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

这个跨学科生物无机化学研究项目的基本主题是研究金属离子在设计的配位环境和体内如何发挥作用。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络合物，用于C-H氧化催化；(2)设计金属结合分子，目标是破坏金属离子的动态平衡，并导致神经退行性疾病和癌症中的蛋白质聚集。 首先，许多化学品的工业生产依赖于离散金属催化剂来提高临界速率和选择性，而当今许多用途最广的金属催化剂使用昂贵的贵金属(Rh、Ir、Pd、Pt)，这些都是最稀缺和最昂贵的元素。我们将开发含有丰富的过渡金属和氧化还原活性配体的化合物，这些化合物能够催化氧化功能选择性地结合到有机分子中，这是一个固有的困难挑战。双金属体系有很大的潜力来促进这种化学，表现出独特的反应活性，这可以部分归因于增强的底物结合，活性中间体的稳定，以及两个金属离子的紧密结合。利用这些特征来促进特定的小分子转化将需要对所研究系统的几何和电子结构的详细了解。通过结合光谱、计算和反应性研究，我们的目标是开发具有不同工业应用的新的高效催化系统。 第二个方向是针对蛋白质错误折叠和聚集，这是许多神经退行性疾病和癌症的常见疾病途径。失调的金属离子被假设在这一过程中发挥重要作用，这一基础研究计划的目的是研究与阿尔茨海默氏症、帕金森氏症、疯牛病和癌症相关的特定金属-离子生物分子相互作用。特定生物分子的聚集和沉淀是一种共同的疾病途径，形成无定形聚集体、低聚物和具有共同形态的纤维。我们将设计能够结合金属离子(铁、铜和锌)的分子，同时通过与与所研究疾病相关的生物分子的特定相互作用表现出额外的抗聚集特性。这项研究的总体目标是开发一套指导性的分子设计原则，用于在存在失调的金属离子存在的情况下调节蛋白质聚集途径。 这一基础生物无机化学研究计划解决了催化领域的重大科学挑战。预测和控制配体自由基化学的能力将提供新的研究机会，并与工业应用直接联系。生物分子错误折叠的研究将为神经退行性疾病和癌症的共同过程提供重要信息。这些研究将为抑制与这些疾病相关的聚集过程的新分子的开发提供信息。总体而言，这项研究为在跨学科环境中培训下一代加拿大研究人员提供了一个独特的机会。

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.