Cytotoxic gold(I) N-heterocyclic carbene complexes with phosphane ligands as potent enzyme inhibitors

Organometallic gold complexes with N-heterocyclic carbene (NHC) ligands have been demonstrating promising properties as novel anticancer agents. Gold(I) NHC complexes containing different phosphanes as secondary ligands were shown to trigger strong cytotoxic effects in cancer cells, and their effective uptake into the cells was quantified by atomic absorption spectroscopy. Moreover, the new compounds strongly inhibited the activity of the seleno-enzyme thioredoxin reductase (TrxR) and of the zinc-finger enzyme poly(ADP-ribose) polymerase 1 (PARP-1). In the case of TrxR inhibition, their activity depended clearly on the size of the alkyl/aryl residues of phosphorus atoms. Density functional theory (DFT) calculations showed that the Au-P bond of the triphenylphosphane complex [Au^I(NHC)(PPh₃)]I had a lower bond dissociation energy compared to trialkylphosphane complexes [Au^I(NHC)(PR₃)]I, indicating a higher kinetic reactivity of this particular compound. In fact, [Au^I(NHC)(PPh₃)]I triggered an enhanced inhibitory activity against PARP-1. Gold renaissance! Gold(I) N-heterocyclic carbene complexes with phosphane ligands effectively inhibit the the seleno-enzyme thioredoxin reductase (TrxR) and the zinc-finger enzyme poly(ADP-ribose) polymerase 1 (PARP-1) and trigger potent cytotoxicity in cancer cells.