,7-dimethoxyquinazol-ine (XIa)
11) 4-(3-(Allyloxy)anilino)-2-chloro-6,7-dimethoxyquinazoline (XIb)
12) 2-Chloro-4-(3-(3,4-dichlorobenzyloxy)anilino)-6,7-dimeth-oxyquinazoline (XIc)
13) 2-Chloro-6,7-dimethoxy-4-(3-(3-methylbenzyloxy)anilino) quinazoline (XId)
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14) 4-(4-(Benzyloxy)anilino)-2-chloro-6,7-dimethoxyquinazo-line (XIe)
15) 2-Chloro-6,7-dimethoxy-4-(3-(2-(morpholin-4-yl)ethoxy)an-ilino)quinazoline (XIf)
16) 2-Chloro-4-(3-(3-fluorobenzyloxy)anilino)-6,7-dimethoxy- quinazoline (XIg)
17) 4-(3-(Benzyloxy)anilino)-6,7-dimethoxyquinazolin-2(1H)-one (XII)
The structures of the synthesized compounds were confirmed by the spectral and micro-analytical analysis. Additionally, the references reviewed were listed at the end of thesis & the whole thesis was summarized in Arabic.