With this award, the Chemical Structure, Dynamics, and Mechanism B Program is supporting the work of Professor John P. Toscano of the Chemistry Department at Johns Hopkins University. The research addresses the generation and solution reactivity of the biologically relevant small molecules, nitroxyl (HNO, azanone) and hydrogen sulfide (H2S). HNO has recently received significant attention as a potential alternative to current treatments of cardiac failure. H2S is a small molecule signaling agent whose physiological effects in the brain have been well documented. The chemical mechanisms responsible for these effects, however, are very poorly understood. This research examines the quantifies and studies the reactivity of HNO and H2S using a number of advanced analytical techniques. This research provides broad, comprehensive training for graduate students and undergraduates, serving them well for future opportunities in both industry and academia. Undergraduate participation in research continues to be a high priority since previous students have indicated that this experience was the highlight of their college careers and was instrumental in clarifying their interests and preparing them for future studies.
Due to its inherent reactivity, HNO must be generated in situ, but only a limited number of appropriate precursors currently exist. This research project focuses on the development of novel precursors to nitrosocarbonyl intermediates (RC(O)N=O), which are reactive electrophiles that react with nucleophiles, including water, to release HNO. In addition, the development of new methods for the mild generation of nitrosocarbonyls are developed for use in synthetic applications. To investigate the chemistry of H2S, specific and sensitive detection methods are required. Membrane inlet mass spectrometry is used to detect H2S directly in aqueous solution and to examine its reactivity in detail. A hallmark of HNO biology is its reactivity with thiols (RSH). Since HNO is also expected to have significant reactivity with the related species, H2S, selenols (RSeH), and persulfides (RSSH), the reactivity of these species with HNO is examined and compared to the well-established reactivity of HNO with thiols. Characterizing this reactivity is critical to understanding the biological roles of H2S, selenols, and persulfides. Selenol studies relies on 77Se Nuclear Magnetic Resonance (NMR) spectroscopic studies to distinguish various selenium-containing species. Since persulfides are inherently difficult to study, as they are unstable and decompose to a variety of species, photoprecursors are developed and utilized in nanosecond time-resolved infrared (TRIR) experiments to examine the reactivity directly. Analogous photoprecursors to thiols, H2S, and selenols are also examined for comparison. Finally, thermal precursors to persulfides are utilized in aqueous solution to investigate their reaction with HNO.
