New Avenues in Bioinorganic Chemistry: Electronic Structure, Catalysis, and Medicinal Inorganic Chemistry

点击翻译按钮获取中文摘要

The underlying theme of this interdisciplinary bioinorganic chemistry research program is to study how metal ions function in designed coordination environments and in vivo. This is critical to two different areas: (1) the investigation of new transition metal complexes incorporating redox-active ligands for C-H oxidation catalysis, and (2) the design of metal-binding molecules that target a breakdown in metal ion homeostasis and resulting protein aggregation in neurodegenerative diseases and cancer. First, the industrial production of many chemicals depends upon discrete metal catalysts for critical rate and selectivity enhancement, and many of the most versatile metal catalysts today employ expensive noble metals (Rh, Ir, Pd, Pt), some of the scarcest and most expensive elements. We will develop compounds containing earth-abundant transition metals and redox-active ligands that are capable of catalyzing the selective incorporation of oxidized functions into organic molecules, which is an inherently difficult challenge. Bimetallic systems have great potential to promote this chemistry, exhibiting unique reactivity that can be ascribed in part to enhanced substrate binding, stabilization of reactive intermediates, and the presence of two metal ions in close proximity. Harnessing these features to promote specific small-molecule transformations will require detailed knowledge of the geometric and electronic structure of the studied systems. By a combination of spectroscopy, calculations, and reactivity studies, we aim to develop new and efficient catalytic systems with diverse industrial applications. The second direction targets protein misfolding and aggregation, which is a common disease pathway in a number of neurodegenerative diseases and cancer. Dysregulated metal ions are hypothesized to play an important role in this process and the aim of this fundamental research program is to study specific metal-ion biomolecule interactions relevant to Alzheimer’s, Parkinson’s, Creutzfeld Jacob (Mad Cow) disease, and cancer. Aggregation and precipitation of specific biomolecules is a shared disease pathway forming amorphous aggregates, and oligomers and fibrils with a common morphology. We will design molecules capable of binding metal ions (Fe, Cu, and Zn) while also exhibiting additional anti-aggregation properties via specific interactions with biomolecules relevant to the diseases under study. The overall goal of this research is to develop a set of guiding molecular design principles for mediating protein aggregation pathways in the presence of dysregulated metal ions. This fundamental bioinorganic chemistry research program addresses significant scientific challenges in catalysis. The ability to predict and control ligand radical chemistry will provide new research opportunities and a direct link to industrial applications. The study of biomolecule misfolding will provide important information on a process common to neurodegenerative diseases and cancer. These studies will inform the development of new molecules that inhibit aggregation processes relevant to these diseases. Overall, this research provides a unique opportunity to train the next generation of Canadian researchers in an interdisciplinary environment.