Synthesis and Optimization of the Aleutianamine Class of Alkaloids

阿留申胺类生物碱的合成与优化

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10799135
• 关键词: Alaska; Aleutian Islands; Alkaloids; Anabolism; Applied Research; Arctic Regions; Basic Science; Biological Models; Chemicals; Chemistry; Construction Materials; Data; Development; Disease; Disease Management; Environment; Generations; Grant; Inflammation; Investigation; Malaria; Methodology; Modeling; National Oceanic and Atmospheric Administration; Natural Products; Parents; Penetration; Pharmaceutical Preparations; Pharmacology; Play; Porifera; Route; Therapeutic; Tissues; Viral Cancer; Virus Diseases; bioactive natural products; cold temperature; deep ocean; design; equipment acquisition; iminoquinone; in vivo; innovation; marine; marine organism; member; metabolomics; ocean ecosystems; parent grant; pressure; programs; research and development; small molecule; ultraviolet irradiation

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.

摘要 对有效的综合方法和战略的巨大需求尚未得到满足，以建设 Aleutianamine和其他天然产品类的不协调成员。这严重阻碍了 对这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 在控制各种疾病方面的价值，显然值得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(NPs)在治疗方面发挥了关键作用。 以及本申请中提供的数据揭示了这些疾病的巨大潜力 分子。在为新的和创新的化学研究海洋生物25年后，我们发现了一种 一种真正值得注意的分子，叫做阿亮硫胺。Aleutianamine已从一种钩端螺旋体中恢复 阿拉斯加国家海洋和大气局从阿留申群岛海岸外的深海收集的海绵。我们有 穷尽地询问提取物中任何可检测到的这种分子的数量，唯一剩下的选择 要产生机理和体内数据，首先要通过可靠的合成来产生药物。这种分子 在化学上是极其独特的，是两类非常罕见的生物活性天然产品的成员，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、高压和缺氧条件下紫外线照射耗尽的海洋环境 为生物合成和重排提供了独特的环境，形成了非常不寻常的分子。 阿亮氨胺和这一类的其他成员以及他们的合成中间体为 包括疟疾、炎症、病毒性疾病和癌症在内的各种疾病有力地支持了 制定战略，以提供持续的药物供应和产生和 阶级的多样化。由于这种分子的稀有和有限的供应，这个计划的具体目标 除了分离和分离外，还涉及使用两种不同路线的合成方法的开发 合成孔径雷达起始原料及相关分子的表征及替代物研究 涉及构建和优化分子的生物合成起始材料的方法。