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 chapters: introduction, aim of the work, results and discussion and experimental sections, as well as references and summary.
1- Introduction
The introduction section shows the recent updates in developing sunitinib and its analogues in addition to their targets; especially vascular endothelial growth factor (VEGFR), EGFR and other kinase enzymes. Also, the introduction includes a brief look on the optimization of sunitinib analogues and the role of various synthesized derivatives as potential anti-cancer agents.
2- Aim of the work
This section covers the objectives and aim for the design of this work, which includes synthesis of the desired compounds (5a-p) and (8a-t), biological assessment of the anti-cancer activity of the synthesized compounds as well as studying the mechanism of their anti-cancer activity induced by some of the target compounds.
3- Results and discussion
This section includes three main sections:
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, and elemental analyses.
In this section, compounds were reported the synthesis of the following:
- Thirteen intermediate products include four reported oxindole derivatives (4a-d), one new alkylated 4-hydroxybenzaldehyde derivative (7d) and eight reported alkylated vanillin and 4-hydroxybenzaldehyde derivatives (3a-d ,7a-c and 7e).
- Thirty-six new final oxindole derivatives (5a-p and 8a-t)
B- Biology section
I- Screening of cytotoxic activity of target oxindole derivatives 5a-p and 8a-t by NCI
This sub-section is concerned with screening of the antiproliferative activity of the oxindole derivatives. Compounds 5a-p and 8a-t have been selected by the National Cancer Institute (NCI) according to the protocol of the Drug Evaluation Branch of the National Cancer Institute, Bethesda, USA. In vitro antiproliferative screening for the synthesized compounds was carried out against 60 cell lines of different nine cancer cell types including CNS, leukemia, prostate, melanoma, ovarian, colon, lung, and breast cancers. Most of compounds showed broad spectrum of anticancer activity against the tested cell lines. Moreover, compounds 5l, 8k, 8l, 8g, 8h, and 8t were selected by NCI for advanced five dose testing against the full panel of 60 human tumor cell lines.
II- In vivo anti-estrogenic (anti-uterotrophic) activity of compound 5o.
The inhibition of uterine growth compared with the growth produced by estradiol alone was used to measure the anti-uterotrophic effect
III- Kinase profiling of the target compound 5l
The percentage of inhibition of the target compound 5l was tested versus a panel of ten kinases representing various signaling cascades including PTK2B, JAK1, CDK2, FGFR1, IGF1R, VEDFR-2, PDGFRα, PDGFRβ, FLT3, and SRC kinases in the presence of 10 µM of tested compound 5l against sunitinib as reference drug.
IV- CDK2 and FLT3 kinase inhibitory activity
Because of the highly promising activities of compound 5l against CDK2 and FLT3, the IC50 value of this compound has to be evaluated versus these two mentioned kinases. Compound 5l was examined for its potential IC50 value against CDK2 and FLT3 using sunitinib as a reference drug.
C- Molecular modelling studies
I- Molecular docking was carried out for compound 5l to explain the binding modes inside the active binding sites of human VEGFR2 (PDB ID: 4AGD), PDGFRA (PDB ID: 6JOK), CDK2 (PDB ID: 3TI1), and FLT3 (PDB ID: 6JQR).
II- Molecular Dynamics (MD) Simulations was carried out for compound 5l through analyses of root-mean-square deviation (RMSD), principal component analysis (PCA), and hydrogen bond dynamics.
III- In silico druglikness and ADMET studies for the most potent compounds 5l, 8g, 8h, 8k, 8l, and 8t.
4- Experimental
I- Chemistry section
This section covered the detailed procedures utilized for the synthesis of the target compounds (3a-d, 5a-p, 7a-e, and 8a-t). It also showed the spectroscopic and analytical data used for structure elucidations for these compounds. Thirty-six new final compounds were synthesized.
II- Biology section
This section describes the detailed procedures used for biological evaluation experiments. It described the procedures of cytotoxic activity of 5a-p and 8a-t at the national institute of cancer (NCI), in vivo anti-Estrogenic activity of Compound 5o, kinase profiling of the target compound 5l and CDK2 and FLT3 kinase inhibitory activity.
III-Molecular docking and simulation
This section describes the methodology and software used for the modelling of the selected compound 5l to investigate its inhibitory activity for the VEGFR2, PDGFRA, CDK2, and FLT3 target.
5- References
The list of references and scientific periodicals includes 123 references and references between ancient and modern until 2023.