Molecular interaction fields vs. quantum-mechanical-based descriptors in the modelling of lipophilicity of platinum(iv) complexes

Abstract

We report QSAR calculations using VolSurf descriptors to model the lipophilicity of 53 Pt (IV) 5 complexes with a diverse range of axial and equatorial ligands. Lipophilicity is measured using an efficient HPLC method. Previous models based on a subset of this data are shown to be inadequate, due to incompatibility of whole molecule descriptors between axial carboxylate and hydroxo ligands. Instead, the interaction surfaces of complexes with various probes are used as independent descriptors. Partial least squares modelling using three latent variables results in an accurate (R 2 = 0.92) and robust model 10 (Q 2 = 0.87) of lipophilicity, that moreover highlights the importance of size and hydrophobicity terms and the modest relevance of hydrogen bonding.3

Development and Validation of Liquid Chromatography-Based Methods to Assess the Lipophilicity of Cytotoxic Platinum(IV) Complexes

“…However, a restricted access to such instrumentation may have favoured the recent emergence of chromatographic lipophilicity parameters for metallodrugs [24,26,31,32]. So far, correlations between Log P and chromatographic parameters have been derived only for relatively homogenous series [20,25,35]. Thus, such approaches are presented and validated here to directly obtain Log P from shake flask experiments and indirectly by converting the chromatographic lipophilicity parameter φ 0 into Log P (Scheme 1).…”

“…The current investigation was performed with a set of 19 structurally diverse cytotoxic platinum(IV) complexes (Table 1). An additional set of 34 platinum(IV) complexes was used to test the conversion of the chromatographic lipophilicity parameter φ 0 into Log P. A detailed list of the additionally employed compounds can be found in Tables S1 and S2. only for relatively homogenous series [20,25,35]. Thus, such approaches are presented and validated here to directly obtain Log P from shake flask experiments and indirectly by converting the chromatographic lipophilicity parameter φ0 into Log P (Scheme 1).…”

“…Hyphenation of microemulsion electrokinetic chromatography to ICP-MS is a promising alternative but is experimentally demanding [23]. Due to restrictions in accessing such instruments, the chromatographically determined lipophilicity parameter Log k w has recently become more popular [24][25][26]. In addition, quantitative structure property relationships have been developed for modelling the lipophilicity of platinum complexes, and a free access database for the prediction of their Log P values is available [20,25,[27][28][29][30].…”

The Block Relevance (BR) analysis to aid medicinal chemists to determine and interpret lipophilicity

“…Despite their statistical robustness, PLS models cannot be easily interpreted in mechanistic terms by medicinal chemists. To 70 overcome this limit, some authors used VIPs plots 19 . Figure 1) the relevance of a certain block in the PLS model: the higher the value, the more important the block.…”

Functional fluorescent nonporous silica nanoparticles as carriers for Pt(IV) anticancer prodrugs

“…Complexes 1 and 2 were prepared according to literature procedures by reacting the dihydroxido precursors 1-OH and 2-OH, obtained from oxidation of cisplatin with hydrogen peroxide in different solvents, with succinic anhydride (Scheme 3) [9,16,48,53].…”