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Includes bibliographical references., The interaction between metal-ions and the penicillin and cephalosporin antibiotics have been studied in an attempt to determine both the site and mechanism of this interaction. The solution conformation of the Cu(II) and Mn(II) complexes were determined using an n.m.r, line broadening, technique. The ligands benzylpenicillin, 6-aminopenicillanic acid, cephalothin, cephalexin, ampicillin and thiaproline were used to study the effect of structural changes in the ligand on the structure of the complex. The stability constants of several metal-ions/penicillin complexes were determined potentiometrically. These were correlated with stability constants determined for several related complexes. Finally the kinetics of the Ni(II) substitution reaction with benzylpenicillin, penicilloic acid, ampicillin and thiaproline was studied.

Copper(II) complexes have anti-inflammatory properties which can alleviate the symptoms of rheumatoid arthritis (RA) and thus control the progression of the disease. In this study two tripeptides, namely sarcosyl-L-leucyl-phenylalanine (Sar-Leu-Phe) and glycyl-L-leucyl-phenylalanine (Gly-Leu-Phe) were studied as potential chelators, which would increase the bioavailability of copper(II) through dermal absorption. Glass electrode potentiometry was used to measure the solution thermodynamics of copper(II), nickel(II) and zinc(II) with Gly-Leu-Phe and Sar-Leu-Phe, at 25 0.01 °C and an ionic strength of 0.15 M (NaCl). The terminal amine of both tripeptides was found to have the same basicity, but the methyl group on the terminal amine decreased the stability constants of the copper(II) ligand species by 0.38 to 1.67 log units. It increased the stability constants of the zinc(II) ligand species by 0.13 to 1.07 log units and it also increased the stability constant of the NiL2H-1 species by 1.3 to 1.4 log units, while not affecting the NiL species. The solution structures of the complexes were determined spectroscopically using Ultraviolet-visible spectrophotometry, Infrared spectroscopy and 1H NMR spectroscopy. The copper(II) complexes tend more towards a square planar geometry, rather than the expected tetragonally distorted octahedral geometry. All the nickel(II) species, were square planar, except for the ML species, which was octahedral. The ligand coordinated to the metal ion via an amine-N, two amide-Ns, two carbonyl-Os and a carboxyl-O. The postulated coordination modes were validated using quantum mechanical calculations. Two methods were used to study percutaneous skin absorption, namely octanol/water partition coefficients and Franz cell permeation.

Among common problems affecting human health and veterinary medicines, helmintic infections are major. The pathogens affect 550-750 Million people worldwide, and affect childhood growth, pregnancies, and development of the intellect. Helminths affects the well-being of animals as well including livestock and reduce the animal populations. However, the current anthelmintics are no longer as effective and some strains have developed resistance thus increasing the need for new anthelmintics. Unfortunately, not too much information is available detailing the physiology of helminths. The published genomic sequence of nematode Caenorrhabdtis elegans as well the primary sequence of the FLP18R1 G-Protein Coupled Receptor are available. GPCRs play a significant role as targets for therapeutics and are responsible for signal transduction in cells. Thus, nematode GPCRs offer an alternative target to design new anthelmintics. Unfortunately, very little information exists about these targets and there are no known x-ray or NMR structures. In this work, the 3D structure of nematode GPCR receptor (FLP18R1) was determined using homology modeling using the beta-2-adrenergic receptor as a template. The homology model developed had 24.87 % sequence identity with the template. Explicit membrane molecular dynamic simulations were used to optimize and refine the helices of the model over 100 ns. The homology model was of acceptable quality.

The principal aims of this thesis were to establish whether soluble calcium-phytate complexes inhibit calcium oxalate crystallisation and whether a higher dietary intake of phytate in South African black subjects compared to white subjects may contribute to the relative rarity of urolithiasis in this group. Potentiometric titrations were conducted to determine thermodynamic binding constants of soluble calcium-phytate complexes. Binding constants of seven complexes were identified. These were included in the data base of the Joint Experts Speciation System computer program to model the effect of phytate on the urinary supersaturation of calcium salts. Physiological concentrations of phytate failed to decrease ionized calcium and hence the urinary supersaturation of calcium salts. These theoretical predictions were then tested in an in vitro model. Calcium oxalate crystallisation experiments were conducted in simple salt solutions, artificial urine and real urine of the respective groups. The following parameters were measured: ionized calcium; calcium oxalate metastable limit; calcium oxalate particle volume-size distribution; calcium oxalate crystal nucleation, aggregation and growth kinetics. Deposited crystals were examined by scanning electron microscopy. The results confirmed those of the theoretical modelling. Furthermore, the results demonstrated that the inhibitory capacity of phytate is of a kinetic nature rather than a thermodynamic one. Phytate inhibited calcium oxalate crystal aggregation and the inhibition of calcium oxalate crystal growth was found to be independent of the physiological concentration of phytate. In vivo studies were conducted in which phytate-deficient, phytate-rich diets and a phytate supplement were administered in healthy black and white male volunteers. The baseline intake of phytate was assessed using food frequency questionnaires; urinary phytate was determined using a novel assay; biochemical and physiochemical urinary risk factors were measured. The black group had a significantly higher baseline intake of phytate culminating in a significantly higher urinary phytate excretion. No significant difference in urinary crystallisation kinetics was observed as being due to phytate per se. The findings of this thesis contribute to the pool of knowledge on urolithiasis and provide insight on the relative rarity of this disease in South Africa's black population.

