Metal Coordination Compounds as Reporters for Biological NO, HNO, and S-Nitrosothiols

在这个由化学系化学结构、动力学和机制B项目资助的项目中，马萨诸塞州理工学院化学系的Stephen J. Lippard教授探索了过渡金属介导的一氧化氮（NO）、硝酰基（HNO）和S-亚硝基硫醇（S-亚硝基硫醇）的反应，这三种不同但化学上相关的生物信号剂。 该项目阐明了NO和HNO的生理和病理作用，对化学，生物学，神经科学和医学产生了影响。利帕德集团积极支持性别和种族多样性，以及在本科，研究生和研究生水平的科学指导和培训代表性不足的少数民族。Lippard教授参加了为生物无机化学注入兴奋的研讨会和讲座。金属配位化学是NO的生物合成和信号转导中所涉及的许多转化的核心。该研究调查并利用这些行动的潜在机制，以解开NO及其衍生物HNO和S-亚硝基硫醇之间的细胞串扰。具体而言，有三个方向。首先，利用NO和HNO与大环和三足配体的合成金属衍生物的化学来通知下一代荧光探针的设计。同时，以铜锌超氧化物歧化酶为仿生模型，研究了NO和HNO在生物学中的相互转化。第二，基于金属的NO和HNO的荧光传感器被制成比率、可逆、快速和近红外发射。这些功能分别实现了分析物定量、信号事件的动态监测、生理时间尺度上的响应率和更深的组织成像。第三，探索Cu（II）或Zn（II）促进的转亚硝化反应，目的是获得第一个荧光传感器，用于直接检测生物介质中的S-亚硝基硫醇。

In this project funded by the Chemical Structure, Dynamics and Mechanisms B Program of the Chemistry Division, Professor Stephen J. Lippard of the Department of Chemistry at Massachusetts Institute of Technology explores transition metal-mediated reactions of nitric oxide (NO), nitroxyl (HNO), and S-nitrosothiols, three distinct but chemically related biological signaling agents. The project elucidates physiological and pathological actions of NO and HNO, with impacts on chemistry, biology, neuroscience, and medicine. The Lippard group actively supports gender and ethnic diversity, as well as the mentoring and training of underrepresented minorities in science at undergraduate, graduate, and postgraduate levels. Professor Lippard participates in workshops and lectures that instill excitement for bioinorganic chemistry.Metal coordination chemistry is central to many of the transformations involved in the biological synthesis and signal transduction of NO. The research investigates and exploits the underlying mechanisms of these actions in order to unravel the cellular crosstalk between NO and its derivatives HNO and S-nitrosothiols. Specifically, three directions are pursued. First, the chemistry of NO and HNO with synthetic metal derivatives of macrocyclic and tripodal ligands are utilized to inform the design of next generation fluorescent probes. At the same time, the putative interconversion of NO and HNO in biology is investigated with biomimetic models of copper-zinc (Cu-Zn) superoxide dismutase. Second, metal-based fluorescent sensors for NO and HNO are made ratiometric, reversible, rapid, and near-IR-emitting. These features enable analyte quantitation, dynamic monitoring of signaling events, response rates on the physiological time scale, and deeper tissue imaging, respectively. Third, Cu(II)- or Zn(II)-promoted transnitrosation reactions are explored with the aim of obtaining the first fluorescent sensor for direct detection of S-nitrosothiols in biological media.