Chiral Approaches to Natural Product Synthesis

描述（由申请人提供）：该更新项目旨在继续和扩展基于天然产物苔藓抑素1所显示的令人兴奋的生物活性概况的合成，生物学和计算化学计划。这种海洋天然产物已被证明具有抗癌活性，并已在80多个临床试验中的人。此外，苔藓抑素1已被证明对记忆，对免疫系统的刺激，和对阿尔茨海默氏病的影响。此外，最近在大鼠中的研究表明，苔藓抑素1在中风的治疗中提供了希望，因为在缺血事件后长达24小时内可以实现受损神经组织的拯救。苔藓抑素的作用模式仅部分了解，但已知涉及与含有C1结构域的信号蛋白家族的相互作用。在该蛋白激酶C超家族的已知配体中，苔藓抑素1是独特的，是促肿瘤佛波醇酯的功能性拮抗剂。提出的研究旨在实现该药物的治疗潜力。我们建议继续研究苔藓抑素1的结构-功能关系，试图定义苔藓抑素1已经建立的各种生物活性的结构特征。我们还建议将该制剂制备成克级规模，为进一步的研究提供更多的材料。我们计划继续研究苔藓抑制素1类似物的生物学，一方面希望找到具有独特生物活性模式的选择性新药物，另一方面也希望使用这些药物作为工具来研究信号传导机制的基础生物学。在上一个赠款期间，我们已经在这些领域中的每一个领域建立了概念证明。苔藓抑素1的新类似物将被制备以研究关于作用机制和结构活性关系的各种假设，并详细评估其在各种类型的活细胞中的作用。将进行详细的生物学研究，以确定在各种系统中观察到的生物学终点的潜在机制。计算方法将被用来帮助解释所观察到的结构效应，并提出有前途的新途径的结构勘探。正在进行的合作与领先的专家在苔藓抑素和蛋白激酶C信号的生物学，并在这些相同的系统的计算调查将继续进行。 公共卫生相关性：该项目旨在实现一种非常有前途的物质苔藓抑素1的潜力，苔藓抑素1最初是从海洋来源中分离出来的。这种物质对多种疾病（包括癌症、阿尔茨海默病和中风）显示出迷人的活性，并已在人体进行临床试验。我们的双重方法是开发这种药物的实验室合成（没有天然来源的供应）以及使用这种化合物作为先导结构。因此，我们正在开发与苔藓抑素类似的其他结构，并研究它们的生物学。希望是确定新的和更容易制备的结构用于治疗，并使用这些结构作为研究潜在疾病的生物工具。

DESCRIPTION (provided by applicant): This renewal project seeks to continue and expand a program of synthesis, biology, and computational chemistry based on the exciting profile of biological activity displayed by the natural product bryostatin 1. This marine natural product has been shown to have anticancer activity, and has been in over 80 clinical trials in man. In addition, bryostatin 1 has demonstrated effects on memory, on stimulation of the immune system, and on Alzheimer's disease. Moreover, recent studies in rats have shown that bryostatin 1 offers promise in the treatment of stroke, in that rescue of damaged neural tissue can be effected for up to 24 hours following the ischemic event. The mode of action of bryostatin is only partially understood, but it is known to involve interaction with a family of signaling proteins containing C1 domains. Amongst the known ligands for this Protein Kinase C superfamily, bryostatin 1 is unique in being a functional antagonist to the tumor-promoting phorbol esters. The studies proposed are aimed at realizing the therapeutic potential of this agent. We propose to continue our studies of structure-function relationships in bryostatin 1, in an attempt to define the structural features responsible for the various biological activities already established for bryostatin 1. We also propose to prepare this agent on gram scale, to provide more material for further studies. We plan to continue to investigate the biology of analogues of bryostatin 1, both in the hope of identifying selective new agents with unique patterns of biological activity, and also in terms of using these agents as tools to study the underlying biology of the signaling mechanisms. We have already established, during the preceding grant period, proof of concept in each of these areas. New analogues of bryostatin 1 will be prepared to investigate various hypotheses regarding mechanisms of action and structure activity relationships, and evaluated in detail for their effects in living cells of various types. Detailed biological investigations will be pursued to establish the underlying mechanisms for the biological endpoints observed in the various systems. Computational methods will be employed both to help interpret the structural effects observed and to suggest promising new avenues for structural exploration. Ongoing collaborations with leading experts in the biology of bryostatin and PKC signaling, and in computational investigations of these same systems will be continued. PUBLIC HEALTH RELEVANCE: This project seeks to realize the potential of a very promising substance, bryostatin 1, which was originally isolated from a marine (ocean) source. This material has shown fascinating activity against a variety of diseases including cancer, Alzheimers' disease, and stroke, and has been in clinical trials in man. Our dual approach is to develop a laboratory synthesis of this agent (there is no supply from natural sources) as well as to use this compound as a lead structure. Thus we are developing other structures, similar to that of bryostatin, and studying their biology. The hopes are to identify new and more easily prepared structures for use in therapy, and also to use these structures as biological tools for study of the underlying disease.