Includes bibliographical references., The Berg River, Western Cape, South Africa, is an example of a catchment region where human pressures and conservation of natural resources collide. The river receives effluents from two large settlements and several smaller adjacent villages, including that of industrial and extensive agricultural activity. The estuary is one of the largest in South Africa and rated as the third most important conservation zone in the country. In this study, the chemical speciation of heavy metals in the river sediment was determined in order to evaluate the extent of pollution. Chemical speciation using sequential chemical extraction of sediment samples was used to measure the mobility and bioavailability of cadmium (Cd), lead (Pb), arsenic (As), chromium (Cr), nickel (Ni), cobalt (Co), iron (Fe), copper (Cu), zinc (Zn) and manganese (Mn). The metals Cd and Zn were found to be the most mobile and bioavailable. The study also examined the vertical distribution of heavy metals in estuarine sediment cores to evaluate the extent of heavy metal contamination with time and the degree to which heavy metals are influenced by other sedimentological parameters such as grain size, sediment composition and organic matter. Three sediment cores, ranging from 160 to 240 em long, were collected using a mechanical vibrating corer. The vertical distribution of metals in the cores showed that the metal concentration was higher at the top and middle of the cores. Based on the enrichment factor (EF) and anthropogenic factor (AF) values, it is suggested that the sediments of the estuary are not polluted with Co, Mn, Cu, Ni, Zn and Fe but moderately to highly polluted with Pb, As, Cd and Cr. The data reported provide a useful baseline for establishing heavy metal concentrations in the estuary and will be an important consideration in future sediment quality studies. The spatial distribution of the metals was also studied to understand how location is linked to metal concentration. The average concentration of metals in the core sediment increased with increasing distance from the mouth of the river. The adsorption behaviour of the estuary sediment with micro-pollutants has a significant influence on the environmental quality of estuary waters. For this reason, the absorption of Pb, Cr, Cu, Ni, and Zn onto sediment was study. It was found that the sediments of the Berg River estuary have a low potential for absorption of Ni and Zn making these metals more mobile and bioavailable.

Includes abstract., Includes bibliographical references., The H⁺ and Cu²⁺ equilibria of four glycine peptides (glycyl-glycine, glycyl-L-leucine, glycyl-L-phenylalanine and glycyl-L-histidine) and four sarcosine peptides (sarcosylglycine, sarcosyl-L-leucine, sarcosyl-L-phenylalanine and sarcosyl-L-histidine) have been studied using glass electrode potentiometry and isothermal titration calorimetry at 25 °C and an ionic strength 0.15 M (NaCl). The terminal amine of the sarcosine peptides is more basic than the glycine analogues. The methyl group on the terminal amine (for sarcosine peptides) does not affect the stability constants of the ML species, significantly. Log K for ML species for all the Cu(II)/peptides complexes ranged between 5.79 and 6.54, except for glycyl-L-histidine that showed log KML = 9.16. Heat accompanying the formation of ML for all the species ranged between -5.1 kcal mol⁻¹ and-6.6 kcal mol⁻¹, except for glycyl-L-histidine that showed ΔHML = -3.6 kcal.mol⁻¹. Structures for the different species in solution were postulated based on nuclear magnetic resonance and ultraviolet-visible spectrophotometry data. Molecular mechanics was used to investigate the possible structures. The minimum energy of the trans form of most the complexes was less than the cis form of the complexes.

Includes abstract., Includes bibliographical references., The need to come up with new and novel antibiotics that utilize unique mechanisms, to which bacteria cannot generate resistance, was the main motivation of this study. Tyrocidine peptides are non-selective antibiotics that have such properties. However, very limited information is available about their mechanism of action. The aim of this study was to determine the mechanism of action of tyrocidine peptides, tyrocidine A, tyrocidine B and tyrocidine C.

This study describes the investigation of the solution chemistry of the copper (II) complexes of homopiperazine and an adamentane derivative of homopiperazine (PCU.homo) using glass electrode potentiometry, UV/VIS spectroscopy, speciation modeling, nuclear magnetic resonance spectroscopy, blood plasma modeling, and dermal absorption.

The aim of this study was to understand and control the gasification rates in ammonium nitrate emulsion explosive using ammonium nitrate-sodium nitrite reaction. This reaction produces N2 gas which is the sensitizer in emulsion explosives. The NH4NO3-NaNO2 gassing reaction produces N2 gas and so the reaction could be followed by the pressure increase in a closed reaction vessel. The reaction is pH sensitive, so the role of pH was investigated in the pH range 2 to 5. Gasification reactions for unbuffered NH4NO3-NaNO2 reaction were found to be rapid below pH = 3 and maximum pressure was attained within 2 hours of starting the reaction. At pH = 4.5 and 5 the reaction failed to attain maximum pressure. Initial rate of reaction showed sensitivity to pH, the rate of reaction decreasing with increasing pH. The reaction was found to be second order with respect to nitrite species. The effects of three different buffers (potassium hydrogen phthalate, sodium formate and sodium citrate) were also investigated. At pH = 3 pressure traces for the buffered reactions had attained maximum pressure while at pH = 3.5 only sodium citrate buffer had reached a pressure stable state. The presence of the buffers resulted in a lower overall pressure change and absolute pH change and higher rate constants and initial rate of reaction than in their absence. iv A Lewis acid (Zinc Nitrate) was added to the buffered and unbuffered NH4NO3-NaNO2 reactions to investigate a patent claim that addition of a Lewis acid would increase the rate of reaction. The presence of zinc nitrate in the buffered reactions resulted in rapid pressure increase; higher initial rate of reactions than the unbuffered with zinc nitrate. Ammonium nitrate solution was emulsified resulting in an ammonium nitrate emulsion explosive and kinetics of gasification was investigated. The gasification reactions were found to be rapid at pH 3.2, slowing significantly with increased pH as indicated by initial rates of reaction and as predicted by the gasification reaction rate law. Maximum pressure increase was attained within three hours at pH 3.2, whereas reactions conducted at pH 4.0 and 4.5 failed to reach maximum pressure even after 24 hours as evidenced by plots of pressure versus time. The effect of buffers in the ammonium nitrate emulsions was also investigated.

