Abstract
AbstractPlatinum complexes are the most widely used anticancer drugs; however, new generations of agents are needed. The organoiridium(III) complex [(η5‐Cpxbiph)Ir(phpy)(Cl)] (1‐Cl), which contains π‐bonded biphenyltetramethylcyclopentadienyl (Cpxbiph) and C^N‐chelated phenylpyridine (phpy) ligands, undergoes rapid hydrolysis of the chlorido ligand. In contrast, the pyridine complex [(η5‐Cpxbiph)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 H2O2 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.
Highlights
Platinum complexes are the most widely used anticancer drugs; new generations of agents are needed
As cancer cells are often under increased oxidative stress compared to normal cells, which is partially due to abnormal mitochondrial functions, an element of selectivity is achieved when an anticancer agent further increases the level of oxidative stress
We investigated the accumulation of complexes 1-Cl oxidative stress
Summary
Platinum complexes are the most widely used anticancer drugs; new generations of agents are needed. We investigated their activity towards a wide range of cancer cells and their selectivity for cancer cells over normal cells and used COMPARE analysis to explore the potential MoAs. We related cellular accumulation of iridium and production of ROS in cells to the redox chemistry of the complexes.
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