Fluoroalkylethers and Fluorinated Ethermimetics

氟烷基醚和氟化醚模拟物

• 批准号: 10193791
• 负责人: Ryan A Altman
• 金额: $ 8.69万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10193791
• 关键词: Fluoroalkylethers; Fluorinated; Ethermimetics

PROJECT SUMMARY Fluoroalkyl ethers and thioethers are important for medicinal chemistry, serving as both active pharmaceutical ingredients and biological probes. Therefore, the ability to access these fluorinated substructures is critical for the development of new therapeutics. Despite recent synthetic improvements that improve access to many fluorinated substructures, the community has not generally addressed the preparation of fluoroalkyl (thio)ethers. Thus, mild, convergent, and practical procedures for accessing these substructures are still lacking, which restricts access to new biological probes and therapeutic candidates. The Altman group aims to overcome the aforementioned limitations by developing new methods and general strategies for accessing fluoroalkyl (thio)ethers directly from simple and ubiquitous alcohol- and thiol-based substrates. More specifically, the proposed work will employ base-catalyzed nucleophilic addition reactions to C–C bonds to access a variety of biomedically important fluoroalkylether substructures. Development of the proposed strategies will enable medicinal chemists to access new and unique biological probes and therapeutics. The recent surge in synthetic organofluorine chemistry has provided a plethora of new methods capable of generating many new fluorinated substructures. In many cases, the creativity of the synthetic chemists for generating these fluorinated substructures has exceeded the experimentally validated uses of these new fluorinated groups. In fact, some synthetic chemists have proposed replacing synthetically challenging fluoroalkyl ethers and metabolically instable non-fluorinated ether substructures with more readily accessible fluorinated ethermimetics. However, no in silico, in vitro and in vivo data supports these claims. The Altman group aims to experimentally characterize the physicochemical and biophysical perturbations imparted by the proposed fluorinated ethermimetics using a combination of computational, physicochemical, in vitro and in vivo methods. This experimental data will enable medicinal chemists to rationally integrate these emerging fluorinated substructures in therapeutic candidates.

项目摘要 氟代烷基醚和硫醚在药物化学中是重要的，既作为活性药物， 成分和生物探针。因此，进入这些氟化亚结构的能力对于 新疗法的发展。尽管最近的合成改进，改善了获得许多 由于氟代亚结构的存在，该领域一般没有解决氟代烷基的制备 （硫）醚。因此，用于访问这些子结构的温和的、收敛的和实用的程序仍然是可行的。 缺乏，这限制了获得新的生物探针和治疗候选物。奥特曼集团的目标是 通过制定新的方法和一般战略， 氟代烷基（硫）醚直接从简单和普遍存在的醇基和硫醇基底物中分离。更 具体地说，所提出的工作将采用碱催化的C-C键的亲核加成反应， 访问各种生物医学上重要的氟烷基醚亚结构。发展拟议的 战略将使药物化学家能够获得新的和独特的生物探针和治疗。 合成有机氟化学的最近激增已经提供了大量的新方法， 产生许多新的氟化亚结构。在许多情况下，合成化学家的创造力， 产生这些氟化的亚结构已经超过了这些新的 氟化基团。事实上，一些合成化学家已经提议用合成取代具有挑战性的合成。 氟烷基醚和代谢不稳定的非氟化醚亚结构， 氟化的芳香剂。然而，没有计算机模拟、体外和体内数据支持这些声明。奥特曼 小组的目的是实验表征物理化学和生物物理扰动所赋予的 使用计算的、物理化学的、体外和体内的组合， 方法.这些实验数据将使药物化学家能够合理地整合这些新兴的 治疗候选物中的氟化亚结构。