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: 10345968
• 负责人: Mark T Hamann
• 金额: $ 56.07万
• 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/10345968
• 关键词: Alaska; Aleut; Aleutian Islands; Alkaloids; Anabolism; Applications Grants; Applied Research; Arctic Regions; Basic Science; Biodiversity; Biological; Biological Assay; Breathing; Cell Cycle; Cellular biology; Chemical Structure; Chemicals; Chemistry; Collaborations; Construction Materials; Data; Development; Disease; Disease Management; Drug Kinetics; Ensure; Environment; Evaluation; Expeditions; Foundations; Generations; Grant; Harvest; High Pressure Liquid Chromatography; Homology Modeling; Human; In Vitro; Inflammation; Investigation; Lead; Life; Ligand Binding; Ligands; Malaria; Methodology; Methods; Microarray Analysis; Modeling; Molecular Biology; National Oceanic and Atmospheric Administration; Natural Products; Natural Products Chemistry; Organism; Pharmaceutical Preparations; Pharmacology; Phenotype; Phylogenetic Analysis; Play; Porifera; Program Development; Proteins; Proteomics; Recording of previous events; Recovery; Reporting; Roentgen Rays; Route; Sampling; Solid; Structure; Structure-Activity Relationship; Surveys; Taxonomy; Territoriality; Testing; Therapeutic; Tissues; Viral Cancer; Virus Diseases; Water; Work; base; bioactive natural products; cold temperature; cytotoxicity; deep ocean; design; disorder control; drug development; drug discovery; exhaustion; flexibility; iminoquinone; in vitro Assay; in vivo; innovation; interest; marine natural product; marine organism; member; metabolomics; molecular modeling; neoplastic cell; novel; ocean ecosystems; pressure; programs; research and development; tool; 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 对于有效的综合方法和战略， 阿留申胺和discorhabdin类天然产物的其它成员。这大大阻碍了 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价值 在控制各种疾病，并明确保证额外的基础研究的合成， 作用机制和基础药理学。天然产物（NPs）作为治疗药物发挥了关键作用 对于各种疾病，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年的研究海洋生物的新的和创新的化学，我们已经确定了一个 一种非常特别的分子叫做阿留申胺阿留申胺已从一个Latrunculia 阿拉斯加国家海洋和大气管理局从阿留申群岛海岸外的深海中采集的海绵。我们有 彻底询问提取物中任何可检测量的该分子， 产生机理和体内数据的方法是首先通过可靠的合成产生药物。该分子 在化学上非常独特，是两种非常罕见的生物活性天然产物的成员， 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、高压和缺氧条件耗尽紫外线辐射的环境提供了 一个独特的环境，生物合成和重排，形成非常不寻常的分子。阿留申胺和 这类的其他成员以及它们的合成中间体为多种生物活性物质提供了独特的控制。 疾病，包括疟疾、炎症、病毒性疾病和癌症， 提供药物持续供应的战略以及药物的产生和多样化的方法 课由于该分子的稀缺性和有限供应，该计划的具体目标涉及 开发了除分离外还使用两种不同路线的合成方法， 用于SAR的起始物料和相关分子的表征以及替代品的研究 涉及用于分子构建和优化的生物合成起始材料的方法。