الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
In this study, five series of (E)-6-(4-(amino-substituted)phenyl)-4-oxohex-5-
enoic acids IIb-f (E), (E)-3-(4-(amino-substituted)phenyl)acrylic acids IIIa-g (E),
4-(4-(amino-substituted) phenylamino)-4-oxobutanoic acids VIa,b,e, 5-(4-(aminosubstituted)
phenylamino)-5-oxo-pentanoic acids VIIa,f and 2-((4-(aminosubstituted)
phenyl)carbamoyl)benzoic acids VIIIa,e were designed and
synthesized. Selected compounds IIb-f (E), IIIf (E), VIb, VIIf were screened in
vitro for their antiproliferative effect on 60 human NCI tumor cell lines.
Compound IIf (E) displayed significant inhibitory activity against NCI Non-Small
Cell Lung A549/ATCC Cancer cell line (68% inhibition) and NCI-H460 Cancer
cell line (66% inhibition). Compound IIIf (E) displayed significant inhibitory
activity against Breast cancer MDA-MB-468 cell line (57.34% inhibition).
Moreover, the target compounds IIb-f (E), IIIa-g (E), VIa,b,e and VIIa,f VIIIa,e
were evaluated in vitro for their antiproliferative activity on HepG2 Cancer cell
line in which histone deacetylase (HDAC) is overexpressed. Compounds IIc (E),
IIf (E), IIIb (E), and IIIg (E) exhibited the highest antiproliferative activity
against HepG2 human cancer cell lines with IC50 ranging from 2.27-10.71 μM. In
addition, selected compounds IIb,c,f (E), IIIb,f,g (E), VIa, VIIa and VIIIa were
tested against (HDAC1) at 10 μM, where none of the tested compounds showed
inhibition activity at this concentration. Furthermore, selected compounds IIf (E),
IIIf (E) and VIIa were tested against (HDAC2-11) at 50 μM, where surprisingly
newly synthesized compound IIf (E) showed remarkable increase in HDAC
activity against different HDAC isoforms instead of the expected inhibitory
activity against class I HDACs and compound IIIf (E) showed potential enzyme
inhibitory activity against different HDAC isoforms (27% inhibition against
HDAC6, 25% inhibition against HDAC8, 20% inhibition against HDAC5).
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Molecular docking simulation was also carried out for HDLP enzyme to
investigate their HDAC binding affinity. In addition, generation of 3Dpharmacophore
model and quantitative structure activity relationship (QSAR)
models were combined to explore the structural requirements controlling the
observed antiproliferative properties.
The thesis is divided into different parts:
1. Introduction:
This part includes a brief survey about cancer, causes of cancer and several
approaches for treatment of cancer in addition to targeted cancer therapy. Recently,
extensive studies have been devoted to histone deacetylase inhibitors (HDACIs)
which present a promising class of targeted anticancer agents. Different classes of
HDACIs are illustrated where they share a common pharmacophore composed of
three-component structural template which has been widely realized as a
successful strategy for the design of efficient new HDACI’s.
2. Rational and design:
It describes the scientific basis upon which the targeted carboxylic acid
compounds were designed, which is based on earlier study of carboxylic acid
derivatives as zinc binding functional group in histone deacetylase metalloenzymes.
In addition, a molecular docking study was performed to support the
design of the proposed compounds.
3. Results and discussion:
This part includes the different chemical methods adopted for the synthesis of
the intermediates and targeted compounds. Also, a brief spectral data concerning
the synthesized compounds are cited. Additionally, the results of the biological
Abstract
xvii
evaluation (in vitro anticancer activity and HDAC enzyme inhibition assay) are
discussed. Molecular modeling techniques as Docking study, 3D QSAR
pharmacophore model and 2D QSAR model are also discussed.
4. Experimental:
It deals with the experimental details for the synthesis of the intermediates and
final compounds, in addition to their physical, spectral and micro elemental
analysis. Also the methods adopted for performing the biological screeing (in vitro
anticancer activity and HDAC enzyme inhibition assay) are cited.
