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

项目摘要 具有治疗疾病潜力的新疗法是公共卫生目标的核心之一 美国国立卫生研究院的使命。虽然传统的策略取得了显著的成功，但具有新奇的分子 仍然需要结构和新的行动模式来充当药物先导。在这项工作中，我们希望研究 小分子独特的立体化学性质，称为阿托品异构体。手性分子中的一种 曾被科学界视为开发风险太大的畸形体轴心，现在正变得 由于化合物的改进，在药物发现和药物化学中越来越常见 效力、选择性、稳定性和药代动力学。在这份提案中，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 含氮杂环，称为β-Caroline。我们鉴定了1-芳基取代-β-卡宾 具有抗菌、神经药理和DNA结合活性，这使它们适合研究 通过国家普通医学科学研究所。我们主要关注的是黑猩猩的变态行为 1-芳基取代-β-卡宾，在其中我们观察到了大于30千卡/摩尔的转动势垒。vt.给出 这些分子的显著构型稳定性，我们将建立三个新的策略来利用 它们作为手性分子改善人类健康和福祉的潜力。我们的第一个目标将是开发一个 1-芳基取代-β-卡宾对映体的快速动力学拆分策略。我们 将使用β-Turn肽来执行这些分子的不对称N-氧化，这项工作将得到 在斯科特·米勒教授的实验室里继续与耶鲁大学的同事们合作。第二 该项目的目标将是合成天然产品茶茶碱F，这是一种β-Caroline天然产品，具有 已知的乙酰胆碱酯酶抑制活性。我们将制备天然产物，拆分对映体， 并进行这种分子的构效关系研究，这将有助于揭示 靶结合中的阿托品异构化。第三个目标是开发基于β-的新的不对称N，P-配体。 卡波林支架。我们将通过交叉偶联策略合成新的配体，然后评估它的能力 通过烯烃加成来诱导亚胺离子合成神经活性生物碱的不对称性。最后，这一点 该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，这将既 在文科环境中提高科学探究的文化，并激励学生继续在STEM或 毕业后进入与健康相关的领域。

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.