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While copper is an essential micronutrient in all living organisms, copper misregulation in humans is associated with neurodegenerative disorders such as Menkes and Wilson’s diseases, amyotrophic lateral sclerosis and Alzheimer’s disease. Furthermore, copper is a widely-produced pollutant and thus the detection of Cu(II) and Cu(I) has received much attention in recent years. Copper can be detected in a number of ways including; quenching of fluorescence upon the binding of paramagnetic Cu(II) (a "turn-off" response); augmentation of fluorescence upon Cu(II) binding due to PET modulation (a "turn-on" response); and selective Cu(II)- or Cu(I)-catalysed reactions where the luminescence of the product is distinctly different to that of the starting material. A review of Cu(I) and Cu(II) sensors is described herein. The Hulme group has previously developed a sensor for ligand-bound copper(I) utilising the copper(I)-catalysed [GS-−Cu(I)] variant of the Huisgen 1,3-dipolar cycloaddition reaction. Cu(I)-catalysed alkyne-azide cycloaddition (CuAAC or “click”) was carried out between an alkynyl Eu(III)-DOTA complex and a dansyl azide yielding a 1,4-triazole with a modest turn-on response (10-fold increase in luminescence). The project described herein aimed to achieve a more significant increase in lanthanide luminescence intensity through alteration of the donor moeity, lanthanide ion, and linker length between donor and acceptor moiety. The synthesis of several lanthanide-DOTA complexes, azido fluorophores and the formation of novel Cu(I)-sensors via CuAAC is described herein. All Cu(I) sensors were excited at their individual λex and their lanthanide luminescence intensity was measured using a timedelayed phosphorimeter. The DOTA structural motif has the ability to complex a plethora of potentially useful radionuclides including; yttrium, indium, gallium, lutetium and gadolinium. In general, DOTA-complexes doped with gadolinium are utilised for the identification of tumour sites while yttrium or indium complexes are used for tumour treatment. Biotin-DOTA conjugates have previously been used for pretargeted cancer imaging and radiotherapy. Biotinidase degradation of the amide bond in some biotin constructs has been reported, rendering them unable to bind to the pre-targeted antibody-(strept)avidin site. A novel biotinyl azide lacking this vulnerable amide bond is reported, with potential for bioconjugation to a variety of biomolecules via “click” chemistry. The synthesis of two novel biotinylated Gd-DOTA complexes, with prospective application as pretargeted MRI contrast agents, are also described.

The following thesis explores the physiological effects on European sea bass (Dicentrarchus labrax) and shore crabs (Carcinus maenas) resulting from the dissolution of anthropogenic carbon dioxide (CO2) into seawater: known as ocean acidification. It assesses how ocean acidification, characterised by elevated seawater pCO2 (1200 µatm) and lowered pH (~7.7), affect the internal chemistry of these animals through the homeostatic process of acid-base regulation. Control conditions used for comparison were close to current ocean average values for CO2 (~400 µatm) and pH (8.2). The proficiency and magnitude of these compensatory mechanisms was explored. Both sea bass and shore crabs were found to be highly effective acid-base regulators and employed the same strategy to compensate the hypercapnia-induced respiratory acidosis: namely an elevation of extracellular bicarbonate (HCO3-). It then considers how these regulatory mechanisms both affect, and are affected by, simultaneous exposure to a ubiquitous coastal metal contaminant, copper. Evidence for a hitherto undocumented protective effect of elevated HCO3- against copper-induced DNA damage was found to be afforded to both sea bass and shore crab cells. DNA damage was used as a sensitive toxicity marker and blood cells were used as proxies for other internal tissues. Erythrocytes exposed in vitro (2 h) to copper (45 µg/L) showed significant DNA damage under control [HCO3-] (6 mM) but were completely protected when exposed under high [HCO3-] (12 mM). A similar protective effect was apparent in crabs under in vivo exposure (14 d) to 10 µg/L waterborne copper. Conversely, during exposure to higher waterborne copper concentrations (sea bass: 80 µg/L, shore crabs: 40 µg/L), animals showed a severe or total inhibition of acid-base regulatory ability in the face of simultaneously elevated seawater CO2 (1200 µatm). The downstream effects of longer-term (28 d) exposure to high CO2 and copper, both individually and in combination was assessed. Food conversion efficiency (FCE), growth and copper accumulation were quantified in juvenile sea bass as economically relevant endpoints. Growth and FCE remained unaffected by either stressor and copper was not accumulated in the muscle tissue: pertinent to human consumption. As a bi-product of this longer term study assessment of gut calcium carbonate production rates in these animals was possible, providing some of the first evidence of excretion rates in fish fed on naturally high calcium diets. A directly proportional influence of feeding rate on gut carbonate excretion rates as a result of increased dietary calcium was observed, and novel evidence provided of the proportional contribution of dietary and seawater calcium to excreted carbonate. Both findings have considerable application to global models of fish contribution to the oceanic carbon cycle.

