M.Com. (Business Management) / Please refer to full text to view abstract

D.Com. (Economics) / The objective of this dissertation was to examine the desirability or not of the local processing of South Africa's gold into jewellery as an instrument for the extension of the life of the gold mining industry. The South African gold mining industry derives its significance not only from its importance as the source of 52 per cent of the country's foreign exchange receipts and a major consumer of labour, agricultural and industrial products, water and electricity, but also from the fact that it is the only long- term future source of gold for the world's jewellery manufacturing industry. The rapidly rising working costs since the early seventies was only neutralised for a few 'years by the increase in the gold price. The decline in profitability since the early eighties as a result of the continuation of the cost escalation and the falling gold price, forced the industry into a prolonged consolidation phase. Measures taken to address its rapidly declining economic position include severe cutbacks in its labour force, the closing down of marginal sections and curtailing expenditure on exploration activities.

Since the discovery of cisplatin as an anti-cancer agent, there has been a broad and multidisciplinary interest over four decades in the development of metal complexes as metallotherapeutic drugs. The principal objective of this thesis was to develop and characterize a novel library of gold(III) complexes of aromatic and non-aromatic quinoline- and pyridine-amido ligands and to test their efficacy as cytotoxic agents against multiple human cancer cell lines. To this end, fifteen novel (16 in total) gold(III) complexes have been prepared and studied by multiple methods including FTIR, NMR, MS, and UV-visible spectroscopy, and in numerous cases, single crystal X-ray diffraction. Ligands H2L1–HL14 were prepared via the reaction of the relevant pyridine or quinoline carboxylic acid in the presence of triphenylphosphite and either picolylamine or 8-aminoquinoline in pyridine, in moderate to good yields. Ligands HL15 and HL16 were prepared via the reaction between benzoyl or 1-naphthoyl chloride and 8-aminoquinoline in good yields. The synthesis of complexes [Au(HL1)Cl2]–[Au(L4)Cl2] were prepared by the reaction between the respective ligand, K[AuCl4] and NaOAc in 1:1 MeOH:DCM. Metal complexes [Au(L5)Cl](PF6)–[Au(L14)Cl](PF6) were synthesised by encouraging the formation of a AuCl4- counter ion in acetic acid and 3-fold excess of NaHCO3. Subsequent metathesis afforded the desired PF6- anion. Complexes [Au(L15)Cl] and [Au(L16)Cl] were synthesised by the reaction of H[AuCl4] and respective ligand in acetic acid and a 3-fold excess of NaHCO3. The solubility of all complexes was assessed, with complexes [Au(L8)Cl](PF6)–[Au(L14)Cl](PF6) proving to be the most stable in biologically relevant media (TBS 50 mM, NaCl 10mM, pH 7.34, 37°C). Complex [Au(L12)Cl](PF6) was further evaluated for its stability in the presence of glutathione and imidazole and found to be sensitive to reduction by thiols, but substitution-inert to N-donor heterocycles such as imidazole. The DNA binding constants of [Au(L8)Cl](PF6)–[Au(L11)Cl](PF6) were subsequently evaluated by UV-vis spectroscopy and found to be in the range of 2.7(5) x 105 to 4.7(6) x 105 M-1. Complexes [Au(L12)Cl](PF6)–[Au(L14)Cl](PF6) were similarly assessed using ethidium bromide displacement fluorescence assays, however their ability to bind DNA could not be conclusively proven. The log Po/w values of complexes [Au(L12)Cl](PF6)–[Au(L14)Cl](PF6) were measured and spanned the range -0.8 to -2.16, consistent with significant hydrophilic character. The solid state structures of all complexes, with the exception of [Au(L10)Cl](PF6), [Au(L14)Cl](PF6) and [Au(L16)Cl](PF6), were determined by X-ray crystallography with the gold(III) ion co-ordinated to the ligand in a square planar geometry. The co-ordination mode in complexes Au(HL1)Cl2]–[Au(HL3)Cl2] was unexpected with the metal centre only co-ordinating to half the tetradentate ligand with a pair of cis-dichloro ions completing the square planar geometry. The average Au–Npy/qu distance is 2.02(2) Å while the average Au–Namide distance is 1.97(4) Å. In all complexes the trans labilising effect of the anionic amide nitrogen was observed through a structural elongation of the respective Au–Cl bond length. Almost all complexes studied exhibited π-stacking interactions, with compound [Au(L12)Cl](PF6) exhibiting a mean plane separation between rings of 3.307 Å. This is a result of the extended aromatic rings present in all compounds DFT geometry optimizations, frequency, NMR, and energy calculations were carried out on all the gold(III) complexes at the HSEH1PBE/6-311G(d,p)/LanL2DZ level of theory. The 6-311G(d,p) basis set was used for all atoms with the exception of the gold atom for which the LanL2DZ basis set was used. In general, the chosen level of theory satisfactorily correlates with the experimental data for all complexes and was instrumental in deconvoluting the UV-vis spectra of all complexes. The lowest energy transitions (300–500 nm) were assigned to a LMCT while the higher energy transitions were assigned to π-π* transitions. The cytotoxicity profiles of all compounds, with the exception of [Au(HL1)Cl2] and [Au(L16)Cl], were evaluated through one-dose screens against the 60 human cancer cell lines at the NCI, where [Au(HL3)Cl2], [Au(L6)Cl](PF6)–[Au(L8)Cl](PF6), [Au(L10)Cl](PF6)–[Au(L13)Cl](PF6) and [Au(L15)Cl](PF6) were deemed sufficiently cytotoxic to proceed further to five-dose screening. The cytotoxicity results for compound [Au(L12)Cl](PF6) were most encouraging with GI50, TGI and LC50 values of 0.11(0.1), 0.70(0.7) and 26.5(1.5) μM, respectively, against the breast cancer cell line MDA-MB-468. Statistical analysis of the GI50 values for complexes [Au(HL3)Cl2] and [Au(L12)Cl](PF6) revealed they may exert their cytotoxicity through the inhibition/poisoning of topoisomerase II and I enzymes, respectively. Both compounds were assessed for this through a topoisomerase IB DNA unwinding assay and a topoisomerase IIα decatenation assay. [Au(HL3)Cl2] was found to be a dual catalytic inhibitor and poison of topoisomerase IIα between concentrations of 500 nM and 50 μM while [Au(L12)Cl](PF6) was found to be a dual catalytic inhibitor and poison of topoisomerase IB between concentrations of 1 and 100 μM. Electrophoretic mobility shift assays were performed on both complexes, with [Au(HL3)Cl2] indicating DNA binding at a concentration of 50 μM, while [Au(L12)Cl](PF6) displayed no evidence for DNA binding despite an unexpected increase in mobility shift of the substrate DNA. This is indicative of an alternative mechanism of DNA interaction such as electrostatic binding. In summary, we present in this thesis, the discovery, synthesis and application of a novel series of gold(III) amide-based metal complexes as anti-cancer agents with the mechanism of action by which the complexes exert their cytotoxic activity being elucidated. The compounds show immense potential in the metallo-drug discovery field of research, and with further development, a leading class of metallotherapeutic drugs may be developed from this research. / Thesis (Ph.D.)-University of KwaZulu-Natal, Pietermaritzburg, 2012.

