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Pure Appl. Chem., 2008, Vol. 80, No. 8, pp. 1799-1810

Catalytic metallodrugs

James A. Cowan

Evans Laboratory of Chemistry, Ohio State University, 100 West 18th Avenue, Columbus, OH 43210, USA

Abstract: Drug discovery remains a top priority in medical science. The phenomenon of drug resistance has heightened the need for both new classes of pharmaceutical, as well as novel modes of action. A new paradigm for drug activity is presented, which includes both recognition and subsequent irreversible inactivation of therapeutic targets. Application to both RNA and enzyme therapeutic targets has been demonstrated, while incorporation of both binding and catalytic centers provides a double-filter mechanism for improved target selectivity and lower dosing. In contrast to RNA targets that are subject to strand scission chemistry mediated by ribose H-atom abstraction, proteins appear to be inactivated through oxidative damage to amino acid side chains around the enzyme active site. Methods to monitor both intracellular delivery and activity against RNA targets have been developed based on plasmid expression of the green fluorescent protein (GFP). Herein, the activity of representative metallodrugs is described in the context of both in vitro and cellular assays, and the mechanism of action is discussed. Studies with scavengers of reactive oxygen species (ROS) confirmed hydrogen peroxide to be an obligatory diffusible intermediate, prior to formation of a Cu-bound hydroxyl radical species generated from Fenton-type chemistry.