Novel Copper-Containing Cytotoxic Agents Based on 2-Thioxoimidazolones

Area of Science:

• Coordination Chemistry
• Medicinal Chemistry
• Biomedical Engineering

Background:

• Copper complexes are investigated for their therapeutic potential.
• Structure-activity relationships are crucial for designing effective drug candidates.

Purpose of the Study:

• To synthesize and characterize copper complexes with varying ligands and oxidation states.
• To establish structure-activity relationships governing redox potentials, ROS generation, and intracellular accumulation.
• To investigate cytotoxicity mechanisms including DNA damage, intercalation, telomerase inhibition, and apoptosis.

Main Methods:

• Synthesis and characterization of 73 copper ligands and their Cu+2/Cu+1 complexes.
• Evaluation of redox potentials, ROS generation in MCF-7 cells and 3D spheroids using Pt-nanoelectrodes.
• Assessment of cytotoxicity mechanisms and in vivo toxicity of selected compounds.

Main Results:

• Substituents at the N(3) position modulate redox potentials, ROS generation, and intracellular accumulation.
• Drug accumulation and ROS formation at depth in 3D spheroids are critical for efficacy, linked to Cu+2/Cu+1 redox potential.
• Two binuclear mixed-valence Cu+1/Cu+2 compounds (72k and 61k) showed no in vivo toxicity in single-dose evaluation.

Conclusions:

• The redox potential of copper complexes is a key determinant of their efficacy in 3D tumor models.
• Targeted drug accumulation and ROS generation within tumor spheroids are essential for therapeutic effect.
• Selected copper complexes demonstrate potential as safe and effective anticancer agents.