Generation and Solution Reactivity of Small Molecule Signaling Agents

有了这个奖项，化学结构，动力学和机制B计划正在支持约翰霍普金斯大学化学系的John P. Toscano教授的工作。 该研究解决了生物相关小分子硝酰基（HNO，azanone）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的潜在替代方案最近受到了极大的关注。 H2S是一种小分子信号传导剂，其在大脑中的生理作用已被充分证明。 然而，对这些影响的化学机制知之甚少。 本研究采用多种先进的分析技术，对HNO和H2S的反应性进行了定量和研究。 这项研究为研究生和本科生提供了广泛，全面的培训，为他们在工业和学术界的未来机会提供了很好的服务。 本科生参与研究仍然是一个高度优先事项，因为以前的学生已经表示，这方面的经验是他们的大学生涯的亮点，并在澄清他们的兴趣和准备他们为未来的study.Due其固有的反应性，HNO必须在原位生成，但只有数量有限的适当的前体目前存在。 该研究项目的重点是开发亚硝基羰基中间体（RC（O）N=O）的新型前体，这些中间体是与亲核试剂（包括水）反应释放HNO的反应性亲电试剂。 此外，开发用于温和生成亚硝基羰基化合物的新方法以用于合成应用。 为了研究H2S的化学性质，需要特异性和灵敏度高的检测方法。 膜进样质谱用于直接检测水溶液中的H2S，并详细检查其反应性。 HNO生物学的标志是其与硫醇（RSH）的反应性。 由于HNO也预计有显着的反应性与相关的物种，H2S，硒醇（RSeH），和过硫化物（RSSH），这些物种与HNO的反应性进行了检查，并比较了公认的反应性HNO与硫醇。 表征这种反应性对于理解H2S、硒醇和过硫化物的生物学作用至关重要。 硒醇研究依赖于77Se核磁共振（NMR）光谱研究来区分各种含硒物质。 由于过硫化物本身很难研究，因为它们不稳定并分解成各种物质，因此开发了一种用于纳秒时间分辨红外（TRIR）实验的化学前体，以直接检查反应性。 硫醇，H2S和硒醇的类似的crosslinkers也进行了检查比较。 最后，在水溶液中利用过硫化物的热前体来研究它们与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.