The essential starting point for all our research is the continuing physicochemical characterization of a versatile class of NO-releasing prodrugs, the diazeniumdiolates. This fundamental chemical research program serves as a promising platform for designing improved biomedical research tools as well as potential clinical applications for them. As one example, current work is aimed at characterizing the mechanisms of NO versus HNO (nitroxyl, a newly identified bioeffector species) release in model diazeniumdiolates in collaboration with K. Miranda, S. Donzelli, and D. Wink. As one example, we have discovered that a compound we have designed called AcOM-IPA/NO generates only HNO (no NO) on hydrolysis in simple aqueous buffer, suggesting its use as an important new research tool. AcOM-IPA/NO also potently strengthens the beating of isolated cardiac myocytes, suggesting it as a lead compound in the search for improved therapies for congestive heart failure. Glycosylated diazeniumdiolates have been shown to be reasonably stable at neutral or acidic pH but to undergo ready cleavage under catalysis by glycosidases. This finding has allowed us to design prodrugs useful for targeting NO to macrophages, thereby boosting their ability to combat parasites resident within their phagolysosomes (collaboration with C. Bogdan) and suggesting their use as a potentially valuable research tool for exploring the role of nitric oxide in macrophage anti-tumor action. The PROLI/NO anion has shown particular promise for biomedical applications because of its favorable toxicological profile and the fact that its dissociation to NO is so rapid (half-life 2 seconds at pH 7.4 and 37 C) that the pharmacological effects can be effectively localized at the point of introduction into the body. But this sensitivity to decomposition has complicated various attempts to formulate it for biomedical use. We have been able to devise an improved general method for synthesizing O-protected derivatives of PROLI/NO for possible therapeutic use;certain of these have been shown to be actively taken up by the cell via proline transporters (collaboration with J. Phang). In another specific application, we are exploring O-vinylated derivatives as non-toxic prodrugs for targeting NO to the liver and kidney (collaboration with M. Waalkes). Work continues on other aspects of the chemistry and pharmacology of NO, HNO, and the diazeniumdiolates, including those in which the NO/HNO-generating functional group is attached to polymers of interest in possible surgical and wound healing applications (collaboration with M. Kibbe and M. Meyerhoff).
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