Chiral Approaches to Natural Product Synthesis

描述(申请人提供)：这个更新项目寻求继续和扩展一项合成、生物和计算化学计划，基于天然产品Bryostatin 1所显示的令人兴奋的生物活性。这种海洋天然产品已被证明具有抗癌活性，并已在人类身上进行了80多次临床试验。此外，Bryostatin 1还显示了对记忆、免疫系统刺激和阿尔茨海默病的效果。此外，最近对大鼠的研究表明，bryostatin 1在治疗中风方面有希望，因为在缺血事件发生后，受损神经组织的救援可以持续长达24小时。目前对Bryostatin的作用方式只有部分了解，但已知它涉及到与含有C1域的信号蛋白家族的相互作用。在已知的该蛋白激酶C超家族的配体中，bryostatin 1是唯一的对促进肿瘤的佛波酯具有功能拮抗剂。建议的研究旨在实现该制剂的治疗潜力。我们建议继续我们对bryostatin 1的结构-功能关系的研究，试图确定bryostatin 1的各种生物活性的结构特征。我们还建议以克为单位制备该试剂，为进一步的研究提供更多的材料。我们计划继续研究bryostatin 1类似物的生物学，既希望识别具有独特生物活性模式的选择性新药物，也希望利用这些药物作为工具来研究信号机制的潜在生物学。在之前的授权期内，我们已经在这些领域中的每一个领域建立了概念验证。将准备新的Bryostatin 1类似物来研究关于作用机制和构效关系的各种假说，并详细评估它们在各种类型的活细胞中的作用。将进行详细的生物学调查，以确定在各种系统中观察到的生物终点的基本机制。计算方法将被用来帮助解释观察到的构造效应，并为构造勘探提出有前景的新途径。将继续与Bryostatin和PKC信号转导生物学领域的领先专家进行合作，并对这些系统进行计算研究。 与公共卫生相关：该项目寻求实现一种非常有希望的物质--Bryostatin 1的潜力，该物质最初是从海洋(海洋)来源分离出来的。这种材料对包括癌症、阿尔茨海默病和中风在内的各种疾病都显示出了令人着迷的活性，并已在人体上进行了临床试验。我们的双重方法是开发这种试剂的实验室合成(没有来自自然来源的供应)，以及使用这种化合物作为先导结构。因此，我们正在开发类似于Bryostatin的其他结构，并研究它们的生物学。他们希望找到新的、更容易准备好的结构用于治疗，并将这些结构用作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.