New Frontiers in Ligand Design: From Electronic Structure to Novel Properties and Reactivity, to Medicinal Inorganic Chemistry

本提案的重点是利用对小分子活化，材料应用和药物无机化学的电子结构和金属配位化学的基本理解。本研究以基础配位化学为基础，为应用研究提供了途径。(1)含有氧化还原活性配体的配合物和材料的性质和反应性：我们计划利用含有氧化还原活性配体的金属配合物来设计用于小分子活化的系统，并将其纳入传感应用的材料中。为了实现这些目标，我们将利用我们在过渡金属配合物的实验和理论表征方面的丰富经验，包括氧化还原活性配体，以控制底物激活过程中的电子结构，从而控制整体反应性模式。例如，我们计划研究由外部刺激（光，应用电位）激活的配体自由基复合物，用于反应性应用，如C-N键形成化学。利用我们对强配体自由基近红外（NIR）跃迁的光谱理解，以及发色团间距离和相对几何形状对光物理性质的影响，我们将设计吸收可调近红外能量的多发色团系统。将配体自由基配合物结合到可溶性自组装配合笼和金属有机框架（mof）中，将为在近红外能量范围内研究新的光学和电子应用提供创新机会。(2)靶向疾病中的蛋白质聚集：生物分子错误折叠和蛋白质聚集是常见的疾病机制，我们计划开发靶向关键生物分子的新化合物，同时表现出额外的治疗效果。与单功能分子相比，多功能分子具有显著的优势，例如通过作用于多个靶标而产生的加性或协同效应。在一个研究方向上，我们计划开发与阿尔茨海默病（AD）中淀粉样蛋白-肽选择性相互作用的金属配合物。通过增强疏水肽-复合物的相互作用，以及开发在光激活或氧化下形成稳定的共价肽键的化合物，我们的目标是发现有希望的靶向疾病标志的新化合物。我们还计划研究癌症中的多功能概念，特别是针对调节抗增殖细胞反应的p53蛋白。在超过50%的癌症诊断中，p53聚集在一起，由于突变而不能发挥其基本功能，我们计划开发作为金属伴侣的化合物，以重新整合结构Zn，同时表现出额外的p53-配体相互作用，以维持关键功能。总的来说，我们在这一领域的基础研究可以为加拿大人带来重大利益的新药物。

The focus of this proposal is to exploit a fundamental understanding of electronic structure and metal coordination chemistry for small-molecule activation, materials applications, and medicinal inorganic chemistry. The foundation of this proposal is basic coordination chemistry, providing avenues for application-oriented research. (1) Properties and Reactivity of Complexes and Materials Incorporating Redox-Active Ligands: We plan to utilize metal complexes incorporating redox-active ligands to design systems for small-molecule activation, and incorporation into materials for sensing applications. To achieve these goals we will use our extensive experience in the experimental and theoretical characterization of transition metal complexes incorporating redox-active ligands to control electronic structure during substrate activation, and thus overall reactivity patterns. For example, we plan to investigate ligand radical complexes activated by external stimulus (light, applied potential) for reactivity applications such as C-N bond forming chemistry. Using our spectroscopic understanding of intense ligand radical near-infrared (NIR) transitions, and the influence of inter-chromophore distance and relative geometry on photophysical properties, we will design multi-chromophore systems that absorb at tunable NIR energies. Incorporation of ligand radical complexes into soluble self-assembled coordination cages and metal-organic frameworks (MOFs) will provide an innovative opportunity to investigate novel optical and electronic applications in the NIR energy range. (2) Targeting Protein Aggregation in Disease: Biomolecule misfolding and protein aggregation are common disease mechanisms, and we plan to develop novel compounds that target critical biomolecules while exhibiting additional therapeutic effects. Multifunctional molecules offer significant advantages over their monofunctional counterparts, such as additive or synergistic effects via acting on multiple targets. In one research direction, we plan to develop metal complexes that show selective interactions with the amyloid-beta peptide in Alzheimer's disease (AD). By enhancing hydrophobic peptide - complex interactions, and developing compounds that form stable covalent peptide linkages upon either light activation or oxidation, we aim to discover promising new compounds targeting a hallmark of the disease. We also plan to investigate the multifunctional concept in cancer, specifically targeting the p53 protein which regulates antiproliferative cellular responses. In over 50% of cancer diagnoses p53 aggregates and does not carry out its essential function due to mutation(s), and we plan to develop compounds that act as metallochaperones to reincorporate a structural Zn while exhibiting additional p53-ligand interactions to maintain critical function. Overall, our fundamental research in this area could lead to new medicinal agents of significant benefit to Canadians.