Development of Transfer Hydrogenation Small-Molecule Intracellular Metal Catalysts (SIMCats) and their Application Toward Toxic Aldehyde Remediation

转移氢化小分子胞内金属催化剂（SIMCats）的开发及其在有毒醛修复中的应用

• 批准号: 10570217
• 负责人: Loi Hung Do
• 金额: $ 30.6万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-02 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570217
• 关键词: Alcohols; Aldehydes; Alkenes; Antioxidants; Atherosclerosis; Behavior; Biochemical; Biological; Biological Markers; Biological Sciences; Brain; Carbamates; Carnosine; Catalysis; Cells; Chemicals; Chemistry; Clinical Treatment; Complex; Consumption; Copper; Coupling; Cytoprotection; Development; Disease; Drug Metabolic Detoxication; Electrons; Enzymes; Event; FDA approved; Glutathione; Goals; Health; Human; Hydrogenation; Hydrolysis; Imaging Techniques; Individual; Kinetics; Life; Malignant Neoplasms; Mammalian Cell; Measures; Metals; Methodology; Methods; Monitor; Nature; Neurodegenerative Disorders; Organism; Outcome; Oxidation-Reduction; Oxidative Stress; Pathologic; Phloretin; Process; Public Health; Reaction; Reactive Oxygen Species; Research; Scientist; Structure-Activity Relationship; System; Techniques; Technology; Testing; Therapeutic; Thermodynamics; Tissues; Toxic effect; Translating; Translations; Visualization; Work; Zebrafish; biological systems; biomaterial compatibility; catalyst; cell injury; chemical stability; cytotoxic; experimental study; flasks; fluorescence imaging; human disease; improved; in vivo; innovation; insight; interest; metal complex; neuroblastoma cell; novel; novel strategies; programs; ratiometric; reaction rate; remediation; single molecule; small molecule; success; superresolution microscopy; synthetic enzyme; toxicant

PROJECT SUMMARY Although small-molecule intracellular metal catalysts (SIMCats) offer potentially powerful new ways to manipulate biological systems, several scientific barriers to their development have unfortunately limited their use in life science research. The long-term goal of this project is to establish a comprehensive SIMCat discovery program that focuses on their development and translation from the reaction flask to living systems. The overall objectives of this research are to 1) identify the factors that are important to obtaining fast, selective, and biocompatible transfer hydrogenation SIMCats; and 2) create new catalytic agents for the remediation of aldehyde overload. We are interested in SIMCats that catalyze transfer hydrogenation reactions because they mimic important redox enzymes that are ubiquitous in all life forms. Our central hypothesis is that these synthetic enzyme mimics could be used to neutralize toxic aldehydes in vivo so that endogenous antioxidants, such as glutathione, are free to sequester reactive oxygen species that damage cells and tissue. The rationale for this project is that by selectively converting toxic aldehydes to non-toxic alcohols, transfer hydrogenation SIMCats could supplement Nature’s defense system against oxidative stress. SIMCats are expected to be highly efficient detoxification agents due to their ability to catalyze continuous reaction turnovers, unlike conventional aldehyde scavengers that get consumed upon each reaction. In Specific Aim 1, a variety of half-sandwich metal complexes will be tested for their activity and the most promising candidates will be subjected to structure-activity relationship and kinetic/thermodynamic studies to obtain chemical insights into their catalytic behavior. In Specific Aim 2, the catalytic rates, speciation, and distribution of SIMCats inside live cells will be determined. This aim will be accomplished by taking advantage of single-molecule super resolution microscopy and ratiometric fluorescence imaging techniques to visualize SIMCats “in action.” In Specific Aim 3, the ability of transfer hydrogenation SIMCats to protect neuroblastoma cells and zebrafish against aldehyde toxicity will be evaluated. The efficacy and aldehyde selectivity of SIMCat detoxification agents will be compared to that of conventional stoichiometric aldehyde traps. The significance of our research is the development of synthetic methodologies that are tailored toward the discovery of novel SIMCats, which considers not only chemical reactivity and substrate selectivity but also biocompatibility. The innovation of our research is the application of organometallic complexes to protect cells against chemical toxicants by exploiting their catalytic capabilities. We expect that this work will help streamline the SIMCat discovery process and lead to new approaches to remedy aldehyde overload, which could have important therapeutic relevance to the treatment of oxidative stress-related diseases in humans.

项目概要 尽管小分子细胞内金属催化剂（SIMCats）提供了潜在的强大新方法 操纵生物系统，不幸的是，其发展的一些科学障碍限制了它们 在生命科学研究中的应用。该项目的长期目标是建立一个全面的SIMCat 发现计划，重点关注它们从反应烧瓶到生命系统的开发和转化。 这项研究的总体目标是 1) 确定对于快速获得、 选择性、生物相容性转移氢化SIMCats； 2）创造新的催化剂 修复醛超载。我们对催化转移氢化反应的 SIMCats 感兴趣 因为它们模仿了所有生命形式中普遍存在的重要氧化还原酶。我们的中心假设是 这些合成酶模拟物可用于中和体内有毒醛，从而使内源性醛类 抗氧化剂，例如谷胱甘肽，可以自由地螯合损害细胞和组织的活性氧。 该项目的基本原理是通过选择性地将有毒醛转化为无毒醇，将 氢化 SIMCats 可以补充大自然对抗氧化应激的防御系统。 SIM猫是 由于其催化连续反应的能力，有望成为高效的解毒剂 与每次反应都会消耗的传统醛清除剂不同。在具体目标 1 中， 将测试各种半夹心金属配合物的活性和最有希望的候选物 将进行结构-活性关系和动力学/热力学研究以获得化学见解 进入他们的催化行为。在具体目标 2 中，SIMCats 内部的催化速率、形态和分布 将确定活细胞。这一目标将通过利用单分子超级 分辨率显微镜和比率荧光成像技术可可视化“运行中”的 SIMCats。在 具体目标3、转移氢化SIMCats保护神经母细胞瘤细胞和斑马鱼的能力 将评估针对醛毒性的效果。 SIMCat解毒功效和醛选择性 试剂将与传统化学计量醛捕获剂进行比较。我们的意义 研究是针对新发现的合成方法的开发 SIMCats，不仅考虑化学反应性和底物选择性，还考虑生物相容性。这 我们研究的创新之处在于应用有机金属配合物来保护细胞免受化学物质的侵害 通过利用其催化能力来去除有毒物质。我们期望这项工作将有助于简化 SIMCat 发现过程并导致补救醛超载的新方法，这可能具有重要意义 与治疗人类氧化应激相关疾病的治疗相关性。