Water-mediated reduction of [Cu(dmp)2(CH3CN)]2+: Implications of the structure of a classical complex on its activity as an anticancer drug

Abstract

The interplay between coordination geometry and reactivity in copper complexes has been widely studied for years. ForCuII, it is known that the reduction is favored when the geometry is closer to that of the CuI state, which is mainly tetrahedral.Conversely, the reduction of CuII complexes in the absence of exogenous reducers has been barely addressed. Herein, wereport on the ability of a classic CuII complex to be partially reduced in acetonitrile solutions containing water, in the absenceof external reducers. The role of the structure on the spontaneous reduction is presented by contrasting the geometricfeatures with a related complex, [Cu(phen)2(CH3CN)]2+, which is inert towards the redox process mediated by water. Theparticipation of water in the reduction of [Cu(dmp)2(CH3CN)]2+ is associated with the production of hydroxyl radical. This,prompted us to evaluate the use of [Cu(dmp)2(CH3CN)]2+ as an anticancer metallodrug, showing an activity stronger than[Cu(phen)2(CH3CN)]2+ on 2D and 3D models of bone, lung, and breast cancer cell lines. Furthermore, both complexes aremore active than cisplatin. The main mechanism of action is the intracellular ROS generation, with a higher production ofcytotoxic species by [Cu(dmp)2(CH3CN)]2+. Certainly, the performance of [Cu(dmp)2(CH3CN)]2+ as an anticancer agent and itsreactivity in solution phase are connected through the geometrical constraints imparted by the dmp ligands.