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.

项目概要 氟烷基醚和硫醚对于药物化学很重要，它们都是活性药物 成分和生物探针。因此，获得这些氟化子结构的能力对于 新疗法的开发。尽管最近的合成改进改善了许多 氟化子结构，业界尚未普遍解决氟代烷基的制备问题 (thio)ethers.因此，访问这些子结构的温和、收敛和实用的程序仍然是 缺乏，这限制了新生物探针和候选治疗药物的获得。 The Altman group aims to 通过开发新的方法和一般策略来克服上述限制 直接从简单且普遍存在的醇基和硫醇基底物中合成氟烷基（硫）醚。更多的 具体来说，拟议的工作将采用碱催化的 C-C 键亲核加成反应 获得各种生物医学上重要的氟代烷基醚子结构。拟议的发展 这些策略将使药物化学家能够获得新的、独特的生物探针和治疗方法。 最近合成有机氟化学的激增提供了大量能够 产生许多新的氟化子结构。在许多情况下，合成化学家的创造力 生成这些氟化子结构已经超出了这些新材料经过实验验证的用途 fluorinated groups.事实上，一些合成化学家已经提议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子结构更容易获得 氟化醚模拟物。然而，没有计算机、体外和体内数据支持这些说法。 The Altman 该小组的目标是通过实验表征物理化学和生物物理扰动所带来的 提出了结合计算、物理化学、体外和体内的氟化醚模拟物 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 候选治疗药物中的氟化子结构。