Unraveling ligand exchange reactions in linear neutral Au(i) and Cu(i) N-heterocyclic carbene complexes for biological applications

Linear complexes of the form [M(NHC)Cl] (M = Au(I) or Cu(I), NHC = N-heterocyclic carbene) are promising drug candidates due to their potent in vitro antitumor, antibacterial, and antiparasitic activities. However, their speciation in biological environments is poorly understood, limiting their clinical translation. This study employed semiempirical GFN-xTB and density functional theory (DFT) calculations to investigate three biologically relevant ligand exchange reactions of these complexes: (1) chloride substitution with dimethylsulfoxide (DMSO), a common solvent used in in vitro studies; (2) ligand scrambling, which involves the rearrangement of ligands to form [M(NHC)2][MCl2]; and (3) chloride substitution with cysteine, a biologically relevant amino acid. Our calculations revealed that chloride replacement by DMSO is less favorable than ligand scrambling, particularly for Cu(I) complexes, suggesting that [M(NHC)Cl] is the most abundant species present in DMSO solution, followed by [M(NHC)2][MCl2]. Cysteine substitution was found to be the most thermodynamically and kinetically favorable reaction, potentially impacting the biological mechanism of action of these complexes. We also compared the reaction mechanisms between Au(I) and Cu(I) complexes by analyzing transition state geometries. Our findings provide new insights into the ligand exchange reactions of linear [M(NHC)Cl] complexes in biologically relevant environments. This information can be used to guide the design of new metal-based drugs with improved efficacy and selectivity.