Thesis (M.S.)--University of Wisconsin--Madison, 1966. / eContent provider-neutral record in process. Description based on print version record. Bibliography: l. 56-57.

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Background: Elevated levels of iron impair immune defence mechanisms specifically cell mediated immunity and macrophage function, favors infection with Mycobacterium tuberculosis (M.tb), its replication, progression to clinical disease and death form tuberculosis (TB). Chelation of iron in individuals with an excessive iron burden may restore host defence mechanisms, decrease M.tb viability and replication and could find application in the prevention and treatment strategies in a setting where both iron overload and TB are prevalent. Aim: The aim of this study was to investigate the effect of iron chelation on mycobacterial replication, host viability and defence mechanisms in iron-loaded monocyte-macrophages during M.tb infection. Materials and Methods: Mycobacterial replication was monitored using the microplate AlamarBlueTM assay (MABA) for M.tb strains H37Ra and H37Rv, or detection of green fluorescent protein (GFP) expression by BCG (GFP-BCG). Mitochondrial membrane potential (MMP), phosphatidylserine (PS) exposure and plasma membrane integrity of premonocytic U937 cells differentiated by vitamin D3 served as indicators of host cell viability after treatment with 500M FeSO4.7H2O alone or in combination with 500 M desferrioxamine (DFO) or silybin, and infection with M.tb at 1:1 infection ratio. Superoxide anion radical (O2-•) and total nitrate/nitrite generation was monitored as host defence mechanisms by absorption spectroscopy and fluorimetry respectively. Results: Iron supplementation enhanced intra- and extracellular growth of M.tb and BCG. Chelation of iron with DFO prevented the enhanced replication of mycobacteria promoted by iron. Iron overload increased host cell death of H37Ra-infected monocyte-macrophages through increased PS exposure and decreased MMP and plasma membrane integrity, while increasing O2-• production and decreasing NO production. DFO restored the iron-related increase in PS exposure, plasma membrane integrity, O2-• and NO production to levels similar in H37Ra-infected, iron-normal cells, while MMP remained suppressed. In contrast, infection of iron-loaded cells with H37Rv reduced the already suppressed monocyte-macrophage MMP while not affecting cell death or NO production. DFO restored the iron-related suppression of O2-• in H37Rv-infected cells, and induced the production of NO while not affecting host cell death. Conclusion: These results confirm the replication enhancing effect of iron-loading on M.tb. Its suppressive influence on macrophage viability and defence mechanisms by increasing cell death and decreasing NO production during infection, is also highlighted. The beneficial effect of iron chelation by DFO through the inhibition of mycobacterial replication and restoration of host viability and defence mechanisms are suggested. / Prof. Liza Bornman

It is fairly well known that alpha-amino dicarboxylic acids combine quite readily with basic metal ions such as the alkaline earths. The nature of the problem includes the synthesis and characterization of six platinum metal chelates of two alpha-animo dicarboxylic acids, namely aspartic and glutamic acids. The metal ion upon which the investigation is focused are platinum (II), palladium (II), and rhodium (III). Several of these are reported as having been repaired. The series is incomplete, however, and little study has been done correlating the abilities and trends of the complexes as a function of the metal ion and carbon chain length of the ligand acid molecule. Hence, the ultimate aim of the investigation is to study the tendency of chelation as the carbon chain length of the alpha-amino dicarboxylic acid increases and also to study the stability of the chelates as the central metal ion is varied. Because there are numerous problems involved here, the investigation extends somewhat beyond the scope of a Master’s research. Therefore the investigation is limited only to aspartic and glutamic acid. The methods of synthesis for the palladium, platinum, and rhodium chelates of aspartic and glutamic acids were studied and outlined. After synthesis, the means which were employed for characterization included elemental analysis, molecular weight determination, and infrared and ultraviolet spectra.

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The reaction of substituted acetylacetonates with R₃B compounds leads to the production of an interesting series of chelates containing the pseudo-metal ion moiety, BR₂. [see document for image of chemical compound] When the substituents on the acetylacetone are capable of extensive delocalization with the chelate ring (e.g., benzoylacetomethane) and/or when the R groups on boron are sufficiently withdrawing (R = F, C₆H₅), these species are capable of reversible one-electron reduction to the radical ion. These ion radicals are extremely stable, having been kept for many months at room temperature under argon atmosphere. Previous studies have indicated that the dianion radical of the substituted acetylacetonate ligand itself is extremely unstable. It has been trapped at extremely low temperatures and its spectral properties have been reported. Obviously, the main group chelate radical ions that we have studied represent a case where the inherently unstable dianion radical system is stabilized by coordination to the pseudometal ion. The spin densities and charge distribution in the boron chelate radicals and the neutral parent have been calculated by Pariser-Parr-Pople SCF techniques, extended Hückel molecular orbital calculations, and CNDO and INDO methods. The ligand dianion radicals have also been successfully handled. In all cases, good agreement between experimentally observed ESR hyperfine coupling constants, assigned by satisfactory simulation, and calculated hyperfine constants have been obtained. The spin density calculations on the radical anions indicated that there are negligible spin delocalization over the moiety, BR₂. The net charge distribution in the neutral and the radical anions demonstrate that the effect of BR₂ on the radical stability is due to its withdrawing effect. The electronic energy levels and electronic transitions allowed in the neutral and the radical ions have been calculated by closed-shell and open-shell (RSCF) methods of Longuet-Higgins and Pople with the CI treatment of Ishitani and Nagakura. Good agreement with the experimental data is observed. Correlation diagrams connecting the MO levels for the neutral and radical ion species reveal information about the perturbations of energy levels caused by the injection of an extra electron into the previous spin-paired system. / Ph. D.