Synthesis of Ananikov-Type N-Heterocyclic Carbene Golden Synthons as Ferroptosis Inducing Anticancer Agents

Abstract

The rational development of metal-based anticancer agents increasingly relies on precise ligand design and mechanistic understanding. Herein, we report the design, synthesis, and comprehensive evaluation of a new family of backbone-functionalized N-heterocyclic carbene (NHC) gold(I) complexes, enabled by a recent one-pot strategy for the preparation of heteroatom-decorated azolium salts. Using this approach, a library of 21 entirely novel Au(I)-NHC complexes was prepared, encompassing chloride, thiolate, aryl, and selenolate derivatives, representing the first systematic investigation of backbone-functionalized NHC ligands in gold-based medicinal chemistry.Efficient access to [Au(NHC)Cl] precursors was achieved via a weak-base metallation protocol, followed by mild, operationally simple, and environmentally benign transformations to structurally diverse Au(I) species. Multinuclear NMR spectroscopy and single-crystal X-ray diffraction confirmed the nature and stereoelectronic features of all complexes, while DFT calculations elucidated key mechanistic pathways, including gold-aryl formation and an unprecedented seleniuminsertion reaction, highlighting the electronic influence of NHC backbone functionalization.Biological evaluation revealed pronounced anticancer activity for selected complexes, with compound 4b exhibiting cytotoxicity exceeding that of cisplatin in several human cancer cell lines. Complementary fluorescence-based assays and confocal microscopy directly linked this activity to hallmark features of ferroptosis, including ROS generation, glutathione depletion, lipid peroxidation, and intracellular Fe²⁺ accumulation. Collectively, this work establishes backbone-functionalized Au(I)-NHC complexes as a new and versatile platform for ferroptosis-inducing metallodrugs, integrating synthetic innovation, mechanistic insight, and biological precision.