Dinuclear Cu(I) mesocate complexes for ROS-mediated DNA cleavage

Area of Science:

• Coordination Chemistry
• Medicinal Inorganic Chemistry
• Biophysical Chemistry

Background:

• Copper complexes offer therapeutic potential in cancer treatment due to their redox activity and cytotoxicity.
• Existing copper anticancer agents often require in situ reduction from Cu(II) to the active Cu(I) state.
• There is a need for stable Cu(I) complexes that can directly exert therapeutic effects.

Purpose of the Study:

• To synthesize and characterize novel dinuclear copper(I) complexes with a mesocate architecture.
• To evaluate the effect of halide ligands (Cl vs. Br) on the artificial nuclease activity of these complexes.
• To elucidate the mechanism of DNA cleavage and DNA-binding interactions.

Main Methods:

• Synthesis and full characterization of dinuclear copper(I) complexes using a hydrazine-based ligand.
• Evaluation of artificial nuclease activity through DNA cleavage assays.
• Mechanistic studies involving reactive oxygen species detection and DNA interaction analysis using cyclic voltammetry, circular dichroism, UV-Vis spectroscopy, and fluorescence assays.

Main Results:

• Two novel dinuclear copper(I) mesocate complexes, [Cu₂L₂Cl₂]·3CH₃OH (C1) and [Cu₂L₂Br₂] (C2), were successfully synthesized and characterized.
• These complexes represent the first Cu(I) mesocates with a [P₂NX] kernel (X = Cl, Br).
• The bromide complex (C2) exhibited significantly enhanced artificial nuclease activity compared to the chloride analogue (C1), proceeding via an oxidative DNA cleavage pathway involving hydrogen peroxide generation. DNA binding predominantly occurred through a groove-binding mode.

Conclusions:

• Dinuclear copper(I) mesocates with a [P₂NX] kernel can be effectively synthesized.
• The halide ligand plays a crucial role in modulating the artificial nuclease activity of these copper(I) complexes.
• The bromide copper(I) mesocate shows promise as a potential anticancer agent due to its potent DNA-cleaving ability.