Gold( i )–indomethacin anticancer candidates with anti-breast cancer stem cell properties

The rational design, sustainable synthesis, and comprehensive biological evaluation of a new family of gold(I)-indomethacin complexes bearing N-heterocyclic carbene (NHC) ligands are reported. The mild, scalable synthetic protocol affords the first reported examples of well-defined [Au(NHC)(indomethacin)] complexes that display robust chemical and thermal stability and exhibit potent antiproliferative activity across a panel of human cancer cell lines, frequently outperforming cisplatin, including in cisplatin-resistant models. Notably, these gold(I)-indomethacin derivatives retain strong cytotoxicity against breast cancer stem cells (CSCs)-like populations and demonstrate superior efficacy in physiologically relevant 3D spheroid models. Mechanistic investigations reveal that their anticancer activity correlates with efficient inhibition of thioredoxin reductase, disruption of intracellular thiol homeostasis, and induction of oxidative stress through reactive oxygen species generation.