A quantitative structure–activity approach for lipophilicity estimation of antitumor complexes of different metals using microemulsion electrokinetic chromatography

Microemulsion electrokinetic chromatography (MEEKC) offers a valuable tool for the rapid and highly productive determination of lipophilicity for metal-based anticancer agents. In this investigation, the MEEKC technique was applied for estimation of n-octanol–water partition coefficient (log Poct) of a series of antiproliferative complexes of gallium(III) and iron(III) with 4N-substituted α-N-heterocyclic thiosemicarbazones. Analysis of relationships between the experimental log Poct and the retention factors of compounds showed their satisfactory consistency in the case of single metal sets, as well as for both metals. Since none of available calculation programs allows for evaluating the contribution of central metal ion into log Poct (i.e. Δlog Poct) of complexes of different metals, this parameter was measured experimentally, by the standard ‘shake-flask’ method. Extension of the log Poct programs by adding Δlog Poct data resulted in good lipophilicity predictions for the complexes of gallium(III) and iron(III) included in one regression set. Comparison of metal-thiosemicarbazonates under examination in terms of log Poct vs. antiproliferative activities (i.e. 50% inhibitory concentration in cancer cells) provided evidence that their cytotoxic potency is associated with the ability to cross the lipid bilayer of the cell-membrane via passive diffusion.