POTENTIAL THERAPEUTICS FOR ALZHEIMER'S DISEASE

阿尔茨海默病的潜在治疗方法

• 批准号: 6193804
• 负责人: RICHARD P HSUNG
• 金额: $ 29.87万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6193804
• 关键词: Alzheimer's disease; acetylcholinesterase; binding sites; biological products; chemical addition; chemical models; chemical structure function; cholinesterase inhibitors; cyclization; drug design /synthesis /production; neuropharmacologic agent; pyrans

Arisugacin, a potent and selective inhibitor of acetylcholinesterase (AchE), has significant implications in the therapeutic treatment of Alzheimer's disease based on the cholinergic hypothesis. Given the biological relevance and the synthetic interest surrounding arisugacin, this research proposal illustrates 1) approaches to the total synthesis of arisugacin, 2) detailed plans for developing a formal [3+3] cycloaddition method, and 3) development of a proposed binding site model for arisugacin. These research ideas are presented in three distinct sections. In the first section, a total synthesis of arisugacin is proposed on the basis on a formal [3+3] cycloaddition reaction involving alpha,beta-unsaturated imuniums that we have developed recently. The synthetic sequence features the utility of the [3+3] cycloaddition strategy in constructing the pentacyclic core of arisugacin. An alternative approach to the same key pentacycle using condensation reactions of alpha,beta-unsaturated acids is also described. This total synthesis is convergent and should be practical for synthesis of structural analogs as well as studies involving a proposed binding-site model. In the second section, efforts are devoted to develop the formal [3+3] cycloaddition reaction involving alpha,beta-unsaturated iminiums and diketo equivalents. This formal cycloaddition reaction represents a unique approach to synthesis of heterocycles. Three specific areas of its synthetic application are proposed: 1) To examine various diketo equivalents and alpha,beta-unsaturated iminiums to widen the scope of this reaction, 2) to develop intramolecular formal [3+3] cycloaddition reactions, and 3) to explore stereoselective formal [3+3] cycloadditions for natural product synthesis. In the final section, a binding-site model for arisugacin is proposed based on structural comparison. Various tricyclic CDE- ring analogs are being evaluated to determine the structural significance of the DE-ring. Synthesis of tetracyclic and pentacyclic analogs are proposed to further examine the binding- site model. These studies should be significant because they can provide a variety of useful synthetic methodologies for natural product synthesis and important insight into the binding property of arisugacin to AChE, thereby leading to potential discovery of novel and effective therapeutics structurally modeled after arisugacin for Alzheimer's disease.

阿里苏甘星是一种有效的选择性乙酰胆碱酯酶（AchE）抑制剂，基于胆碱能假说，在阿尔茨海默病的治疗中具有重要意义。考虑到亚硫酸根酸的生物学相关性和合成兴趣，本研究计划阐述了1)亚硫酸根酸的全合成方法，2)开发正式的[3+3]环加成方法的详细计划，以及3)亚硫酸根酸的拟议结合位点模型的开发。这些研究思路分为三个不同的部分。在第一部分中，我们提出了一种基于正式的[3+3]环加成反应的全合成方法，该反应涉及我们最近开发的α， β不饱和免疫。合成的序列具有[3+3]环加成策略在构建亚柳糖酸五环核心中的实用性。还描述了使用α， β -不饱和酸的缩合反应的同一键五环的替代方法。这种全合成是收敛的，对于结构类似物的合成以及涉及提议的结合位点模型的研究应该是实用的。在第二部分中，我们致力于发展涉及α、β -不饱和最小和双酮等价物的形式[3+3]环加成反应。这种形式的环加成反应是合成杂环的一种独特方法。提出了其合成应用的三个具体领域：1)研究各种双酮等价物和α， β -不饱和最小物以扩大该反应的范围；2)开发分子内形式[3+3]环加成反应；3)探索天然产物合成的立体选择性形式[3+3]环加成。最后，通过结构比较，提出了亚柳糖酸的结合位点模型。各种三环CDE-环类似物正在被评估，以确定de -环的结构意义。提出了四环和五环类似物的合成，以进一步研究结合位点模型。这些研究具有重要意义，因为它们可以为天然产物的合成提供多种有用的合成方法，并对亚柳糖酸与乙酰胆碱的结合特性有重要的了解，从而可能发现以亚柳糖酸为结构模型的新型有效治疗阿尔茨海默病的药物。