The potent oxidant anticancer activity of organoiridium catalysts.
Bottom Line: The pyridine ligand protects 1-py from rapid reaction with intracellular glutathione.The unprecedented ability of these iridium complexes to generate H2 O2 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.
Affiliation: Department of Chemistry, University of Warwick, Coventry, CV4 7AL (UK).Show MeSH
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Mentions: Our studies of the aqueous chemistry of 1-Cl and 1-py (summarized in Figure 5) provide a molecular basis for their anticancer activity and for their differences in potency. Complex 1-Cl is more reactive towards hydrolysis, GSH, and NADH than 1-py. Such a high reactivity can lead to side reactions (deactivation) so that the amount of iridium species that reach intracellular target sites is reduced. The relatively unreactive complex 1-py shows enhanced accumulation in cancer cells, which is followed by the reaction with NADH and the generation of the ROS hydrogen peroxide. In cells, this also appears to lead to a build-up of superoxide. The higher level of iridium accumulation in A2780 ovarian cancer cells after treatment with 1-py is consistent with its ability to generate higher levels of ROS compared to 1-Cl and its higher anticancer potency.
Affiliation: Department of Chemistry, University of Warwick, Coventry, CV4 7AL (UK).