Fluoroalkylethers and Fluorinated Ethermimetics

氟烷基醚和氟化醚模拟物

基本信息

批准号：
9978833
负责人：
Ryan A Altman
金额：
$ 37.55万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
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

项目摘要

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.

项目摘要氟烷基醚和硫代剂对于医学化学很重要，既是活性药物成分和生物问题。因此，访问这些氟化子结构的能力对于新疗法的发展。尽管最近的合成改进可以改善对许多的访问氟化子结构，社区通常没有解决氟烷基的准备（Thio）以太剂。那是访问这些子结构的温和，收敛和实用的程序仍然是缺乏，这限制了访问新的生物学问题和治疗候选者的机会。 Altman Group的目标是通过制定新方法和访问的一般策略来克服优先考虑的限制直接来自简单和无处不在的酒精和基于硫硫代的底物的氟烷基（Thio）醚。更多的具体而言，拟议的工作将对CC键对CC键采用碱基催化的核螺旋反应。访问各种重要的生物医学重要氟烷基子结构。提议的发展策略将使医学化学家能够解决新的和独特的生物学问题和治疗。最近的合成器官氟化化学激增提供了多种能够的新方法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产生这些氟化的子结构已超过了这些新的实验验证的用途氟化基团。实际上，一些合成化学家提出了替换合成挑战氟烷基醚和代谢上不稳定的非氟化以太子结构，更容易访问氟化的乙醇酸。但是，在计算机中，体外和体内数据中没有NO支持这些主张。阿尔曼小组旨在实验表征由赋予的物理和生物物理扰动拟议的氟化乙基仪，结合了计算，物理，体外和体内方法。该实验数据将使医学化学家能够合理整合这些新兴治疗候选物中的氟化子结构。