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计划资助的项目中，麻省理工学院化学系的Stephen J.Lippard教授探索了过渡金属介导的一氧化氮(NO)、硝基(HNO)和S-亚硝硫醇的反应，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，以及对化学、生物学、神经科学和医学的影响。理柏小组积极支持性别和种族多样性，以及在本科生、研究生和研究生各级指导和培训未被充分代表的少数民族。利帕德教授参加了为生物无机化学灌输兴奋的研讨会和讲座。金属配位化学是参与NO生物合成和信号转导的许多转化的核心。本研究对这些作用的潜在机制进行了研究，旨在揭示NO及其衍生物HNO和S-亚硫醇之间的细胞串扰。具体地说，我们追求三个方向。首先，利用NO和HNO与合成的大环和三脚架配体的金属衍生物的化学作用来指导下一代荧光探针的设计。同时，利用铜锌超氧化物歧化酶的仿生模型，研究了NO和HNO在生物学上的相互转化。其次，制作了比率式、可逆式、快速和近红外发射的NO和HNO金属基荧光传感器。这些功能分别实现了分析物定量、信号事件的动态监控、生理时间尺度上的响应率和更深层次的组织成像。第三，探索了铜(II)或锌(II)促进的转亚硝化反应，目的是获得第一个直接检测生物介质中S-亚硝硫醇的荧光传感器。

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.