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

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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.