Amphiphilic Cu(II) Oxacyclen Complexes: From Oxidative Cleavage to Condensation of DNA

TL;DR

This study shows that Cu(II) complexes with different alkyl chain lengths can either cut or condense DNA, depending on the chain length, making them promising DNA modulators.

Contribution

The study reveals that alkyl chain length in Cu(II) oxacyclen complexes determines whether DNA is cleaved or aggregated.

Findings

Shorter alkyl chains enable ROS-mediated DNA cleavage through hydroxyl radicals and hydrogen peroxide.

Longer alkyl chains cause DNA condensation and aggregation in a concentration-dependent manner.

Alkylation enhances DNA-binding affinity, with the chain length influencing interaction with the DNA major groove.

Abstract

Cu(II) complexes with monoalkylated oxacyclen ligands (C12, C16, and C18) have been investigated regarding their interaction with DNA by different methods: circular dichroism, UV/VIS (ultraviolet‐visible) and fluorescence spectroscopy as well as by gel electrophoresis. The results demonstrate that the complexes can cleave DNA through both hydrolytic and oxidative mechanisms, with hydroxyl radicals and hydrogen peroxide identified as the reactive oxygen species involved. The targeted incorporation of alkyl chains significantly enhances the DNA‐binding affinity of the Cu(II) complexes, and the length of the alkyl substituents plays an important role, as they can interact with the major groove of the DNA. Alkylation is the determining structural factor responsible for the enhanced DNA interaction, since such an interaction is not observed with unsubstituted complexes. Moreover, the length of the alkyl chains significantly influences this behavior, as longer substituents induce a concentration‐dependent DNA aggregation, a phenomenon absent in the nonalkylated analog. This aggregation and condensation behavior is examined using atomic force microscopy and dynamic light scattering. Moreover, DNA/small molecule interactions are also investigated using molecular dynamics simulations.

Monoalkylated Cu(II) oxacyclen complexes show a dual DNA effect: shorter alkyl chains enable ROS‐mediated DNA cleavage, whereas longer chains cause strong DNA condensation/aggregation. Thus, chain length controls activity. Using circular dichroism, UV/visible and fluorescence spectroscopy, atomic force microscopy, dynamic light scattering, and molecular dynamics, we demonstrate that amphiphilic Cu(II) complexes are promising DNA modulators.© 2026 WILEY‐VCH GmbH

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