Ir(III) Diamine Transfer Hydrogenation Catalysts in Cancer Cells

The development of catalytic metallodrugs is an emerging field that may offer new approaches to cancer chemotherapeutic design. By exploiting the unique properties of transition metal complexes, in-cell catalysis can be applied to modulate the cellular redox balance as part of a multi-targeting mechanism of action. We describe the synthesis and characterization of six coordinatively unsaturated iridium(III) diamine catalysts that are stable at physiological pH in aqueous solution. Reduction of the colorimetric substrate 2,6-dichlorophenolindophenol by transfer hydrogenation under biologically compatible conditions achieved turnover frequencies up to 63 +/- 2 h-1 and demonstrated that the source of hydride (sodium formate) is the limiting reagent, despite being in a 1000-fold excess of the catalyst. The catalyst showed low in vivo acute toxicity in zebrafish embryos and modest in vitro potency towards cancer cells. When administered alone, the catalyst generated oxidative stress in cells (an effect that was conserved in vivo), but co-treatment with a nontoxic dose of sodium formate negated this effect. Co-treatment with sodium formate significantly enhanced catalyst potency in cancer cells (A2780 ovarian and MCF7 breast cancer cells) and drug-resistant cells (A2780cis and MCF7-TAMR1) but not in non-tumorigenic cells (MRC5), demonstrating that a redox-targeting mechanism may generate selectivity for cancer cells. Modulation of cellular redox using an in-cell catalyst exploits an inherent vulnerability of cancer cells. Iridium sulfonamide catalysts generate oxidative stress in cells (an effect that is conserved in vivo), and potency is significantly enhanced upon coadministration of nontoxic sodium formate to initiate in-cell transfer hydrogenation. This redox-targeting mechanism can overcome drug resistance and shows selectivity for cancer cells over non-tumorigenic cells. image