الفهرس 
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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