A Dogma in Doubt: Hydrolysis of Equatorial Ligands of Pt^IV Complexes under Physiological Conditions

Abstract

Due to their high kinetic inertness and consequently reduced side reactions with biomolecules, PtIV complexes are considered to define the future of anticancer platinum drugs. The aqueous stability of a series of biscarboxylato PtIV complexes was studied under physiologically relevant conditions. Unexpectedly and in contrast to the current chemical understanding, especially oxaliplatin and satraplatin complexes underwent fast hydrolysis in equatorial position (even in cell culture medium and serum). Notably, the resulting hydrolysis products strongly differ in their reduction kinetics, a crucial parameter for the activation of PtIV drugs, which also changes the anticancer potential of the compounds in cell culture. The discovery that intact PtIV complexes can hydrolyze at equatorial position contradicts the dogma on the general kinetic inertness of PtIV compounds and needs to be considered in the screening and design for novel platinum‐based anticancer drugs.

Theoretical Prediction of Dual-Potency Anti-Tumor Agents: Combination of Oxoplatin with Other FDA-Approved Oncology Drugs

“…Despite increasing interest in the possible associations between oxoplatin and other drugs [ 41 , 42 , 43 , 44 , 45 , 46 ], there is currently no recommended approach to systematically improving the anti-cancer activity of bifunctional drugs based on Pt(IV). With the aim of contributing to the design of enhanced anti-cancer drugs, we used a state-of-the-art computational approach to screen the latest FDA-approved oncology drugs.…”

Luminescent PtII and PtIV Platinacycles with Anticancer Activity Against Multiplatinum‐Resistant Metastatic CRC and CRPC Cell Models

“…The stability of the Pt IV compound 3 a in the aqueous biological medium was evaluated by 1 H NMR spectroscopy in D 2 O and two drops of [D 6 ]DMSO. The obtained spectra (Figure S12, Supporting Information) suggests the formation of a mixture of solvato complexes, which is in line with recent observations of aquation of equatorial ligands of Pt IV compounds …”

Pt(IV) Anticancer Prodrugs – A Tale of Mice and Men

“…We developed new procedures for oxidation of Pt(II) compounds [29–31] and new protocols for conjugation of hydroxyl and amino containing molecules to the axial positions via carbonate and carbamate links [27,28] . We learned that Pt(IV) complexes are less stable than originally assumed [32,33] and that rates of reduction do not necessarily correlate with reduction potentials [34] and that reduction of Pt(IV) complexes can yield several products [35] …”