Generation and Solution Reactivity of Nitroxyl (HNO)

该研究将涉及硝基（HNO）的生成和溶液反应性，最近受到了极大的关注，特别是作为当前心力衰竭治疗的潜在替代方案。由于其固有的反应性，HNO必须在原位生成，但目前只有非常有限数量的合适前体存在。目前还没有一种可行的方法可以在溶液或生物相关制剂中直接检测HNO，这增加了研究HNO化学的难度。为了解决目前在HNO化学和生物化学、可用的HNO供体分子和实际有用的HNO直接检测技术方面的不足，本研究将开发(1)新的生理上有用的HNO热前体，(2)新的适用于纳秒时间分辨红外（TRIR）研究的HNO光化学前体，以及(3)用于水溶液中HNO检测和研究的新分析工具。新的HNO供体的开发，结合反应性研究和HNO诱导蛋白修饰的评估，不仅将为HNO的生物活性提供基本的见解，而且可能最终导致开发一类用于治疗心力衰竭的新型化合物。此外，关于开发新的HNO热和光化学前体、检测HNO的新分析工具以及阐明HNO诱导的PLN修饰的拟议研究将为研究生和本科生提供广泛的培训。将继续积极鼓励本科生参与研究。

The research will involve the generation and solution reactivity of nitroxyl (HNO), which has recently received significant attention, especially as a potential alternative to current treatments of cardiac failure. Due to its inherent reactivity, HNO must be generated in situ, but only a very limited number of appropriate precursors currently exist. Adding to the difficulty of studying HNO chemistry is that a viable method for its direct detection in solution or biologically relevant preparations is not currently available.To address current deficiencies in the understanding of HNO chemistry and biochemistry, in available HNO donor molecules, and in practically useful direct HNO detection techniques, the proposed research will develop (1) new physiologically useful thermal precursors to HNO, (2) new photochemical precursors to HNO suitable for nanosecond time-resolved infrared (TRIR) investigations, and (3) new analytical tools for its detection and study in aqueous solutions. The development of new HNO donors, combined with reactivity studies and the evaluation of HNO-induced protein modifications, will not only provide fundamental insight into the biological activity of HNO, but may also ultimately lead to the development of a new class of compounds for the treatment of heart failure. In addition, proposed research on the development of new thermal and photochemical precursors to HNO, new analytical tools for its detection, and elucidation of HNO-induced modifications of PLN will afford broad training for graduate students and undergraduates. Undergraduate participation in research will continue to be actively encouraged.