Harnessing Atropisomerism in beta-Carbolines for the Discovery of New Reactions and Small Molecule Probes

利用 β-咔啉中的阻转异构现象来发现新反应和小分子探针

• 批准号: 10730343
• 负责人: Seann Patrick Mulcahy
• 金额: $ 40.73万
• 依托单位: PROVIDENCE COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730343
• 关键词: 3-Dimensional; Acetylcholinesterase; Alkaloids; Alkynes; Alzheimer' s disease model; Anti-Bacterial Agents; Area; Aspartic Acid; Behavior; Beta Carbolines; Binding; Biochemical; Biological; Biology; Biomedical Research; Carbolines; Catalysis; Chemicals; Colchicine; Collaborations; Communities; Coupling; DNA Binding; Development; Disease; Drug Kinetics; Evaluation; FDA approved; Goals; Hand; Handedness; Health; Human; Hydrogen Peroxide; Image; Individual; Ions; Kinetics; Laboratories; Ligands; Methodology; Methods; Microtubule Polymerization; Mission; Modeling; Molecular; Molecular Conformation; Muscarinics; Naphthalene; National Institute of General Medical Sciences; Natural Products; Nitrogen; Peer Review; Peptides; Personal Satisfaction; Pharmaceutical Chemistry; Pharmaceutical Preparations; Positioning Attribute; Property; Public Health; Publications; Reaction; Research; Research Infrastructure; Research Personnel; Resolution; Rest; Rotation; Scientific Inquiry; Seminal; Structure; Structure-Activity Relationship; Students; Therapeutic; Training and Education; Transition Elements; United States National Institutes of Health; Universities; Work; analog; bioactive scaffold; catalyst; chemical reaction; chiral molecule; college; design; drug development; drug discovery; enantiomer; health goals; improved; inhibitor; novel; novel therapeutics; oxidation; professor; programs; public health relevance; racemization; scaffold; serotonin receptor; small molecule; success; telenzepine; tool; undergraduate student

Project Summary New therapeutics that have potential for treating disease are among the public health goals that are central to the mission of the NIH. While traditional strategies have had remarkable success, molecules with novel structures and new modes of action are still needed to serve as drug leads. In this work, we wish to study the unique stereochemical property of small molecules known as atropisomerism. Chiral molecules with an atropisomeric axis, once seen by the scientific community as too risky for development, are now becoming increasingly common in drug discovery and medicinal chemistry because of improvements made to compound potency, selectivity, stability, and pharmacokinetics. In this proposal, our team of undergraduate student researchers at Providence College will continue to shift the paradigm by exploiting stable atropisomerism in the nitrogen-containing heterocycle known as the β-carboline. We have identified 1-aryl-substituted-β-carbolines with antibacterial, neuropharmacological, and DNA-binding activity, which make them appropriate for study through the National Institute of General Medical Sciences. Our main focus is on the atropisomeric behavior of 1-aryl-substituted-β-carbolines, in which we have observed barriers to rotation greater than 30 kcal/mol. Given the remarkable configurational stability of these molecules, we will establish three new strategies for harnessing their potential as chiral molecules for improving human health and well-being. Our first goal will be to develop a kinetic resolution strategy for rapidly accessing the individual enantiomers of 1-aryl-substituted-β-carbolines. We will use β-turn peptides to perform an asymmetric N-oxidation of these molecules, work which will be aided by a continuing collaboration with colleagues at Yale University in the laboratory of Professor Scott Miller. The second goal of the project will be the synthesis of the natural product chaetogline F, a β-carboline natural product with known inhibitory activity of acetylcholinesterase. We will prepare the natural product, resolve the enantiomers, and perform a structure-activity relationship study of this molecule which will shed light on the importance of atropisomerism in target binding. The third goal is to develop a new asymmetric N,P-ligand based on the β- carboline scaffold. We will synthesize the new ligand via a cross-coupling strategy and then assess its ability to induce asymmetry in the synthesis of neuroactive alkaloids via alkyne additions to iminium ions. Finally, this proposal will expose undergraduate students at Providence College to impactful research, which will both improve the culture of scientific inquiry in a liberal arts setting and inspire students to continue in a STEM or health-related field upon graduation.

项目摘要 具有治疗疾病潜力的新疗法是核心的公共卫生目标之一 执行NIH的任务。尽管传统策略取得了巨大的成功，但分子与新颖 仍然需要结构和新的作用方式来充当药物铅。在这项工作中，我们希望研究 小分子的独特立体化学特性被称为肉骨异构体。手性分子 抗体异构体轴曾经被科学界视为发展的风险，现在已经变得 由于对化合物的改善，在药物发现和医学化学方面越来越普遍 效力，选择性，稳定性和药代动力学。在这个建议中，我们的本科生团队 普罗维登斯学院的研究人员将通过利用稳定的萎缩性在 含氮的杂环称为β-碳酸盐。我们已经确定了1-芳基取代的β-碳酸盐 具有抗菌，神经药理学和DNA结合活性，使其适合研究 通过美国国家一般医学科学研究所。我们的主要重点是 1-芳基取代的β-果碱，其中我们观察到大于30 kcal/mol的旋转障碍。给出 这些分子的显着配置稳定性，我们将建立三种新的策略来利用 它们作为手性分子的潜力来改善人类健康和福祉。我们的第一个目标是开发 动力学分辨率策略，用于快速访问1-芳基取代-β-碳酸盐的单个对映异构体。我们 将使用β-转弯肽对这些分子进行不对称的N氧化，这将由A 斯科特·米勒（Scott Miller）教授实验室与耶鲁大学的同事继续合作。第二个 该项目的目标将是合成天然产品Chaetogline F，这是一种β-碳酸盐天然产品 乙酰胆碱酯酶的已知抑制活性。我们将准备天然产品，解决对映异构体， 并对该分子进行结构性关系研究，该研究将阐明 目标结合中的萎缩症。第三个目标是基于β-开发一种新的不对称n，p-crigand caroline脚手架。我们将通过交叉耦合策略合成新的配体，然后评估其能力 通过在亚米尼离子中添加炔烃的神经活性生物碱的合成中诱导不对称性。最后，这个 提案将使普罗维登斯学院的本科生接触有影响力的研究，这两个都将 改善文科环境中的科学探究文化，并激发学生继续在茎上或 毕业后与健康有关的领域。