الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Cancer Is A Major Public Worldwide Health Problem With A Non-Stop Increasingly Number Of Patients Being Diagnosed With Cancerous Histories Each Coming Yea. The Multiple Survival Strategies Of Cancer And Its Cross-Linked Relationship With Other Serious chronic Diseases Have Been Demonstrated Widely Through Several Research Aspects And Exemplified By Various Interesting Reversible Relationship With Inflammation, Heart Attack, High Blood Pressure Or Even Diabetes. The Effectiveness Of Chemotherapy As A Principal Mode Of Treatment For Cancer Has Been Limited By Drug Resistance And Severe Side Effects And So Targeted And Continuously Upgraded Multi-Targeted Therapies, Either In Combination Or In Sequential Order, Have Been Advocated To Combat Intrinsic And Acquired Resistance To Anti-Cancer Drugs.
In Doing So, A Panel Of Novel Series Of Spirobenzo[H]Chromene And Spirochromane Derivatives Was Designed, Synthesized And Evaluated As Potential Anticancer Agents Against MCF-7 (Human Breast Carcinoma), HT-29 (Human Colorectal Adenocarcinoma) And A549 (Human Lung Carcinoma) Cell Lines Using MTT Assay. Eight Compounds 130, 131e, 136a-E And 139, from The First Series, Showed A Better Anticancer Activity Than That Of Sorafenib, The Multi-Kinase Inhibitor With IC50 Values Between 1.78 And 5.47 M Or Erlotinib With IC50 Values Over 20 M. Representative Compounds 131e, 136c And 139 Were selected For Further Mechanistic Investigation Via EGFR, B-RAF And Tubulin Polymerization Assays. Compound 139 Was The Most Potent EGFR Inhibitor (IC50 = 1.2 M), Yet Compounds 131e, 136c And 139 Displayed Moderate Tubulin Polymerization Inhibition Effects. Molecular Docking Studies Of Those Compounds Revealed Their Possible Binding Modes Into The Active Sites Of Both EGFR And B-RAF Kinases. The Newly Developed Compounds Represent A Therapeutically Promising Approach For The Treatment Of Different Types Of Cancer.
A Nother Series Of Spiro[Chroman-2,4′-Piperidin]-4-One Derivatives Was Synthesized And Evaluated As Cytotoxic Agents Against Three Human Cancer Cell Lines; MCF-7 (Human Breast Carcinoma), A2780 (Human Ovarian Cancer) And HT-29 (Human Colorectal Adenocarcinoma) Using MTT Assay. Compound 145 With A Sulfonyl Spacer Exhibited The Most Potent Activity With IC50 Values Between 0.31 And 5.62 Μm. However, The Trimethoxyphenyl Derivative 144 Was The Least Potent With IC50 Values Between 18.77 And 47.05 Μm. The Most Active Compound 145 Was selected For Further Mechanistic Studies, Which Revealed That It Induced More Than Three Folds Early Apoptosis In MCF-7 Cells Treated For 24 H. Additionally, It Increased MCF-7 Cells In The Sub-G1 And G2-M Cell Cycle Phases, Following The Same Treatment Duration.
The Last Piperazine-Bearing Series (149a-F, 150 And 151) Was Evaluated For Their Anti-Inflammatory Activity In Vitro Against Coxs Subtypes And In Vivo In Carrageenan-Induced Rat Paw Edema Animal Model. The Overall Results Showed Moderate Anti-Inflammatory Activity With Low Cytotoxicity Potential Against Three Cancer Cell Lines. Compound 149d Was The Most Potent Derivative As COX-2 Inhibitor With 61.91% Inhibition Of Edema Thickness In Vivo.
Together, These Compounds Could Be Promising Anticancer And Anti-Inflammatory Candidates, Thus Further Structural Optimization, In Vitro And In Vivo Studies Are Recommended To Be Developed Into Potential Drugs.
The Thesis Consists Of The Following Parts:
1. Introduction
This Section Discusses The Medicinal Chemistry Attributes Of Spirochromanes, Spirochromanones And Spirobenzo[H]Chromenes. On The Other Hand, The Chemistry And Common Synthetic Pathways Used For Preparation Of Spirochromane, Spirochromanone And Spirobenzo[H]Chromene Were Included. Finally, The Biological Importance And Various Classes Of This Spiro-Scaffold As A Common And Frequent Used Heterocycle System In Various Chemical Entities With Pharmacological Interest Were Presented In Detail.
2. Rationale
This Part Presents The Aims, Rationale And Drug Design Approach Used For The Design And Synthesis Of The Different Classes Of The Novel Spiro-Compounds.
3. Results And Discussion
This Section Deals With The Discussion Of The Experimental Methods Adopted For Synthesis Of Designed Compounds. Schemes 1-5 Illustrate All Synthetic Pathways Followed For Preparation Of Designed Compounds. In Addition, The Biological Results Of The In Vitro Evaluation Of The Newly Synthesized Compounds Against Different Cancerious Cell Lines Were Discussed. The Mechanisteic Studies To Explain The Anticancer Activity Of These Newly Synthesized Compounds Were Investigated Agsint EGFR, B-Raf And Apoptosis Inducing Activity. Finally, The In Vivo And In Vitro Anti-Inflammatory Results Of The Last Series Of These Compounds Were Also Discussed.
4. Molecular Docking Study
This Study Was Conducted In order To Determine The Structural Features Required For A Compound To Be Active And selective On Either EGFR Or B-Raf As Molecular And Valid Anticancer Targets. In Addition, The Reasons Behind The Inactivity Of Some Compounds Were Explained Based On Their Binding Mode, Interaction And Energy Score Of The selected Ligands Into The Active Sites Of The Targeted Enzymes.
5. Experimental Protocols
This Part Displays The Practical Procedures Used For Synthesis Of All Targeted Final Spiro-Compounds. Physical, Spectral And Micro-Analytical Data Are Included In This Part Too. On Other Hand, The Pharmacological Methodology Of The In Vitro And In Vivo Assays Used For The Assessment Of The Anticancer And Anti-Inflammatory Potential Of The Newly Synthesized Compounds Was Explained In Detail.
6. Conclusion
This Section Concludes Our Findings And The Most Important Results In Brief.
7. References
This Part Includes All References That Have Been Cited Throughout The Whole Thesis And They Are Equal To 166 References.
8. Appendix
It Contains Representative Samples Of Spectral H1-NMR, C13-NMR And Mass charts Of Some Of The Intermediates And Final Compounds. 9-Arabic Summary.