4. Electronic Theses and Dissertations (ETDs) - Faculties submissions
Permanent URI for this communityhttps://hdl.handle.net/10539/37773
Browse
Search Results
Item Insights into silver(I) phosphine complexes in targeting cell death and metastatic mechanisms in malignant cell lines(University of the Witwatersrand, Johannesburg, 2023-09) Roberts, Kim Elli; Engelbrecht, Zelinda; Cronjé, Marianne J.Cancer is the leading cause of death worldwide, with 18.1 million new cases and 9.6 million deaths reported annually. Cisplatin, a popular chemotherapeutic drug, exhibits certain limitations in terms of selectivity and efficacy. This emphasizes the necessity for novel therapeutic approaches in addressing a variety of cancer types. Multiple studies have shown that silver-based compounds suppress cancer cell proliferation and induce apoptosis. Thirteen novel silver(I) mono-dentate phosphine complexes were investigated for their anticancer effects on seven different human malignant cell lines; A375 non-pigmented melanoma, A549 lung adenocarcinoma, HEP-G2 hepatocellular carcinoma, HT-29 colorectal adenocarcinoma, MCF-7 and MDA-MB-231 breast adenocarcinoma, and SNO oesophageal squamous cell carcinoma. Two non-malignant human cell lines, HEK-293 embryonic kidney cells and MRHF foreskin fibroblast cells, were used to assess the selectivity of the complexes. Cisplatin and the efficient silver(I) phosphine complexes were selected for dose-response experiments to determine IC50 concentrations for the respective cell lines. On the basis of these screening results (chapter two), five difficult-to-treat cancer cell lines, and their most efficient complexes were selected for further investigation. Various cellular characteristics were investigated in chapter three (A549, HEP-G2, HT-29); these included morphological changes, ATP levels, GAPDH levels, Ptd-L-Ser externalization, mitochondrial membrane potential, oxidative stress levels, and the activity of a metabolic enzyme, cytochrome P450 isoform CYP1B1. The antimetastatic activity of the selected complexes was assessed by evaluating their ability to impede the migration of A549 cells. The fourth chapter examines the anticancer effect of selected complexes on hormone-dependent (MCF-7) versus triple-negative (MDA-MB-231) breast cells. Changes in morphology, Ptd-L-Ser externalization, alterations in mitochondrial membrane potential, oxidative stress levels, cytochrome c release, and DNA damage were studied. Furthermore, in chapter five, molecular docking simulations were used to determine whether the most potent silver(I) phosphine complex across all cell lines bonds to estrogen receptor alpha (ER-α) and estrogen receptor beta (ER-β). Seven of the thirteen silver(I) phosphine complexes significantly reduced cell viability in malignant cell lines while being less toxic to non-malignant cells. Complex 4 best targeted all cancer types, with IC50 values ranging from 5.75 to 10.80 µM across malignant cell lines. In the malignant treated cells, morphological changes, reactive oxygen species production, mitochondrial membrane depolarization, and Ptd-L-Ser externalization were observed. Complexes 1 and 4 repressed cell migration in the A549 cells. The presence of damaged nuclei, metabolically inactive mitochondria and cytochrome c translocation from the mitochondria’ intermembrane to the cytosol in MCF-7 cells were observed. These findings suggest that complexes 2, 4 and 7 induced apoptotic cell death. Furthermore, in silico computational predictions suggested a promising interaction between complex 4, and ER-α and ER-β. Overall, this study demonstrates the potential of silver(I) phosphine complexes as anticancer agents, with promising effects on various cancer cell lines.Item The Synthesis of Pyrido-fused 8-Methoxy Carbazoles by Using a Light-Assisted, Base Mediated Cyclization Reaction(University of the Witwatersrand, Johannesburg, 2023) Magagula, Bongi Florence; Ntsimango, Songeziwe; De Koning, Charles B.Nitrogen-containing compounds such as indoles and carbazoles are significant classes of the N-heterocycles that show great promise as anti-cancer compounds. Indoles such as 2,3-diarylindole, 3-pyranyl indole and carbazoles such as 9-methoxyellipticine are compounds which possess anticancer or antitumor properties. Due to the favourable biological activities of N-heterocyclic compounds, medicinal and synthetic chemists have developed numerous methodologies for their synthesis. In this research project, the broad aim was to synthesize pyrido-fused carbazoles from 5-methoxyindole using methodologies that have been previously used in our laboratories and by other chemists while changing the position of the nitrogen atom on the pyrido-fused carbazoles. The first step in the synthesis of these carbazoles was the treatment of 5-methoxyindole with di-tert-butyl dicarbonate in the presence of 4-dimethylaminopyridine (DMAP) which gave the desired protected indole, tert-butyl 5-methoxy-1H-indole-1-carboxylate in excellent yields (90-99%). Exposure of the tert-butyl 5-methoxy-1H-indole-1-carboxylate to lithium 2,2,6,6-tetramethypiperidide followed by quenching with triisopropyl borate and hydrochloric acid gave (1-(tert-butoxycarbonyl)-5-ethoxy-1H-indol-2-yl)boronic acid. Using this and various halogen substituted pyridines, for example 3-bromo-4-methylpyridine in the Suzuki-Miyaura coupling reaction gave tert-butyl 5-ethoxy-2-(4methylpyridin-3-yl)-1H-indole-1-carboxylate (83% yield). This was further reacted with paraformaldehyde and iron (III) chloride or phosphorus oxychloride and DMF. After the removal of tert-butoxycarbonyl protecting group utilizing various methods this produced 5-methoxy-2-(4-methylpyridin-3-yl)-1H-indole-3-carbaldehyde (48% yield). 5-Methoxy-2-(4-methylpyridin-3-yl)-1H-indole-3-carbaldehyde possesses all the carbons of the final compounds and is suitably functionalized to partake in the key photo-induced and ase-mediated cyclization reaction. Previous studies pointed to the necessity of an alkyl protecting group on the indole-N atom. As a result, the indole nitrogen atom was then protected again with a methyl or a benzyl group; where the N-benzyl could be removed at a later stage. For example, reaction of 5-methoxy-2-(4-methylpyridin-3-yl)-1H-indole-3-carbaldehyde dissolved in THF, potassium hexamethyldisilazide and benzyl bromide furnished 1-benzyl-5-methoxy-2-(4-methylpyridin-3-yl)-1H-indole-3-carbaldehyde (83% yield). The key step in this synthesis was the light-assisted, base-mediated cyclization reaction which has been reported by de Koning and co-workers, where a solution of 1-benzyl-5-methoxy-2-(4-methylpyridin-3-yl)-1H-indole-3-carbaldehyde dissolved in dry DMF and potassium tert-butoxide was heated and irradiated with medium mercury lamp yielding the desired pyrido fused carbazole, 11-benzyl-8-methoxy-11H-pyrido[3,4-a]carbazole in a good yield of 70%. Following the outlined synthetic procedure depicted above, we were able to synthesize 5 analogues of 11-benzyl-8-methoxy-1H-pyrido[3,4-a]carbazole.