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 an example, the PROLI/NO anion, an NO donor prepared by diazeniumdiolating the natural amino acid proline, 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). Current work is aimed at characterizing the mechanisms of NO versus HNO (nitroxyl, a newly identified bioeffector species) release in model diazeniumdiolates. We have discovered, for example, 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 (collaboration with K. Miranda, D. Wink, and S. Donzelli). We are currently working to design caged HNO compounds with tunable rates of HNO delivery in physiological fluids for use as tools for research on this bioeffectors chemical biology. Studies of the prodrugs utility as anti-cancer agents are also being contemplated. 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 (collaborations with M. Kibbe, M. Reynolds, and M. Meyerhoff). Work conducted wholly within our research group is aimed at developing new protecting group strategies needed for preparing novel target compounds, troubleshooting synthesis procedures that fail to reach the desired target compound or that proceed in low yield, and fully characterizing previously unknown compound types that appear as by-products of intended syntheses, often serendipitously.
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