Proline‐Derived N ‐Heterocyclic Carbene Gold(I) Complexes With Dual DNA Binding and Thioredoxin Reductase Inhibition

A new family of proline‐derived N ‐heterocyclic carbene (NHC) gold(I) complexes was synthesized and fully characterized by multinuclear NMR spectroscopy and HRMS analysis. The incorporation of a proline‐based fragment into the NHC scaffold enabled the generation of both neutral and cationic Au(I) complexes with distinct electronic and steric properties. Stability studies demonstrated that the complexes remain stable under physiological‐like conditions for at least 48 h. Biological evaluation against A549 lung adenocarcinoma and MDA‐MB‐231 triple‐negative breast cancer cells revealed that the cationic complexes 3 and 4 display remarkable cytotoxic activity, with IC ₅₀ values in the low micromolar range, outperforming cisplatin and, in some cases, auranofin. Mechanistic investigations showed that complex 4 induces apoptotic cell death associated with intracellular reactive oxygen species (ROS) generation and depolarization of the mitochondrial membrane potential, indicating a mitochondria‐mediated pathway. In addition, DNA‐binding studies demonstrated that all complexes interact with calf thymus DNA predominantly through an intercalative mode, with complexes 2 , 3 , and 4 exhibiting the highest binding affinities. In addition, thioredoxin reductase inhibition assays revealed significant enzyme inhibition for the cationic complex 4 , supporting disruption of cellular redox homeostasis. Overall, these results identify proline‐functionalized Au(I)–NHC complexes as promising multifunctional anticancer agents.