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虫素所显示的令人兴奋的生物活性的合成，生物学和计算化学计划。这种海洋天然产品已被证明具有抗癌活性，并已在人体进行了80多次临床试验。此外，苔藓抑素1已被证明对记忆、刺激免疫系统和阿尔茨海默病有影响。此外，最近对大鼠的研究表明，苔藓抑素1在中风治疗中提供了希望，因为在缺血事件发生后长达24小时内，受损的神经组织可以得到拯救。苔藓抑素的作用方式仅部分被了解，但已知它与含有C1结构域的信号蛋白家族相互作用。在已知的蛋白激酶C超家族的配体中，苔藓抑素1是一种独特的肿瘤促进磷酯的功能性拮抗剂。所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，试图确定苔藓抑素1已经建立的各种生物活性的结构特征。我们还建议以克为单位制备该制剂，为进一步研究提供更多的材料。我们计划继续研究苔藓抑素1类似物的生物学，既希望找到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研究信号传导机制的潜在生物学工具。在前一个赠款期间，我们已经在每一个领域建立了概念证明。将制备苔藓抑素1的新类似物，研究其作用机制和构效关系的各种假设，并详细评估其在各种类型活细胞中的作用。将进行详细的生物学调查，以建立在各种系统中观察到的生物学终点的潜在机制。计算方法将用于帮助解释所观察到的结构效应，并为结构勘探提出有希望的新途径。将继续与苔藓虫素和PKC信号传导生物学方面的领先专家进行合作，并对这些相同系统进行计算研究。

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.