Abstract
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 φ0 and Log kw 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 φ0 = 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 φ0 that can be interconverted and easily expanded to other metal-based compound classes.
Highlights
Optimising lipophilicity is a crucial process in drug discovery [1,2], because it significantly affects the diffusion of drugs through cell membranes and plays a role in pharmacokinetic processes, including absorption, distribution, metabolism, and excretion [2,3]
The Organisation for Economic Cooperation and Development (OECD) has outlined the standard method for experimentally obtaining partition coefficients of investigational compounds by the shake flask method [7], which is followed by an appropriate detection technique such as photometry, gas chromatography, or high-performance liquid chromatography (HPLC) [7,8,9]
Results and Typically, lipophilicity is determined by the shake flask method as the logarithmic partition coefficient
Summary
Optimising lipophilicity is a crucial process in drug discovery [1,2], because it significantly affects the diffusion of drugs through cell membranes and plays a role in pharmacokinetic processes, including absorption, distribution, metabolism, and excretion [2,3]. Some authors have suggested that an optimal lipophilicity might increase the chances of success during drug development [1]. Lipophilicity is typically determined by means of a compound’s partition coefficient between octanol and water on a logarithmic scale, commonly abbreviated as Log Po/w , called. Log P [4,5,6]. The Organisation for Economic Cooperation and Development (OECD) has outlined the standard method for experimentally obtaining partition coefficients of investigational compounds by the shake flask method [7], which is followed by an appropriate detection technique such as photometry, gas chromatography, or high-performance liquid chromatography (HPLC) [7,8,9]. The partition coefficient obtained by the shake flask method is typically found between −2 < Log P. Hydrophilic compounds are characterised by negative values and lipophilic compounds by positive values
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