Chemical Synthesis of Kendomycin and Garsubellin A

肯多霉素和加苏贝林 A 的化学合成

• 批准号: 7184317
• 负责人: Erik J. Sorensen
• 金额: $ 24.15万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/7184317
• 关键词: Achievement; Address; Agonist; Anabolism; Anti-Bacterial Agents; Applications Grants; Architecture; Biological; Biological Factors; Biomimetics; Calcitonin Receptor; Chemical Models; Chemical Structure; Chemicals; Chemistry; Complex; Core Assembly; Development; Disease; Endothelin Receptor Antagonist; Evolution; Exhibits; Facility Construction Funding Category; Future; Investigation; Lead; Maps; Methods; Molecular; Molecular Structure; Oxidation-Reduction; Process; Production; Property; Reaction; Research; Research Personnel; Skeleton; Structure; Therapeutic; analog; base; chemical synthesis; garsubellin A; hyperforin; innovation; insight; kendomycin; neurotransmitter biosynthesis; novel; programs; tool

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(申请人提供)：这项拨款申请解决了两种结构复杂的天然产品肯德霉素和加苏贝林A的化学合成问题。研究计划的广泛目标是开发创新策略，有效地合成具有治疗疾病潜力的分子制剂，并开发强大的化学方法，广泛用于生产生物医学研究所需的化合物。本建议的具体目标是：1)使用一种新的大糖基化方法，实现有效的全合成肯德霉素，它是一种有效的内皮素受体拮抗剂和降钙素受体激动剂，具有显著的抗菌、抗肿瘤和抗骨质疏松活性；2)基于机械退化的串联方法开发创新策略，适合快速合成肯德霉素的核心骨架；3)建立化学模型，通过使用基于新的内部氧化还原和大迈克尔加成过程的仿生级联方法进行全合成，深入了解肯德霉素的生物合成；以及4)利用多组分串联方法快速组装金丝桃素天然产物的核心结构，实现了简明的全合成Garsubellin A，这是一种诱导神经递质生物合成的有效神经营养剂。拟议的合成研究利用了多组分级联方法的优点，这种方法最有效地解决了构建复杂分子结构的问题。因此，我们寻求通过这项赠款申请开发的化学可以在许多方面得到扩展，从而在生物活性化合物的化学合成方面取得重大进展。