POTENTIAL THERAPEUTICS FOR ALZHEIMER'S DISEASE

阿利沙星是一种有效的选择性乙酰胆碱酯酶(AChE)抑制剂，在胆碱能假说的基础上，对阿尔茨海默病的治疗具有重要意义。考虑到阿利沙星的生物学相关性和合成兴趣，本研究方案说明了1)阿利沙星的全合成方法，2)开发形式[3+3]环加成方法的详细计划，以及3)拟议的阿利沙星结合部位模型的开发。这些研究思路分为三个不同的部分。在第一部分中，基于我们最近开发的涉及α，β-不饱和亚胺的形式[3+3]环加成反应，提出了阿利沙星的全合成方法。该合成序列的特点是[3+3]环加成策略在构建五环阿利沙星核心中的应用。还描述了使用α，β-不饱和酸的缩合反应来实现相同关键五环的另一种方法。这种全合成是收敛的，应该适用于结构类似物的合成以及涉及所提出的结合位点模型的研究。在第二部分中，我们致力于发展包括α，β-不饱和亚胺和二酮基当量的形式[3+3]环加成反应。这种形式的环加成反应代表了一种合成杂环的独特方法。提出了其合成应用的三个具体领域：1)研究各种二烷基化合物和α，β-不饱和亚胺，以扩大该反应的范围；2)发展分子内的形式[3+3]环加成反应；3)探索用于天然产物合成的立体选择性形式[3+3]环加成反应。最后，在结构比较的基础上，提出了阿利沙星的结合部位模型。正在对各种三环CDE环类似物进行评估，以确定DE环的结构意义。建议合成四环和五环类似物，以进一步研究结合位点模型。这些研究应该具有重要意义，因为它们可以为天然产物的合成提供各种有用的合成方法，并对阿里沙星与AChE的结合特性进行重要的洞察，从而潜在地发现在结构上模仿阿里沙星治疗阿尔茨海默病的新型有效疗法。

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.