Synthesis of Neurologically Active Small Molecules

项目摘要-摘要 对正常认知功能的认识与神经退行性疾病的治疗进展 是通过对天然产物及其合成同系物的研究而实现的。在这一领域取得的广泛发现 领域主要限于大量可获得的天然产品或简单衍生品的特定活动 其中之一。这一提议的长期目标是开发实验室路线，以获得作用于蛋白质的复杂分子。 与神经系统疾病有关。 这项提案概述了作用于PTP1B并缓解神经元功能障碍的柠檬苦素类化合物的方法。出发 与使用第二排和第三排金属的传统策略不同，该建议描述了第一排金属的发展 催化转化，使实验室路线能够到达含有杂环的复杂分子。这一现状-- 多步合成的ART方法将导致用于碳-碳键形成的广泛有用的化学转化， 以及高效的获取复杂小分子的途径。将使用强大的药物化学方法 对柠檬苦素类化合物进行深层次的结构修饰，这将被用来研究柠檬苦素的分子机制 行动。 通过这些路线产生的新类似物将被用于评估PTP1B的小分子抑制作用，PTP1B具有 与神经退行性变有关。通过对构效关系的研究和结合情况的考察 在分子水平上，抑制PTP1B改善神经退行性变的治疗潜力将很容易 调查过了。

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 develop laboratory routes to complex molecules that act on proteins associated with neurological disease. This proposal outlines approaches to limonoids that act on PTP1B and mitigate neuronal dysfunction. Departing from conventional strategies using second- and third-row metals, this proposal describes the development of first-row metal catalyzed transformations to empower laboratory routes to complex molecules that contain heterocycles. This state-of-the- art approach to multistep synthesis will result in broadly useful chemical transformations for carbon-carbon bond formation, and highly step-efficient routes to access complex small molecules. Powerful medicinal chemistry approaches will be used to make deep-seated structural modifications to limonoids, which will be used to interrogate molecular mechanisms of action. Novel analogs produced by these routes will be used to evaluate small molecule inhibition of PTP1B, which has been implicated in neurodegeneration. Through structure activity relationship studies and investigations into the binding mechanism on a molecular level, the therapeutic potential of PTP1B inhibition to improve neurodegeneration will be readily investigated.