At the onset of this study, the work presented in Chapter 3 of this thesis was the primary focus. The work was motivated by JF Prins where he observed the formation of diamond layers on copper followed by C+ implantation into copper. This initial result suggested that it may be possible to generate single crystal diamond layers on single crystal copper. Subsequent efforts to reproduce this result failed. A unique end station was developed where a number of parameters could be altered during the implantation process. A series of carbon ion implantations were carried out on copper and copper-nickel (FCC) single crystals in this end station. The layers were characterised using initially Auger Electron Spectroscopy (AES), Low Energy Electron Diffraction (LEED) and later Raman Spectroscopy. During the early period of this study, the surface science equipment at the then Wits-Schonland Research Institute for Nuclear Sciences, was constantly giving problems. The time constraints on waiting for funds to be made available to repair the equipment, urged me to pursue alternative research endeavours and the results of this research is presented in chapter 4 and 5. The initial work will be investigated further in the future. Details of the end station are presented and the initial results of carbon layers generated in this end station are presented. In chapter 4, a study of C+ implantation into a type IIa (FCC single crystal) diamond using the cold implantation rapid annealing (CIRA) technique is reported. The Raman spectrum was recorded as a function of annealing temperature and C+ ion dose. De- fect peaks at 1450, 1498 and 1638 cm−1 appear in the Raman spectra, which have been previously considered to be unique to MeV implantation. The maximum energy of implantation used in this study was 170 keV. The peaks were monitored as a function of annealing temperature and ion dose. The annealing behaviour of the peaks were similar to those observed in the MeV implantation experiments. It is thus concluded that the defects that give rise to these peaks are related to the point-defect interac- tions that occur within the implantation regime and not to the implantation energy. 1 Understanding the nature of the defects that arise during the implantation annealing process, allows one to manipulate the implantation-annealing cycle, so as to generate defect structures that are useful in the fabrication of an active device in a diamond substrate. This is shown in chapter 5. A p-type (type IIb, FCC crystal) diamond was implanted with either carbon or phos- phorus ions using the cold implantation rapid annealing (CIRA) process. In each case, the energies and doses were chosen such that upon annealing, the implanted layer would act as an n-type electrode. The electroluminescence (EL) emitted from these carbon and phosphorus junctions, when biased in the forward direction, was compared as functions of annealing and diode temperatures. Typical luminescence bands such as those observed in cathodoluminescence (CL), in particular blue band A (2.90 eV) and green band (2.40 eV) were observed. Two bands centred around 2.06 and 4.0 eV were also observed for both the carbon and phosphorus junctions, while a band at 4.45 eV appeared only in the phosphorus implanted junction. This was the first time that the 4.45 eV band was observed in an electroluminescent junction.

