The potent oxidant anticancer activity of organoiridium catalysts

Platinum complexes are the most widely used anticancer drugs; however, new generations of agents are needed. The organoiridium(III) complex [(η⁵-Cp^xbiph)Ir(phpy)(Cl)] (1-Cl), which contains π-bonded biphenyltetramethylcyclopentadienyl (Cp^xbiph) and C^N-chelated phenylpyridine (phpy) ligands, undergoes rapid hydrolysis of the chlorido ligand. In contrast, the pyridine complex [(η⁵-Cp ^xbiph)Ir(phpy)(py)]⁺ (1-py) aquates slowly, and is more potent (in nanomolar amounts) than both 1-Cl and cisplatin towards a wide range of cancer cells. The pyridine ligand protects 1-py from rapid reaction with intracellular glutathione. The high potency of 1-py correlates with its ability to increase substantially the level of reactive oxygen species (ROS) in cancer cells. The unprecedented ability of these iridium complexes to generate H ₂O₂ by catalytic hydride transfer from the coenzyme NADH to oxygen is demonstrated. Such organoiridium complexes are promising as a new generation of anticancer drugs for effective oxidant therapy. Protective pyridine: A novel half-sandwich organoiridium(III) complex with a pyridine ligand is more potent than both its chloride analogue and cisplatin towards a wide range of cancer cells. The pyridine ligand protects the iridium complex from rapid reactions with glutathione, and its potency correlates with a substantial increase in the amount of reactive oxygen species in the cancer cells.