Synthesis and Mechanistic Studies on the Reactions of Photoactive Nitrosyl Hydride (HNO) Precursors with Biological Reductants

光活性亚硝酰氢化物（HNO）前体与生物还原剂反应的合成及机理研究

• 批准号: 1306644
• 负责人: Paul Sampson
• 金额: $ 40万
• 依托单位: Kent State University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1306644&HistoricalAwards=false
• 关键词: Synthesis; Mechanistic; Studies; Reactions; Photoactive

With this award the Chemistry of Life Processes Program is funding Dr. Nicola Brasch and Dr. Paul Sampson from Kent State University to synthesize and study the reactivity of two new classes of HNO donors with the goal of rapidly generating HNO via photocleavage of an O-protecting group followed by facile HNO elimination. There is an urgent need for HNO donors which rapidly generate HNO, given that HNO reacts rapidly with biomolecules in addition to reacting rapidly with itself. Although it is well established that HNO reduces biomolecules, the redox potential of the HNO,2H+/NH2OH couple suggests that HNO could also be a versatile oxidant. The plan is to utilize laser flash photolysis for HNO release from these precursors to study the kinetics and mechanism of reactions between HNO and three important classes of biological reductants. This proposal brings together an interdisciplinary team of researchers with expertise in kinetics and mechanism, organic synthesis, and laser flash photolysis. HNO (nitrosyl hydride) is attracting increasing attention as a species potentially formed in biological systems, and also shows potential in treating cardiovascular disease. However, understanding the chemical and biological properties of HNO is hampered by the fact that HNO itself is not stable, requiring the development of compounds that decompose to release HNO; HNO donor molecules. In this research novel HNO donor molecules are being targeted, with the goal of achieving the rapid release of HNO upon exposure to laser light. If successful, this research will provide masked HNO-precursors as tools for the Chemical Biology and Medicinal Chemistry communities. The research will provide multi-disciplinary training to undergraduate and graduate students as part of this multi-faceted research team. A new seminar course for junior undergraduate Chemistry majors will also be developed in which students will learn to critically evaluate scientific literature and give effective oral presentations.

通过这一奖项，生命过程化学计划资助肯特州立大学的Nicola Brasch博士和Paul Sampson博士合成和研究两类新的HNO捐赠者的反应性，目标是通过光裂解O-保护基团，然后简单地消除HNO来快速生成HNO。鉴于HNO除了与自身快速反应外，还能与生物分子快速反应，因此迫切需要能够快速产生HNO的HNO供体。虽然HNO可以减少生物分子，但HNO，2H+/NH_2OH对的氧化还原电位表明，HNO也可能是一种多功能的氧化剂。计划利用激光闪光光解从这些前驱体中释放HNO，以研究HNO与三类重要的生物还原剂的反应动力学和机理。这项提议汇集了一个跨学科的研究团队，他们在动力学和机理、有机合成和激光闪光光解方面具有专业知识。亚硝基氢化物作为一种在生物系统中潜在形成的物种正受到越来越多的关注，并在治疗心血管疾病方面显示出潜在的潜力。然而，HNO本身并不稳定，需要开发分解释放HNO供体分子的化合物，这一事实阻碍了人们对HNO的化学和生物学特性的了解。在这项研究中，以新型HNO供体分子为目标，目标是实现HNO在激光照射下的快速释放。如果成功，这项研究将为化学生物学和药物化学界提供掩蔽的HNO前体作为工具。这项研究将为本科生和研究生提供多学科培训，作为这个多方面研究团队的一部分。还将为化学专业的三年级本科生开发一门新的研讨会课程，在该课程中，学生将学习批判性地评估科学文献并进行有效的口头陈述。