Ruthenium Coordination Complexes as Tools for Studying Biological Hydrogen Sulfide

在化学系生命过程化学（CLP）项目的支持下，康奈尔大学的Justin J. Wilson正在开发新的工具来研究硫化氢气体在生物环境和人类健康中的作用。硫化氢（H2S）是一种小气体分子，有时被称为气体递质，是生物合成的，在调节与正常和健康细胞功能相关的许多过程中起重要作用。由于硫化氢是一种气体，在体内控制其向生物系统的输送是一项挑战。因此，更深入地了解这种气体信号分子如何在生命系统中运作是非常有趣的。该项目将开发新的化学工具，在选择性刺激激活细胞时，可以向细胞输送少量的、生物相关的硫化氢。如果成功，这些工具将使研究人员能够探索H2S在人类健康中的生物学相关性和重要性。此外，该项目还将为高中STEM（科学、技术、工程和数学）教师开发新的教育活动。这些活动的目的是强调如何在“天然”或“有机”食品中以足够低的浓度存在硫化氢等可能有毒的化合物，而不会对健康造成危害。相反，这种化合物在人类生物学中起着至关重要的作用，这些活动将被设计成教育公众关于气体传递素的迷人作用，它们对健康的人类生物学至关重要。康奈尔大学威尔逊研究小组将设计新的钌基硫化氢释放分子作为化学工具，研究气体发射器硫化氢（H2S）的生物学作用。硫化氢调节真核细胞中广泛的关键生物过程，已知对心脏病、中风和癌症的管理产生治疗作用。然而，将H2S直接施用于生物系统受到其气体性质和高浓度毒性的限制。为了克服这些挑战，研究人员开发了易于处理的化合物，可以缓慢释放这种气体递质，以研究其生物学功能。这些努力主要集中在通过不受控制的水解、蓝光或紫外光照射、活性氧氧化、酶活性和硫醇反应释放硫化氢的有机化合物上。该项目的目标是通过开发基于过渡金属钌的化合物来扩展硫化氢释放分子的工具箱。通过使用钌配位配合物，Wilson团队的目标是获得硫化氢释放剂，这种药物可以被传统有机化合物无法获得的刺激选择性激活。通过这些努力，钌配位化合物的氧化还原化学和光化学将被利用来制造硫化氢供体，分别由化学还原和光照射触发。最后，Wilson小组将使用这些新工具来了解硫化氢在体外保护免受缺血再灌注损伤的机制。总的来说，这项研究将扩大可用的硫化氢供体工具包，并将通过应用它们来确定这种气体递质在健康人类生物学中的新作用来证明它们的价值。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

With the support of the Chemistry of Life Processes (CLP) Program in the Division of Chemistry, Justin J. Wilson of Cornell University is developing new tools to study the role of the gas hydrogen sulfide in biological settings and human health. Hydrogen sulfide (H2S) is a small gaseous molecule, sometimes referred to as a gasotransmitter, that is biosynthesized and plays an important role in regulating a number of processes associated with normal and healthy cellular function. Because hydrogen sulfide is a gas, its controlled delivery to biological systems, in vivo, is challenging. Therefore, a deeper understanding of how this gaseous signaling molecule operates in livings systems is of great interest. This project will develop new chemical tools that can deliver small, biologically relevant amounts of hydrogen sulfide to cells upon activation by selective stimulation. If successful, these tools will enable researchers to probe the biological relevance and importance of H2S in human health. In addition, this project will develop new educational activities for high school STEM (science, technology, engineering and mathematics) teachers. These activities will be designed to highlight how compounds such as hydrogen sulfide, that can be toxic, may be present in “natural” or “organic” foods at sufficiently low concentrations that do not present a health hazard. Rather, this compound has a critically important role in human biology and these activities will be designed to educate the public about the fascinating roles of gasotransmitters that are so critical to heathly human biology. The Wilson research group at Cornell University will design new ruthenium-based hydrogen sulfide-releasing molecules as chemical tools to study the biological roles of the gasotransmitter, hydrogen sulfide (H2S). Hydrogen sulfide regulates a wide range of critical biological processes in eukaryotic cells and is known to elicit therapeutic effects for the management of heart disease, stroke, and cancer. The direct administration of H2S to biological systems, however, is limited by its gaseous nature and toxicity at high concentrations. To overcome these challenges, researchers have developed easily handled compounds that slowly release this gasotransmitter to study its biological function. These efforts have been focused on organic compounds that are designed to release hydrogen sulfide via uncontrolled hydrolysis, blue or ultraviolet light irradiation, oxidation by reactive oxygen species, enzymatic activity, and reactions with thiols. The objective of this project is to expand the toolkit of hydrogen sulfide-releasing molecules by developing compounds based on the transition metal ruthenium. By using ruthenium coordination complexes, the Wilson team aims to gain access to hydrogen sulfide-releasing agents that are selectively activated by stimuli that are inaccessible with conventional organic compounds. Through these efforts, the redox chemistry and photochemistry of ruthenium coordination compounds will be leveraged to make hydrogen sulfide donors that are triggered by chemical reduction and light irradiation, respectively. Lastly, the Wilson group will use these new tools to understand the mechanisms by which hydrogen sulfide can protect against ischemia-reperfusion injury in vitro. Collectively, this research will expand the toolkit of available hydrogen sulfide donors and will demonstrate their value by applying them to identify new roles for this gasotransmitter in healthy human biology.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.