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 postfunctionalization, 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 operationally 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 antiproliferative 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.