Structure–Activity Relationships of Silver(I)- and Gold(I)–NHC Complexes Reveal Distinctly Different Responses of Cisplatin-Resistant Ovarian Cancer to Bis-NHC–Gold(I) Derivatives

Ovarian cancer (OC) is the most lethal gynecological malignancy, with platinum resistance posing a major therapeutic challenge. To explore alternatives, we synthesized silver- and gold-based N-heterocyclic carbene (NHC) complexes differing only in their central metal ion and evaluated their activity in platinum-resistant OC. Structure–activity relationships revealed distinct metal-dependent behaviors. Silver complexes showed little variation with ligand modifications, whereas gold complexes displayed pronounced differences. Two bis-NHC–gold compounds were of particular interest: In an isogenic OC resistance model (A2780 and A2780/cis), [(NHC2)2Au]Br showed cross-resistance, while [(NHC1)2Au]Br induced collateral sensitivity. These effects were independent of intracellular accumulation, apoptosis induction, or TrxR inhibition. Instead, proteomic and metabolic analyses demonstrated that [(NHC1)2Au]Br inhibited oxidative phosphorylation, forcing a metabolic shift to aerobic glycolysis. As A2780/cis cells already rely on maximal glycolysis, [(NHC1)2Au]Br caused an energy collapse. These findings highlight a metabolic vulnerability in cisplatin-resistant OC that may be exploited for the development of novel therapeutic candidates.