Fluorination and Fluoroalkylation Strategies for Synthetic and Medicinal Chemistry

合成和药物化学的氟化和氟烷基化策略

• 批准号: 10406418
• 负责人: Ryan A Altman
• 金额: $ 40.79万
• 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 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406418
• 关键词: Affect; Alcohols; Alkenes; Area; Biological; Biophysics; Development; Drug Kinetics; Drug Stability; Electrochemistry; Fluorine; Goals; In Vitro; Ligands; Metabolism; Methodology; Methods; Modernization; Natural Products; Parents; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Phase; Property; Proteins; Reaction; Reagent; Synthesis Chemistry; System; Therapeutic; Transition Elements; Work; analog; catalyst; design; drug market; functional group; improved; in vivo; innovation; metabolic profile; next generation; novel therapeutics; physical property; programs; therapeutic candidate

SUMMARY Fluorination of an organic compound affects physicochemical properties, which in medicinal settings perturbs pharmacodynamic, pharmacokinetic, distribution, and/or metabolic profiles both in vitro and in vivo. Thus, the ability to selectively install fluorinated groups under mild conditions is essential for accessing new therapeutics and biological probes. However, the unique physical properties of fluorinated substrates and/or reagents typically perturb fundamental organic reactivities, which can complicate synthetic sequences to access fluorinated compounds. Thus, many routine organic reactions simply do not work in the presence of fluorinated reagents or with fluorinated substrates. Additionally, the unique properties of fluorinated substrates enable new reactivities that cannot be achieved by the respective non-fluorinated counterparts, which provides opportunities to develop innovative reactions and strategies for accessing medicinally relevant substructures With this R35 program, the Altman group has a long-term goal of developing innovative catalyst systems, reagents, and/or synthetic strategies for accessing medicinally relevant fluorinated substructures. In this area, we develop fluorination and fluoroalkylation methodologies using innovative strategies (e.g. electrochemistry, C– H functionalization, deoxyfluoroalkylation, transition metal catalyzed reactions) that enable synthetic chemists to convert simple and readily available functional groups (e.g. alcohols, carbonyls, fluorinated alkenes) into a broad spectrum of highly valuable fluorinated analogs. Additionally, we explore synthetic transformations in which fluorinated substructures react through distinct mechanisms and/or deliver products with distinct selectivities relative to analogous reactions of nonfluorinated substrates. Development of the proposed strategies will enable medicinal chemists to access new and unique biological probes and therapeutics. A second long-term goal is to explore physicochemical perturbations imparted by fluorinated substructures that might influence drug stability, distribution, metabolism, and/or ligand-protein interactions, and to apply such principles in the design of next- generation fluorinated therapeutic candidates with improved drug-like properties. In the next phase of our work, we will apply modern innovative synthetic reactions to deliver next-generation fluorinated analogs of natural products that will retain the therapeutically valuable pharmacodynamic action and also improve stability and distribution relative to the parent compounds.

摘要 有机化合物的氟化会影响物理化学性质，这在医药环境中会造成干扰。 体外和体内的药效学、药动学、分布和/或代谢情况。因此， 能够在温和的条件下选择性地安装氟化基团是获得新疗法的关键 和生物探头。然而，氟化底物和/或试剂的独特物理性质通常 扰乱基本的有机反应性，这可能会使合成序列复杂化，从而访问氟化 化合物。因此，许多常规的有机反应在氟化试剂或 使用氟化的底物。此外，氟化底物的独特性质使新的反应性成为可能。 这是相应的非氟对应物无法实现的，这提供了发展的机会 用于获取与医学相关的亚结构的创新反应和策略 有了这项R35计划，奥特曼集团有一个长期目标，即开发创新的催化剂系统， 试剂和/或用于访问医学上相关的氟化亚结构的合成策略。在这一地区， 我们使用创新策略开发氟化和氟烷基化方法(例如，电化学、C- H官能化、脱氧氟烷基化、过渡金属催化反应)，使合成化学家能够 将简单易得的官能团(如醇、羰基、氟化烯)转化为广泛的 高价值氟化类似物的光谱。此外，我们还探讨了合成变换，在这些变换中 氟化亚结构通过不同的机制反应和/或提供具有不同选择性的产品 相对于非氟化底物的类似反应。拟议战略的制定将使 药物化学家获得新的和独特的生物探针和疗法。第二个长期目标是 探索可能影响药物稳定性的氟化亚结构带来的物理化学扰动， 分布、代谢和/或配基-蛋白质相互作用，并将这些原理应用于下一步的设计- 产生具有改进的类药物特性的氟化治疗候选药物。在我们下一阶段的工作中， 我们将应用现代创新的合成反应来提供新一代天然氟化类似物 产品将保留有治疗价值的药效学作用，并提高稳定性和 相对于母体化合物的分布。