Includes bibliographical references., The present study has been designed to investigate the effect of different ligands on the dermal absorption of copper.

Methyliminodiacetylhistidine dimethyl ester could not be synthesised. However the other two ligands, glycine and glycyl-L-histidine were purchased and used for this study. The equilibrium constants of the ligand (glycyl-L-histidine) and the ligand complexes with Cu(II), Ni(II) and Zn(II) were investigated with glass electrode potentiometry and isothermal titration calorimetry at 25±0.01oC at an ionic strength 0.15M with NaCl. Potentiometric studies show that glycyl-L-histidine has three dissociable protons, and the neutral form of the ligand forms around pH 6.60. Potentiometric results of copper(II) complexes with glycyl-L-histidine were compared to the potentiometric titration of the ligand with Ni(II) and Zn(II). Copper(II) complexes of glycyl-L-histidine were more stable than Ni(II) and Zn(II) complexes of glycyl-L-histidine. The potentiometric results for these systems were in good agreement with the literature results. From the potentiometric studies, the LH form of glycine was more stable than the LH form of glycyl-L-histidine by 1.19 log units. The second protonation of glycyl-Lhistidine is on the imidazole ring and hence there is so comparable protonation site for glycine. Instead the third protonation step of glycyl-L-histidine is comparable to the second protonation step of glycine. The ML form of Cu(II)-glycyl-L-histidine complexes was more stable than that of Cu(II)-glycine complexes by 1.07 log units. ML was the only common species for the two systems. The interaction between copper(II) and glycyl-L-histidine was also studied with isothermal titration calorimetry (ITC) from pH 5 to pH 8. This was compared to a simpler system of glycine. The change in speciation for this method was characterized by the N value. The speciation from ITC results followed that of potentiometric results. The ML species of Cu(II) and glycine formed in acidic solutions, and the ML2 formed in basic solutions. In this pH range, the ML species of Cu(II) and glycyl-L-histidine were the most predominant species in solution. The ITC results agreed with the potentiometric results. At pH 5 where ML was the most predominate species in both the Cu(II)-glycine system and the Cu(II)-glycyl-L-histidine v system (N 1) Log K of the glycyl-L-histidine system was greater than that of the glycine system. The structures of the complexes were predicted with ultraviolet-visible (UV-Vis) spectrophotometry. The visible spectra obtained for the different Cu(II)/Glycyl-Lhistidine species in solution were typical of Cu(II) complexes in a tetragonally distorted, octahedral environment. The molar extinction coefficients are also typical of Cu(II) complexes and reflect the distortion of the metal-ion environment. The sequence of protonation/deprotonation of the ligand was studied with 1H NMR spectroscopy. The first deprotonation of glycyl-L-histidine occurred at very acidic environments, and this was the deprotonation of the carboxylate proton. The second deprotonation occurred at one of the imidazole nitrogens and the last one occurred in highly basic environments. This was the deprotonation of the NH2 terminal. The structure of complexes of Cu(II) with glycyl-L-histidine were also studied by 1H NMR. Form 1H NMR results, the active binding sites for glycyl-L-histidine are the imidazole nitrogens, the amide nitrogen and the terminal NH2 group. The imidazole nitrogen involved in coordination first, followed by the amide nitrogen, followed by the terminal NH2 group The capacity with which the ligand can increase the low molecular weight Cu(II) complexes in blood plasma was studied using a computer model of blood plasma. At reasonable concentrations, the ligand was not able to mobilise endogenous copper. Most of the ligand existed as LH and LH2 in blood plasma. Moreover, glycyl-Lhistidine increased the low molecular weight complexes of Zn(II) more than of Cu(II).

Includes abstract., Includes bibliographical references (leaves 183-184)., G-proton coupled receptors (GPCRs) are excellent drug targets that occupy a central position in the physiology of insects and are involved in transmission of signal from the extracellular to the intracellular side of the cell. Adipokinetic hormone receptors (AKHRs) are GPCRs that mediate physiological functions of the neurohormones, adipokinetic hormones (AKHs) that regulate mobilisation of energy reserves during mosquito flight. Ligand binding to GPCRs depends on the three dimensional (3D) structures of the receptors but to date no crystal structures of insect GPCRs are available. This work focused on building molecular models of AKHR from the genome of the malaria mosquito, identifying its binding site and studying the conformational and structural changes during molecular dynamics of the active and inactive receptor.

