الفهرس 
Biological Activity of Quinazoline and Quinazolinone derivatives
MethodologyOnly 14 pages are availabe for public view
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Abstract
In this thesis, eighteen novel quinazolinone and triazinoquinazolinone
derivatives were designed and synthesized as antineoplastic agents. Molecular
modeling techniques were used to support the design. All the synthesized
compounds were biologically evaluated for their cytotoxic activity in MCF-7 and HCT-
116 cell lines. Most of the synthesized compounds showed excellent antiproliferative
activity ranging from 0.35 μM to 3.8 μM in MCF-7 cell line and from 0.02 μM to 0.84
μM in HCT-116 cell line. Six compounds (Va, VIa, VId, Xa, XIIa and XIId) were
further evaluated for their apoptotic activity as activators of caspases 3, 8 and 9 in
HCT-116 cell line. Finally, compounds VId, Xa and XIIa showing potent effect on
caspase 3,8, and 9 were further analyzed by cell cycle flow analysis where they
showed cell cycle arrest mainly in G1/S phase.
The thesis included the following parts:
1. Introduction
This part is a comprehensive review for covering the therapeutic agents that target
different pro-apoptotic proteins involved in the apoptotic process either through the
extrinsic or intrinsic pathways, some agents interfere with both apoptotic pathways.
Novel heterocyclic compounds based on quinazoline scaffold are reported to be
promising agents as potent caspases activators and Bcl-2 inhibitors.
2. Aim and Rationale
The objective of this work was to design and synthesize new compounds as anticancer agents bearing quinazoline core with potential pro-apoptotic activity. The
design of these compounds was based on structural modification of a selected lead
compound and was supported by a molecular modeling study.
3. Discussion of the Synthetic Part
Synthesis of the target compounds was carried out adopting the chemical pathways
in schemes (1 and 2). The chemical methods for preparing the starting materials and
intermediates were mentioned. Also, this part a summarized data about the spectral
methods adopted for verification of the structures of the prepared compounds
Reported synthetic intermediates: (5 compounds)
2-(2-Ethoxy-2-oxoacetamido)benzoic acid (II) Ethyl 4-oxo-4H-benzo[d][1,3]oxazine-2-carboxylate (III)
2-Aminobenzohydrazide (VIII)
Ethyl 3-amino-4-oxo-3,4-dihydroquinazoline-2-carboxylate (IX)
Ethyl(E)-3-((ethoxymethylene)amino)-4-oxo-3,4-dihydroquinazoline-2-
carboxylate (XI)
New final compounds: (18 compounds)
4-(2-(Ethoxycarbonyl)-4-oxoquinazolin-3(4H)-yl)benzoic acid (IV)
Ethyl 4-oxo-3-(4-sulfamoylbenzyl)-3,4-dihydroquinazoline-2-carboxylate (Va)
Ethyl 4-oxo-3-((4-sulfamoylphenyl)amino)-3,4-dihydroquinazoline-2-
carboxylate (Vb)
Ethyl 4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazoline-2-carboxylate (VIa)
Ethyl3-(4-(N-(diaminomethylene)sulfamoyl)phenyl)-4-oxo-3,4-
dihydroquinazoline-2-carboxylate (VIb)
4-(4,10-Dioxo-4,10-dihydro-3H-[1,2,4]triazino[6,1-b]quinazolin-3-yl)-N-(pyridin-
2-yl)benzenesulfonamide (VIc)
Ethyl 4-oxo-3-(4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)-3,4-dihydroquinazoline-
2-carboxylate (VId)
Ethyl-3-(4-(N-(5-methylisoxazol-3-yl)sulfamoyl)phenyl)-4-oxo-3,4-
dihydroquinazoline-2-carboxylate (VIe)
3-Phenyl-1H-[1,2,4]triazino[6,1-b]quinazoline-2,4,10(3H)-trione (Xa)
3-(4-Chlorophenyl)-1H-[1,2,4]triazino[6,1-b]quinazoline-2,4,10(3H)-trione (Xb)
4-(4,10-Dioxo-4,10-dihydro-3H-[1,2,4]triazino[6,1-b]quinazolin-3-
yl)benzenesulfonamide (XIIa)
N-(diaminomethylene)-4-(4,10-dioxo-4,10-dihydro-3H-[1,2,4]triazino[6,1-
b]quinazolin-3-yl)benzenesulfonamide (XIIb)
4-(4,10-Dioxo-4,10-dihydro-3H-[1,2,4]triazino[6,1-b]quinazolin-3-yl)-N-(pyridin-
2-yl)benzenesulfonamide (XIIc)
Ethyl 4-oxo-3-(4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)-3,4-dihydroquinazoline-
2-carboxylate (XIId)
4-(4,10-Dioxo-4,10-dihydro-3H-[1,2,4]triazino[6,1-b]quinazolin-3-yl)-N-(5-
methylisoxazol-3-yl)benzenesulfonamide (XIIe)
4-(4,10-Dioxo-4,10-dihydro-3H-[1,2,4]triazino[6,1-b]quinazolin-3-yl)-N-(thiazol-
2(3H)-ylidene)benzenesulfonamide (XIIf) N-(4,6-dimethylpyrimidin-2-yl)-4-(4,10-dioxo-4,10-dihydro-3H-
[1,2,4]triazino[6,1-b]quinazolin-3-yl)benzenesulfonamide (XIIg)
4-((4,10-Dioxo-4,10-dihydro-3H-[1,2,4]triazino[6,1-b]quinazolin-3-
yl)amino)benzenesulfonamide (XIII)
4. Biological Evaluation
All the synthesized compounds were biologically evaluated for their cytotoxic activity
in MCF-7 and HCT-116 cell lines. Most of the synthesized compounds showed
excellent antiproliferative activity ranging from 0.35 μM to 3.8 μM in MCF-7 cell line
and from 0.02 μM to 0.84 μM in HCT-116 cell line. Six compounds (Va, VIa, VId, Xa,
XIIa and XIId) showing the highest cytotoxic activity and are representative to
different series if the synthesized compounds were further screened for their
apoptotic activity as activators of caspases 3, 8 and 9 in HCT-116 cell line. Finally,
three compounds VId, Xa and XIIa exhibiting potent effect on caspases 3, 8, and 9
were further analyzed by cell cycle flow analysis where they showed cell cycle arrest
mainly in G1 phase.
5. Experimental of the Synthetic Part
This part explains laboratory detailed procedures used for the synthesis of the
designed compounds. The elemental analyses, physical and spectral data were also
included.