الفهرس 
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Abstract
A Novel Series Of Benzophenone Hydrazone Derivatives Was Designed, Synthesized, characterized By Several Spectroscopic Techniques And Investigated As Potential Antiproliferative Agents. All The Synthesized Compounds Va-J, Via-J And Viia-I Were Screened Against 60 Cell Line Panels To Determine Their Antiproliferative Activities. The Thiosemicarbazone Derivative Vc And Guanylhydrazone Derivatives Vid-F Showed Potent Antiproliferative Activities Against Renal A498 Cancer Cells Line Line With IC50= 14.5 Μm, 0.28 Μm, 0.36 Μm And 0.30 Μm, Respectively. Compounds Vc, Vid, Vie And Vif Showed Inhibitory Activities Against Cathepsin L And Cathepsin B (IC50 Ranged from 0.071 To 0.303 Μm). A Mechanistic Study Revealed That Compound Vie Induced Apoptosis On The Renal A498 Cancer Cell Line By 38.02 % Compared To 1.64% In The Control. This Apoptotic Effect Was Supported By An 8.58-Fold Increase In The Level Of Caspase-3 Compared To The Control Cells. Additionally, Compound Vie Inhibited A498 Cell Growth Mostly At The S Phase. Furthermore, Molecular Modeling Studies Showed That Compound Vie Possessed Good Fitting With Cathepsin L And Cathepsin B Binding Sites Through Its Interaction With Essential Amino Acids Through Hydrophobic H-Bonding Interactions. Therefore, Compound Vie Could Be Considered As A Prospective Anticancer Lead Compound And It Is Worth For Further Exploration/Optimization As An Antiproliferative Agent Via Cathepsins Inhibition.
This Thesis Consists Of The Following Parts:
I. Introduction:
In This Section, A Literature Review About Pharmacological Activities Of Benzophenone Derivatives And A Survey On The Cathepsins Was Reported.
II. Aim Of The Work
The Goal Of This Research To Find New Anticancer Cathepsins Inhibitors By Designing And Synthesizing New Compounds Was Demonstrated In This Section.
III. Results And Discussions
3.1. Chemistry
It Discussed The Theoretical Basis Of The Reactions Used For The Synthesis Of The Targeted Compounds And Their Structures Elucidation Using Different Physical And Spectral Analyses. The Steps For The Synthesis Of The Target Compounds Were Depicted In Schemes 1 And 2.
3.2. Biological Evaluation
This Section Illustrated The Findings Of Screening Of The Target Compounds Against Various Biological Activities.
3.2.1. In Vitro Antiproliferative Activity
It Included The Screening Results Of Thirteen selected Compounds Against NCI 60 Cell Line Panels (Six Cell Lines Of Leukemia, Nine Cell Lines Of Lung Cancer, Six Cell Lines Of CNS Cancer, Seven Cell Lines Of Colon Cancer, Eight Cell Lines Of Melanoma, Six Cell Lines Of Ovarian Cancer, Eight Cell Lines Of Renal Cancer, Two Cell Lines Of Prostate Cancer And Eight Cell Lines Of Breast Cancer) Represented On Full Nine Human Systems As Leukemia, Melanoma, Cancers Of Lung, Colon, Brain, Breast, Ovary, Kidney And Prostate According To Their Applied Protocol. Compounds Vc, Vid, Vie And Vif Showed Promising Anticancer Activities.
3.2.2 Cathepsin L And Cathepsin B Inhibition Assay.
Compounds Vc, Vid, Vie And Vif, Showed The Most Potent Anticancer Activity Against Renal A498 Cancer Cell Lines (IC50 =14.5 Μm, 0.28 Μm, 0.36 Μm And 0.30 Μm, Respectively), Were Evaluated For Cathepsins Inhibitory Activity where They Showed IC50 Ranged from 0.071 To 0.303 Μm.
3.2.3 Cell Cycle Analysis.
Human Kidney Carcinoma A498 Cells Were Exposed To Compound Vie For 24 And 48 H At Its IC50 Concentration (0.36 µm) To Induce A Significant Disruption In The Cell Cycle Profile And Cell Cycle Arrest At The S Phase.
3.2.5 Effect Of Compound Vie On A498 Cells Apoptosis.
Compound Vie Resulted In A 38.02% Increase In The Percentage Of Apoptotic A498 Cells (1.64%). It Also Triggered Apoptosis In Both Early (13.28%) And Late (18.62%) Cell Stages.
3.3. Molecular Modeling Study.
The Design Of The Present Work Was Based On A Molecular Modelling Investigation Of The Target Compounds Critical Binding characteristics To Compound E64 (Positive Control) At The Cathepsin L And Cathepsin B Binding Regions. MOE 2021 Software Was Used To Conduct A Molecular Docking Investigation On Compound E64 (Positive Control) Binding As A Positive Control In Combination With Cathepsins.