archives@tulane.edu / Metalloenzymes containing copper or molybdenum have attracted considerable attention during the past several decades, as they play significant roles in a variety of biological and chemical areas. In those enzymes, their active sites exhibit unique structural features for fundamental studies in coordination chemistry and for applications in various catalytic reactions. The work described in this dissertation focuses on systematic syntheses of organometallic complexes for use in enzymatic systems as nitrous-oxide reductases (N2OR), acetyl-CoA (acetyl coenzyme A) synthases, or carbon monoxide dehydrogenases (ACS/CODH). Synthesis of diaminobisthiolate (N2S2) ligands with phenyl-connected sulfur and nitrogen atoms are introduced in Chapter 1. The importance of the N2S2 donor atoms in functionalizing the overall enzyme active sites are discussed in Chapter 1. Compared to the previously reported procedures, the new routes in this work allow for improved synthetic control, resulting in enhanced synthetic yields under mild reaction conditions. In Chapter 2, we focus on the synthesis, characterizations and applications of Ni(N2S2) complexes. We start with a new Ni complex with a tetradentate diaminobisthiolate ligand which is a continuation of one of the focuses in the previous chapter. The differences between the new Ni(N2S2) complex and other previously reported complexes with similar structures are discussed. We use both theoretical method (density functional theory calculation) and electrochemical measurements to explore the structural-property characteristics of those complexes. Chapter 3 details the synthesis of several multi-copper clusters for assembling in CuZ active-site analogues for nitrous oxide reduction. In those complexes, tetradentate diaminobisthiolate (N2S2) is used as a backbone ligand. Those complexes exhibit unique redox features due to the mixed valence of the CuI/CuII couple. Their structures are characterized by detailed X-ray crystallography measurements. In chapter 4, we extend the studies in synthesizing analogues in molybdenum- dependent carbon monoxide dehydrogenases (Mo-CODH) active site. Two different synthetic routes are explored to yield a number of Mo- and Cu-based complexes. Electrochemical characterizations are used to investigate the redox features of those complexes. / 1 / bo Wang

The primary aim of this work was to provide an alternative method of synthesis of the non-steroidal anti-inflammatory drug copper indomethacin (Cu-Indo) and to produce alternative forms of the drug to increase its marketability. Dense gases as anti-solvents were used to achieve these aims. The study involved the synthesis, purification, micronisation and co-precipitation of Cu-Indo with polyvinylpyrrolidone (PVP) using dense carbon dioxide as an anti-solvent. Initially the volumetric and solubility behaviours of the solvent???anti-solvent systems were investigated to determine the optimum processing conditions. The solubility of Cu-Indo in an expanded solution was found to be a complex function of the solvent and other solutes. Copper indomethacin was successfully synthesised and purified in a single vessel using dense carbon dioxide as an anti-solvent. Drug yields of 98 % and purities near 100 % were achieved at optimum conditions with the advantages of less residual solvent in the drug, less solvent waste, reduced processing time and increased yields over the conventional synthesis process. Copper indomethacin was produced in a variety of morphologies and particle sizes using dense carbon dioxide as an anti-solvent. An investigation of the effect of process parameters on the particle characteristics showed that solute concentration was the dominant variable. Spherical particles with diameters less than 8 mm were obtained at optimum conditions. The immediate benefit of micronising Cu-Indo was demonstrated with an eight fold increase in dissolution rate when compared to the conventionally produced drug. Polyvinylpyrrolidone was successfully co-precipitated with Cu-Indo using dense carbon dioxide as an anti-solvent. The PVP???Cu-Indo co-precipitates were found to increase the solubility of the drug in ethanol with a 36 fold solubility enhancement at optimum conditions. The use of dense carbon dioxide as anti-solvent in this work demonstrates the potential of the GAS and ASES processes in the pharmaceutical industry. Copper indomethacin was synthesised, purified and micronised in a single vessel at a substantial saving in terms of time and solvent usage. The micronisation of Cu-Indo and the formation of the PVP???Cu-Indo co-precipitate provided alternative forms of the drug substantially increasing its marketability.