Reactivity of Auranofin with Selenols and Thiols – Implications for the Anticancer Activity of Gold(I) Compounds

The enzyme thioredoxin reductase (TrxR) is attracting much interest as a potential target for cancer therapy. The presence of a selenium atom in the catalytic site makes it sensitive to inhibition by electrophilic molecules, including the Au I complex auranofin [2,3,4,6‐tetra‐ O ‐acetyl‐1‐thio‐β‐ D ‐glucopyranosato‐ S ‐(triethylphosphane)gold]. The reactions between auranofin and models of thiol and selenol nucleophiles present in TrxR (PhSH and PhSeH) have been investigated in chloroform and methanol by means of 1 H, 31 P, and 77 Se NMR spectroscopy. In chloroform, auranofin undergoes ligand substitution of the tetraacetylthioglucose moiety by a PhS or PhSe group. The reaction is reversible in both cases, but it is characterized by widely different equilibrium constants (ca. 1 for S and at least 10 3 for Se). In polar solvents, such as methanol, the reaction is more complex, and the phosphane moiety also undergoes ligand exchange. Some features have been clarified through the investigation of Et 3 PAuCl. The elementary processes involved have been characterized by DFT calculations.