Synthesis of Bioactive Natural Products and Unnatural Congeners

生物活性天然产物和非天然同系物的合成

基本信息

批准号：
10714398
负责人：
Joel Michael Smith
金额：
$ 36.72万
依托单位：
FLORIDA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-05-31
项目状态：
未结题

项目摘要

Project Summary/Abstract Alkaloid natural products have had an immense impact on the field of therapeutic medicine, and hold promise for the discovery of new neuropharmacological treatments. One area of proposed research in the Smith Lab concerns the development of new psychoplastogenic compounds based on the psychedelic lysergic acid diethylamide (LSD). Although derivatives of LSD have been explored previously over many decades, derivatives bearing various substitutions on the indole ring of the ergoline scaffold have never been explored. All of these derivatives are currently only accessible through total synthesis, and potentially can serve as therapeutic leads for various neuropsychiatric diseases including Parkinson's disease, PTSD, severe depression, and addiction. Our concise synthetic approach to the scaffold of LSD hinges on the utilization and chemical modification of widely available heterocyclic aromatic precursors. This strategy allows for the exploration of chemical space that would otherwise be inaccessible, however therapeutically enabling. Synthetic inspiration drawn from our route to these LSD analogs has led us to investigate the synthesis of marine macrocyclic diamine alkaloids such as the halicyclamines and the sarains. None of these targets have been synthesized previously. Our modular, yet redox-economic platform for assembling these structurally complex compounds hinges on employing heterocyclic starting materials at higher oxidation levels to efficiently access their congeners with lower redox levels. Innovation in this research direction is mainly strategic, demanding a navigation of synthetic assembly that has not been traversed previously. This will also demand tactical advances in chemistry that will undoubtedly shed light on novel reactivity patterns that will be broadly important within the realm of heterocyclic chemistry.

项目摘要/摘要生物碱天然产品对治疗医学领域产生了巨大影响，并有望发现新的神经药物治疗。一个区域史密斯实验室的拟议研究涉及新的精神碎裂性的发展基于迷幻的乳糖酸二乙酰胺（LSD）的化合物。虽然是衍生物 LSD以前已经探索了数十年，具有各种取代的衍生物在ergoline脚手架的吲哚环上，从未探索过。所有这些衍生物都是目前仅通过总合成才能访问，并且有可能充当治疗铅对于包括帕金森氏病，PTSD，严重抑郁症在内的各种神经精神疾病，和成瘾。我们对利用率LSD铰链支架的简洁合成方法以及广泛可用的杂环芳香族前体的化学修饰。这个策略允许探索原本无法访问的化学空间，但是在治疗上启用。从我们到达这些LSD类似物的路线中得出的合成灵感使我们调查了海洋大环菊花生物碱的合成，例如降烷胺和纱丽。这些目标均未合成。我们的模块化但氧化还原经济用于组装这些结构复杂化合物的平台，用于采用异环的平台较高氧化水平的起始材料可有效使用较低的氧化还原的同类物水平。在这个研究方向上的创新主要是战略性的，要求导航以前尚未遍历过的合成组装。这也需要战术化学的进步无疑会揭示出新的反应性模式在杂环化学领域中至关重要。