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.

概括 有机化合物的氟化会影响物理化学特性，在医疗环境中 药效，药代动力学，分布和/或代谢谱在体外和体内。那， 能够在轻度条件下选择性安装氟化组的能力对于获得新疗法至关重要 和生物问题。但是，氟化底物和/或试剂的独特物理特性通常 扰动基本有机反应率，这可能使合成序列复杂化以获取氟化 化合物。这是许多常规有机反应在存在氟化试剂或 With fluorinated substrates.此外，氟化底物的独特特性使新的反应率 相对非氟化的对应物无法实现，这为发展提供了机会 创新的反应和访问药物相关子结构的策略 有了这个R35计划，Altman Group的长期目标是开发创新的催化剂系统， 试剂和/或合成策略，用于访问与药物相关的氟化子结构。在这个领域， 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功能化，脱氧氟烷基化，过渡金属催化反应），使合成化学家能够 将简单且随时可用的功能组（例如醇，羰基，氟烷烃）转换为宽阔 高度有价值的氟化类似物的光谱。此外，我们探讨了合成转换 氟化子结构通过不同的机制和/或提供不同选择性的产品做出反应 相对于非荧光底物的类似反应。拟议策略的制定将实现 医学化学家可以获得新的独特生物学问题和治疗。第二个长期目标是 探索可能影响药物稳定性的氟化子结构所赋予的身体扰动， 分布，代谢和/或配体 - 蛋白质相互作用，并在下一步的设计中应用此类原理 具有改善类似药物的特性的氟化治疗候选者。在我们的下一阶段， 我们将应用现代创新的合成反应，以提供自然的下一代氟化类似物 将保留具有治疗价值的药效动作并提高稳定性和的产品 相对于母体化合物的分布。