Spectroscopic studies of auranofin, an antirheumatic drug, and its metabolites under biomimetic conditions

Chrysotherapy is the treatment of rheumatoid arthritis using gold(I) drugs. Gold drug metabolism remains unclear despite seven decades of use and hence, in order to improve the treatment and new generation gold (I) drugs better drugs, a fuller understanding of the mechanism of action is essential. Gold in vivo exists predominantly in the +1 oxidation state, although recent immunological studies suggested evidence for the presence of gold in the +3 state. Extensive biomimetic studies, supporting the immunological findings that gold(III) metabolites can be generated in vivo, is presented.;The chemical feasibility of oxidation of the second-generation drug, auranofin [Et3PAuSAtg = triethylphosphine-(2,3,4,6-tetra-O-acetyl-1-beta-D-glucopyranasato-S-) gold(I)] to a gold(III) metabolite was investigated under biomimetic conditions using spectroscopic techniques. It was determined that the gold(I) in auranofin is oxidized to the gold(III) complex, [AuCl4]-, which undergoes hydrolysis and occurs via oxidation of the ligands to Et 3PO and SO42-.;Biomimetic studies supporting the formation of other gold(III) metabolites, [Au(CN)2X2]- (X = CN- or Cl-), generated from [Au(CN)2] -, a common metabolite of the gold(I) drugs, are also reported in this thesis. The OCl- oxidation of auranofin and [Au(CN) 2]- provides kinetically and thermodynamically feasible routes for gold(III) formation, and supports the immunological studies.;[Au(CN)2]- is generated at the inflammation site following immunogenesis of cyanide during the oxidative burst and was identified in the blood and urine of chrysotherapy patients. In this thesis, the ability of serum albumin to act as a transport mechanism for [Au(CN) 2]- has been unequivocally established using Mossbauer and 13C NMR spectroscopic techniques. The dominant binding mechanism is the non-covalent association of intact [Au(CN)2] - ions at strong and weak binding sites.;The rationale for bulk of gold in vivo remaining gold(I) is provided in a preliminary spectroscopic study of [Au(CN)4] - reduction by various model thiols. The [Au(CN)4] - is reduced to the gold(I) metabolite, [Au(CN)2] -.;The favorable oxidation of gold(I) to gold(III) metabolites, and its re-reduction to gold(I) by thiolates suggest that a gold(I)/gold(III) redox cycle can be established in vivo. In this thesis, two mechanisms for the oxidation of gold(I) to gold(III) and one for the reduction of gold(III) to gold(I) are presented. (Abstract shortened by UMI.).