Rhodium and copper: chemical approaches to biological problems
Martin, Samuel Cody
Ball, Zachary T
Doctor of Philosophy
Often, the development of a tool in one field of study allows researchers in another field to address questions and solve problems previously inaccessible. Chemical biology as a field seeks to develop and use chemical tools in the study of biological processes. This body of work was intended to develop chemical tools (synthetic procedures, chemical or organometallic probes, protein-binding design strategy, bioorthogonal protein modification reactions) which might one day achieve use toward the study of biological systems. The first two chapters review the history and previous developments within the chemical biology space. The first chapter discusses techniques for the metalation of peptides and proteins with transition metals. The second chapter reviews the role of rhodium metal in biological catalysis, specifically in the alteration of nucleic acids and polypeptides. Research toward advancing scientific knowledge in this broad field is discussed in chapters 3–5. Novel hybrid organic–inorganic protein ligands, consisting of a dirhodium-metallated aminoquinoline, are designed, prepared, and shown to confer potency and selectivity in a challenging class of kinases in chapter 3. In chapter 4, selective dirhodium–diazo peptide modification is developed as a tool to enable more comprehensive analysis of protein-based systems, including purification, on-gel analysis, and exogenous ligand binding affinity determination. Finally, in chapter 5, a copper-catalyzed peptide cross-coupling reaction is applied for use in caging and photoreleasing a full-length natural protein.
rhodium; copper; protein modification; protein–protein interaction; metalation