Synthesis of Neurologically Active Small Molecules

神经活性小分子的合成

• 批准号: 9929899
• 负责人: Timothy Newhouse
• 金额: $ 9.99万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9929899
• 关键词: Alzheimer' s Disease; Architecture; Area; Attenuated; Biological; Caspase; Cause of Death; Cell Death; Chemicals; Combinatorial Synthesis; Common Core; Complex; Core Assembly; Coupling; Development; Disease model; Economics; Elderly; Elements; Etiology; Evaluation; Family; Furans; Glutamates; Goals; Laboratories; Libraries; Long-Term Potentiation; Malignant Neoplasms; Mediating; Memory; Methodology; Methods; Modification; Molecular; Natural Products; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Parkinson Disease; Pathway interactions; Pharmacology; Phosphotransferases; Process; Production; Property; Proteins; Reactive Oxygen Species; Reporting; Research; Role; Route; Structure; Structure-Activity Relationship; Testing; Therapeutic; Therapeutic Intervention; Tropomyosin; United States; aging population; analog; base; care costs; cognitive function; dehydrogenation; disability; drug discovery; flexibility; improved; inhibitor/antagonist; member; mouse model; nervous system disorder; neuron loss; novel; oxidation; prevent; protein kinase R; receptor; rhodotoxin; scaffold; small molecule; social; therapy development

Project Summary/Abstract The understanding of normal cognitive function and the development of treatments for neurodegenerative diseases have been enabled by the study of natural products and their synthetic congeners. The extensive discoveries made in this realm have been limited primarily to the specific activities of abundantly available natural products or simple derivatives thereof. The long-term goal of this proposal is to use fragment-coupling approaches to synthesize varied, stereochemically rich, polycyclic natural product architectures with the potential to further the understanding of neurodegenerative disorders. This proposal outlines two convergent approaches for the synthesis of two families of natural products, the grayanotoxins and the limonoids, both of which have been shown to attenuate neuronal cell death caused by reactive oxygen species. By departing from conventional strategies that cyclize linear precursors, this proposal utilizes the convergent and scalable assembly of building blocks into structurally differentiated scaffolds. In line with conventional approaches, the molecular architectures obtained through this approach will be subsequently modified through the application of a dehydrogenation methodology recently reported by our laboratory, as well as by other chemical strategies. Novel analogs produced by these routes will be evaluated for their ability to alleviate the effects of reactive oxygen species on neurodegeneration. Through increased understanding of neurodegeneration on a molecular level, potential avenues for drug discovery and therapeutic intervention will be revealed.

项目摘要/摘要 对正常认知功能的认识及治疗进展 通过对天然产物及其合成同系物的研究，神经退行性疾病成为可能。 在这一领域取得的广泛发现主要局限于丰盛的特定活动 可获得的天然产品或其简单的衍生产品。这项提议的长期目标是使用 片段偶联方法合成多种立体化学丰富的多环天然产物 有可能进一步了解神经退行性疾病的体系结构。 这一建议概述了合成两个天然化合物家族的两种收敛方法。 灰霉毒素和柠檬苦素，这两种物质都被证明可以削弱神经细胞。 由活性氧类引起的死亡。通过背离传统的线性循环策略 作为先驱，该提议利用构建块的聚合和可扩展组装在结构上 差异化的支架。与常规方法一致，通过 随后将通过应用脱氢方法对这一方法进行修改 最近由我们实验室以及其他化学策略报告的。 通过这些路线产生的新的类似物将被评估它们是否能够缓解 活性氧对神经退行性变的影响。通过增加对神经退行性变的了解 分子水平，潜在的药物发现和治疗干预的途径将被揭示。