Nitric Oxide- and Nitroxyl-Releasing Diazeniumdiolates in Pharmaceutical and Biomedical Research Applications
AuthorSalmon, Debra J.
AdvisorMiranda, Katrina M.
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractNitric oxide (NO) has been extensively studied due to its importance as a signaling agent. More recently, the pharmacological benefits of nitroxyl (HNO) in the treatment of cardiovascular disease, cancer, and alcoholism have been discovered.That HNO readily dimerizes complicates analysis and necessitates the use of donors. Diazeniumdiolates (NONOates), which can release either NO or HNO, are particularly attractive in this regard. NONOates from primary amines release HNO at physiological pH, and since the few existing examples have relatively short half-lives, a major research goal was to extend the lifetime range. The effect of amine structure on the lifetimes of ionic primary amine NONOates having the general structure Na(RN(H)[N(O)NO]) was unexpectedly small. This prompted the use of O2-protecting group methodology as an alternate method to stabilize donors toward decomposition. A detailed analysis of the decomposition mechanisms of a representative ionic primary amine NONOate and its O2-protected derivative is presented.NONOates were used as analytical tools to compare several commonly-used methods for detection of HNO. While these methods are used routinely for qualitative analysis of HNO, optimization for quantitative measurements was difficult. To improve method sensitivity, an HPLC assay using the fluorogenic reagent o-phthalaldehyde was developed, which may ultimately allow detection of endogenously-produced HNO.HNO donors such as cyanamide have been utilized in the treatment of alcoholism through the inhibition of aldehyde dehydrogenase (AlDH), which is critical for ethanol metabolism. Cyanamide also releases cyanide, and alternate HNO donors are thus desired for this clinical use. The efficacy of NONOates in the inhibition of AlDH was assayed in purified yeast AlDH and in mouse liver homogenate. However, efficacy was limited in a mouse model, perhaps due to a lack of selective delivery. This drug discovery project provided useful information for the future development of potentially liver-selective HNO-releasing NONOates.Together, these studies demonstrate the utility of NONOates as biomedical research tools, with synthetic modifications allowing for the modulation of decomposition profiles. As analytical tools for the development of HNO detection methods and potential pharmaceuticals in the treatment of alcoholism, NONOates provide convenience and control as donors of NO and HNO.
Degree ProgramGraduate College