Gold Acyclic Diaminocarbene Complexes as Selective and Potent Agents for Multitarget Cancer Therapy

Gold acyclic diaminocarbene (ADC) complexes represent a promising, yet underexplored, class of chemotherapeutics. ADCs offer superior flexibility and stronger sigma donation compared with traditional N-heterocyclic carbenes, making them ideal ligands for stable gold-based drugs. In this study, a series of gold ADC complexes were synthesized via the nucleophilic addition of amines to [AuCl(CNCy)], yielding three structural families: gold-chloride-ADC (chiral and achiral), bis(carbene), and thiolate-gold-ADC complexes. Extensive characterization, including X-ray diffraction, revealed noncovalent interactions, such as hydrogen bonding and aurophilic contacts, that significantly shape their molecular architecture. These complexes exhibit potent cytotoxicity (IC₅₀ in submicromolar) against drug-resistant cancer cell lines (A549, HCT116 WT, Jurkat, MiaPaca2), with some showing high selectivity toward cancer cells over healthy lymphocytes (selectivity index up to 74). Mechanistic investigations indicate that they disrupt mitochondrial function, elevate reactive oxygen species (ROS), and, in the case of bis(carbene) species, bind DNA. Apoptosis is induced at low concentrations, while higher doses trigger alternative death pathways. Notably, they also strongly inhibit thioredoxin reductase (TrxR), comparable in potency to auranofin. The combination of ROS induction, DNA interaction, mitochondrial disruption, and TrxR inhibition highlights the multitargeted anticancer potential of gold-ADC complexes and supports their further development as selective and effective chemotherapeutic agents.