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Dr. Julian Heinrich Dr. Karolina Bossak-Ahmad Mie Riisom Dr. Haleh H. Haeri Tasha R. Steel Vinja Hergl Alexander Langhans Corinna Schattschneider Jannis Barrera Dr. Stephen M. F. Jamieson Prof. Matthias Stein Prof. Dariush Hinderberger Prof. Christian G. Hartinger Prof. Wojciech Bal Prof. Nora Kulak 《Chemistry (Weinheim an der Bergstrasse, Germany)》2021,27(72):18093-18102
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. 相似文献
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