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

生物无机化学的新途径：电子结构、催化和药用无机化学

• 批准号: RGPIN-2014-05240
• 负责人: Storr, Tim
• 金额: $ 3.13万
• 依托单位: Simon Fraser University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=611520
• 关键词: New; Avenues; Bioinorganic; Chemistry; Electronic

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.

这个跨学科的生物无机化学研究项目的基本主题是研究金属离子如何在设计的协调环境和体内发挥作用。这对两个不同的领域至关重要：(1)研究含有氧化还原活性配体的新型过渡金属配合物，用于C-H氧化催化；(2)设计金属结合分子，以破坏金属离子稳态并导致神经退行性疾病和癌症中的蛋白质聚集。