Electronic Theses and Dissertations (PhDs)
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Item Biophysical studies of metal chelate binding by HSA: Towards an understanding of metallodrug transport(University of the Witwatersrand, Johannesburg, 2023) Sookai, Sheldon; Munro, OrdeHuman serum albumin (HSA) is the most abundant blood protein, transporting many exogenous compounds including clinically deployed and investigational drugs that are generally organic in nature. HSA may largely influence the pharmacokinetics and pharmacodynamics of these drugs. Therefore, studying their interactions with HSA is vital in progressing drug development. In this thesis we present work on the synthesis and characterisation of five Schiff base bis(pyrrolide-imine) ligands that were metalated with either Au(III) (Chapters 2 and 3) or Pt(II) (Chapters 4 and 5). One of the ligands H2L1 was further metalated with Ni(II) and Pd(II) (Chapter 6). In Chapters 2 and 3 focus on a patented class of anti-cancer bis(pyrrolide-imine) Au(III) Schiff base chelates. Three Au(III) chelates were synthesized in Chapter 2 and underwent National Cancer Institute (NCI)-60 cytotoxic screening. Among them, AuL1 and AuL3 underwent full-five dose testing and recorded GI50 values of 7.3 µM and 11.5 µM, and IC50 values of 15.7 µM and 30.9 µM, respectively. AuL1 was tested further and found to be an interfacial poison of topoisomerase II at 0.5–5 µM and a catalytic inhibitor at 50 µM. In Chapter 3, two chiral tetradentate cyclohexane-1,2-diamine-bridged bis(pyrrole-imine) Au(III) complexes were reported, both of which were found to be cytotoxic in the NCI-60 screen. The chiral Au(III) chelates had a different mode of action compared to AuL1. Hierarchical cluster analysis suggest that their mode of action is similar to that of taxol. All five Au(III) chelates bound to HSA with moderate affinity (104–105 M–1) and minimally perturbed the structure of the protein. This highlights the potential for the Au(III) complexes to be transported by the HSA-mediated pathway. Chapters 4 and 5 focused on the synthesis of novel and previously reported Pt(II) Schiff base chelates to spectroscopically and computationally study their interaction with HSA and elucidate if the chelates could act as theranostic agents. It was found that switching the linking bis(imine) carbon linkage altered the binding affinity of the complex. However, the Pt(II) ion ensured that all three Pt(II) chelates preferred binding to Sudlow’s site II of HSA. The data was corroborated by molecular docking simulations and ONIOM calculations. Only 2 was found to be cytotoxic when irradiated with UV light but was found to act as a photosensitizer rather than a theranostic agent. Chapter 6 investigated the influence of d8 metal ions (Ni(II), Pd(II) and Pt(II) within the same ligand scaffold (H2PrPyrr) binding to HAS, which was investigated by steady state fluorescence quenching. The affinity constants, Ka, ranged from -3.5 -103 M−1 to-1- 106 M–1 at 37 C, following the order Pd(PrPyrr) > Pt(PrPyrr) > Ni(PrPyrr) >H2PrPyrr. The Pd(II) chelate was prone to hydrolysis and had a unique binding mode which we attribute to the unusually high binding affinity. The complexes uptake is enthalpically driven, hinging mainly on London dispersion forces. In summation, twelve metal complexes were successfully synthesized, of which 11 bound to HSA with a moderate binding affinity. The Au(III) chelates preferred Sudlow’s site I, while the Pt(II) chelates preferred Sudlow’s site II. Overall, the metal complexes bound fully intact to HSA.Item Quantitative analysis of gold in low-grade tailings from different matrices, coupled with a study into the associated uncertainties(University of the Witwatersrand, Johannesburg, 2023) Mashale, Kedibone Nicholine; Tshilongo, James; Chimuka, LukeGold is one of the precious group elements that is used for various purposes, such as jewellery, auto catalysts and as a form of investment. Various countries have gold reserves, with South Africa being the leading gold producer between 1980 and 2007. However, as of 2022, it is ranked as the eighth largest producer of gold, contributing 3% to the global contribution. The majority of gold is mainly mined from the Witwatersrand Basin in Johannesburg. It is well known that mining has been ongoing for decades, which means that a significant amount of land has been mined across the country. During gold mining, a large proportion of the ore material from which the gold is extracted is waste, together with the chemicals that were used, and this waste is termed mine tailings. This implies that based on the years that gold mining has occurred for and the depth of mining, a significant amount of the tailings have been deposited into free land around the mines, some of which are close to communities. The tailings consist of traces of gold that were left due to inefficient extraction processes and other components, such as base metals. The disadvantage of this is that due to the other chemical composition of these tailings, they have the potential to be dangerous to the environment. Some tailings contain minerals such as jarosite (KFe2(SO4)2(OH)6) that cause acid mine drainage, while heavy metals such as lead, mercury, arsenic and chromium can leach into surface and ground waters, causing pollution. Furthermore, they pose a danger if the dams that they are stored in collapse, which was recently witnessed in South Africa. Because of these factors, there have been various advances made towards the beneficiation of tailings, such as utilizing them to make glass or bricks for construction. A major advancement was the reprocessing of these mine tailings to recover or extract the remaining gold, which benefits both the environment and the mining houses. Therefore, in a move to support this initiative, scientists have taken to the laboratory to develop new or optimize existing methods for the extraction and quantification of gold, which is expected to be of a low grade over time. Various methods can be used for the quantification of gold, including the conventional fire assay, wet and dry chlorination and acid digestion. Most of these are suitable for medium- to high-grade gold ores but are known to experience challenges in regard to low-grade ores. The aim of this research was therefore to find the optimum method for the quantification of gold from mine tailings emanating from the Ventersdorp Contact Reef (VCR) and Barberton Greenstone Belt (GBS). Subsequent to chemical analysis, the samples were characterized for mineralogy using X-ray diffraction (XRD) and Brunauer‒Emmett‒Teller (BET) surface area