Imidazolinium-Based NHC–Metal Complexes Overcome Both Cancer Multidrug Resistance and Cisplatin Resistance In Vitro

We report the synthesis and biological characterization of N-heterocyclic carbene (NHC) complexes with gold(I), silver(I), copper(I), and palladium(II) metal centers, and 3-(2,6-diisopropyl-phenyl) imidazolinium- and imidazolium-based ligands, including their biscarbene complexes, along with metal complexes of 4-(S)-tert-butyl-imidazolinium-derived carbenes carrying various substituents in position 1. Compared to the imidazolium complexes, the corresponding imidazolinium complexes displayed superior cytotoxicity against the Mes-Sa uterine sarcoma cell line, while the biscarbene complexes exhibited greatly enhanced cytotoxicity with nanomolar activity. The ABCB1-overexpressing multidrug-resistant sublines of Mes-Sa demonstrated only marginal resistance to monocarbene imidazolinium complexes lacking a 4-(S)-tert-butyl group, whereas significant resistance was observed for all other complexes, with its extent further influenced by the nature of the metal center. Probing a subset of the complexes confirmed their strong cytotoxicity against the CST murine breast cancer cell line and its cisplatin-resistant variant, with little or no cross-resistance observed. Within a defined subset, compounds triggered apoptosis, and intracellular ROS production was consistently induced by the copper complexes. Collectively, these results indicate that imidazolinium-based metal NHCs are promising anticancer drug candidates, with copper and silver centers standing out for their potent cytotoxicity and evasion of both ABCB1-mediated and cisplatin resistance.