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

Abstract

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 III → Au I 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 III (C^N^C)(SHCys-R)] + adduct, with the [Au III (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 III (C^N^C)Cl] has E°= −1.20 V, which enlarges to −0.72 V for [Au III (C^N^C)CH 3 SH] + 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 −1 . 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.

Computational Studies of Au(I) and Au(III) Anticancer MetalLodrugs: A Survey

“…The biological milieu also has a crucial effect on the reactivity of the Au III -CˆNˆC antitumor complexes (Figure 17, structure 35a), as shown in a recent computational study [96]. As mentioned above, the activation of Au(III) complexes can be described as occurring in two steps.…”

“…This study disentangles the reaction mechanism of Au(III) complex and its biomolecular targets and elucidates the processes behind the therapeutic effects. The biological milieu also has a crucial effect on the reactivity of the Au III -C^N^ antitumor complexes (Figure 17, structure 35a), as shown in a recent computational stud [96]. As mentioned above, the activation of Au(III) complexes can be described as occu ring in two steps.…”

“…The cyclometalated complexes 35a-35c, 36a-36f, 37a-37c (Figure 17) feature a remarkable redox activity, giving rise to peculiar pathways of protein targeting. Theoretical investigations on the structure and reactivity of such complexes [95][96][97][98] are reported below (vide infra, Section 3.2. Redox stability).…”

High-Valent Iridium Complexes Containing a Tripodal Bis-Cyclometalated C^N^C Ligand

“…While cyclometalated Ir complexes containing bidentate C^N and tridentate N^C^N and N^N^C ligands are well-known, less attention has been paid to related complexes with bis-cyclometalated C^N^C ligands such as 2,6-diarylpyridines. By contrast, Au­(III) as well as Pt­(II) complexes with bis-cyclometalated 2,6-diarylpyridine ligands have been studied extensively owing to their interesting luminescent properties and anticancer activity. − …”

Antibactericidal Ir(III) and Ru(II) Complexes with Phosphine‐Alkaloid Conjugate and Their Interactions with Biomolecules: A Case of N‐Methylphenethylamine

“…Moreover, phosphines are σ‐donor and π‐acceptor ligands that stabilize mainly low oxidation states of soft metals. Furthermore, their electronic properties can be extensively modified by changing the R groups [22,24,25] . For example, auranofin (Au(I) complex) and RAPTA‐C (Ru(II) complex) are compounds composed of a phosphine fragment and are/were present in the clinical trials as potential anticancer drugs [26,27] …”