Novel Copper-Containing Cytotoxic Agents Based on 2-Thioxoimidazolones

Abstract

A series of 73 ligands and 73 of their Cu⁺² and Cu⁺¹ copper complexes with different geometries, oxidation states of the metal, and redox activities were synthesized and characterized. The aim of the study was to establish the structure-activity relationship within a series of analogues with different substituents at the N(3) position, which govern the redox potentials of the Cu⁺²/Cu⁺¹ redox couples, ROS generation ability, and intracellular accumulation. Possible cytotoxicity mechanisms, such as DNA damage, DNA intercalation, telomerase inhibition, and apoptosis induction, have been investigated. ROS formation in MCF-7 cells and three-dimensional (3D) spheroids was proven using the Pt-nanoelectrode. Drug accumulation and ROS formation at 40-60 μm spheroid depths were found to be the key factors for the drug efficacy in the 3D tumor model, governed by the Cu⁺²/Cu⁺¹ redox potential. A nontoxic in vivo single-dose evaluation for two binuclear mixed-valence Cu⁺¹/Cu⁺² redox-active coordination compounds, 72k and 61k, was conducted.