الفهرس 
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Abstract
The introduction part presents a literature survey about quinoline and thiazolidinedione derivatives, their marketed drugs, and their different biological activities. In addition, this part involves an overview of their synthetic procedures and important chemical reactions of thiazolidinedione.
2. Aim of the work
This section outlines the goals and objectives for the design of this research including synthesis of new quinoline-thiazolidinedione hybrids and their biological evaluation as antidiabetic and anticancer agents, in addition to the molecular study of anticancer activity induced by some of the synthesized compounds. Moreover, molecular docking studies were conducted to investigate the binding mode of some target compounds within PPARγ and VEGFR-2.
3. Results and discussion
This part is subdivided into two main sections:
A. Chemistry section
It includes the description of different methods used for synthesis of the intermediates as well as final compounds. Also, it displayed structural elucidations of these compounds by different spectroscopic techniques including 1H NMR and 13C NMR. The purity of the compounds was assessed using High-Performance Liquid chromatography (HPLC). In this work, the synthesis of the following compounds was reported:
Thirty-two reported intermediates (1-4, 6a-o, and 7a-m).
Five new intermediates including intermediates 10a-c, 12, and 13.
New twenty-four final compounds (8a-k, 11a-c, and 14a-j).
B- Biological evaluation section
Biology section, this section is subdivided into two sections:
I. Evaluation of the antidiabetic activity
a. In vivo blood glucose lowering effect
Antidiabetic activity was evaluated at Deraya university, Minia, Egypt. Compound 8a was evaluated for its blood glucose lowering effect on alloxan-induced diabetic rats for 15 days with a 38 mg/kg oral dose. The results revealed that compound 8a showed a promising blood glucose lowering effect with 22.3% along with reference drug Pioglitazone 48.46%.
b. PPARγ gene expression study
The ability of compound 8a to increase the expression of PPARγ gene was evaluated and recorded. It was observed that compound 8a showed an increase in gene expression in contrast to the diabetic group.
c. Body weight gain study
Compound 8a was further analyzed for body weight gain study for 15 days. Administration of compound 8a resulted in a more modest increase in body weight, indicating that compound 8a has a less pronounced effect on body weight compared to both the normal and diabetic control groups.
d. Hepatotoxicity studies
Compound 8a was analyzed for increase or decrease in the levels of aspartate transaminase (AST) and alanine transaminase (ALT) followed by computational prediction for the metabolism of 8a using GLORYx. Compound 8a was found to decrease the level of these enzymes to the normal, when compared to Pioglitazone which elevated level of AST compared to the normal control group. Also, the computational study revealed that TZD moiety of 8a is less susceptible to metabolic transformations.
e. Morphological changes in pancreatic tissue
Histopathological studies were performed to evaluate the effect of 8a and PGZ on pancreatic islets. The pancreatic tissue of 8a-treated group showed marked improvement which was observed in the morphological features. As a result, compound 8a could have a protective effect on pancreatic tissue as PGZ.
f. Molecular docking study on PPARγ
This section encompasses the results obtained from the study of the binding mode of synthesized compound 8a with PPARγ (PDB code: 3T03). The results revealed a strong binding of compound 8a to protein (PDB code: 3T03) compared to the reference inhibitor GQ-16.
II. Evaluation of the anticancer activity
Anticancer activity was evaluated for the synthesized compounds 12, 13, 11a-c, and 14a-j at the National Cancer Institute, Bethesda, MD, USA. Among these derivatives, compounds 12, 13, 11a-c, 14a-e, and 14h-j were selected according to the protocol of drug evaluation branch of the National Cancer Institute. The selected compounds were screened against sixty different cancer cell lines (NCI-60 cell line panel). Screening results revealed that compounds 12, 13, 14a, 14i, and 14j possess a high activity against some of cell lines tested, especially HCT-116 and MCF-7. Compound 13 revealed excellent results and was selected for the advanced five-dose testing. It showed a potent and broad-spectrum antitumor activity.
a. In vitro anti-proliferative assay
In vitro anti-proliferative activity of the selected compounds 12, 14a, 14b, 14i, and 14j was evaluated against breast cancer cell line HCT-116 and MCF-7. Results revealed that compounds 12 and 14i have the highest cytotoxicity against HCT-116 cell line with IC50 of 1.26 and 0.33 M, respectively, compared to Doxorubicin (IC50 = 0.07 M).
b. Cytotoxicity on normal cell line
In order to evaluate the safety of compound 14i, it was subjected to testing against the human diploid lung fibroblast cell line (WI-38). The results revealed that compound 14i exhibited a notable lack of cytotoxicity towards the normal WI-38 cells.
c. Cell cycle analysis
Cell cycle arrest of HCT-116 cell line induced by 12 and 14i was analyzed by FACScan flow cytometer (Becton Dickinson). The results showed that the tested compound 14i arrested the cell cycle at the G2 phase.
d. Apoptosis assay
Apoptosis assay was evaluated for compound 14j. The results showed that the tested compounds 12 and 14i have weak apoptotic effect on cancer cells.
e. VEGFR-2 enzyme inhibition assay
VEGFR-2 enzyme inhibition assay for compound 14i was carried out by Nawah Scientific Center, Cairo, Egypt. The results showed that compound 14i has a significant VEGFR-2 inhibitory activity (IC50 of 0.410 µM) with comparable IC50 of Sorafenib (IC50 of 0.129 µM).
f. Molecular docking study on VEGFR-2
Molecular docking was used to investigate the binding mode of 14i within the binding site of VEGFR-2. The results obtained showed good fitting of 14i with VEGFR-2 which agreed with the results obtained from biological evaluation of the tested compounds.