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

配体设计的新前沿：从电子结构到新颖的性质和反应性，再到药用无机化学

• 批准号: RGPIN-2019-06749
• 负责人: Storr, Tim
• 金额: $ 3.5万
• 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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=716078
• 关键词: New; Frontiers; Ligand; Design; Electronic

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.

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。