Role of the Enzymatic Environment in the Reactivity of the Au-C^N^C Anticancer Complexes.

The action mechanism of anticancer gold(III) complexes is a multi-step process and depends on their redox stability. First, the gold(III) complex undergoes a ligand exchange reaction in the presence of cellular thiols, such as those available in the active site of the enzyme TrxR, and then, the Au → Au reduction occurs. Most experimental and theoretical studies describe these processes under chemical conditions without considering the enzyme structure effect. In the present study, molecular models are proposed for the [Au(C^N^C)(SHCys-R)] adduct, with the [Au(C^N^C)] moiety bonded to the Cys498 residue in the C-terminal arm of the TrxR. This one represents the product of the first ligand exchange reaction. Overall, our results suggest that the exchange of the auxiliary ligand (for instance, Cl to S-R) plays a primary role in increasing the reduction potential, with the enzyme structure having a small effect. The parent compound [Au(C^N^C)Cl] has ° = -1.20 V, which enlarges to -0.72 V for [Au(C^N^C)CHSH] and to -0.65 V for the largest model studied, Au-trx. In addition to the effect of the enzyme structure on the redox stability, we also analyze the Au transfer to the enzyme using a small peptide model (a tetramer). This reaction is dependent on the Cys497 protonation state. Thermodynamics and kinetic analysis suggests that the C^N^C ligand substitution by Cys497 is an exergonic process, with an energy barrier estimated at 20.2 kcal mol. The complete transfer of the Au ion to the enzyme's active site would lead to a total loss of enzyme activity, generating oxidative damage and, consequently, cancer cell death.