Oxidation of the Platinum(II) Anticancer Agent [Pt{(p-BrC6F4)NCH2CH2NEt2}Cl(py)] to Platinum(IV) Complexes by Hydrogen Peroxide

Abstract

PtIV coordination complexes are of interest as prodrugs of PtII anticancer agents, as they can avoid deactivation pathways owing to their inert nature. Here, we report the oxidation of the antitumor agent [PtII(p-BrC6F4)NCH2CH2NEt2}Cl(py)], 1 (py = pyridine) to dihydroxidoplatinum(IV) solvate complexes [PtIV{(p-BrC6F4)NCH2CH2NEt2}Cl(OH)2(py)].H2O, 2·H2O with hydrogen peroxide (H2O2) at room temperature. To optimize the yield, 1 was oxidized in the presence of added lithium chloride with H2O2 in a 1:2 ratio of Pt: H2O2, in CH2Cl2 producing complex 2·H2O in higher yields in both gold and red forms. Despite the color difference, red and yellow 2·H2O have the same structure as determined by single-crystal and X-ray powder diffraction, namely, an octahedral ligand array with a chelating organoamide, pyridine and chloride ligands in the equatorial plane, and axial hydroxido ligands. When tetrabutylammonium chloride was used as a chloride source, in CH2Cl2, another solvate, [PtIV{(p-BrC6F4)NCH2CH2NEt2}Cl(OH)2(py)].0.5CH2Cl2,3·0.5CH2Cl2, was obtained. These PtIV compounds show reductive dehydration into PtII [Pt{(p-BrC6F4)NCH=CHNEt2}Cl(py)], 1H over time in the solid state, as determined by X-ray powder diffraction, and in solution, as determined by 1H and 19F NMR spectroscopy and mass spectrometry. 1H contains an oxidized coordinating ligand and was previously obtained by oxidation of 1 under more vigorous conditions. Experimental data suggest that oxidation of the ligand is favored in the presence of excess H2O2 and elevated temperatures. In contrast, a smaller amount (1Pt:2H2O2) of H2O2 at room temperature favors the oxidation of the metal and yields platinum(IV) complexes.