الفهرس 
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Abstract
Abstract
Abstract
Curcumin was extensively studied within the past years and research revealed that it possess anti-proliferative activities against tumor cells in vitro, anti-inflammatory, antibacterial, antiviral, anti-hepatotoxic, hypotensive and anti-cholesterolemic activities. The multi-targeting ability of curcumin may be the key to its therapeutic potential against cancer, and hence new researches were focused on the development and the evaluation of curcumin derivatives that could target cancer cells and track the mechanism of their activities. In this thesis, four different series of curcumin derivatives were designed, synthesized and tested for their anti-tumor activity.
The presented thesis comprises the following chapters:
The thesis includes six parts:
1. Introduction:
Introduction contains a survey covering the definition of cancer, possible causes, types of treatments and statistics of its incidence in Egypt and worldwide. It also, covers the definition of tubulin and microtubules, their structures and the newly developed drugs that target tubulin inside cancer cells. On the other hand, it covers extensive literature review on curcumin and its activities and mechanisms, and the newly developed chalcone and curcumin derivatives, the strategies used in their design and their evaluated activities and mechanisms.
2. Rational & Design:
In our current study, novel curcumin analogs were designed based on comprehensive Structural Activity Relationship (SAR) study of curcumin and its literature reported derivatives, also based on previously reported molecular XV
Abstract
docking studies of curcumin, chalcones, and their derivatives. A new molecular docking study was performed in silico on β-chain of tubulin protein compared to podophyllotoxin using Discovery Studio 2.5 software which also aided in selecting most expected active designed analogs to synthesize. This led to the design of 22 new target analogs III f and IV a-f, VI c and VII a-e, IX a and X a-c, XII a-e. Synthesis of the designed compounds was accomplished adopting the chemical pathway outlined in schemes (1-4).
3. Results and Discussion:
This part contains the theoretical discussions for the obtained results
3.1 Chemistry:
The chemical methods for preparing the starting material and intermediates were mentioned. In addition, the final products (22 compounds) were discussed regarding their physical and the spectroscopic data.
3.2 Molecular docking in silico assay:
A thorough molecular docking study was attempted using C-Docker software (Discovery Studio 2.5) to investigate the binding mode and the binding affinity of the targeted compounds and obtain their interaction energy scores with β-Chain of tubulin compared to podophyllotoxin.
3.3 Biological study:
The Novel Curcumin analogs were evaluated for their antitumor activities in 5 different cell lines; [ovarian cancer (A2780), renal adenocarcinoma (ACHN), prostate cancer (PC-3), colorectal cancer (Hct-116) and a leukemic monocyte lymphoma (U937-GTB)]. Compound XII b was the only one tested by the American National Cancer Institute on 60 different cell lines for different types of cancer as (leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, prostate cancer, renal cancer, and breast cancer). Also, XVI
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in vitro study was performed to test the ability of the newly synthesized analogs to inhibit tubulin assembly and destabilize microtubules compared to Vincristine and Paclitaxel as control drugs.
3.4 Compare results:
This section comprises a collective data of all the results obtained from the different testings performed in silico and in vitro to be able to compare the results and reach a constructive conclusion.
4. Experimental:
This part explains the laboratory detailed procedures in the synthesis of the chemical compounds and record of the physical and spectral properties of the new products. In addition, the biological evaluation procedure was mentioned. Steps of molecular modeling were detailed using Discovery Studio 2.5 software.
The chemistry section comprises:
The synthesis of the following unavailable reported intermediates:
1. 4-Formyl-2-methoxyphenyl butyrate (II a).
2. 4-Formyl-2-methoxyphenyl propionate (II b).
3. Tricyclo[3.3.1.13,7]decane-1-carboxylic acid, 4-formyl-2-methoxyphenyl ester (II c).
4. 4-Formyl-2-methoxyphenyl heptanoate (II d).
5. 2-Ethoxy-4-formylphenyl propionate (II e).
6. 2-Ethoxy-4-formylphenyl butyrate (II f).
7. 3-Methoxy-4-propoxybenzaldehyde (V a).
8. 3-Ethoxy-4-propoxybenzaldehyde (V b).
9. 3-Iodo-5-methoxy-4-propoxybenzaldehyde (V c). XVII
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10. 3-Methoxy-4-propoxycinnamaldehyde (V d).
11. 3,4-Dimercaptobenzaldehyde (VIII b).
12. 3,5-Bis(4-hydroxy-3-methoxybenzylidene) piperidin-4-one (XI a).
13. 3,5-Bis(3, 4, 5-trimethoxybenzylidene) piperidin-4-one (XI c).
14. 3,5-Bis(3, 4-dihydroxybenzylidene) piperidin-4-one (XI d).
