New Photocatalytic Coupling Reactions to Prepare Bioactive Molecules

制备生物活性分子的新光催化偶联反应

• 批准号: 10218222
• 负责人: David Martin
• 金额: $ 37.45万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10218222
• 关键词: Adamantane; Alzheimer' s Disease; Biochemistry; Biological; Chemicals; Clinical; Cobalt; Complex; Coupling; Development; Exhibits; Family; Goals; Guidelines; Investigation; Light; Lipids; Medicine; Methods; Natural Products; Nerve Degeneration; Pathway interactions; Pharmaceutical Preparations; Phenols; Process; Reaction; Reporting; Research; Research Personnel; Structure; Technology; Terpenes; Testing; Therapeutic Intervention; Virus Diseases; Vitamin B 12; alcohol availability; bioactive natural products; catalyst; design; human disease; insight; novel; novel therapeutics; pharmacophore; programs; scaffold

The overarching goal of this research program is to discover new catalytic methods for the synthesis of biologically active targets, both natural and unnatural. We have previously reported the synthesis of phenolic lipid natural products and efforts toward two families of polycyclic terpenes, as well as a general process for the synthesis of the cobalt complexes used in the photocatalytic investigations described in Project 2. The targets described in this proposal include molecules that will serve as mechanistic probes to study neurodegeneration and viral diseases, as well as leads that may provide new therapeutic opportunities. We are investigating methods to target specific structural motifs with established biological activity, such as amino-adamantanes and limonoid natural products, as well as catalytic methods designed to apply to a broad spectrum of chemical targets. The enabling technology behind these methods is photocatalysis, which harnesses light energy to drive complex catalytic processes. Photocatalysis continues to provide new mechanisms and transformations that are difficult or impossible to access otherwise. Understanding the governing principles of these processes allows us to apply that insight to the discovery of new, broadly useful synthesis methods. Substituted adamantanes appear in a wide variety of molecules with important function including clinically approved drugs for Alzheimer’s dementia and viral diseases, however efficient synthesis remains a challenge. In Project 1, new amino-adamantane derivatives will be accessed through a new aminoalkylation reaction and new catalytic strategies that enable unique selectivity that is complementary to existing approaches. The unique strategies described here include a detailed study of the selectivity of new and established H-atom transfer methods, providing guidelines necessary for selecting the proper HAT catalyst for different substrate classes. In Project 2, a novel polar/radical crossover manifold inspired by the biochemistry of vitamin B12 will be developed for the efficient use of inexpensive and readily available alcohols for bioactive molecule construction. These methods will be applied to the synthesis of promising natural product targets such as the neuroprotective limonoids. The investigation of the neuroprotective activity of limonoids is of central importance, therefore alternative pathways will be explored to access to these molecules and derivatives for mechanism of action studies. Overall, the concepts described here will provide general platforms for the rapid construction of pharmacophores and bioactive natural product derivatives that can be immediately deployed by biomedical researchers.

该研究计划的总体目标是发现新的催化方法来合成 天然和非天然的生物活性目标。我们之前报道过酚类化合物的合成 脂质天然产物和对两个多环萜烯家族的努力，以及一般工艺 项目 2 中描述的光催化研究中使用的钴络合物的合成。 该提案中描述的目标包括将作为机制探针进行研究的分子 神经退行性疾病和病毒性疾病，以及可能提供新治疗机会的线索。我们是 研究针对具有已确定生物活性的特定结构基序的方法，例如氨基金刚烷 和柠檬苦素天然产物，以及旨在应用于广泛的催化方法 化学目标的光谱。这些方法背后的支持技术是光催化， 利用光能来驱动复杂的催化过程。光催化不断提供新的 很难或不可能通过其他方式获得的机制和变革。了解 这些过程的控制原则使我们能够将这种洞察力应用于发现新的、广泛有用的 合成方法。 取代金刚烷出现在多种具有重要功能的分子中，包括 临床批准用于治疗阿尔茨海默氏痴呆和病毒性疾病的药物，但有效的合成仍然是一个难题 挑战。在项目1中，将通过新的氨烷基化获得新的氨基金刚烷衍生物 反应和新的催化策略，能够实现与现有技术互补的独特选择性 接近。这里描述的独特策略包括对新的和新的选择性的详细研究。 建立了 H 原子转移方法，为选择合适的 HAT 催化剂提供了必要的指导 不同的基材类别。在项目 2 中，一种受生物化学启发的新型极性/自由基交叉流形 将开发维生素 B12，以有效利用廉价且容易获得的生物活性醇 分子结构。这些方法将应用于有前景的天然产物靶标的合成 例如具有神经保护作用的柠檬苦素。柠檬苦素类化合物神经保护活性的研究 至关重要，因此将探索替代途径来获取这些分子和 用于作用机​​制研究的衍生物。总的来说，这里描述的概念将提供一般性的 用于快速构建药效基团和生物活性天然产物衍生物的平台 生物医学研究人员立即部署。