During neoplastic development cellular requirements for the micronutrients and macronutrients increase dramatically for the primary metabolites, sugar and amino-acids. This concept of increased cellular needs lead to the development of antimetabolites as anticancer agents. Antimetabolites, are structurally similar to that of physiological metabolites, but have the ability to interfere with normal metabolic functioning of the cell that eventually leads to cell death. One such agent used in chemotherapy is 6-thioguanine. Another group of agents that also only recently showed potential for the used in cancer therapy are the Au containing anti-arthritic gold compounds, such as Auranofin. Both these groups, antimetabolites and Au containing compounds have different intracellular targets e.g. DNA(6-Thioguanine) and thioredoxin reductase [Au(I) and Au(III)], respectively. No study thus far has attempted to combine gold to 6-thioguanine nor has it been tested on non-cancerous and cancer cell lines. In this study two novel Au(I) compounds were synthesized i.e. a Au (I) metal 6-thioguanine (EKJC56) compound and Au (I)-phoshine 6-thioguanine (EKJC80A) compound (Figure 1). The cytotoxic effect and selectivity of these novel compounds were determined on several cancerous and normal cell cultures using the MTT assay. The cells were exposed to varying concentrations of these compounds. The novel compounds (EKJC56ST, EKJC56, and EKJC80A) showed higher toxicity towards all the cancerous cell lines tested, while EKJC56ST and EKJC56 showed only slight inhibition of the proliferation of normal cell cultures. These novel compounds proved to be more selective towards the hormone dependent cell line compared to the non-hormonal cell lines. The Au-phoshine compound, EKJC80A were non selective for both cancerous cells and normal cell cultures. The mechanism of action of these compounds were evaluated and showed a higher percentage of induction early apoptosis compared to an untreated control group. These results were supported when the effect of these derivatives were evaluated on the activation of caspase-3 activity, a known marker of early apoptosis. On evaluation of the effect of these compounds on the mitochondrial membrane it was observed that the mitochondrial membrane of the HeLa cell line became hyperpolarized, but did not prove to be statistical significant. No significant changes in cell cycle phases were observed when cell cycle progression was investigated. Due to limited amounts of thioredoxin reductase enzyme an observational study was conducted to determine the possible involvement of the Au(I) side chain of the novel compounds on the functionality of this enzyme. It was observed that these novel Au(I) containing compounds were as effective as Auranofin to inhibit this enzyme at a concentration as low as 0.1ìM. Further enzymatic studies are still required to support the hypothesis. This study can assist in developing new multi-acting chemotherapeutic drugs that may have the potential to effectively and selectively treat cancer and minimize the development of resistance during treatment. / Dissertation (MSc)--University of Pretoria, 2009. / Pharmacology / unrestricted