Also, the study involved the synthesis of the following unavailable unseparated intermediates:
1. 3,5-Bis(4-butyryloxy-3-methoxybenzylidene) piperidin-4-one (III a).
2. 3,5-Bis(3-methoxy-4-propyloyloxybenzylidene) piperidin-4-one (III b).
3. 3,5-Bis(4-adamantoyloxy-3-methoxybenzylidene) piperidin-4-one (III c).
4. 3,5-Bis(4-heptanoyloxy-3-methoxybenzylidene) piperidin-4-one (III d).
5. 3,5-Bis(3-ethoxy-4-propyloyloxybenzylidene) piperidin-4-one (III e).
6. 3,5-Bis(3-methoxy-4-propoxybenzylidene) piperidin-4-one (VI a).
7. 3,5-Bis(3-ethoxy-4-propoxybenzylidene) piperidin-4-one (VI b).
8. 3,5-Bis[(3-methoxy-4-propoxyphenyl) allylidene] piperidin-4-one (VI d).
9. (E)-3-(4-mercapto-3-methoxyphenyl) acrylaldehyde (VIII a).
10. 3,5-Bis(3, 4 dimercaptobenzylidene) piperidin-4-one (IX b).
11. 3,5-Bis(3, 4-dioxymethylene-6-methylbenzylidene) piperidin-4-one (XI b).
In addition, the study compromised the synthesis and characterization of the following new intermediates:
1. 3,5-Bis(4-butyryloxy-3-ethoxybenzylidene) piperidin-4-one (III f).
2. 3,5-Bis(3-iodo-5-methoxy-4-propoxybenzylidene) piperidin-4-one (VI c).
3. 3,5-Bis[(4-mercapto-3-methoxyphenyl) allylidene] piperidin-4-one (IX a).
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Furthermore, it compromised the synthesis and characterization of the following targeted new compounds:
1. 3,5-Bis(4-butyryloxy-3-methoxybenzylidene)-N-acetylpiperidin-4-one (IV a).
2. 3,5-Bis(3-methoxy-4-propyloyloxybenzylidene)-N-benzoylpiperidin-4-one (IV b).
3. 3,5-Bis(4-adamantoyloxy-3-methoxybenzylidene)-N-acetylpiperidin-4-one (IV c).
4. 3,5-Bis(4-heptanoyloxy-3-methoxybenzylidene)-N-acetylpiperidin-4-one (IV d).
5. 3,5-Bis(3-ethoxy-4-propyloyloxybenzylidene)-N-acetylpiperidin-4-one (IV e).
6. 3,5-Bis(4-butyryloxy-3-ethoxybenzylidene)-N-benzoylpiperidin-4-one (IV f).
7. 3,5-Bis(3-methoxy-4-propoxybenzylidene)-N-acetylpiperidin-4-one (VII a).
8. 3,5-Bis(3-ethoxy-4-propoxybenzylidene)-N-acetylpiperidin-4-one (VII b).
9. 3,5-Bis(3-iodo-5-methoxy-4-propoxybenzylidene)-N-acetylpiperidin-4-one (VII c).
10. 3,5-Bis[(3-methoxy-4-propoxyphenyl) allylidene]-N-acetylpiperidin-4-one (VII d).
11. 3,5-Bis(3-methoxy-4-propoxybenzylidene)-4-oxo-N-phenylpiperidine-1-carbothioamide (VII e).
12. 3,5-Bis[(4-mercapto-3-methoxyphenyl) allylidene]-N-acetylpiperidin-4-one (X a).
13. 3,5-Bis(3, 4 dimercaptobenzylidene)-N-acetylpiperidin-4-one (X b). XIX
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14. 3,5-Bis[(4-mercapto-3-methoxyphenyl)allylidene]-4-oxo-N-phenylpiperidine-1-carbothioamide (X c).
15. 3,5-Bis(4-hydroxy-3-methoxybenzylidene)-N-acetylpiperidin-4-one (XII a).
16. 3,5-Bis(3,4-dioxymethylene-6-methylbenzylidene)-N-acetylpiperidin-4-one (XII b).
17. 3,5-Bis(3, 4, 5-trimethoxybenzylidene)-N-benzoylpiperidin-4-one (XII c).
18. 3,5-Bis(3, 4-dihydroxybenzylidene)-N-benzoylpiperidin-4-one (XII d).
19. 3,5-Bis(4-hydroxy-3-methoxybenzylidene)-4-oxo-N-phenylpiperidine-1-carbothioamide (XII e).
5. Conclusion:
A conclusion was set based on the results obtained throughout the study, this conclusion highlights on the novel and urgent points obtained and developed which could be used for further future investigations.
6. References:
Several recent references were recorded showing the literature survey for this research.
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