Department of Chemistry, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Quebec, H7S 2G5, Canada.
J Med Chem. 2013 Sep 12;56(17):7073-83. doi: 10.1021/jm4008714. Epub 2013 Aug 22.
A simple NMR assay was applied to monitor the tendency of compounds to self-aggregate in aqueous media. The observation of unusual spectral trends as a function of compound concentration appears to be signatory of the formation of self-assemblies. (1)H NMR resonances of aggregating compounds were sensitive to the presence of a range of molecular assemblies in solution including large molecular-size entities, smaller multimers, and mixtures of assembled species. The direct observation of aggregates via unusual NMR spectra also correlated with promiscuous behavior of molecules in off-target in vitro pharmacology assays. This empirical assay can have utility for predicting compound promiscuity and should complement predictive methods that principally rely on the computing of descriptors such as lipophilicity (cLogP) and topological surface area (TPSA). This assay should serve as a practical tool for medicinal chemists to monitor compound attributes in aqueous solution and various pharmacologically relevant media, as demonstrated herein.
一种简单的 NMR 分析方法被应用于监测化合物在水相介质中自聚集的趋势。观察到化合物浓度的异常光谱趋势似乎是自组装形成的标志。聚集化合物的 (1)H NMR 共振对溶液中存在的各种分子组装体敏感，包括大的分子尺寸实体、较小的多聚体以及组装物种的混合物。通过异常 NMR 光谱直接观察到的聚集物也与分子在体外药理学非靶标测定中的杂乱行为相关。这种经验性测定方法可用于预测化合物的杂乱性，并应补充主要依赖于计算脂溶性 (cLogP) 和拓扑表面积 (TPSA) 等描述符的预测方法。如本文所示，该测定方法可以作为药物化学家监测水溶液和各种药理学相关介质中化合物属性的实用工具。
