Nitric oxide (NO) is a potent and multifaceted bioregulatory agent. This project is aimed at finding ways to target NO to specific sites in the body for important research and/or therapeutic applications. The essential starting point for all our research is the continuing physicochemical characterization of a versatile class of NO prodrugs, the diazeniumdiolates. During the past year, we have probed the NO release characteristics of two carbon-based diazeniumdiolates, one a propeller-shaped ion formed by exposing the common solvent acetonitrile to NO in base and the other a bis-diazeniumdiolate that spontaneously generated NO in 100% yield at physiological pH. Considerable progress has been made in elucidating the seemingly anomalous reaction courses observed for O2-glycosylated diazeniumdiolates in base, for certain O2-arylated diazeniumdiolates in solutions containing glutathione, and for an O2-vinyl diazeniumdiolate on metabolism by certain cytochrome P450 isoforms. A paper describing a chromatography-based analytical system for assaying spontaneously reactive diazeniumdiolate ions was also published. This fundamental chemical research program serves as a versatile platform for designing improved biomedical research tools as well as potential clinical applications. One of the O2-arylated diazeniumdiolates has displayed promising antileukemic activity in mice (collaboration with P. Shami), and another has been shown to increase the toxicity of the antileukemic agent arsenite in an arsenite-resistant transformed cell line (collaboration with M. Waalkes and J. Liu). These agents were designed to be activated for NO release by glutathione S-transferase (GST); since the Pi isoform of GST is overexpressed in many cancer cells, we are endeavoring to design substrates that are preferentially metabolized by this enzyme as a means of targeting cytolytic NO selectively to tumors (collaboration with X. Ji and S. Singh).
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