EXPLORING AND DEFINING THE ROLE OF LIGAND OXIDATION IN RU(II) ARENE-BASED DRUGS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Defining and understanding the mechanisms of action of pharmaceutical agents is an ongoing research challenge that requires detailed information on the reactivity of these drugs within a biological environment. The challenge is generally more complex for metal-based drug candidates due to their broader reactivity and the correspondingly greater possibilities for interactions during transport to the biological target. We are investigating the fundamental biochemical properties of a series of ruthenium-based drug targets with demonstrated antitumor activity. Ru arene complexes of the form [Ru(ar)(en)L]X have shown excellent activity as anticancer agents but the nature of L has an important, yet somewhat unpredictable effect on bioactivity. We note particularly that thiolato complexes (L=RS-) are extremely bioactive under acidic and oxidative conditions. The properties of different oxidized forms of these complexes (e.g. L=RSO-, RSOH, RSO2-, RSO2H) and their related selenium analogs are currently being explored and show unusual bonding characteristics that are believed to be very relevant to their bioactivity. We therefore propose to utilize S K-edge and Se K-edge XAS (as well as other ligand K-edges where appropriate) to evaluate the nature of Ru-X bonding in these and related species.