To achieve a systems-based approach to target the antioxidant pathway, ferrocene and quinone functionalized N-heterocylcic carbene Au(I) complexes were designed, synthesized, and biologically tested in a series of human cancer cells. Redox reversible complexes were revealed by electrochemical and spectroelectrochemical studies. Complexes containing both a redox active moiety (to accentuate exogenous ROS via redox cycling) centered around a Au(I) atom (to irreversibly inhibit thioredoxin reductase (TrxR)) significantly inhibited cancer cell proliferation compared to controls (i.e. Au(I)-NHC alone, naphthaquinone alone, ferrocene alone). Treatment of A549 lung cancer cells with redox active Au(I)-NHCs led to increased levels of exogenous reactive oxygen species (ROS) via flow cytometry. Inhibition of TrxR, an essential mediator of ROS homeostasis, was also achieved in the same cell line. TrxR inhibition by a bis-naphthaquinone-Au(I)-NHC was comparable to that of auranofin, a Au(I) complex known to irreversibly inhibit TrxR. The complexes presented herein were found to induce ER stress related mechanisms (via RNA microarray), activate cell death via an apoptotic mechanism (confirmed by annexin-V), and were shown to be efficacious in zebrafish embryos containing A549 human lung xenografts. These results illustrate that the dual targeting approach of reducing ROS tolerance while increasing ROS production leads to antioxidant homeostasis being perturbed from both ends, thus overwhelming the network and promoting cell death.<br/>

Dual targeting of the cancer antioxidant network with redox active gold(I) N-heterocyclic carbene complexes

253rd National Meeting (2017)

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