Mechanism of Action of Antitumor Au(I) N-Heterocyclic Carbene Complexes: A Computational Insight on the Targeting of TrxR Selenocysteine

Abstract

The targeting of human thioredoxin reductase is widely recognized to be crucially involved in the anticancer properties of several metallodrugs, including Au(I) complexes. In this study, the mechanism of reaction between a set of five N-heterocyclic carbene Au(I) complexes and models of the active Sec residue in human thioredoxin reductase was investigated by means of density functional theory approaches. The study was specifically addressed to the kinetics and thermodynamics of the tiled process by aiming at elucidating and explaining the differential inhibitory potency in this set of analogous Au(I) bis-carbene complexes. While the calculated free energy profile showed a substantially similar reactivity, we found that the binding of these Au(I) bis-carbene at the active CysSec dyad in the TrxR enzyme could be subjected to steric and orientational restraints, underlining both the approach of the bis-carbene scaffold and the attack of the selenol group at the metal center. A new and detailed mechanistic insight to the anticancer activity of these Au(I) organometallic complexes was thus provided by consolidating the TrxR targeting paradigm.

Keywords: DFT calculations; N-heterocyclic carbenes; anticancer metallodrugs; gold(I) complexes; proteins; thioredoxin reductase TrxR.

Figure 1

The studied complexes 1 (R=H), 2 (R=Br), 3 (R=Ph), 4 (R=F-Ph), and 5 (R=Br-Ph).

Figure 2

Pseudomolecular model of the carbene substitution reaction in complexes 1–5 by ethylselenolate assisted by dihydrogen phosphate. RA, TS, and PA stand for reactant-adduct, transition state, and product-adduct, respectively.

Figure 3

Calculated Gibbs free energy profiles for the reaction of 1–5 complexes with ethylselenolate via phosphate assistance (left), and for the reaction of 1 with the CysSec dipeptide or with (non-assisted) ethylselenolate (right). All values in kcal/mol.

Figure 4

Rendition of the calculated transition state structure for the reaction of 1 with ethylselenolate via no assistance (c), phosphate buffer assistance (a), and for the reaction with the CysSec peptide (b). The forming/breaking coordination bonds and the assisting interactions are reported as dashed lines. The orientation of the C-Se bond of each nucleophile (corresponding to the orientation of the attack) is also depicted (black arrow). Bond distances in angstrom. Color scheme: Au (plum), Se (orange), S (yellow), P (burgundy), O (red), N (blue), C (grey), H (white).