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The impact of the equatorial coordination sphere on the reduction behavior (i.e. rate of reduction) of platinum(IV) complexes with axial carboxylato ligands was studied. Moreover, the influence of equatorial ligands on the stability, lipophilicity and cytotoxicity of platinum(IV) compounds was evaluated. For this purpose, a series of platinum(IV) complexes featuring axial carboxylato ligands (succinic acid monoesters) was synthesized; anionic carboxylato (OAc - , oxalate) and halido (Cl - , Br - , I - ) ligands served as leaving groups and am(m)ine carrier ligands were provided by monodentately (isopropylamine, ammine+cyclohexaneamine) or bidentately (ethane-1,2-diamine) coordinating am(m)ines. All platinum(IV) products were fully characterized based on elemental analysis, high resolution mass spectrometry and multinuclear ( 1 H, 13 C, 15 N, 195 Pt) NMR spectroscopy as well as by X-ray diffraction in some cases. The rate of reduction in the presence of ascorbic acid was determined by NMR spectroscopy and the lipophilicity of the complexes was investigated by analytical reversed phase HPLC measurements. Cytotoxic properties were studied by means of a colorimetric microculture assay in three human cancer cell lines derived from cisplatin sensitive ovarian teratocarcinoma (CH1/PA-1) as well as cisplatin insensitive colon carcinoma (SW480) and non-small cell lung cancer (A549)., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The current study aims to elucidate the possible reasons for the significantly different pharmacological behavior of platinum(IV) complexes with cisplatin-, carboplatin- or nedaplatin-like cores and how this difference can be related to their main physicochemical properties. Chlorido-containing complexes are reduced fast (within hours) by ascorbate and are able to unwind plasmid DNA in the presence of ascorbate, while their tri- and tetracarboxylato analogs are generally inert under the same conditions. Comparison of the lipophilicity, cellular accumulation and cytotoxicity of the investigated platinum compounds revealed the necessity to define new structure-property/activity relationships (SPRs and SARs). The higher activity and improved accumulation of platinum(IV) complexes bearing Cl(-) in equatorial position cannot only be attributed to passive diffusion facilitated by their lipophilicity. Therefore, further platinum accumulation experiments under conditions where active/facilitated transport mechanisms are suppressed were performed. Under hypothermic conditions (4°C), accumulation of dichloridoplatinum(IV) complexes is reduced down to 10% of the amount determined at 37°C. These findings suggest the involvement of active and/or facilitated transport in cellular uptake of platinum(IV) complexes with a cisplatin-like core. Studies with ATP depletion mediated by oligomycin and low glucose partially confirmed these observations, but their feasibility was severely limited in the adherent cell culture setting., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The octanol/water partition coefficient, logP, is one of the most important physico-chemical parameters for the development of new metal-based anticancer drugs with improved pharmacokinetic properties. This study addresses an issue with the absence of publicly available models to predict logP of Pt(IV) complexes. Following data collection and subsequent development of models based on 187 complexes from literature, we validate new and previously published models on a new set of 11 Pt(II) and 35 Pt(IV) complexes, which were kept blind during the model development step. The error of the consensus model, 0.65 for Pt(IV) and 0.37 for Pt(II) complexes, indicates its good accuracy of predictions. The lower accuracy for Pt(IV) complexes was attributed to experimental difficulties with logP measurements for some poorly-soluble compounds. This model was developed using general-purpose descriptors such as extended functional groups, molecular fragments and E-state indices. Surprisingly, models based on quantum-chemistry calculations provided lower prediction accuracy. We also found that all the developed models strongly overestimate logP values for the three complexes measured in the presence of DMSO. Considering that DMSO is frequently used as a solvent to store chemicals, its effect should not be overlooked when logP measurements by means of the shake flask method are performed. The final models are freely available at http://ochem.eu/article/76903., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A series of novel symmetrically and unsymmetrically coordinated platinum(IV) complexes with monodentate carboxylato ligands was synthesized. The compounds exhibit a general coordination sphere of [Pt(en)(OCOR)2(OCOR')(OCOR″)], where the carboxylato ligands are represented by acetato and succinic acid monoester ligands. Dicarboxylatoplatinum(II) complexes were synthesized and oxidized symmetrically or unsymmetrically to obtain platinum(IV) complexes, which were subsequently carboxylated with noncyclic anhydrides. The compounds were investigated in detail by elemental analysis, mass spectrometry, infrared and multinuclear ((1)H, (13)C, (15)N, (195)Pt) NMR spectroscopy as well as by X-ray diffraction in some cases. The reduction behavior was followed by NMR spectroscopy, while stability and lipophilicity were examined by analytical reversed phase HPLC measurements. Cytotoxic properties were studied in three human cancer cell lines derived from cisplatin sensitive ovarian teratocarcinoma (CH1/PA-1), cisplatin insensitive colon carcinoma (SW480) and non-small cell lung cancer (A549). Thereby, the most lipophilic (yet water soluble) platinum(IV) complexes showed promising IC50 values in the low micromolar and even nanomolar range, demonstrating the significant advantage of using equatorially coordinated monodentate carboxylato ligands., (Copyright © 2015 Elsevier Inc. All rights reserved.)