Development and Validation of Liquid Chromatography-Based Methods to Assess the Lipophilicity of Cytotoxic Platinum(IV) Complexes
Development and Validation of Liquid Chromatography-Based Methods to Assess the Lipophilicity of Cytotoxic Platinum(IV) Complexes
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DOI：
10.3390/inorganics6040130
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发表时间：
2018-12-01
期刊：
影响因子：
2.9
通讯作者：
Keppler, Bernhard K.
中科院分区：
文献类型：
--
作者：
Klose, Matthias H. M.;Theiner, Sarah;Keppler, Bernhard K.
亲脂性是药物发现的关键参数，通常由辛醇和水之间的对数分配系数（Log P）确定。然而，可用的检测方法限制了分配系数在无机药物化学中的广泛使用，并且最近的研究已经转向色谱亲脂性参数，通常没有转换以导出Log P。由于高效液相色谱（HPLC）仪器易于为研究组所用，提出并验证了一种基于HPLC的方法，以获得一组19种结构多样且具有细胞毒性的铂（IV）络合物的分配系数，该络合物表现出至少四个数量级的动态范围。通过实验测定了同一组化合物的色谱亲脂性参数phi（0）和Log k（w），并获得了允许两个亲脂性标度之间相互转换的相关性，该相关性适用于另外一组34种铂（IV）候选药物。因此，phi（0）= 58对应于Log P = 0。成功地评价了相同的方法，以确定五种可电离铂（IV）化合物的分配系数（Log D），从而对亲脂性产生pH依赖性影响。本研究提供了直接的基于HPLC的方法，以确定Log P和phi（0）形式的细胞毒性铂（IV）络合物的亲脂性，这些络合物可以相互转化并易于扩展到其他金属基化合物类别。
Lipophilicity is a crucial parameter for drug discovery, usually determined by the logarithmic partition coefficient (Log P) between octanol and water. However, the available detection methods have restricted the widespread use of the partition coefficient in inorganic medicinal chemistry, and recent investigations have shifted towards chromatographic lipophilicity parameters, frequently without a conversion to derive Log P. As high-performance liquid chromatography (HPLC) instruments are readily available to research groups, a HPLC-based method is presented and validated to derive the partition coefficient of a set of 19 structurally diverse and cytotoxic platinum(IV) complexes exhibiting a dynamic range of at least four orders of magnitude. The chromatographic lipophilicity parameters phi(0) and Log k(w) were experimentally determined for the same set of compounds, and a correlation was obtained that allows interconversion between the two lipophilicity scales, which was applied to an additional set of 34 platinum(IV) drug candidates. Thereby, a phi(0) = 58 corresponds to Log P = 0. The same approaches were successfully evaluated to determine the distribution coefficient (Log D) of five ionisable platinum(IV) compounds to sample pH-dependent effects on the lipophilicity. This study provides straight-forward HPLC-based methods to determine the lipophilicity of cytotoxic platinum(IV) complexes in the form of Log P and phi(0) that can be interconverted and easily expanded to other metal-based compound classes.