The study involved the synthesis of the following unavailable reported
intermediates:
1. 4-(1H-Imidazol-1-yl) benzaldehyde Ia
2. 4-(Pyrrolidin-1-yl) benzaldehyde Ib
3. 4-(Piperidin-1-yl) benzaldehyde Ic
4. 4-Morpholinobenzaldehyde Id
5. 4-(4-Methylpiperazin-1-yl) benzaldehyde Ie
6. 4-(4-Phenylpiperazin-1-yl) benzaldehyde If
7. 1-(4-Nitrophenyl)-1H-imidazole IVa
8. 1-(4-Nitrophenyl) pyrrolidine IVb
9. 1-Methyl-4-(4-nitrophenyl) piperazine IVe
10. 1-(4-Nitrophenyl)-4-phenylpiperazine IVf
11. 4-(1H-Imidazol-1-yl) aniline Va
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12. 4-(Pyrrolidin-1-yl) aniline Vb
13. 4-(4-Methylpiperazin-1-yl) aniline Ve
14. 4-(4-Phenylpiperazin-1-yl) aniline Vf
In addition, it has involved the synthesis and characterization of the new
intermediate:
1. 4-(4-(4-Chlorophenyl) piperazin-1-yl) benzaldehyde Ig
The study has comprised the synthesis and characterization of the following
reported unavailable target compounds:
1. (E)-3-(4-(1H-Imidazol-1-yl) phenyl) acrylic acid IIIa (E)
2. (E)-3-(4-(Pyrrolidin-1-yl) phenyl) acrylic acid IIIb (E)
3. (E)-3-(4-Morpholinophenyl) acrylic acid IIId (E)
4. (E)-3-(4-(4-Methyl piperazin-1-yl) phenyl) acrylic acid IIIe (E)
Furthermore, it has comprised the synthesis and characterization of the following
new target compounds:
1. (E)-6-(4-(Pyrrolidin-1-yl) phenyl)-4-oxo-hex-5-enoic acid IIb (E)
2. (Z)-6-(4-(Pyrrolidin-1-yl) phenyl)-4-oxo-hex-5-enoic acid IIb (Z)
3. (E) 6-(4-(Piperidin-1-yl) phenyl)-4-oxo-hex-5-enoic acid IIc (E)
4. (E)-6-(4-Morpholinophenyl)-4-oxo-hex-5-enoic acid IId (E)
5. (E)-6-(4-(4-Methylpiperazin-1-yl) phenyl)-4-oxo-hex-5-enoic acid IIe (E)
6. (E)-6-(4-(4-Phenylpiperazin-1-yl) phenyl)-4-oxohex-5-enoic acid IIf (E)
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7. (Z)-6-(4-(4-Phenylpiperazin-1-yl) phenyl)-4-oxohex-5-enoic acid IIf (Z)
8. (E)-3-(4-(Piperidin-1-yl) phenyl) acrylic acid IIIc (E)
9. (E)-3-(4-(4-Phenylpiperazin-1-yl) phenyl) acrylic acid IIIf (E)
10. (E)-3-(4-(4-(4-Chlorophenyl) piperazin-1-yl) phenyl) acrylic acid IIIg (E)
11. 4-(4-(1H-Imidazol-1-yl) phenylamino)-4-oxobutanoic acid VIa
12. 4-(4-(Pyrrolidin-1-yl) phenylamino)-4-oxobutanoic acid VIb
13. 4-(4-(4-Methylpiperazin-1-yl) phenylamino)-4-oxobutanoic acid VIe
14. 5-(4-(1H-Imidazol-1-yl) phenylamino)-5-oxopentanoic acid VIIa
15. 5-(4-(4-Phenylpiperazin-1-yl) phenylamino)-5-oxopentanoic acid VIIf
16. 2-((4-(1H-Imidazol-1-yl) phenyl) carbamoyl) benzoic acid VIIIa
17. 2-((4-(4-Methylpiperazin-1-yl) phenyl) carbamoyl) benzoic acid VIIIe
5. Conclusion:
It includes the correlation between biological activities, docking study, 3D QSAR
pharmacophore model.
6. Future perspectives:
It includes synthesis of novel hydroxamic acid compounds and future
investigations (biological testings) for the synthesized compounds.
7. References:
The thesis contains 460 references covering the period till 2014.