Synthesis and Optimization of the Aleutianamine Class of Alkaloids

阿留申胺类生物碱的合成与优化

基本信息

批准号：
10799135
负责人：
Mark T Hamann
金额：
$ 16.57万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2026-06-30
项目状态：
未结题

项目摘要

ABSTRACT There is a tremendous unmet need for effective synthesis methodologies and strategies for the construction of aleutianamine and other members of the discorhabdin class of natural products. This has significantly hindered the mechanistic, basic and applied science studies for this unique class of alkaloids which offers significant value in the control of a variety of diseases and clearly warrants additional basic research into the synthesis, mechanism of action and basic pharmacology. Natural Products (NPs) have played a key role as therapeutics for a variety of diseases and the data presented in this application reveals the tremendous potential for these molecules. After 25 years of studying marine organisms for new and innovative chemistry we have identified a single truly remarkable molecule called aleutianamine. Aleutianamine has been recovered from a Latrunculia sponge collected from the deep ocean off the coast of the Aleutian Islands by NOAA Alaska. We have exhaustively interrogated extracts for any detectable quantities of this molecule and the only remaining option to generate mechanistic and in vivo data is to first generate the drug through a reliable synthesis. This molecule is extremely unique chemically and is a member of two very rare groups of bioactive natural products including the iminoquinones and the thioalkaloids and is certain to be a product of the extreme conditions of these deep ocean environments where cold temperatures, high pressure, and anoxic conditions deplete of UV irradiation provides a unique environment for biosynthesis and rearrangement to form highly unusual molecules. Aleutianamine and other members of this class as well as their synthetic intermediates offer unique controls for a diversity of diseases including malaria, inflammation, viral diseases and cancer strongly supporting the development of strategies to provide consistent supply of the drug and approaches to the generation and diversification of the class. Due to the rare and limited supply of this molecule the specific aims of this program involve the development of synthesis methodologies using two different routes in addition to the isolation and characterization of starting materials and related molecules for SAR and investigations into alternative approaches involving biosynthetic starting materials for the construction and optimization of the molecule.

抽象的对有效的合成方法和构建策略的需求尚未得到满足阿留申胺和 discorhabdin 类天然产物的其他成员。这极大地阻碍了对这一类独特的生物碱的机理、基础和应用科学研究提供了重要的意义在控制多种疾病方面具有价值，显然需要对合成进行额外的基础研究，作用机制和基础药理学。天然产物 (NP) 作为治疗药物发挥着关键作用对于多种疾病，本申请中提供的数据揭示了这些疾病的巨大潜力分子。经过 25 年对海洋生物的新化学和创新化学的研究，我们发现了一种一个真正非凡的分子，称为阿留申胺。阿留申胺已从 Latrunculia 中回收美国国家海洋和大气管理局阿拉斯加从阿留申群岛海岸附近的深海采集海绵。我们有详尽地询问提取物中是否有任何可检测到的该分子的数量以及唯一剩下的选择要生成机械和体内数据，首先要通过可靠的合成来生成药物。这个分子化学性质极其独特，是两类非常稀有的生物活性天然产物的成员，其中包括亚氨基醌和硫代生物碱，肯定是这些深海极端条件的产物低温、高压和缺氧条件会耗尽紫外线照射的海洋环境为生物合成和重排形成极不寻常的分子提供了独特的环境。阿留申胺和此类的其他成员及其合成中间体提供了独特的控制包括疟疾、炎症、病毒性疾病和癌症在内的多种疾病强烈支持制定战略以提供持续的药物供应以及产生和使用的方法班级多元化。由于该分子的稀有且供应有限，该计划的具体目标涉及使用除了分离和分离之外的两种不同途径的合成方法的开发 SAR 起始材料和相关分子的表征以及替代品的研究涉及用于构建和优化分子的生物合成起始材料的方法。