Synthesis of Neurologically Active Small Molecules

项目总结/摘要 对正常认知功能的理解和治疗的发展 通过研究天然产物及其合成同类物，使神经变性疾病成为可能。 在这一领域的广泛发现主要限于丰富的特定活动， 可获得的天然产物或其简单衍生物。该提案的长期目标是利用 合成多种立体化学丰富的多环天然产物的片段偶联方法 具有进一步理解神经退行性疾病的潜力的架构。 该建议概述了两种收敛的方法，用于合成两个自然家族， 产品，grayanotoxins和柠檬苦素，这两者都已被证明可以减弱神经细胞 由活性氧引起的死亡通过偏离传统的策略， 前体，该提案利用构建块的聚合和可扩展组装， 差异化支架。与常规方法一致，通过以下方法获得的分子结构： 这种方法随后将通过应用脱氢方法进行修改 我们的实验室以及其他化学策略最近报道的。 通过这些途径产生的新类似物将评估其减轻以下影响的能力： 活性氧对神经退行性变的影响通过增加对神经变性的了解， 分子水平，药物发现和治疗干预的潜在途径将被揭示。

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.