Half-Sandwich Ir(III) and Ru(II) Complexes Featuring a Coumarin-Based Chelating Core for Mitochondrial-Targeted...

Area of Science:

• Organometallic Chemistry
• Medicinal Chemistry
• Cancer Biology

Background:

• Coumarin derivatives are known fluorophores and have been used in developing metal-based anticancer agents.
• Previous designs incorporated coumarin as a peripheral moiety, influencing fluorescence but not direct coordination.
• A novel approach is needed to integrate the coumarin scaffold into the coordination sphere for enhanced therapeutic effects.

Purpose of the Study:

• To synthesize and characterize novel half-sandwich organometallic iridium(III) and ruthenium(II) complexes.
• To investigate the structural impact of directly coordinating coumarin-derived acylhydrazone ligands.
• To evaluate the cytotoxic potential and cellular mechanisms of these new complexes against cancer cell lines.

Main Methods:

• Synthesis of Ir(III) and Ru(II) complexes with N,O-chelating coumarin-derived acylhydrazone ligands.
• Characterization of complexes using spectroscopic and analytical techniques.
• In vitro cytotoxicity assays against A549 and HeLa cancer cells.
• Cellular uptake studies, including assessment of energy dependence and subcellular localization (mitochondria).
• Apoptosis induction studies (mitochondrial membrane depolarization, ROS generation) and cell-cycle analysis.

Main Results:

• Novel half-sandwich Ir(III) and Ru(II) complexes with coumarin-acylhydrazone ligands were successfully synthesized.
• The coumarin moiety was integrated into the N,O-coordination sphere, acting as a key structural element.
• Complexes displayed slow hydrolysis kinetics and significant cytotoxic activity against A549 and HeLa cells (IC50 values ranging from 6.49 to 43.11 μM).
• Increased positive charge and hydrophobicity led to energy-dependent cellular uptake and preferential accumulation in mitochondria.
• Mechanistic studies revealed induction of apoptosis via mitochondrial dysfunction and increased reactive oxygen species (ROS), cell-cycle arrest, and inhibition of tumor cell migration.

Conclusions:

• The direct incorporation of coumarin into the coordination sphere of Ir(III) and Ru(II) complexes enhances their anticancer properties.
• These complexes represent a promising new class of metallodrugs with mitochondria-targeting capabilities.
• The observed mechanisms of action, including apoptosis induction and cell-cycle disruption, warrant further investigation for therapeutic development.