The Potent Oxidant Anticancer Activity of Organoiridium Catalysts

• Published in: Angewandte Chemie International Edition Vol. 53; no. 15; pp. 3941 - 3946
• Main Authors: Liu, Zhe, Romero-Canelón, Isolda, Qamar, Bushra, Hearn, Jessica M., Habtemariam, Abraha, Barry, Nicolas P. E., Pizarro, Ana M., Clarkson, Guy J., Sadler, Peter J.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 07.04.2014; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: anticancer drugs; Antineoplastic Agents - chemistry; biocatalysts; Cancer; Catalysis; Catalysts; Chemotherapy; Cisplatin - chemistry; Communications; Correlation; Drugs; Glutathione; Humans; hydride transfer; Hydrogen peroxide; Iridium; Iridium - chemistry; Ligands; Medical research; Models, Molecular; Organometallic Compounds - chemistry; Oxidants; Oxidizing agents; Pyridines; Reactive Oxygen Species; Structure-Activity Relationship; iridium; biocatalysts; hydride transfer; anticancer drugs; reactive oxygen species
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.201311161

Platinum 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. 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.