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.'

项目总结/摘要 生物测定引导的细胞分级分离通常会发现结合的小分子 以新的和意想不到的方式靶向大分子。探索化学反应性和 这些代谢产物的靶向选择性为开发 新的生物学工具和疗法。次级代谢物的分子结构是 具有挑战性且与大多数药物化学探索的化学空间不同 运动：存在公认的“类天然产品”空间，但我们缺乏探索这一空间的工具 与“毒品”空间的深度相同。我们的实验室开发了新的工具， 获取天然产品，并将我们的努力集中在次级代谢产物家族， 似乎共价修饰其靶点作为其表型效应的基础。我们的化学 综合是故意简洁和易于缩放，使后续调查 反应性和生物活性。本申请显著地推进了这些努力， 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 在这个建议中，两个研究领域被描述：1。确定和 与海鞘生物碱相关的共价反应性药效团的研究， 努法尔二聚体和异氰萜烯;和2.交叉耦合技术的发展， 更普遍地进入“自然产品空间”。在第一个方面，我们披露了一个初步的 阿斯玛林不寻常的N-羟基二氮杂嘌呤（HAP）药效团的细胞靶点 生物碱并解决了由该基序引起的未解决的问题。作为主题的一部分， 在我们的工作中，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物。我们还研究了硫亲电性的 Nuphar二聚体，我们的实验室最近证明了在有机溶剂中操作的特性， 细胞环境。我们提出了解决具有挑战性的立体化学问题所提出的 并展示我们实验室开发的化学方法如何产生 硫亲电体的组合文库。在第三个领域，我们调查了具有挑战性的 结构和反应性的异氰萜烯，我们最近证明可以杀死 疟原虫通过血红素解毒途径的另一种机制来解毒。 我们还提出了一种新的笼策略，使异腈系统可行。在第二部分， 我们研究了一种能够解决化学工业中长期存在的问题的催化循环， 合成.所提出的方法是支持的原则证明的例子，并提供 化学家们制造出逃离平原所必需的反应载体。'