Generation and Solution Reactivity of Small Molecule Signaling Agents

通过这一奖项，化学结构、动力学和B机制计划正在支持约翰·霍普金斯大学化学系约翰·P·托斯卡诺教授的工作。这项研究涉及与生物相关的小分子氮氧基(HNO、氮酮)和硫化氢(H2S)的生成和溶液反应性。HNO作为目前心力衰竭治疗方法的潜在替代品，最近受到了极大的关注。硫化氢是一种小分子信号转移剂，其在大脑中的生理作用已得到很好的证实。然而，导致这些效应的化学机制却知之甚少。这项研究使用一些先进的分析技术对HNO和H2S的反应性进行了考察、量化和研究。这项研究为研究生和本科生提供广泛、全面的培训，为他们在未来的行业和学术界提供良好的机会。本科生参与研究仍然是一个高度优先的问题，因为以前的学生已经表示，这段经历是他们大学生涯中的亮点，有助于澄清他们的兴趣，并为他们未来的学习做好准备。由于HNO固有的反应性，必须在原位产生HNO，但目前只有有限数量的适当前体存在。本研究项目的重点是开发新型的亚硝基甲酰中间体(RC(O)N=O)，它是一种反应性的亲电试剂，可以与包括水在内的亲核试剂反应，释放HNO。此外，还开发了用于合成应用的温和生成亚硝酰基的新方法。为了研究硫化氢的化学组成，需要有特异和灵敏的检测方法。膜进样质谱仪用于直接检测水溶液中的硫化氢，并详细考察其反应活性。HNO生物学的一个标志是它与硫醇(RSH)的反应。由于HNO还被认为与相关物种硫化氢、硒醇(RSeH)和过硫化物(RSSH)具有显著的反应性，因此检测了这些物种与HNO的反应性，并将其与HNO与硫醇的反应性进行了比较。表征这种反应活性对于理解硫化氢、硒醇和过硫化物的生物学作用至关重要。Selenol研究依靠~(77)Se核磁共振波谱研究来区分不同的含硒物种。由于过硫化物本身就很难研究，因为它们不稳定，可以分解成各种物种，因此开发了光再生物质，并将其用于纳秒时间分辨红外(TRIR)实验，以直接检测反应活性。与硫醇、硫化氢和硒醇类似的光再生剂也被检测以进行比较。最后，利用过硫化物的热前驱体在水溶液中研究了它们与HNO的反应。

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.