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 introduced the O2-sulfonylated diazeniumdiolates to the literature via a description of their synthesis and solvolysis chemistry. We have also successfully devised a stable formulation for an anionic diazeniumdiolate that is especially sensitive to decomposition but that has been shown to reverse cerebral vasospasm in monkeys; we plan to use this formulation procedure in a Phase I stroke trial to be conducted by NINDS clinicians in collaboration with the NIH Clinical Center Pharmacy. This fundamental chemical research program serves as a versatile platform for designing improved biomedical research tools as well as potential clinical applications. One of our O2-arylated diazeniumdiolates has displayed promising activity against human leukemia and prostate cancer (collaboration with P. Shami) as well as ovarian cancer (collaboration with K. Tew) in mice, 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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