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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10714398
• 关键词: Alkaloids; Area; Breathing; Chemicals; Chemistry; Complex; Development; Diamines; Economics; Hallucinogens; Indoles; Laboratories; Lysergic Acid Diethylamide; Medicine; Mental Depression; Modification; Natural Products; Oxidation-Reduction; Parkinson Disease; Pattern; Post-Traumatic Stress Disorders; Research; Route; Therapeutic; addiction; analog; bioactive natural products; improved; innovation; marine; neuropsychiatric disorder; novel; oxidation; scaffold; small molecule

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 生物碱天然产物对治疗医学领域产生了巨大的影响， 并有望发现新的神经药物治疗方法。某一领域 史密斯实验室提出的研究涉及到新的心理成形学的发展 基于迷幻麦角酸二乙胺(LSD)的化合物。虽然衍生品 LSD在之前的几十年里已经被探索过了，它的衍生品具有不同的取代 在麦角林支架的吲哚环上从未被探索过。所有这些衍生产品都是 目前只能通过全合成才能获得，并有可能作为治疗线索 治疗各种神经精神疾病，包括帕金森氏症、创伤后应激障碍、严重抑郁症、 还有毒瘾。我们对LSD支架的简明合成方法取决于对 以及广泛使用的杂环芳香族前体的化学改性。这一战略 然而，允许探索原本无法进入的化学空间 在治疗上是可行的。 我们从这些LSD类似物的路线中获得的合成灵感引导我们研究 海洋大环二胺生物碱的合成，如柳氮杂环素和沙拉宁。 这些目标都不是以前合成过的。我们的模块化，但氧化还原经济 组装这些结构复杂的化合物的平台取决于使用杂环 氧化水平较高的起始材料有效地访问氧化还原程度较低的同系物 级别。这一研究方向的创新主要是战略性的，需要导航 以前未遍历过的合成装配。这也需要战术上的 化学方面的进展无疑将阐明新的反应模式 在杂环化学领域具有广泛的重要性。