A new generation of N-heterocyclic carbene (NHC) gold-selenolato complexes as potent anticancer agents: distinct synthetic routes and evaluation in 2D and 3D cancer models

Two distinct synthetic pathways are disclosed that lead to new gold-selenolato complexes, stabilized by N-heterocyclic carbenes (NHCs). The weak base route can provide facile access to phenylselenolate complexes of gold, using both NHC and phopshine ligands. In addition, the pathway based on the carbometallation of elemental selenium enables the construction of a more diverse library of products, based on substituted aryl-selenide fragments whose selenol congeners are not commercially available. Biological studies performed on human cancer cell lines (A-549, H-T29, and MCF-7) and mammal healthy cell lines (Vero-E6) reveal that a selection of these complexes exhibit cytotoxic activity and are selective towards cancerous cells. In vitro experiments confirmed that our lead candidate is indeed a TrxR inhibitor. Finally, this complex showed strong cytotoxic activity even in advanced biological models, including patient-derived 3D tumor organoids. Noteworthily, it remained effective in both colon cancer and HGSOC organoids, even in patients resistant to standard chemotherapy agents.