Incorporation of β‐Alanine in Cu(II) ATCUN Peptide Complexes Increases ROS Levels, DNA Cleavage and Antiproliferative Activity

Redox‐active Cu(II) complexes are able to form reactive oxygen species (ROS) in the presence of oxygen and reducing agents. Recently, Faller et al. reported that ROS generation by Cu(II) ATCUN complexes is not as high as assumed for decades. High complex stability results in silencing of the Cu(II)/...

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Published in:Chemistry : a European journal 2021-12, Vol.27 (72), p.18093-18102
Main Authors: Heinrich, Julian, Bossak‐Ahmad, Karolina, Riisom, Mie, Haeri, Haleh H., Steel, Tasha R., Hergl, Vinja, Langhans, Alexander, Schattschneider, Corinna, Barrera, Jannis, Jamieson, Stephen M. F., Stein, Matthias, Hinderberger, Dariush, Hartinger, Christian G., Bal, Wojciech, Kulak, Nora
Format: Article
Language:English
Subjects:
Alanine
Amino acids
Antineoplastic Agents - pharmacology
ATCUN peptides
beta-Alanine - pharmacology
Cell Line, Tumor
Chemistry
Cleavage
Coordination Complexes - pharmacology
Copper
Cytotoxicity
Deoxyribonucleic acid
DNA
DNA Cleavage
Electrical measurement
Electrostatic properties
Emission spectroscopy
Fluorescence
Humans
Hydrogen peroxide
Nuclease
Oxidation
Peptides
Peptides - pharmacology
Plasmids
Potentiometric analysis
Reactive Oxygen Species
Reducing agents
Spectroscopy
Spectrum analysis
Toxicity
Tumor cell lines
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Summary:Redox‐active Cu(II) complexes are able to form reactive oxygen species (ROS) in the presence of oxygen and reducing agents. Recently, Faller et al. reported that ROS generation by Cu(II) ATCUN complexes is not as high as assumed for decades. High complex stability results in silencing of the Cu(II)/Cu(I) redox cycle and therefore leads to low ROS generation. In this work, we demonstrate that an exchange of the α‐amino acid Gly with the β‐amino acid β‐Ala at position 2 (Gly2→β‐Ala2) of the ATCUN motif reinstates ROS production (•OH and H2O2). Potentiometry, cyclic voltammetry, EPR spectroscopy and DFT simulations were utilized to explain the increased ROS generation of these β‐Ala2‐containing ATCUN complexes. We also observed enhanced oxidative cleavage activity towards plasmid DNA for β‐Ala2 compared to the Gly2 complexes. Modifications with positively charged Lys residues increased the DNA affinity through electrostatic interactions as determined by UV/VIS, fluorescence, and CD spectroscopy, and consequently led to a further increase in nuclease activity. A similar trend was observed regarding the cytotoxic activity of the complexes against several human cancer cell lines where β‐Ala2 peptide complexes had lower IC50 values compared to Gly2. The higher cytotoxicity could be attributed to an increased cellular uptake as determined by ICP‐MS measurements. Generation of reactive oxygen species was achieved with a redox‐silent Cu(II) ATCUN complex by replacing the α‐amino acid glycine with β‐alanine. Increased ROS production led to higher oxidative DNA cleavage activity. The reasons for this higher activity were elucidated via potentiometry, cyclic voltammetry, EPR, UV/VIS spectroscopy and DFT. In cytotoxicity assays, β‐alanine peptide complexes showed lower IC50 values in several cancer cell lines compared with the glycine analogs, which could be correlated with the amounts of Cu taken up by cells.
ISSN:0947-6539
1521-3765
1521-3765
DOI:10.1002/chem.202102601