Dual Role of Glutathione as a Reducing Agent and Cu-Ligand Governs the ROS Production by Anticancer Cu-Thiosemicarbazone Complexes.

α-Pyridyl thiosemicarbazones (TSC) such as Triapine (3AP) and Dp44mT are a promising class of anticancer agents. Contrary to Triapine, Dp44mT showed a pronounced synergism with Cu II , which may be due to the generation of reactive oxygen species (ROS) by Dp44mT-bound Cu II ions. However, in the intracellular environment, Cu II complexes have to cope with glutathione (GSH), a relevant Cu II reductant and Cu I -chelator. Here, aiming at rationalizing the different biological activity of Triapine and Dp44mT, we first evaluated the ROS production by their Cu II -complexes in the presence of GSH, showing that Cu II -Dp44mT is a better catalyst than Cu II -3AP. Furthermore, we performed density functional theory (DFT) calculations, which suggest that a different hard/soft character of the complexes could account for their different reactivity with GSH.