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Development and Validation of Liquid Chromatography-Based Methods to Assess the Lipophilicity of Cytotoxic Platinum(IV) Complexes
by
Matthias H. M. Klose 1,2
, Sarah Theiner 3, Hristo P. Varbanov 1,4, Doris Hoefer 1, Verena Pichler 1,5, Markus Galanski 1, Samuel M. Meier-Menches 2,3,* and Bernhard K. Keppler 1,2,*
Matthias H. M. Klose 1,2, Sarah Theiner 3, Hristo P. Varbanov 1,4, Doris Hoefer 1, Verena Pichler 1,5, Markus Galanski 1, Samuel M. Meier-Menches 2,3,* and Bernhard K. Keppler 1,2,*
1
Institute of Inorganic Chemistry, University of Vienna, 1090 Vienna, Austria
2
Research Cluster ‘Translational Cancer Therapy Research’, University of Vienna, 1090 Vienna, Austria
3
Department of Analytical Chemistry, University of Vienna, 1090 Vienna, Austria
4
Institute of Chemistry—Inorganic Chemistry, University of Graz, 8010 Graz, Austria
5
Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, 1090 Vienna, Austria
*
Authors to whom correspondence should be addressed.
Inorganics 2018, 6(4), 130; https://doi.org/10.3390/inorganics6040130
Received: 2 October 2018 / Revised: 19 November 2018 / Accepted: 29 November 2018 / Published: 4 December 2018
(This article belongs to the Special Issue Unconventional Anticancer Metallodrugs and Strategies to Improve their Pharmacological Profile)
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.
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Keywords:
φ0; anticancer agents; chromatographic lipophilicity parameter; distribution coefficient; HPLC; lipophilicity; Log kw; Log P; partition coefficient; platinum(IV)
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
MDPI and ACS Style
Klose, M.H.M.; Theiner, S.; Varbanov, H.P.; Hoefer, D.; Pichler, V.; Galanski, M.; Meier-Menches, S.M.; Keppler, B.K. Development and Validation of Liquid Chromatography-Based Methods to Assess the Lipophilicity of Cytotoxic Platinum(IV) Complexes. Inorganics 2018, 6, 130.
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