Novel Copper-Containing Cytotoxic Agents Based on 2-Thioxoimidazolones
Olga O. Krasnovskaya, Dmitry A. Guk, Alexey Naumov, Вита Н. Никитина, Alevtina S. Semkina, Kseniya Yu. Vlasova, Vadim S. Pokrovsky, O. O. Ryabaya, Saida Sh. Karshieva, Dmitry A. Skvortsov, Irina V. Zhirkina, Radik R. Shafikov, Petr V. Gorelkin, Alexander N. Vaneev, Alexander S. Erofeev, Dmitrii M. Mazur, В. А. Тафеенко, V. I. Pergushov, Mikhail Ya. Melnikov, Mikhail A. Soldatov, В. В. Шаповалов, А. В. Солдатов, Roman Akasov, Vasily M. Gerasimov, Dmitry Sakharov, Anna A. Moiseeva, Н. В. Зык, Елена К. Белоглазкина, Alexander G. Majouga
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.