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