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：
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
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

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

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

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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.

抽象的有效的合成方法和策略是建设的巨大未满足的需求阿留丁胺和迪斯特拉黑素类天然产品的其他成员。这极大地阻碍了这种独特的生物碱的机械，基本和应用科学研究，可提供重要的价值在控制各种疾病的过程中，显然需要对合成的其他基础研究，作用机理和基本药理学。天然产品（NPS）作为治疗学的关键作用对于各种疾病和本应用程序中提供的数据，都揭示了这些疾病的巨大潜力分子。在研究新的和创新化学的海洋生物25年后，我们确定了单个真正的非凡分子称为阿留丁胺。阿留丁胺已从latrunculia中回收海绵从阿拉斯加的诺阿阿岛（Noaa Alaska）从阿留申群岛海岸的深海收集。我们有对任何可检测量的该分子的详尽询问的提取物，也是唯一的选择生成机械和体内数据是首先通过可靠的合成生成药物。该分子是化学上极为独特，是两个非常罕见的生物活性天然产品组的成员氨基喹酮和硫烷烃，肯定是这些深海极端条件的产物较低的温度，高压和缺氧条件耗尽紫外线照射的环境可提供生物合成和重排的独特环境，形成高度不寻常的分子。阿留丁胺和该课程的其他成员及其合成中间体为多样性提供了独特的控制包括疟疾，炎症，病毒疾病和癌症在内的疾病强烈支持提供一致的毒品供应的策略，并为产生和多样化的生成和多样化提供班级。由于该分子的罕见和有限的供应，该程序的具体目的涉及除了隔离外，还使用两种不同途径开发合成方法论对SAR的起始材料和相关分子的表征以及对替代性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。