4. Experimental:
4.1. Chemistry
This Part Offered The Practical Procedures Used For The Synthesis Of The Reported Intermediates As Well As For The Novel Final Compounds. Also, It Summarized Their Spectral And Elemental Data. The Following Compounds Were Synthesized.
Newly Synthesized Final Compounds: Included 29 New Compounds:
• 2-((3,4-Dimethoxyphenyl)(Phenyl)Methylene)Hydrazine-1-Carbothioamide (Va)
• 2-((3,4-Dimethoxyphenyl)(4-Fluorophenyl)Methylene)Hydrazine-1-Carbothio Amide (Vb)
• 2-((4-Chlorophenyl)(3,4-Dimethoxyphenyl)Methylene)Hydrazine-1-Carboth Iooamide (Vc)
• 2-((4-(Methylthio)Phenyl)(Phenyl)Methylene)Hydrazinecarbothioamide (Vd):
• 2-((4-Fluorophenyl)(4-(Methylthio)Phenyl)Methylene)Hydrazine-1carbothio Amide (Ve)
• 2-((4-Chlorophenyl)(4-(Methylthio)Phenyl)Methylene)Hydrazine-1-`Carboth Ioamide (Vf)
• 2-((4-(Methylsulfonyl)Phenyl)(Phenyl)Methylene)Hydrazine-1-Carbothio Amide ( Vg)
• 2-((4-Fluorophenyl(4-(Methylsulfonyl)Phenyl)Methylene)Hydrazine-1-Carbo Thioamide(Vh)
• 2-((4-Chlorophenyl)(4-(Methylsulfonyl)Phenyl)Methylene)Hydrazine-1-Carbothioamide (Vi)
• 2-(Bis(4-Hydroxyphenyl) Methylene) Hydrazine-1-Carbothioamide( Vj)
• 2-((3,4-Dimethoxyphenyl)(Phenyl)Methylene)Hydrazine-1-Carboximidamide (Via)
• 2-((3,4-Dimethoxyphenyl)(4-Fluorophenyl)Methylene)Hydrazine-1-Carboxi Midamide (Vib)
• 2-((4-Chlorophenyl)(3,4-Dimethoxyphenyl)Methylene)Hydrazine-1-Carboxi Midamide (Vic)
• 2-((4-(Methylthio)Phenyl)(Phenyl)Methylene)Hydrazine-1-Carboximidamide (Vid)
• 2-((4-Fluorophenyl)(4-(Methylthio)Phenyl)Methylene)Hydrazine-1-Carboxi Midamide (Vie):
• 2-((4-Chlorophenyl)(4-(Methylthio)Phenyl)Methylene)Hydrazine-1-Carboxi Midamide (Vif)
• 2-((4-(Methylsulfonyl)Phenyl)(Phenyl)Methylene)Hydrazine-1-Carboxi Midamide (Vig)
• 2-((4-Fluorophenyl)(4-(Methylsulfonyl)Phenyl)Methylene)Hydrazine-1-Carboximidamide (Vih)
• 2-((4- Chlorophenyl)(4(Methylsulfonyl)Phenyl)Methylene)Hydrazine-1-Carb Oximidamide (Vii)
• 2-(Bis(4-Hydroxyphenyl)Methylene)Hydrazine-1-Carboximidamide (Vij)
• N’-((3,4-Dimethoxyphenyl)(Phenyl)Methylene)-4-Methylbenzenesulfono Hydrazides (Viia)
• N’-((3,4-Dimethoxyphenyl)(4-Fluorophenyl)Methylene)-4-Methylbenzene Sulfonohydrazide (Viib)
• N’-((4-Chlorophenyl)(3,4-Dimethoxyphenyl)Methylene)-4-Methylbenzene Sulfonohydrazide (Viic)
• 4-Methyl-N’-((4-(Methylthio)Phenyl)(Phenyl)Methylene)Benzenesulfono Hydrazide (Viid)
• N’-((4-Fluorophenyl)(4-(Methylthio)Phenyl)Methylene)-4-Methylbenzene Sulfonohydrazide (Viie)
• N’-((4-Chlorophenyl)(4-(Methylthio)Phenyl)Methylene)-4-Methylbenzene Sulfonohydrazide (Viif)
• N’-((4-Fluorophenyl)(4-(Methylsulfonyl)Phenyl)Methylene)-4-Methyl Benzenesulfonohydrazide (Viig)
• N’-(4-Chlorophenyl)(4-(Methylsulfonyl)Phenyl)Methylene)-4-Methylbenzene Sulfonohydrazide (Viih)
• N’-(Diphenylmethylene)-4-Methylbenzenesulfonohydrazid (Viii)