Unraveling Ligand Exchange Reactions in Linear Neutral Au(I) and Cu(I) N-heterocyclic carbene complexes for Biological Applications.

This study employed semiempirical GFN-xTB and density functional theory (DFT) calculations to investigate ligand exchange reactions of linear complexes [M(NHC)Cl] (M = Au(I) or Cu(I), NHC = N-heterocyclic carbenes) relevant to medicinal chemistry. Despite their potent in vitro antitumor, antibacterial, and antiparasitic activities, speciation limits their application. The research explored three biologically relevant reactions. Firstly, chloride substitution with dimethylsulfoxide (DMSO), the solvent used to prepare stock solutions before in vitro studies. Secondly, ligand scrambling involves the rearrangement of ligands in solution forming [M(NHC)2][MCl2]. Lastly, chloride substitution with cysteine, a biologically relevant ionic amino acid. Thermodynamically and kinetically, chloride replacement by DMSO is less favorable than ligand scrambling, particularly for Cu(I) complexes, suggesting [M(NHC)Cl] is the most abundant species present followed by [M(NHC)2][MCl2], the last mainly in Cu(I) complexes. Cysteine substitution proves to be the most thermodynamically and kinetically favorable, potentially impacting the biological mechanism of action. The study also compares reaction mechanisms between Au(I) and Cu(I) complexes by analyzing transition state geometries. This research enhances understanding of ligand exchange reactions in linear complexes, shedding light on thermodynamic and kinetic preferences and biological mechanisms. The insights from the current work aid the interpretation of in vitro and in vivo data, unlocking the potential of these complexes for medicinal applications.