الفهرس 
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Abstract
The current work focuses on the design and synthesis of novel oxindole derivatives, as well as the biological evaluation of their anti-cancer effects. The thesis includes four main sections: introduction, aim of the work, results and discussion and experimental sections, as well as references and summary.
1- Introduction
Introduction section shows the recent updates in developing indole derivatives as anti-cancer agents in addition to the targets for anti-cancer indoles especially tubulin, EGFR and kinase enzyme. Also the introduction includes brief look on oxindole and their availability in nature and the role of synthesized derivatives as potential anti-cancer agents.
2- Aim of the work
This section covers the objective and aim for the design of this work, which includes synthesis of the desired compounds, biological assessment of anti-cancer activity of the prepared compounds and analyses the mechanism of anti-cancer activity induced by some of the target compounds.
3- Results and discussion
This section includes three parts:
A- Chemistry section
Chemistry section which provides a discussion of the various methods utilized to synthesize intermediates and their corresponding final compounds. It also demonstrated structure elucidations of these compounds using different spectroscopic techniques including 1H-NMR, 13C-NMR, LC-MS/ MS and elemental analysis.
In this we reported the synthesis of the following:
- Nine reported and three new oxindole derivatives (3a-f and 4a-f).
- Eleven novel alkylated oxindole derivatives and a reported one (6a-f and 7a-f)
- Two new ester derivatives of oxindole (9a and 9b)
B- Biology section
Subdivided into 6 sections:
I- Evaluation of the anti-cancer activity
Twenty six compounds (3a-f, 4a-f, 6a-f, 7a-f. 9a and 9b) were selected for in vitro anti-cancer screening against three cancer cell lines; breast MCF-7, prostate PC-3 and colorectal COLO-205 cancer cells. Results showed that some compounds are promising as anti-cancer agents against these cancer cells with more selectivity towards colorectal COLO-205 cancer cells. The most promising compounds were 4b, 4d, 4e, 6e and 6f, so they were chosen for testing their anti-proliferative activity against COLO-205 cancer cells.
II- In vitro anti-proliferative activity
The anti-proliferative effect of the chosen compounds (4b, 4d, 4e, 6e and 6f) was tested in vitro against colorectal COLO-205 cancer cells. Results revealed that Compounds 4b and 4e were almost equipotent to 4a, with 4b being the most potent among the test compounds and used for further mechanistic investigations.
III- Cell cycle analysis
The effect of 4b on cell cycle progression and induction of apoptosis on COLO-205 cell line was carried out using DNA flow cytometric analysis. Results stated that treating COLO-205 cells by compound 4b increased the percentage of accumulation of cells at G0-G1 (from 41.46 to 47.15) combined with the decrease in the portion at G2/M phase and S phase indicating that compound 4b arrest cell cycle at G0-G1phase. Additionally, compound 4b induced apoptosis as observed from the increase in cells at pre-G1 phase by 16.99-fold.
IV- Tubulin polymerization inhibition assay
Results showed that compound 4b (IC50 = 1.66 ± 0.08 ) preserve a tubulin polymerization inhibitory activity though slightly less than that of the reference combretastatin A4 (IC50 = 0.42 ± 0.02).
V- EGFR inhibition assay
Results showed that compound 4e exhibited good inhibition of EGFR-TK with IC50 of 0.40g/mL, while compound 4b was about two folds more potent than compound 4e with IC50 = 0.19 g/mL, which demonstrated good activity compared to the positive reference drug Geftinib (IC50 = 0.057 g/mL).
VI- Casein Kinase inhibition assay
The results showed that compound 4e was of good anti-cancer activity on CK1 with IC50 = 13.08 g/mL which was about 6.8 folds less potent than compound 4b with IC50 = 1.92 g/mL. It is clear that compound 4b is an effective inhibitor on CK1 with comparable activity to the reference standard 4a (IC261, IC50 = 2.39 g/mL).
C- Molecular docking study
The obtained data from molecular docking assured that the target compounds (4b and 4e) exhibited good inhibitory activity against tubulin, EGFR and acsein kinase enzyme which was consistent with the obtained results.
4- Experimental
This section describes the detailed procedures of the performed experiments and consists of 3 parts
I- chemistry section
This section covered the detailed procedures utilized for synthesis of the target compounds (3a-f, 4a-f, 6a-f, 7a-f. 9a and 9b). It also showed the spectroscopic and analytical data used for structures elucidations.
II- Biology section
This section described the detailed procedures used to study the anti-cancer activity of the target compounds at Nawah, Al-Mokatam, Egypt, in vitro anti-proliferative assay, tubulin inhibition assay, cell cycle analysis, EGFR inhibition assay and Casein kinase inhibition assay.
III- Molecular docking
This section covers the methodology and software utilized in the modeling of the selected molecules to investigate their inhibitory activity for the targets (tubulin, EGFR and CK).