Synthesis and Mechanisms of Bioactive Natural Products

描述（由申请人提供）：该项目的长期目标是实现洛马维菌素B和帕劳胺的合成。这两种分子都是海洋天然产物，具有前所未有的结构和独特的生物活性。我们将利用立体选择性氧化酮烯醇偶联反应作为合成洛马维菌素B的关键步骤。此外，还原性级联反应将用于传递洛马维菌素B结构。帕劳胺将使用复杂的自由基级联反应和潜在的仿生氧化环化来构建。这两种化合物都挑战了有机合成的最新技术。通过lomaivitticin B的合成，我们将能够研究它被激活和切割DNA的机制。帕劳胺的合成将有助于确定其生物合成步骤的可行性，并为今后的生物学研究提供材料。洛麦维菌素B是一种有效的抗肿瘤抗生素，似乎通过一种新的机制起作用。这个项目的一部分是研究这种机制，它可能会揭示小分子与DNA反应的新途径。帕劳胺能有效抑制受刺激淋巴细胞的增殖，并可能为免疫抑制的新机制提供洞见。我们将在哺乳动物细胞中进行彗星尾试验，以确定洛马维汀是否能切割DNA。此外，我们将与哺乳动物细胞和Western blots合作，以确定哪些细胞信号通路受到帕劳胺的干扰。

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.