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公共卫生的核心目标之一 国家卫生研究院的使命。虽然传统的策略取得了显着的成功，但具有新颖的分子 仍然需要有新的结构和新的行动方式来作为毒品的先导。在这项工作中，我们希望研究 小分子独特的立体化学性质称为阻转异构。手性分子 曾经被科学界认为对发展来说风险太大的阻转异构轴，现在正在成为 在药物发现和药物化学中越来越常见，因为化合物的改进， 效力、选择性、稳定性和药代动力学。在这个提案中，我们的本科生团队 普罗维登斯学院的研究人员将继续通过利用稳定的阻转异构体来改变范式。 含氮杂环称为β-咔啉。我们鉴定了1-芳基取代-β-咔啉 具有抗菌，神经药理学和DNA结合活性，使其适合于研究 通过国家普通医学科学研究所我们的主要重点是对阻转异构行为的 1-芳基取代的-β-咔啉，其中我们已经观察到大于30千卡/摩尔的旋转势垒。给定 这些分子的显着构型稳定性，我们将建立三个新的战略， 它们作为手性分子用于改善人类健康和福祉的潜力。我们的第一个目标是开发一个 用于快速获得1-芳基取代的-β-咔啉的各个对映体的动力学拆分策略。我们 将使用β-转角肽来进行这些分子的不对称N-氧化，这项工作将得到 继续与耶鲁大学斯科特米勒教授实验室的同事合作。第二 该项目的目标是合成天然产物毛蕊花碱F，一种β-咔啉天然产物， 已知乙酰胆碱酯酶抑制活性。我们将制备天然产物，拆分对映体， 并对该分子进行构效关系研究，这将有助于阐明 靶结合中的阻转异构性。第三个目标是开发一种新的基于β-环己基的不对称N，P-配体， 咔啉脚手架。我们将通过交叉偶联策略合成新的配体，然后评估其 在神经活性生物碱的合成中通过炔加成到亚胺离子上诱导不对称性。最后 一项提案将使普罗维登斯学院的本科生接触到有影响力的研究， 改善文科环境中的科学探究文化，并激励学生继续在STEM或 健康相关专业毕业。