Ruthenium Coordination Complexes as Tools for Studying Biological Hydrogen Sulfide

钌配位配合物作为研究生物硫化氢的工具

• 批准号: 2203369
• 负责人: Justin Wilson
• 金额: $ 45万
• 依托单位: Cornell University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2203369&HistoricalAwards=false
• 关键词: Ruthenium; Coordination; Complexes; Tools; Studying

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.

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，以研究硫化氢气体在生物环境和人类健康中的作用。硫化氢是一种小的气体分子，有时被称为气体递质，它是由生物合成的，在调节与正常和健康的细胞功能相关的许多过程中发挥着重要作用。由于硫化氢是一种气体，它在体内向生物系统的受控输送是具有挑战性的。因此，更深入地了解这种气体信号分子是如何在生命系统中运作的是非常有意义的。该项目将开发新的化学工具，通过选择性刺激，在激活时将少量生物相关的硫化氢输送到细胞。如果成功，这些工具将使研究人员能够探索硫化氢对人类健康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)教师开展新的教育活动。这些活动将旨在强调，硫化氢等可能有毒的化合物可能存在于不会对健康造成危害的“天然”或“有机”食品中，浓度足够低。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气体传输器的迷人作用，这些作用对健康的人类生物学是如此关键。康奈尔大学的威尔逊研究小组将设计新的基于Ru的硫化氢释放分子，作为研究气体传递器硫化氢(硫化氢)的生物作用的化学工具。硫化氢调节真核细胞中广泛的关键生物学过程，并已知在心脏病、中风和癌症的管理方面产生治疗效果。然而，硫化氢的气态性质和高浓度下的毒性限制了其对生物系统的直接给药。为了克服这些挑战，研究人员开发了易于操作的化合物，这些化合物可以缓慢释放这种气体传递器，以研究其生物学功能。这些努力主要集中在有机化合物上，这些有机化合物旨在通过不受控制的水解、蓝光或紫外光照射、活性氧物种的氧化、酶活性以及与硫醇的反应来释放硫化氢。该项目的目标是通过开发基于过渡金属Ru的化合物来扩展硫化氢释放分子的工具包。通过使用Ru配位络合物，威尔逊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地激活。通过这些努力，Ru配位化合物的氧化还原化学和光化学将被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，威尔逊小组将使用这些新工具来了解硫化氢在体外对缺血再灌注损伤的保护机制。总而言之，这项研究将扩展现有硫化氢捐赠者的工具包，并将通过应用它们来确定这种气体发射器在健康人体生物学中的新角色，从而展示它们的价值。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。