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: 9891859
• 负责人: Ryan Ashok Shenvi
• 金额: $ 64.24万
• 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/9891859
• 关键词: Address; Alkaloids; Architecture; Area; Binding; Biological; Biological Assay; Biology; Cell Fractionation; Chemicals; Chemistry; Coupling; Data; Development; 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; 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.'

项目摘要/摘要 生物测定引导的细胞分离通常发现结合的小分子 以新的和意想不到的方式成为大分子靶标。关于化学反应性的探讨 这些代谢物的靶向性为新药的开发奠定了化学基础 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领域不同，具有挑战性 宣传活动：有公认的类似天然产品的空间，但我们缺乏探索它的工具 具有与毒品一样的深度空间。我们的实验室已经开发出新的工具，可以更轻松地 获得天然产品，并将我们的努力集中在次生代谢物家族上 似乎共价修饰它们的靶标，作为其表型效应的基础。我们的化学品 合成是故意简洁和容易缩放的，以便于后续的研究 反应性和生物活性。本申请极大地推进了这些努力， 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 化学的新领域。 在该方案中，描述了两个方面的研究：1.识别和 与海藻生物碱相关的共价活性药效团的研究， Nuphar二聚体和异氰基萜烯；以及2.交叉偶联技术的发展 更广泛地进入“自然产品--空间”。在第一个方面，我们披露了一个初步的 非同寻常的N-羟基二氮杂嘌呤(HAP)海藻药效团的细胞靶点 生物碱和解决这一主题提出的悬而未决的问题。作为运行的主题的一部分 通过我们的工作，我们展示了化学和生物学的目标如何在研究 共价反应性次级代谢物。我们还研究了该化合物的硫亲电性。 Nuphar二聚体，这是我们实验室最近证明的一种在有机溶剂和 蜂窝环境。我们为具有挑战性的立体化学问题提出解决方案。 并展示了我们实验室发展的化学如何产生一个 硫亲电体组合文库。在第三个领域，我们调查具有挑战性的 异氰基萜烯的结构和反应性，我们最近证明了它可以杀死 通常认为，疟原虫通过替代血红素解毒途径的机制。 我们还提出了一种新的笼化策略，使异腈类化合物具有系统可行性。在第二部分， 我们研究了一种能够解决化学中长期存在的问题的双金属催化循环。 综合。所提出的方法得到了原则证明实例的支持，并提供了 化学家们发现了“逃离平地”所必需的反应工具。