Fluoroalkylethers and Fluorinated Ethermimetics

项目总结 氟烷基醚和硫醚在药物化学中非常重要，它们都是活性药物。 配料和生物探针。因此，获得这些氟化亚结构的能力对于 新疗法的发展。尽管最近的综合改进改善了许多 氟化亚结构，目前社会上还没有普遍涉及到氟烷基的制备 (硫代)醚。因此，访问这些子结构的温和、收敛和实用的过程仍然是 缺乏，这限制了获得新的生物探针和治疗候选药物。Altman小组的目标是 通过开发新的方法和一般战略来克服上述限制 氟烷基(硫代)醚直接来自简单和普遍存在的醇和硫醇基底物。更多 具体地说，拟议的工作将使用碱催化的C-C键的亲核加成反应来 访问各种生物医学上重要的含氟烷基醚亚结构。建议的发展 战略将使药物化学家能够获得新的和独特的生物探针和疗法。 最近合成有机氟化学的激增提供了大量的新方法，能够 产生了许多新的氟化亚结构。在许多情况下，合成化学家的创造力 产生这些氟化亚结构已经超过了这些新的实验验证的用途 氟化基团。事实上，一些合成化学家已经提出了取代具有合成挑战性的 氟烷基醚和代谢不稳定的非氟醚亚结构，更容易获得 氟化的乙醚模拟物。然而，在硅胶、体外和体内的数据中，没有支持这些说法。奥特曼 该小组的目标是从实验上表征由 建议使用计算、物理化学、体外和体内相结合的氟化醚类化合物 方法：研究方法。这一实验数据将使药物化学家能够合理地整合这些新兴的 候选治疗中的氟化亚结构。

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.