The role of tridentate ligands on the redox stability of anticancer gold(III) complexes

Gold(III) complexes are promising compounds for cancer chemotherapy, whose action depends on their redox stability. In this context, the choice of ligands is crucial to adjust their reactivity and biological response. The present study addressed the effect of the gold coordination sphere on the reduction potential (Eo) for ten gold(III) complexes containing five or six-membered rings tridentate ligands – [AuIII(trident)Cl]3+n (trident = N^N^N, C^N^N, C^C^N, C^N^C, and N^C^N). The calculated Eocovered a broad range of 2500 mV with the most stable complexes containing two AuC bonds (Eo = −1.85 V for [AuIII(C^C^N)Cl] – f). For complexes with one AuC bond, the N^C^N ligands stabilize the gold(III) complex more efficiently than N^N^C; however, the inclusion of the non-innocent ligand bipy (2,2′-bipyridine) in N^N portion provides an extra stabilization effect. Among the derivatives with one AuC bond, [AuIII(N^N^C)Cl]+ (N^N = bipy) (a) showed Eo = −1.20 V. For the complexes with N^N^N ligands, Eo was positive and almost constant (+0.60 V). Furthermore, the kinetics for ligand exchange reactions (Cl−/H2O, H2O/Cys and Cl−/Cys) were monitored for the most stable compounds and the energy profiles compared to the reduction pathways. The reduction process of gold(III) complexes is strongly dependent on the chelating mode and can be modulate by selecting appropriate tridentate ligand. [Display omitted] •Redox stability of Au(III) complexes is dependent on the chelating mode of tridentate ligand.•Ligands containing the bipyridine portion contribute to the gold(III) complex stabilization.•Stability of Au(III) complexes with N^N^N tridentate ligands is enhanced by imidazole groups.•Charge transfer to the tridentate ligand upon reduction favors Au(III) stability.