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: 7347528
• 负责人: CHRISTOPHER M BEAUDRY
• 金额: $ 4.96万
• 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/7347528
• 关键词: Affinity; Behavior; Biological; Biological Factors; Biology; Biotin; Cell physiology; Chemical Agents; Chemistry; Class; Coumarins; Goals; Golgi Apparatus; Investigation; Ions; Localized; Location; Mammalian Cell; Marines; Mitosis; Nature; Organelles; Preparation; Proteins; Regulation; Research; Role; Structure; Vesicle; Work; alpha benzopyrone; analog; chemical synthesis; interest; marine natural product; scaffold

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.

罗维德。 高尔基体分裂成小泡是细胞分裂所必需的。已经观察到了 ：用一种结构有趣的海洋天然产品Macfarlandin E进行HAT治疗，导致不可逆转 高尔基体碎裂，不会导致所产生的碎片的非局部化。这其中的第一个目标是 研究是对马法兰素E的化学合成，它本身就是对 一类不寻常的海洋海绵代谢物。所提议的化学的主要转变是 共轭加成以设置两个相邻的立体中心(一个是四元)和分子内捕获 氧碳正离子构筑独特的2，7-二氧杂双环[3.2.1]Octan-3-酮支架 天然产品。此外，该合成允许制备包含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和分泌的高尔基体蛋白 本地化。研究的第二个目标是确定Macfarlandin E和Macfarlandin E的生物靶标。 确定其在调节高尔基体囊泡形成和定位中的作用。了解 负责高尔基行为的成分不仅是对高尔基生物学的重要贡献，而且 这是朝着更全面地了解导致有丝分裂的细胞过程迈出的第一步。 这项拟议的研究涉及海洋天然产物Macfarlandin E的化学合成及其 类比。初步工作表明，马法兰素E导致了一种不同寻常和有趣的碎裂 高尔基体在哺乳动物细胞中没有非定位化的片段。这些化合物将被用于 作为化学试剂用于研究高尔基体碎裂的性质。

项目成果

Divergent synthesis and chemical reactivity of bicyclic lactone fragments of complex rearranged spongian diterpenes.

复杂重排海绵二萜双环内酯片段的不同合成和化学反应性。

• DOI: 10.1021/ja207727h
• 发表时间: 2011-11-02
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Schnermann, Martin J.;Beaudry, Christopher M.;Genung, Nathan E.;Canham, Stephen M.;Untiedt, Nicholas L.;Karanikolas, Breanne D. W.;Suetterlin, Christine;Overman, Larry E.
• 通讯作者: Overman, Larry E.