Novel Copper-Containing Cytotoxic Agents Based on 2-Thioxoimidazolones.
Olga O KrasnovskayaDmitry A GukAlexey E NaumovVita N NikitinaAlevtina S SemkinaKseniya Yu VlasovaVadim PokrovskyOksana O RyabayaSaida S KarshievaDmitry A SkvortsovIrina V ZhirkinaRadik R ShafikovPetr V GorelkinAlexander N VaneevAlexander S ErofeevDmitrii M MazurViktor A TafeenkoVladimir I PergushovMikhail Ya MelnikovMikhail A SoldatovVictor V ShapovalovAlexander V SoldatovRoman A AkasovVasily M GerasimovDmitry A SakharovAnna A MoiseevaNikolay V ZykElena K BeloglazkinaAlexander G MajougaPublished in: Journal of medicinal chemistry (2020)
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.
Keyphrases
- dna damage
- aqueous solution
- metal organic framework
- cell death
- oxidative stress
- cell cycle arrest
- reactive oxygen species
- structure activity relationship
- induced apoptosis
- electron transfer
- nitric oxide
- dna repair
- emergency department
- endoplasmic reticulum stress
- circulating tumor
- mass spectrometry
- high resolution
- breast cancer cells
- climate change
- adverse drug
- molecular dynamics simulations