An organometallic gold(I) bis-N-heterocyclic carbene complex with multimodal activity in ovarian cancer cells.

The organometallic Au(I) bis-N-heterocyclic carbene complex [Au(9-methylcaffeine-8-ylidene)2]+ (AuTMX2) was previously shown to selectively and potently stabilise telomeric DNA G-quadruplex (G4) structures. This study sheds light into the molecular reactivity and mode of action of AuTMX2 in the cellular context using mass spectrometry-based methods, including shotgun proteomics in A2780 ovarian cancer cells. In contrast to other metal-based anticancer agents, this organogold compound is less prone to form coordinative bonds with biological nucleophiles, and is expected to exert its drug effects mainly by non-covalent interactions. Global protein expression changes of treated cancer cells revealed a multi-modal mode of action of AuTMX2 by alterations in the nucleolus, telomeres, actin stress-fibers and stress-responses, which were further supported by pharmacological assays, fluorescence microscopy and cellular accumulation experiments. Proteomic data are available via ProteomeXchange with identifier PXD020560.