The influence of different carbonate ligands on the hydrolytic stability and reduction of platinum(iv) prodrugs

Abstract

Pt(IV) complexes bearing axial carbonate linkages have drawn much attention recently. A synthetic method behind this allows the hydroxyl group of bioactive ligands to be attached to the available hydroxyl group of Pt(IV) complexes, and the rapid release of free drugs is achieved after the reduction of carbonate-linked Pt(IV) complexes. Further understanding on the properties of Pt(IV) carbonates such as hydrolytic stability and reduction profiles, however, is hindered by limited research. Herein, six mono-carbonated Pt(IV) complexes in which the carbonate axial ligands possess various electron-withdrawing powers were synthesized, and the corresponding mono-carboxylated analogues were also prepared as references to highlight the different properties. The influence of the coordination environment towards the hydrolysis and reduction rate of Pt(IV) carbonates and carboxylates was explored. The mono-carbonated Pt(IV) complexes are both less stable and reduced faster than the corresponding mono-carboxylated ones. Moreover, the hydrolysis and reduction profiles are dependent not only on the electron-withdrawing ability of the carbonates but also on the nature of the opposite axial ligands. Besides, the exploration of the hydrolytic pathway for Pt(IV) carbonates suggests that the process proceeds by an attack of OH⁻ on the carbonyl carbon, followed by elimination, which is different from that of Pt(IV) carboxylates. This study provides some information on the influence of axial carbonate ligands with different electron-withdrawing abilities on the properties of the Pt(IV) center, which may inspire new thoughts on the design of “multi-action” Pt(IV) prodrugs.