Mixed-ligand Cu(II) hydrazone complexes designed to enhance anticancer activity

Area of Science:

• Coordination Chemistry
• Medicinal Chemistry
• Anticancer Drug Development

Background:

• Ligand quantity, type, and coordination geometry significantly influence metal-based anticancer complex activity.
• Previous 1:1 Cu(II)/ligand complexes (1a, 2a, 3a) provided a structural basis for new designs.

Purpose of the Study:

• To design, develop, and characterize novel 1:1:1 Cu(II)/ligand/co-ligand complexes.
• To evaluate the in vitro anticancer properties of these new complexes against various human cancer cell lines, including cisplatin-resistant ones.

Main Methods:

• Synthesis and characterization of six Cu(II) complexes: [Cu(L1)(Py)Cl]·H2O (1b), [Cu(L2)(Py)Cl] (2b), and [Cu(L2)(Py)NO3] (3b), alongside their 1:1 precursors.
• In vitro cytotoxicity assays against a panel of human cancer cells.
• Mechanistic studies involving DNA damage assessment and apoptosis induction.
• Evaluation in a 3D spheroid model.

Main Results:

• The 1:1:1 mixed-ligand Cu(II) complexes exhibited enhanced anticancer activity compared to their 1:1 counterparts.
• Complex 3b showed the highest toxicity, with IC50 values ranging from 1.12-3.77 μM, surpassing cisplatin.
• Complex 3b induced DNA damage and triggered mitochondria-mediated apoptosis.
• Pronounced cytostatic effects were observed for complex 3b in the MCF-7 3D spheroid model.

Conclusions:

• Mixed-ligand copper complexes represent a promising strategy for developing potent anticancer agents.
• Complex 3b demonstrates significant potential as an anticancer drug candidate due to its superior efficacy and targeted mechanism of action.