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，康奈尔大学的贾斯汀·J·威尔逊正在开发新的工具来研究气体硫化氢在生物环境和人类健康中的作用。硫化氢（H2S）是一种小的气体分子，有时也被称为气体递质，它是生物合成的，在调节与正常和健康细胞功能相关的许多过程中起着重要作用。由于硫化氢是一种气体，其在体内向生物系统的受控递送是具有挑战性的。因此，更深入地了解这种气体信号分子如何在生命系统中发挥作用是非常有意义的。该项目将开发新的化学工具，可以通过选择性刺激激活细胞后向细胞提供少量生物相关量的硫化氢。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。这些活动旨在强调硫化氢等有毒化合物如何以足够低的浓度存在于“天然”或“有机”食品中，不会对健康造成危害。相反，这种化合物在人类生物学中具有至关重要的作用，这些活动将旨在教育公众了解对健康人类生物学至关重要的气体传递素的迷人作用。康奈尔大学的威尔逊研究小组将设计新的基于铼的硫化氢释放分子作为化学工具，以研究气体传输器硫化氢（H2S）的生物作用。硫化氢调节真核细胞中广泛的关键生物过程，并且已知其对心脏病、中风和癌症的管理具有治疗作用。然而，将H2S直接施用到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，研究人员已经开发出易于处理的化合物，可以缓慢释放这种气体递质，以研究其生物学功能。这些努力一直集中在被设计为通过不受控制的水解、蓝光或紫外光照射、活性氧物质氧化、酶活性和与硫醇的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包。通过使用钌配位络合物，Wilson团队的目标是获得硫化氢释放剂，这些硫化氢释放剂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分别由化学还原和光照射触发的硫化氢供体。最后，Wilson小组将使用这些新工具来了解硫化氢在体外保护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捐助者的工具包，并将通过应用它们来确定这种气体传输器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NSF的法定使命，并被认为值得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来支持。

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.