Includes bibliographical references., It has been shown that copper complexes are able to alleviate inflammation associated with Rheumatoid Arthritis (RA). Serum copper levels are elevated in RA and it has been postulated that endogenous copper might have a protective function in chronic inflammatory conditions. In designing Cu(I1) anti-inflammatory drugs, one needs to know the stability constants of the ligand together with Cu(I1) and the competitive metal ions, Zn(I1) and Ca(I1) in blood plasma. For this purpose glass electrode potentiometry, infrared (lR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, UV/Visible spectroscopy as well as blood plasma modelling were used to explore the coordination chemistry of a newly designed ligand, PCUL (Bis-(3- aminoethy-2-aminomethylpyridine )-oxahexacyclo-dodecane). PCUL protonation and formation constants with Cu(I1) and Zn(I1) were investigated by potentiometric analysis at 2SoC and 0.ISmol/dm3 Na + (CI) The potentiometric analysis showed that CU(I1) formed far more stable complexes at physiological pH with PCUL than the in vivo competitor Zn(I1). In this study the IR spectroscopic analysis was used to determine the Cu(I1)-PCUL complexation sequence. The IR spectra show that the central amines are coordinated to the metal ion first. The small frequency shift between pH 4.02 to 6.91 proves that the pyridyl nitrogen atoms are also coordinated to CU(I1).

Includes abstract., Includes bibliographical references., Methods currently available for the accurate activity resolution of dual-label solutions of pure β-emitting radionuclides are mostly time consuming and involve much effort. The goal of this thesis was therefore to devise a simpler method to achieve the same objective. The technique developed is based on elements of two liquid scintillation counting techniques that are widely used to measure single-radionuclide solutions, namely the triple-to-double coincidence ratio (TDCR) efficiency calculation technique and the CIEMAT/NIST efficiency tracing method. Double- and triple-coincidence count rates, together with the figure-of-merit P determined from an external tracer, provide sufficient information to extract the component activities of a source in a simple manner.

Word processed copy., Includes bibliographical references., The solution studies aimed to determine the conformations of a series of DMSO solubilised gastrin peptides, G-4, [ß-Ala ¹] G-5 and G-17, so as to establish how the configurations of the biologically relevant sequence were related to each other, and to resolve whether they adopted preferred and conserved conformations in solution. Interproton distance restraints were calculated from measured NOe crosspeak intensities for each peptide.

Includes bibliographical references (leaves 158-161)., The objective of this study was to develop copper based anti-inflammatory agents for the treatment of inflammation associated with Rheumatoid Arthritis. Four low molecular ligands, N,Nt-di(aminoethylene)-2,6-pyridine dicarbonylamine (PrDH), Bis-(N,N-dimethylethyl)-2,6-pyridinedicarboxamide (PrDM), N,N'-bis[2(2-pyridyl)-methyl]pyridine-2,6-dicarboxamide (PrDPr) and 3,5-bis[(aminoethyl)ethanediamide]-4-oxahexacyclo-dodecane (PCUA) were designed and synthesised. The formation constants of these ligands with H+, Cu2+, Niz+, Znz+ and Caz+ were determined potentiometrically at 25°C and 0.15 mol dm-3 Na+Cr. The Cu(II) formed relatively more stable complexes than other three metal ions. The structures of the different Cu(II) species formed with these ligands were investigated using nuclear magnetic resonance(NMR), infrared (IR) spectroscopy, ultraviolet-visible (UV-visible) spectroscopy as well as molecular mechanics calculations. For the NMR spectroscopy, results showed that the central pyridyl nitrogen and amide nitrogen(s) as well as the terminal amino/pyridyl groups coordinate to the Cu(II) ion in solution. The IR results indicated that an amide nitrogen is coordinated to the Cu(II). The UV-visible study gave the smooth deconvoluted spectra of the individual species for the Cu(II)-PrDH, Cu(II)-PrDM and Cu(II)-PrDPr systems in support of the potentiometric results. The three studied ligands form tetragonally distorted octahedral MLH-l and MLH-z species with Cu(II). The molecular mechanics was used to calculate the internal strain energies of the different possible geometries of related complex species. A comparison of these energies was used to rationalize the different stabilities of these structures.

Includes bibliographical references (leaves 103-104).

Includes bibliographical references., Copper and Diclofenac (DCL) separately, are used to alleviate inflammation associated with RA. It has been postulated that their combination would have a synergistic effect i.e., their combination would be more effective than when administered independently. Cu(II)-DCL system is studied potentiometrically in order to evaluate this hypothesis.

Includes bibliographical references., The application of physicochemical methods for the analysis of small and complex pharmaceutical drugs was investigated. The methods were applied to small chiral molecules and further extended to analysis of complex glycoconjugate vaccines.

Includes bibliographical references., It has been found that low molecular mass copper(II) complexes are effective in the treatment of rheumatoid) arthritis (RA). Increasing the amount of copper associated with low molecular mass ligands in plasma helps to alleviate the symptoms of rheumatoid arthritis. Low molecular weight ligand, 3,5-bis[(aminoethyl)ethanediamideJ-4-oxahexacyclododecane (PCUA) was investigated using glass electrode potentiometry, UV/Visible spectroscopy, nuclear magnetic resonance spectroscopy, speciation modelling as well as blood plasma modelling.

