Synthesis of Macfarlandin E and Investigation of Localized Golgi Vesiculation

Macfarlandin E 的合成及局部高尔基体囊泡的研究

• 批准号: 7221109
• 负责人: CHRISTOPHER M BEAUDRY
• 金额: $ 4.75万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7221109
• 关键词: Synthesis; Macfarlandin; Investigation; Localized; Golgi

DESCRIPTION (provided by applicant): Fragmentation of the Golgi into small vesicles is a requirement for cellular division. It has been observed that treatment with a structurally interesting marine natural product, macfarlandin E, causes irreversible fragmentation of the Golgi, without causing delocalization of the resulting fragments. The first goal of this research is a chemical synthesis of macfarlandin E, which in itself would be an important contribution to an unusual class of marine spongian metabolites. The key transformations of the proposed chemistry are a conjugate addition to set two adjacent stereocenters (one being quaternary) and a intramolecular trapping of a oxocarbenium ion to build a unique 2,7-dioxabicyclo[3.2.1]octan-3-one scaffold found in several spongian natural products. Additionally, the synthesis allows for preparation of analogs containing biotin affinity tags and coumarin moieties for investigation and isolation of the Golgi proteins responsible for vesiculation and localization. The second goal of the research is to identify the biological target of macfarlandin E and determine its role in the regulation of vesiculation and localization of the Golgi. Understanding the components responsible for Golgi behavior would not only be an important contribution to Golgi biology, but it is the first step toward a more complete understanding of the cellular processes leading up to mitosis. The proposed research involves the chemical synthesis of a marine natural product, macfarlandin E, and its analogs. Preliminary work indicates macfarlandin E causes an unusual and interesting fragmentation of the Golgi aparatus in mammalian cells without delocalization of the fragments. These compounds will be used as chemical agents for the investigation of the nature of Golgi fragmentation.

描述（由申请方提供）：高尔基体破碎成小泡是细胞分裂的必要条件。已经观察到，用结构上令人感兴趣的海洋天然产物macfarcene处理，会导致高尔基体的不可逆片段化，而不会导致所得片段的离域。这项研究的第一个目标是化学合成macfarcane，这本身将是一个重要的贡献，一类不寻常的海洋海绵代谢物。所提出的化学的关键转化是共轭加成以设置两个相邻的立构中心（一个是季中心）和氧代碳正离子的分子内捕获以构建在几种海绵天然产物中发现的独特的2，7-二氧杂双环[3.2.1]辛烷-3-酮支架。此外，合成允许制备含有生物素亲和标签和香豆素部分的类似物，用于研究和分离负责囊泡形成和定位的高尔基体蛋白。本研究的第二个目标是鉴定macfarlane E的生物学靶点，并确定其在高尔基体囊泡形成和定位调节中的作用。了解负责高尔基体行为的组件不仅是对高尔基体生物学的重要贡献，而且是更完整地了解导致有丝分裂的细胞过程的第一步。拟议的研究涉及海洋天然产物macfarcaseE及其类似物的化学合成。初步工作表明，macfarcene导致一个不寻常的和有趣的片段高尔基体在哺乳动物细胞中没有离域的片段。这些化合物将被用作研究高尔基体断裂性质的化学试剂。