Unusual Pharmacophores and New Tools for Cross-Coupling

不寻常的药效团和交叉偶联的新工具

• 批准号: 9277221
• 负责人: Ryan Ashok Shenvi
• 金额: $ 63.29万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9277221
• 关键词: Address; Alkaloids; Architecture; Area; Binding; Biological; Biological Assay; Biology; Cell Fractionation; Chemicals; Chemistry; Coupling; Data; Development; Dimerization; Drug Metabolic Detoxication; Environment; Family; Foundations; Heme; Investigation; Libraries; Methodology; Molecular; Natural Products; Nuphar; Organic solvent product; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phenotype; Plasmodium; Property; Purines; Reaction; Research; Running; Sulfur; Technology; Therapeutic; Work; cellular targeting; chemical reaction; chemical synthesis; combinatorial; dimer; human disease; inhibitor/antagonist; invention; killings; novel; novel therapeutics; pharmacophore; small molecule; tool

Project Summary/ Abstract Bioassay-guided fractionation of cells often uncovers small molecules that bind macromolecular targets in new and unexpected ways. Exploration of the chemical reactivity and target selectivity of these metabolites has laid the chemical foundation for the development of new biological tools and therapeutics. The molecular architecture of secondary metabolites is challenging and different than the chemical space explored by most medicinal chemistry campaigns: there is recognized `natural product-like' space and we lack the tools to explore it with the same depth as `drug-like' space. Our lab has developed new tools to more easily access natural products, and has focused our efforts on secondary metabolite families that appear to covalently modify their targets as the basis for their phenotypic effects. Our chemical syntheses are deliberately concise and easily-scaled to enable subsequent investigation into reactivity and biological activity. The current application significantly advances these efforts, provides compelling preliminary data as a foundation for the proposed work, and delves into new areas of chemistry. In this proposal, two areas of research are described: 1. the identification and investigation of covalently-reactive pharmacophores associated with the asmarine alkaloids, Nuphar dimers and isocyanoterpenes; and 2. the development of cross-coupling technology to access `natural product-space' more generally. In the first area, we disclose a preliminary cellular target of the unusual N-hydroxydiazepine purine (HAP) pharmacophore of the asmarine alkaloids and address unsolved problems posed by this motif. As part of a theme that runs throughout our work, we show how the aims of chemistry and biology intersect in the study of covalently reactive secondary metabolites. We also investigate the sulfur-electrophilicity of the Nuphar dimers, a property recently demonstrated by our lab to operate in organic solvent and cellular environments. We propose solutions to the challenging stereochemical problems posed by the monohydroxy dimers and show how chemistry developed in our lab can generate a combinatorial library of sulfur electrophiles. In a third area, we investigate the challenging architecture and reactivity of the isocyanoterpenes, which we recently demonstrated can kill Plasmodia by an alternative mechanism to the heme detoxification pathway often suggested. We also propose a novel caging strategy to render the isonitriles systemically-viable. In part two, we investigate a bimetallic catalytic cycle capable of solving long-standing problems in chemical synthesis. The proposed methodology is supported by proof-of-principle examples and provides chemists the reaction vehicles necessary to `escape from flatland.'

项目概要/摘要 生物测定引导的细胞分离通常会发现结合的小分子 以新的、意想不到的方式实现大分子靶标。化学反应性的探索 这些代谢物的靶点选择性为开发 新的生物工具和疗法。次生代谢物的分子结构是 与大多数药物化学探索的化学空间相比，具有挑战性且不同 活动：存在公认的“类似天然产品”的空间，但我们缺乏探索它的工具 与“毒品般”的空间具有相同的深度。我们的实验室开发了新工具，可以更轻松地 获取天然产品，并将我们的努力重点放在次生代谢家族上 似乎共价修饰其靶标作为其表型效应的基础。我们的化学品 合成故意简洁且易于扩展，以便后续研究 反应性和生物活性。当前的应用程序显着推进了这些努力， 提供令人信服的初步数据作为拟议工作的基础，并深入研究 化学新领域。 在该提案中，描述了两个研究领域：1. 识别和 与阿斯玛丽生物碱相关的共价反应药效团的研究， Nuphar 二聚体和异氰萜烯； 2. 交叉耦合技术的发展 更广泛地访问“自然产品空间”。在第一个领域，我们初步披露了 阿斯马林异常 N-羟基二氮杂嘌呤 (HAP) 药效团的细胞靶点 生物碱并解决该主题引起的未解决的问题。作为运行主题的一部分 在我们的整个工作中，我们展示了化学和生物学的目标如何在研究中交叉 共价反应性次级代谢产物。我们还研究了硫的亲电性 Nuphar 二聚体，我们的实验室最近证明了可以在有机溶剂中操作的特性， 细胞环境。我们针对所提出的具有挑战性的立体化学问题提出解决方案 由单羟基二聚体组成，并展示我们实验室开发的化学如何产生 硫亲电子试剂组合库。在第三个领域，我们研究具有挑战性的 异氰萜的结构和反应性，我们最近证明它可以杀死 通常认为，疟原虫是通过血红素解毒途径的替代机制来实现的。 我们还提出了一种新颖的笼养策略，使异腈具有系统活性。在第二部分中， 我们研究了一种能够解决化学领域长期存在问题的双金属催化循环 合成。所提出的方法得到原理验证示例的支持，并提供 化学家提供了“逃离平原”所需的反应工具。