Six phosphorescent (2-phenyl)pyridine (ppy) gold(III) 2,4,6-tris(- trifluoromethyl)phenyl (FMes) complexes were synthesized and investigated for their anticancer potential. The compounds demonstrated strong antiproliferative activity, with EC50 values in the low micromolar range, along with significant accumulation in HeLa cancer cells after treatment for only 6 h (up to 119 ng gold per milligram of protein as measured by high-resolution continuum source atomic spectroscopy). Enzyme inhibition studies showed interaction of the gold(III) complexes with thioredoxin reductase (TrxR), a key homeostasis-regulation flavoprotein. TrxR was inhibited with IC 50 values in the micromolar range. Furthermore, five of the complexes displayed selectivity toward TrxR against glutathione reductase (GR, a disulfide reductase structurally related to TrxR) by up to >49-fold. Because no major differences in bioactivity were observed across the series, [(ppy)Au(FMes)(PPh 3)OTf] (complex 4) was chosen for further in-depth biological characterization. Complex 4 was also found to interact with guanosine monophosphate in 1H NMR studies under long incubation times. Interestingly, 4 induced a significant increase in intracellular levels of reactive oxygen species, which led to late apoptotic events and cytocidal effects.
- Antitumor agents
- Gold(III) complexes
- Inorganic chemical biology
- Medicinal organometallic chemistry
- Thioredoxin reductase