Synthesis and Mechanisms of Bioactive Natural Products

生物活性天然产物的合成及作用机制

• 批准号: 7469446
• 负责人: Matthew D. Shair
• 金额: $ 31.73万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-13 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7469446
• 关键词: Address; Amines; Anabolism; Arts; Biological; Biological Assay; Biological Factors; Biomimetics; Cells; Cleaved cell; Complex; Condition; Coupling; Cyclization; DNA; Evaluation; Future; Grant; Immunosuppression; In Vitro; Interleukin-2; Ketones; Knowledge; Lymphocyte; Mammalian Cell; Marines; Organic Synthesis; Palau' amine; Physiological; Property; Reaction; Reporting; Role; Signal Pathway; Signal Transduction; Source; Staging; Structure; System; T-Cell Activation; Tail; Therapeutic immunosuppression; Western Blotting; Work; antineoplastic antibiotics; cell killing; cellular targeting; cytotoxicity; design; enolate; insight; interest; lomaiviticin A; lomaiviticin B; marine natural product; research study; small molecule

DESCRIPTION (provided by applicant): The long-term objectives of this project are to achieve syntheses of lomaiviticin B and palau'amine. Both molecules are marine natural products that have unprecedented structures and unique biological activities. We will utilize a stereoselective oxidative ketone enolate coupling reaction as the key step in the lomaiviticin B synthesis. Furthermore, a reductive cascade reaction will be used to deliver the lomaiviticin B structure. Palau'amine will be constructed using a complex radical cascade reaction and a potentially biomimetic oxidative cyclization. Both compounds challenge the state-of-the art of organic synthesis. Through the synthesis of lomaiviticin B, we will be able to study the mechanism by which it is activated and cleaves DNA. The palau'amine synthesis will help address the feasibility of steps proposed for its biosynthesis as well as provide material for future biological studies. Lomaiviticin B is a potent antitumor antibiotic that appears to act through a new mechanism. Part of this project is to study that mechanism which may illuminate new ways that small molecules can react with DNA. Palau'amine potently inhibits the proliferation of stimulated lymphocytes and may well provide insight into new mechanisms for immunosuppression. We will be performing Comet tail assays in mammalian cells to determine whether the lomaiviticins cleave DNA. Also, we will be working with mammalian cells and Western blots to determine which cell signaling pathways are perturbed by palau'amine.

描述（由申请人提供）：该项目的长期目标是实现Lomaiviticin B和Palau'amine的合成。这两个分子都是海洋天然产品，具有前所未有的结构和独特的生物学活性。我们将利用立体选择性的氧化酮烯醇偶联反应作为Lomaiviticin B合成的关键步骤。此外，还将使用还原性的级联反应来递送Lomaiviticin B结构。 Palau'amine将使用复杂的自由基级联反应和潜在的仿生氧化环化构建。两种化合物都挑战了有机合成的最新技术。通过合成Lomaiviticin B，我们将能够研究其激活并切割DNA的机制。 Palau'amine合成将有助于解决提出的生物合成步骤的可行性，并为未来的生物学研究提供材料。 Lomaiviticin B是一种有效的抗肿瘤抗生素，它似乎通过一种新机制起作用。该项目的一部分是研究该机制可能会阐明小分子可以与DNA反应的新方法。 palau'amine有效抑制刺激的淋巴细胞的增殖，并可以很好地洞悉免疫抑制的新机制。我们将在哺乳动物细胞中进行彗星尾巴测定，以确定洛氏素蛋白是否裂解DNA。另外，我们将使用哺乳动物细胞和蛋白质印迹，以确定哪些细胞信号通路受到palau'amine的干扰。