Exploring the Anticancer Activity of Ruthenium(II)–Arene and Copper(I) Complexes Bearing N-Heterocyclic Carbene Ligands Containing Azido, Pyridinium, and Ethisterone- Derived Triazole Groups

The design and functionalization of N-heterocyclic carbene (NHC) ligands provide a versatile platform for tuning the chemical and biological properties of metallodrugs. Herein, we report the synthesis of a series of backbone functionalized imidazolium precursors incorporating chloromethyl, azidomethyl, triazole–steroid, and pyridinium motifs, introduced to enable postfunction- alization, exploit the bioactive and bio-orthogonal properties of azides, confer potential hormone-receptor interactions through a steroidal fragment, and promote mitochondrial targeting through a lipophilic cationic unit, respectively, while maintaining steric protection around the metal binding site. These precursors were efficiently converted into Cu(I)–NHC complexes via a weak-base protocol and into Ru(II)–arene carbonato and dichloro NHC complexes using an analogous methodology, highlighting opera- tionally simple, scalable approaches suitable for sensitive or multifunctional ligands. Structural characterization confirmed the formation of well-defined metal–carbene species. Biological evaluation revealed that Cu(I)–NHC complexes exhibit potent anti- proliferative activity against ovarian (A2780, A2780cis) and breast (MCF-7) cancer cells, including cisplatin-resistant models, and induce apoptosis with moderate selectivity over nontumorigenic keratinocytes. In contrast, Ru(II)–NHC complexes displayed moderate cytotoxicity but are consistent with profiles favoring anti-metastatic and mechanistically distinct actions. These results underscore the potential of backbone-functionalized NHC ligands to fine-tune metallodrug activity and highlight Cu(I)–NHC complexes as promising candidates for further development against resistant cancers.