Synthesis of Macfarlandin E and Investigation of Localized Golgi Vesiculation

已送达。 高尔基体分裂成小泡是细胞分裂的必要条件。已经观察到 ：用一种结构上有趣的海洋天然产品麦克法鲁E治疗， 高尔基体的破碎，而不引起所得片段的离域。第一个目标是 研究是一种化学合成的macfarlene，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。提出的化学的关键转变是 共轭加成以设置两个相邻的立构中心（一个是四元的）和分子内捕获 一种氧碳正离子，用于构建在几种海绵中发现的独特的2，7-二氧杂双环[3.2.1]辛烷-3-酮支架 天然产品。此外，该合成允许制备含有生物素亲和标签的类似物 和香豆素部分，用于研究和分离负责囊泡形成的高尔基体蛋白， 本地化研究的第二个目标是确定麦克法兰素E的生物学靶点， 确定其在囊泡形成和高尔基体定位的调节中的作用。了解 负责高尔基体行为的成分不仅对高尔基体生物学有重要贡献， 这是对有丝分裂的细胞过程有更全面了解的第一步。 拟议的研究涉及海洋天然产物麦克法鲁E的化学合成及其 类似物初步工作表明，麦克法罗事件导致了一个不寻常的和有趣的碎片， 高尔基体在哺乳动物细胞中无离域的片段。这些化合物将用于 作为研究高尔基体断裂本质的化学试剂。

ROVIDED. Fragmentation of the Golgi into small vesicles is a requirement for cellular division. It has been observed :hat treatment with a structurally interesting marine natural product, macfarlandin E, causes irreversible ragmentation 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.