Includes bibliographical references., Ab-initio, semi-empirical, and empirical calculations are used in computer programs separately or in conjunction with one another to calculate predicted chemical shifts for a wide range of chemical compounds. 1H-spectra for several flexible and rigid organic compounds were acquired on Oxford-Broker spectrometer and interpreted using two-dimensional NMR techniques. ACD-V 4 and CHARGE-V7 programs were used to predict 1H chemical shifts for these compounds. 1H and 13C_spectra for alkaloids were also collected using a Varian spectrometer and also interpreted with the use of multi-pulse techniques. CHARGE-V7, ACD-V4 (1H and 13C) predictor programs together with SpecInfo-V3.2 (1H and 13C) predictor program were used in the prediction of chemical shifts for alkaloids. The results obtained for flexible and rigid organic compounds indicate good calculation of 1H-chemical shifts by both CHARGE-V7 and ACD-V4 programs. These results are contrary to the poor chemical shifts generated by these programs for a1kaloids. The poor prediction of alkaloids could be due to the absence of similar fragments in ACD-V4 and SpecInfo-V3.2 program's databases. Poor parameterisation of CHARGE-V7 program coupled with complex spectra of a1kaloids could be contributing to the inaccurate predicted chemical shifts. Increasing the size of the user database for SpecInfo and ACD programs would improve the accuracy in prediction of both 1H and 13C chemical shifts. Improvement in the accuracy of parameterisation of CHARGE-V7 to cater for rare compounds such as natural products is also required.

Formation constants of Cu²⁺, Ni²⁺, Zn²⁺, Ca²⁺ and Gd³⁺ with the polyamine(amide) ligands N,N' -bis(2-hydroxyiminopropionyl) propane-1,3-diamine (L² ) and (1, 15)- bis(N,N-dimethyl)-5, 11-dioxo-8-(N-benzyl)-l ,4,8, 12, 15-pentaazapentadecane (L³ ) as well as those of Gd³⁺ with 3,3,9,9-tetramethyl-4,8-diazaundecane-2,10-dione dioxime (L 1 ) were investigated by glass electrode potentiometry at 25°C and an ionic strength (I) of 0.15 mol dm-³.

Bibliography: leaves 105-111., NMR has been used to study the metabolites found in body fluids, like urine, in the past three decades. It has more recently been used to study a lare range of diseases and the toxicolgoical effect of drugs on animals, by looking at metabolite patterns in the urine. The major advanteges of using NMR are that it is fast, non-invasive, non-destructive and non-equilibrium pertubing technique, allowing the detection of a diverse range of compounds in a single experiment.

Includes bibliographical references., Biomaterials have recently gained significance as a result of environmental pressures and their increased viability through crop engineering. Starch harvested from maize crops is one example of a cheap and abundant biopolymer, which could substitute conventional polymers such as polyethylene as a material in manufacturing. Its practical application, however, will depend on understanding its physical behaviour, so that intelligent modifications can be made to enhance its properties. The most effective way of changing a polymer's properties is by modification at the chemical level, since ultimately it is this which determines the macroscopic features, such as viscosity, plasticity and tensile strength. Since the origin of these features is difficult to study experimentally, this thesis will tackle the problem by means of computer simulation of small carbohydrate fragments. In particular, the two principal types of carbohydra te linkage (namely 0: (1--+4) and 0: (1--+6)) will be examined in this thesis, since these are the chief elements of conformational flexibility in these molecules. The 0(1--+4) and 0:(1--+6) linkages are studied both separately in the maltose and isomaltose molecules respectively and together in panose and the resultant water structuring and dynamic behaviour are studied. Although the computational approach provides insights not available experimentally, it is nonetheless important to compare the results obtained with an experimental reference as a check on their validity. N!vlR T1 relaxation measurements, which give indirect information on the atomic scale dynamics, have been measured for each of the model fragments and compared with values calculated directly from simulation.

Bibliography: pages 62-67., Creosote treated timber "bleeds" profusely in hot weather and develops tarry, oily surfaces that are difficult to handle and pose a health hazard. The objective of this work is to investigate the possibility of improving the surface condition of the creosote treated timber. The possibility of using creosote macroemulsions for wood impregnation purposes was investigated. Creosote emulsions also present the possibility of improving other creosote characteristics such as penetration and distribution of creosote in wood during treatment. Creosote emulsions were successfully developed by identifying the suitable class of surfactants (anionic}, chemical type of surfactant (unsaturated fatty acids), and type of emulsion (water-in-oil). However, these emulsions could not improve the surface condition of the creosote treated timber. The penetration and distribution characteristics of both the creosote emulsion and unemulsified creosote were satisfactory. Both the creosote emulsion and the unemulsified creosote penetrated the sapwood completely but there was no penetration into the hardwood.

Bibliography: leaves 125-130.

Includes bibliographical references., Acute and Chronic inflammations in Rheumatoid Arthritis are characterized by, among other features, changes in the metabolism of copper. Previous studies have shown that administration of exogenous copper, and the in vivo manipulation of endogenous copper may provide new ways of coping with the problem of anti-inflammatory/anti-arthritic therapies. Computer models of blood plasma have attempted to rationalize the use of copper complexes in this regard. This thesis describes the design and commissioning of an ultrafiltration apparatus to study metal interactions with blood proteins. The results are compared with equilibrium dialysis. The systems studied using this technique includes, the binding of Cu(ll) to HSA and BSA, ternary Cu(ll)-HSA-amino acid systems, as well as competitive studies of the Cu(ll)-HSA system with Mg(ll), Ca(ll) and Zn(ll). The ultrafiltrate was analysed using HPLC and atomic absorption spectroscopy. Protein preparation was found to be important and the different methods used for protein purification were compared using gel electrophoresis and atomic absorption. Binding studies of chelating agents as well as several pharmaceuticals in human blood serum were carried out and compared with computer modelling studies.

