Chemical Synthesis of Kendomycin and Garsubellin A

肯多霉素和加苏贝林 A 的化学合成

基本信息

批准号：
7360288
负责人：
Erik J. Sorensen
金额：
$ 25.92万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-05 至 2010-01-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): This grant application addresses the chemical synthesis problems of two architecturally complex natural products, kendomycin and garsubellin A. The broad objectives of the research program are to develop innovative strategies for the efficient synthesis of molecular agents possessing therapeutic potential for the treatment of diseases and to develop powerful chemical methods of broad utility in the production of the compounds required in biomedical investigations. The specific aims of the present proposal are: 1) the achievement of an efficient total synthesis of kendomycin, a potent endothelin receptor antagonist and calcitonin receptor agonist that exhibits pronounced antibacterial, antitumor, and anti-osteoporotic activities, using a novel macroglycosylation approach; 2) the development of innovative strategies based on a mechanistically degenerative tandem approach that are appropriate for the expeditious synthesis of the core skeleton of kendomycin; 3) the establishment of a chemical model to gain insights into the biosynthesis of kendomycin through a total synthesis using a biomimetic cascade approach based on novel internal redox and macro-Michael addition processes; and 4) the achievement of a concise total synthesis of garsubellin A, a potent neurotrophic agent that induces the biosynthesis of neurotransmitters, using a multicomponent tandem approach that allows for rapid assembly of the core structure of hyperforin natural products. The proposed synthetic investigations take advavantage of multicomponent cascade approaches which most efficiently address the problem of constructing complex molecular structures. Thus, the chemistry we seek to develop through this grant application can be extended in many ways to bring significant advances in the chemical synthesis of bioactive compounds.

描述（由申请人提供）：该赠款申请解决了两种建筑复杂的天然产品，Kendomycin和Garsubellin A的化学合成问题A。研究计划的广泛目标是为有效地综合具有疾病治疗的治疗潜力的分子剂制定创新的策略，从而开发了较广泛的矿体化学方法，这些化学方法是在范围内进行了强大的化学方法。本提案的具体目的是：1）实现Kendomycin的有效总合成，Kendomycin是一种有效的内皮蛋白受体拮抗剂和降石蛋白受体激动剂，使用一种新型的型乳糖糖基化方法，表现出明显的抗菌，抗肿瘤，抗肿瘤和抗心pro的抗恐惧症； 2）基于机械性退化串联方法的创新策略的发展，该方法适合于迅速合成肯多霉素的核心骨架； 3）建立了一种化学模型，以使用基于新型的内部逆转录物和宏观 - 迈克尔添加过程的仿生级联反应方法，通过总合成来深入了解Kendomycin的生物合成； 4）使用多组分串联方法诱导神经递质的有效神经营养剂Garsubellin A的简洁总合成，该神经营养剂诱导神经递质的生物合成，从而可以快速组装Hyperforin天然产物的核心结构。拟议的合成研究采用了多组分级联方法的先验，最有效地解决了构建复杂分子结构的问题。因此，我们寻求通过此赠款应用开发的化学反应可以通过多种方式扩展，以在生物活性化合物的化学合成中带来重大进展。