Reactivity of auranofin with S-, Se- and N-containing amino acids

Gold complexes have been extensively studied due to their promising therapeutic properties against serious diseases such as cancer. In this diffuse scenario, auranofin is an outstanding gold derivative with a proven efficacy. In spite of the intense focus on this compound, the molecular mechanism behind its enzyme inhibition is still under investigation. The present study describes details of the ligand exchange mechanisms for the reactions of auranofin with the following important amino acids recognized as potential targets in biofluids: Cys, Sec, His and Lys. The replacement of thioglucose (path-S) was found to be more favorable and faster than the replacement of triethylphosphane (path-P) in aqueous solution at 298.15 K. The order of reactivity of the amino acids with auranofin, based on the activation enthalpy values for path-S, was Lys > His > Sec > Cys. Nonetheless, the order of spontaneity was Sec ≫ Cys ≫ Lys > His, supporting the high affinity of gold(I), a soft Lewis acid, for sulfur and selenium metals. In addition, the reactivity of auranofin was correlated with the TS structure, described by the angle between the groups entering and leaving (reactive angle). This analysis suggests, as a first approximation, that the activation enthalpy can be reduced by increasing the reactive angle, which might be achieved using ligands with bulky groups near the reaction center.