Date of Award

2011

Level of Access

Campus-Only Thesis

Degree Name

Master of Science (MS)

Department

Chemistry

Advisor

Mitchell R. M. Bruce

Second Committee Member

Alice E. Bruce

Third Committee Member

François G. Amar

Abstract

Although some aspects of rheumatoid arthritis (RA) remain unresolved and others undefined, the disease involves oxidative stress by inflammation. Auranofin, an orally-active gold(I) complex, is approved to treat RA and is thought to affect the extent of oxidative damage in RA. Whereas, its chief mechanism of action is unknown, auranofin is known to undergo rapid ligand exchange in vivo. Thus, reactions that involve thiolate ligand exchange may be important to the pharmacology of this gold(I) prodrug. UV-Vis spectrophotometry is used to study the thiolate-disulfide exchange reaction between auranofin (RSAuPEt3; RS-= 2,3,4,6-tetra-O-acetyl-1-thio-ß-D-glucopyranosato-S) and bis(4-nitrophenyl) disulfide (R'SSR'; R' = 4-NO2C6H4) in various solvents {viz.,CH2CL2, THF, acetone, DMF, DMSO, and propylene carbonate). The influence of solvent was experimentally measured as the time-resolved formation of R'SAuPEt3, a reaction product. Based on several observations the primary reaction pathway is described by the following chemical equation: RSAuPEt3 + R'SSR'-> R'SAuPEt3 + R'SSR. Furthermore, under conditions of excess RSAuPEt3, a sequential reaction pathway also may occur as follows: RSAuPEt3 + R'SSR ->R'SAuPEt3 + RSSR. With respect to the experimentally measured parameter, product R'SAuPEt3, the sequence of the above reaction pathways constitutes a composite reaction. The kinetics data of the reaction are analyzed by two curve-fitting methods for second-order reactions: the first uses a simple second-order integrated rate expression; the second uses a consecutive second-order integrated rate expression. The results of both empirical methods of kinetics analysis are consistent with the postulated chemical equations. These studies on the overall reaction between RSAuPEt3 and R'SSR' demonstrate that for the gold(I)-assisted thiolate-disulfide exchange the reaction kinetics (log k) increase as the relative permittivity (dielectric constant), er of the carrier solvent increases. This conclusion is opposite to the solvent effect that has been established for thiolate-disulfide exchange, i.e., the pathway in the absence of transition metals. In addition, preliminary, variable temperature studies in two solvents of high er values (DMSO, er = 47 and propylene carbonate, er = 65) show that the activation energy barrier is lower by a factor >2 for this gold(I)-assisted thiolate-disulfide exchange than for previously studied thiolate-disulfide exchange reactions in aqueous solution. A mechanism for the general gold(I)-assisted thiolate-disulfide exchange reaction and possible pharmacological implications are discussed.

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