This research study is concerned with the effects and dynamics of 'integrated' schemes of employee participation, where workers are involved in both work-related decision-making, and also share in the profits of their employer. Prior research and the literature on employee participation has tended to concentrate on the process and effects of either financial participation in isolation, or of decision-making participation, but seldom on situations where both are employed simultaneously. Based on a thorough literature review, this study presents a 'Model of Integrated Employee Participation (incorporating moderating effects)'. The model explicates a process through which both types of worker involvement may operate together, leading to a set of behavioural and performance outcomes. Where the formal participation schemes are operationalised such that, combined, they lead to perceptions equivalent to 'psychological ownership', a substantial goal-congruence and integration of the employee with the organisation occurs. These processes lead, in turn, to influences on individual and organisational outcomes. Antecedent and moderating variables to the operation of such 'integrated' participation schemes are identified in the model. Specifically, the effects of the schemes are postulated to be moderated by employees' biographical and personality factors, by their perceptions of managerial commitment to employee participation, and by their perceptions of aspects of the organisation's managerial system of communication and control. The relevance and implications of the model to the South African gold-mining industry are discussed. Major pillars of this 'Model of Integrated Employee Participation (incorporating moderating effects)' were tested within a detailed investigation of the participation schemes in operation at a profitable South African gold-mining company. This investigation was longitudinal in nature, with two major surveys being performed over a ten-month period. The findings suggested that while the effects of the 'integrated' schemes on employees' job satisfaction, performance and stability were as anticipated, the proposed moderating effects were generally non-existent or insignificant. In order to obtain greater clarity of the dynamics of 'integrated' schemes of employee participation, a path analytic exploration of the interrelationships between the measured variables of the study was then undertaken. A detailed path model was developed and then tested, at three levels of the organisational hierarchy as well as on the entire workforce. The path model was substantially supported for the 'entire workforce', and for the largest stratum of the mine's employees, being the 'unskilled and semi-skilled' workers. Satisfaction with participation was found to be positively and significantly associated with perceived extent of participation. This applied to both the financial and decisional elements of the schemes. Job satisfaction and employee performance were also found to be positively associated with perceived extent of participation and / or satisfaction therewith. Employees' perceptions of managerial commitment to 'integrated participation' predicted their satisfaction therewith. Aspects of the organisation's system of managerial communication and control were found to significantly affect levels of job satisfaction and employee performance in the participative environment of the mine. The model was only partially supported, however, at the more senior levels of 'management' and 'supervisors and artisans'. It thus appeared that 'integrated participation' schemes may not enhance job satisfaction and performance at the higher levels of the organisational hierarchy, and that the schemes' effects may thus be moderated by employee seniority. The empirical findings were supportive of much of the literature on participation programmes. They were particularly consistent with 'affective' and 'contingency' explanatory models of the effects of -participation. The findings did not, however, support 'cognitive' explanatory models of the effects of participation. / Thesis (Ph.D.)-University of Natal, 1995.