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

这个跨学科的生物无机化学研究计划的基本主题是研究金属离子如何在设计的配位环境和体内发挥作用。这对于两个不同的领域是至关重要的：（1）研究新的过渡金属络合物，其并入用于C-H氧化催化的氧化还原活性配体，以及（2）设计金属结合分子，其靶向金属离子稳态的破坏和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的金属催化剂来提高临界速率和选择性，并且当今许多最通用的金属催化剂使用昂贵的贵金属（Rh、Ir、Pd、Pt），其中一些是最稀缺和最昂贵的元素。我们将开发含有地球上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。双金属系统具有很大的潜力，以促进这种化学，表现出独特的反应性，可以部分归因于增强的底物结合，稳定的反应性中间体，和存在的两个金属离子在紧密接近。利用这些功能，以促进特定的小分子转换将需要详细的知识的几何和电子结构的研究系统。通过光谱学、计算和反应性研究的结合，我们的目标是开发具有多种工业应用的新型高效催化系统。 第二个方向靶向蛋白质错误折叠和聚集，这是许多神经退行性疾病和癌症中的常见疾病途径。假设失调的金属离子在这一过程中发挥重要作用，这个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，Creutzfeld Jacob（疯牛病）疾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形成无定形聚集体以及具有共同形态的寡聚体和原纤维的共有疾病途径。我们将设计能够结合金属离子（Fe，Cu和Zn）的分子，同时还通过与所研究疾病相关的生物分子的特异性相互作用表现出额外的抗聚集特性。本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的情况下介导蛋白质聚集途径。 这个基础生物无机化学研究计划解决了催化方面的重大科学挑战。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。对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。这些研究将为开发抑制与这些疾病相关的聚集过程的新分子提供信息。总的来说，这项研究提供了一个独特的机会，在跨学科的环境中培养下一代加拿大研究人员。

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.