S-Se oxidative addition to auranofin derivatives: a DFT study.

Oxidative addition of the S-Se bond to Au(I) complexes is discussed for a series of 26 auranofin (AF) derivatives. AF and its analogues are Au(I) complexes with recognized anticancer activity that act by binding and inhibiting the thioredoxin reductase (TrxR) enzyme. Generally, the oxidative addition to Au(I) is a sluggish reaction under mild conditions (, a high activation barrier - Δ), which is also verified here for AF, Δ = 33.0 kcal mol. However, we predicted that subtle changes in the AF ligands can make the process feasible under standard conditions. For instance, the exchange of -PEt by -P(Et)(OEt), which is a weaker electron σ-donor, reduced the activation barrier to 17.1 kcal mol. Furthermore, substitution of the -SAtg ligand by -Cl leads to a Δ value of 22.5 kcal mol. Overall, the reaction is driven by the nucleophilic attack of the S-Se bond on the Au(I) center, attributed mainly to the charge transfer (4p) → (6p), which characterizes the addition step. At the transition state (TS) point, the (5d) → σ*(S-Se) charge transfer becomes relevant, facilitating the S-Se bond breakage and the oxidation step. In addition to the electron transfers, the strain energy to deform the linear Au(I) geometry to the tetracoordinated Au(III) arrangement in the TS structure plays a primary role in explaining the trends in the activation barriers. Finally, the activation barrier (Δ) and reaction energy (Δ°) were correlated for most of the complexes studied, which suggests that the reaction passes through a late or product-like TS and, therefore, the steric and electronic factors affecting Δ also act on Δ°. Overall, the results presented here might open up a new field of investigation for interactions between AF derivatives and TrxR, which contributes to a full understanding of the biological mechanism of action of these species.