It has been shown that ¹⁵³Sm complexed with the bone seeking ligand ethylene-diaminetetramethylene phosphonate (EDTMP) is effective in pain palliation therapy of bone cancer. Blood plasma models for this ligand with Sm(III) and Ho(III) have been successfully constructed explaining the differences between ¹⁵³SmEDTMP and ¹⁶⁶HoEDTMP. The latter isotope is preferred because of its more energetic β particle, thought to improve the therapeutic effect of the radiopharmaceutical. However, ¹⁶⁶HoEDTMP is not an effective pain palliation agent and consequently the search for a more effective bone cancer therapeutic radiopharmaceutical involving ¹⁶⁶Ho continues. A ligand is being sought which complexes Ho(III) with a formation constant high enough to survive competition from blood plasma ligands but not so high to prevent ¹⁶⁶Ho from being accessible to metastases. EDTMP is unsuitable as such a ligand because of its inability to compete with citrate for complexation of Ho(III). For this study three diphosphonate ligands applied in radiation imaging of bone or nonradiative treatment of osteoporosis were chosen. They are APD (1-hydroxy-3-aminopropylidene- diphosphonic acid), MDP (methylenediphosphonic acid) and HEDP (1- hydroxy-ethylene-diphosphonic acid). Formation constants for the complexation of Ca(II), Mg(II), Zn(II), Sm(III) and Ho(III) with all of these ligands were measured using potentiometry and polarography. The latter was used to complement potentiometry in systems where precipitates formed. The complexation of Cd(II) by HEDP was used to compare the two techniques and to show that the values found by either technique are comparable. NMR studies were attempted on some complexes in solution to investigate the role the of the hydroxy-group (APD and HEDP) in complexation. The program ECCLES was used together with the formation constants measured in this study to predict the speciation of Ho(III) and Sm(III) with these three ligands in blood plasma. The results gathered for Ho(III) and APD were used as an indication and in an application to an ethical committee before animal testing. A baboon test was carried out using ¹⁶⁶HoAPD, the most promising system. The resulting bone-uptake and side-effects found in the animal study confirmed the predictions made by ECCLES. It proved that ¹⁶⁶HoAPD would be ineffective as a therapeutic agent due to high liver uptake. Valuable information on how a future radiopharmaceutical should be designed was obtained in this study.

Includes bibliographical references., Insect neuropeptides play a vital role in the hormone release processes associated with insect flight Elucidation of the metabolic flight pathways requires a knowledge of the peptide secondary structure to allow predictions to be made regarding hormone-receptor binding processes. The three insect neuropeptides under investigation were taken from the corpora cardiaca of the migratory locust (Locusta migratoria) and belonged to the Lom peptide series - Lom-AKH-I, II and Ill. The secondary structure of these hormones was investigated using high-resolution nuclear magnetic resonance (NMR) techniques and various molecular mechanics computations. The interproton distances and φ torsion angles obtained from the NMR data were used to constrain the peptides in subsequent Monte Carlo and molecular dynamics (simulated annealing) calculations. The results of these calculations indicated that Lom-AKH-I and Lom-AKH-III adopt a definite structure in d⁶-DMSO solution, while Lom-AKH-II appeared to be fluctional with a minimum of three structures being required to satisfy the experimental data. Lom-AKH-I and ill were shown to adopt a loose open turn structures stabilised by the presence of a single hydrogen bond. Both had an additional concave structure with hydrophobic clustering on the convex surface of the molecule. The results suggest that Lom-AKH-I and Lom-AKH-III are more reactive than Lom-AKH-II. These predictions are in agreement with literature results obtained for Lom-AKH-I and II for lipid mobilisation and phosphorylase activation. However, when measured against cAMP production, Lom-AKH-II has higher activity. Insufficient literature was available to make structure/activity comparisons for Lom-AKH-III.

Relative stabilities of paraffin oil-in-water emulsions were determined empirically as a function of increasing ionic strength, surfactant type or concentration, droplet size, pH and calcium(II) concentration. Stabilities were measured by droplet size changes, planar interface oil droplet coalescence times, creaming rates and photography. Stability trends between methods were compared. Conclusions were derived in terms of creaming and coagulation. The trends below were discussed in terms of theories of emulsion stability. 1. Increased surfactant concentrations stabilised the emulsions against creaming. Coalescence trends were complex: an optimal cetylpyridinium chloride concentration stabilised the emulsions. Beyond that concentration, stability was reduced. Because of its low HLB, increased sorbitan sesquioleate concentrations destabilised emulsions towards coalescence. 2. Smaller droplets stabilised all the emulsions despite the increased polydispersity. 3. Increased ionic strengths accelerated creaming. Coalescence was faster for cetylpyridinium chloride because of reduced droplet repulsion. Sodium dodecyl sulphate resisted coalescence at all ionic strengths due to the restabilisation predicted by the Stochastic model. 4. pH did not affect emulsions containing a pH-stable surfactant (sodium dodecyl sulphate). Emulsion stability was reduced with acid- or base-labile labile surfactants (sorbitan sesquioleate, cetylpyridinium chloride) due to reduced ability to lower the surface tension during emulsification, or hydrolysis. 5. Ca⁺² destabilised emulsions containing anionic surfadants (sodium dodecyl sulphate and laurate) by co-ordination, but had little effect on a cationic emulsifier (cetylpyridinium chloride) to which it did not co-ordinate. The destabilisation of anionic-based emulsions was due to the formation of oil-wettable solid salts and the removal of the o/w surfactant. 6. Low stabilities of sorbitan sesquioleate-based emulsions were attributed to Bancroft's rule and the low hydrophile-lipophile balance of sorbitan sesquioleate.

