Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States.
Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, 1051 Biomedical Science Tower 3, 3501 Fifth Avenue, Pittsburgh, Pennsylvania 15261, United States.
Anal Chem. 2021 Jun 15;93(23):8210-8218. doi: 10.1021/acs.analchem.1c00784. Epub 2021 Jun 3.
Fluorine-containing compounds comprise 20 to 30 percent of all commercial drugs, and the proportion of fluorinated pharmaceuticals is rapidly growing. While magic angle spinning (MAS) NMR spectroscopy is a popular technique for analysis of solid pharmaceutical compounds, fluorine has been underutilized as a structural probe so far. Here, we report a fast (40-60 kHz) MAS F NMR approach for structural characterization of fluorine-containing crystalline pharmaceutical compounds at natural abundance, using the antimalarial fluorine-containing drug mefloquine as an example. We demonstrate the utility of 2D F-C and F-F dipolar-coupling-based correlation experiments for F and C resonance frequency assignment, which permit identification of crystallographically inequivalent sites. The efficiency of F-C cross-polarization and the effect of H and F decoupling on spectral resolution and sensitivity were evaluated in a broad range of experimental conditions. We further demonstrate a protocol for measuring accurate interfluorine distances based on 1D DANTE-RFDR experiments combined with multispin numerical simulations.
含氟化合物占所有商业药物的 20%至 30%，含氟药物的比例正在迅速增长。虽然魔角旋转（MAS）NMR 光谱学是分析固体药物化合物的常用技术，但迄今为止，氟在结构探针方面的应用一直不足。在这里，我们报告了一种快速（40-60 kHz）MAS F NMR 方法，用于在自然丰度下对含氟晶态药物化合物进行结构表征，以抗疟药物氟氯喹为例。我们展示了二维 F-C 和 F-F 偶极耦合相关实验在 F 和 C 共振频率分配中的应用，这允许鉴定晶体学不等同的位点。在广泛的实验条件下，评估了 F-C 交叉极化的效率以及 H 和 F 去耦对光谱分辨率和灵敏度的影响。我们进一步展示了一种基于 1D DANTE-RFDR 实验结合多自旋数值模拟测量准确的氟氟距离的方案。
