Bruce Bioinorganic Chemistry Projects

An Introduction

auranofin	solganol	myochrisine

     Shown above are some gold-based drugs used to treat rheumatoid arthritis. The biological activty of gold-based drugs is interesting for several reasons.

     First, despite decades of research  , the specific avenues by which gold drugs modify the infammatory response is not completely understood. It is likely, though, that gold drugs have multiple effects in the body, including reactivity with soft atoms like sulfur in the form of thiolate, thiols, disulfides, or thioethers. Our group has pioneered the investigation of how gold-thiolates react with disulfide, and have shown how the form of gold (e.g. charge or ligand bonding mode) can influence the rate of this thiolate-disulfide exchange reaction by a factor of over 20.

     Second, since gold is not a naturally occuring metal, we believe that the activity of gold implies (1) competition at active sites designed for other metals or (2) reaction at substrates that are also reactive with other metals. This leads us to have a particular interest in using gold to probe biological systems, especially involving disease states, e.g. a diseased protein in a non-active form. Since thiolate-disulfide exchange is important to many biological processes, competition involving metal-mediated thiolate-disulfide exchange may be an important biological factor in control and regulation of many disease states.

    Third, our research has shown that gold thiolate complexes (including auranofin) can undergo electron transfer catalysis reactions with iron based complexes (e.g ferrocene) that is best described as either "associated outersphere" or "innersphere" electron transfer. Since iron based complexes such as ferrocene are usually described as predominately "outersphere" electron transfer, the unusual behavior of our gold-iron system implies that gold and iron can team-up in some interesting electron transfer reactions. There are many biological processes in which electron transfer is a key step. These results suggest a mechanism by which mutli-nuclear electron-transfer reactions can influence biological activity. It is interesting to note that gold has been shown to have anti-cancer activity (along with iron) as well as activity against the HIV virus. Since redox reactions may influence control and regulation of cancer states as well as inflammation, metal-mediated eletron transfer could be critical in understanding these disease states as well as the design of new strategies for repair.

    For these reasons (and others) we suggest that the biological activity of gold (especially in association or reaction with other metals including iron, copper, and zinc) deserves additional attention.