Include bibliographical references., In this thesis, a stochastic computer model of water-in-oil emulsion coagulation, a two stage process of aggregation and coalescence, is presented. The theoretical basis of the model, including equations for the van der Waals, electrostatic and steric energy barriers between dissimilar droplets, is described. Many of these equations have been derived by the author. A chemical speciation study of the aqueous phase typically found in emulsion explosives is presented. A potentiometric investigation of the protonation equilibria of propionate, succinate and mono-methyl succinate in tetraethyl ammonium bromide, ammonium nitrate, sodium nitrate, potassium nitrate and calcium nitrate at 25°C and 3 mol/dm³ ionic strength was performed. Nuclear Magnetic Resonance titrations for succinate and propionate in varying concentrations of the same salts are also shown. A method of converting thermodynamic stability constants from one ionic strength to another using a modified form of the Pitzer equations is presented with a computer program which performs the conversion. A novel method of obtaining complexation constants from protonation constants in varying media is proposed. Using optical microscopy, creaming rates and laser particle sizing, the affects of changing surfactant concentration, salt concentration, pH and shearing time for emulsions of ammonium nitrate solution in heptane with CRILL 43 are shown. Equations are derived for converting creaming rate data to droplet size information and a computer program for converting Malvern light intensity data in the anomalous regime (typical of water-in-oil emulsions) to size distribution data is presented. The computer model is validated against experimental data from this work and the literature and is used to make stability predictions for systems for which no data exists. Further uses for the model are discussed.

Includes bibliographical references., Multipulse Nuclear Magnetic Resonance (NMR) techniques were investigated via structural assignment of various natural products. The natural products chosen for investigation of 2D NMR spectroscopy as a structural tool were the opium alkaloids codeine and papaverine, the diterpenoid alkaloids delphinine and aconitine and the triterpenoid derivatives of cucurbitaceae. One dimensional NMR spectroscopy viz 1H, 13C and Distortionless Enhancement by Polarisation Transfer (DEPT) spectroscopy was initially applied to obtain a level of indication of the complexity of the structural problem solving. Various multipulse techniques were chosen depending on the sample quantity available, the sensitivity of the technique, the information provided and its applicabilty in the field of natural products. Both homonuclear scalar and dipolar correlation as well as short and long range heteronuclear correlation was investigated. The homonuclear Correlation Spectroscopy (COSY) experiment which revealed scalar 1H-1H scalar correlations was adequate for the structural assignment. The Heteronuclear Multiple Quantum Coherence (HMQC) experiment offered greater sensitivity on small sample quantities whilst the long range Heteronuclear Correlation (HETCOR) and Heteronuclear Multiple Bond Coherence (HMBC) experiments were essential for complete assignment of the quaternary groups. The stereochemical designation of some of the compounds was confirmed using the Rotating Frame Overhauser Enhancement Spectroscopy (ROESY) experiment which proved to be a more applicable pulse sequence for the natural products under investigation. The 1H and 13C assignments of these derivatives and the experimental approach used to obtain this data was compared to that present in the literature. The results indicate that apart from offering tremendous versatility depending on the special attributes of the compound, two dimensional NMR techniques are imperative for the unambiguous structural assignment of natural products.

Includes bibliographical references., This thesis describes the investigation of a series of diamino diamide copper(II) complexes with respect to their potential as anti-inflammatory agents in the treatment of rheumatoid arthritis. Several physico-chemical techniques were employed in the investigation including glass electrode potentiometry, UV/VIS spectroscopy, molecular mechanics calculations, speciation modelling as well as X-ray crystallography. Animal experiments were also carried out.

Bibliography: pages 107-110., Aluminium forms a highly neurotoxic complex with maltol (3-hydroxy-2-methyl-4H-pyran-one). The stability of this complex has been determined using glass-electrode potentiometry. Owing to the effect on nuclear relaxation behaviour, paramagnetic contrast agents have immense diagnostic potential and have recently received a great deal of attention in the literature. The gadoliniummaltol complex was studied with the view to developing a potential tissue-specific magnetic resonance imaging contrast agent. Because of the interest in medical applications of radioactive isotopes of group 1118 elements, the indium-maltol complex was studied in order to assess its radiopharmaceutical usefulness. The major analytical techniques used in this study are potentiometry and high resolution nuclear magnetic resonance spectroscopy.

Includes bibliographical references., The primary aim of this thesis is to establish a computer model of the chemical elements in seawater and to use this model to gain insight into the chemical processes controlling dissolution, precipitation, redox levels and coordinative interactions in surface seawater. In order to accomplish this task a relatively extensive database consisting of about 580 complexation equilibria arising from 32 inorganic and 10 organic components has been set up. Constants have been selected from critical compilations. Included in these equilibria are solubility products for the formation of potential solids, redox reactions and interactions with the atmospheric gases carbon dioxide and oxygen.

