Novel Copper-Containing Cytotoxic Agents Based on 2-Thioxoimidazolones
| Autor: | Nikolay V. Zyk, Dmitry A Sakharov, Dmitry A. Guk, Vita N. Nikitina, Alexander Erofeev, Dmitrii M. Mazur, Vadim S. Pokrovsky, Anna A. Moiseeva, Alexey E Naumov, Petr V. Gorelkin, Mikhail A. Soldatov, Roman Akasov, Alexander G. Majouga, Victor V. Shapovalov, A. S. Semkina, Mikhail Ya. Melnikov, Irina V Zhirkina, Olga O. Krasnovskaya, Elena K. Beloglazkina, Vladimir I. Pergushov, Viktor A. Tafeenko, Kseniya Yu. Vlasova, Dmitry A. Skvortsov, Saida S Karshieva, Oksana O Ryabaya, Alexander V. Soldatov, Radik R. Shafikov, Vasily M. Gerasimov, Alexander Vaneev |
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| Rok vydání: | 2020 |
| Předmět: |
DNA damage
Molecular Conformation chemistry.chemical_element Antineoplastic Agents Apoptosis Crystallography X-Ray Ligands Models Biological 01 natural sciences Redox Coordination complex Metal Structure-Activity Relationship 03 medical and health sciences Coordination Complexes Spheroids Cellular Drug Discovery Humans Structure–activity relationship Cytotoxicity Telomerase 030304 developmental biology chemistry.chemical_classification 0303 health sciences Chemistry Imidazoles Copper Combinatorial chemistry 0104 chemical sciences 010404 medicinal & biomolecular chemistry DNA Intercalation visual_art MCF-7 Cells visual_art.visual_art_medium Molecular Medicine Reactive Oxygen Species Oxidation-Reduction DNA Damage |
| Zdroj: | Journal of Medicinal Chemistry. 63:13031-13063 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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