The impact of highly electron withdrawing carboxylato ligands on the stability and activity of platinum(IV) pro-drugs

Abstract

Recent developments in the design of platinum(IV) pro-drug candidates have demonstrated the importance of the coordination sphere of the complex in determining the resistance to reduction by endogenous reductants and the stability in biologically relevant environments. Diaminetetracarboxylatoplatinum(IV) complexes exhibit many desirable properties as platinum(IV) pro-drugs, exhibiting unusual resistance to reduction by endogenous reductants and in blood serum, but are rapidly reduced within cells. In this study, we used 19F NMR to monitor the aquation of complexes with highly electron withdrawing trifluoroacetato ligands in the axial positions of platinum(IV) and reinterpreted the reduction of these complexes by ascorbate and cysteine and their biological behaviour in the light of the aquation results. We concluded that the potential for aquation needs to be taken into account in interpreting reduction and cytotoxicity studies. While we show that this is possible for the reduction studies, we conclude that it is not possible for cytotoxicity studies and other studies in complex biological environments. We also note that the low stability of the complexes is not expected to be compatible with their use as pro-drugs.