Bibliography: page 154., Towards the labelling of biological macromolecules in contrast media, a synthesis of the novel bifunctional amido-ligands N,N' -bis[2-(N'',N''-dimethylamino)ethyl]-4-aminobenzylmalondiamide (67) and the 3-aminopropyl derivative (66) from appropriately C-functionalized malonates by amidation with N,N-dimethylethylenediamine (62) followed by reduction of the respective nitro (64) and cyano (63) groups is described. The synthesis of N,N'-bis[2-(N'',N''-dimethylamino)ethyl]iminodiacetamide (73) from diethyl N-benzyliminodiacetate (79) by amidation· with (62) followed by debenzylation is described. Herein is also reported the unsuccessful attempts to prepare a functionalized pentaamine ligand similar to (73) via the intermediacy of N,N'-bis[2-(N'',N''-dimethylamino)ethyl]-N'''-(2,2-diethoxyethyl) iminodiacetamide (112) whose preparation is also detailed. Attempts to this end via the Mitsunobu and Steglich coupling of N,N' -bis[2-(N'',N''- dimethylamino)ethyl]-N'''-(2-hydroxyethyl)iminodiacetamide (100) with N-tertbutyloxycarbonylglycine (105) also met with failure .. Further failed attempts to secure suitably functionalized intermediates by N-alkylation of diethyl iininodiacetate (70) with appropriate electrophiles are described. The successful functionalization of the pentaamine series of ligands by N-alkylation of (73) withpnitrobenzoyl chloride (118) to give N,N' -bis[2-(N'',N''- dimethylamino)ethyl] N''' -(4-nitrobenzamido)iminodiacetamide (119) is presented. The preparation of the non-functionalized novel trioxo heptaamine ligand N,N' ,N''-tris[2-(N'',N''-dimethylamino)ethyl]nitrilotriacetamide hydrochloride (86a) is also described. An investigative study towards the assembly of a novel triamine system for encapsulating NMR or isotopic NMR-active metal ions for possible use in diagnostic medicine is reported. The key facet to this end is the reported preparation of N,N' ,N''-tris(2-aminoethyl)propane-1,2,3-tricarboxamide (89) by controlled amidation of trimethyl propane 1,2,3-tricarboxylate (88) with ethylenediamine. The syntheses of functionalized and non-functionalized novel tetraamine dioxo and trioxo ligands from glycine, ethyl N-benzylglycinate (78), L-valine, and L-lysine via classical peptide synthesis methodology (in part) are described.

Includes bibliographical references., The diamino-diamide ligands have been investigated in an attempt to develop an antirheumatic drug. The ligands N,N'-di-(2-dimethylamino)ethyloxamide and N,N'di-(2-diethylamino)ethyloxamide, were synthesised and characterised using the physical techniques, NMR, mass- and infrared spectrometry. The stability constants of the complexes of Mg, Ca, Zn and several first transition metal-ions with the ligands were determined potentiometrically. The solution conformation of the CuII complexes were determined using visible spectrophotometry. Finally the physico-chemical studies were carried out. Firstly by studying the interaction of the copper complex with albumin at the physiological pH 7.4 using visible spectrophotometry. Secondly by determining the superoxide dismutase activity of the ligand by reduction of nitrobluetetrazolium using visible spectrophotometry. Lastly the ligands and the carr, CuII, MgII and ZnII metalions were monitored in vitro using the computer blood plasma model.

Ninety square planar Rh(I) complexes of the type cis-[Rh(CO)₂(X)(L)], [Rh(COD)(X)(L)], [Rh(CO)₂(L)₂]ClO₄ and [Rh(COD)(L)₂]ClO₄ (X is Cl or Br; COD is 1,5-cyclooctadiene; L is aniline, pyridine, pyridine N-oxide, imidazole and ammonia), as well as their isotopically labelled derivatives (¹³CO, ²H and ¹⁵N) were prepared, characterized by microanalysis and melting point, and investigated by the following spectroscopic techniques: infrared, Raman, ultraviolet, mass spectrometry, and 1H, ¹³C and ¹⁵N nmr spectroscopy. The comprehensive isotopic labelling studies allowed unambiguous assignment of the infrared modes in the 4000-50 cm⁻¹ region. The infrared assignments are discussed with reference to their vᴰ/Vᴴ ratios, the various ligands and halogens used, the charges on the complexes, and are compared to similar compounds. The 1H, ¹³C and ¹⁵N nmr runs were performed at room and low temperatures. Fluxionality of the ligands (L) was observed and the exchange process was monitored by variable temperature nmr. The enthalpy and entropy values for the intermolecular exchange of L in the complexes cis-[Rh(CO)₂(X)(L)] were obtained by a complete computer simulated band shape analysis of the carbonyl region of the ¹³C nmr spectra. The non-equivalence, and specific assignment of the carbonyl groups in the cis- [ Rh(CO)₂(X)(L)] complexes were determined by recording the variable temperature ¹³C nmr spectra of the doubly enriched species cis[Rh(¹³CO)₂(X)(¹⁵N-ligand)]. ²J(¹³C-Rh-¹⁵N) values are reported for the first time. The ¹J(¹⁵N-¹⁰³Rh) coupling constants are rationalized in terms of the metal-nitrogen bonding, and correlate with the s-character of the bonding electron on nitrogen. While the solution electronic spectra reveal that the complexes are discrete monomeric entities in solution, there are indications of metal-metal interactions in the solid-state. The normal coordinate analysis study of the complexes cis-[Rh(CO)₂(X)(L)] involved the calculation of a general valence force field by applying the eigenvector method of Becher and Mattes. The results show that point-mass-modelling and simplified force field, as assumed in our treatment, describes, to a good approximation, the vibrational properties of the complexes. The potential energy distribution provided further support for the proposed infrared assignments of the complexes.