Novel Copper-Containing Cytotoxic Agents Based on 2-Thioxoimidazolones

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. ©

Krasnovskaya O.O.1, 2 , Guk D.A.2 , Naumov A.E.2 , Nikitina V.N.2 , Semkina A.S.3, 4 , Vlasova K.Y.2 , Pokrovsky V. 5, 6 , Ryabaya O.O.5 , Karshieva S.S.5 , Skvortsov D.A.2, 7 , Zhirkina I.V.2 , Shafikov R.R.2 , Gorelkin P.V.1 , Vaneev A.N.1, 2 , Erofeev A.S.1 , Mazur D.M.2 , Tafeenko V.A.2 , Pergushov V.I.2 , Melnikov M.Y.2 , Soldatov M.A.8 , Shapovalov V.V.8 , Soldatov A.V.8 , Akasov R.A.1, 9 , Gerasimov V.M.10 , Sakharov D.A.10 , Moiseeva A.A.2 , Zyk N.V.2 , Beloglazkina E.K.2 , Majouga A.G.1, 2, 10
American Chemical Society
Номер выпуска
  • 1 Department of Materials Science of Semiconductors and Dielectrics, National University of Science and Technology MISIS, Leninskiy Prospect 4, Moscow, 101000, Russian Federation
  • 2 Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, 1/3, Moscow, 119991, Russian Federation
  • 3 Department of Medical Nanobiotechnologies, Pirogov Russian National Research Medical University, Ostrovityanova 1, Moscow, 117997, Russian Federation
  • 4 Department of Basic and Applied Neurobiology, Serbsky National Medical Research Center for Psychiatry and Narcology, Kropotkinskiy 23, Moscow, 119991, Russian Federation
  • 5 N.N. Blokhin National Medical Research Center of Oncology, The Ministry of Health of the Russian Federation, Kashirskoe Highway 23, Moscow, 115478, Russian Federation
  • 6 People's Friendship University, Moscow, Russia, Miklukho-Maklaya 6, Moscow, 117198, Russian Federation
  • 7 Department of Biology and Biotechnologies, Higher School of Economics, Myasnitskaya 13, Moscow, 101000, Russian Federation
  • 8 The Smart Materials Research Institute, Southern Federal University Sladkova, 178/24, Rostov-on-Don, 344090, Russian Federation
  • 9 I.M. Sechenov First Moscow State Medical University, Trubetskaya 8-2, Moscow, 119991, Russian Federation
  • 10 Mendeleev University of Chemical Technology of Russia, Miusskaya Sq. 9, Moscow, 125047, Russian Federation
Ключевые слова
antineoplastic agent; coordination compound; copper; imidazole derivative; imidazolone; ligand; reactive oxygen metabolite; telomerase; apoptosis; biological model; chemistry; conformation; DNA damage; drug effect; human; MCF-7 cell line; metabolism; multicellular spheroid; oxidation reduction reaction; structure activity relation; X ray crystallography; Antineoplastic Agents; Apoptosis; Coordination Complexes; Copper; Crystallography, X-Ray; DNA Damage; Humans; Imidazoles; Ligands; MCF-7 Cells; Models, Biological; Molecular Conformation; Oxidation-Reduction; Reactive Oxygen Species; Spheroids, Cellular; Structure-Activity Relationship; Telomerase
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