Rational design of gold(<scp>i</scp>)-NHC complexes as anticancer agents: induction of necroptosis and paraptosis in lung adenocarcinoma

Gold(i)-NHC complexes bearing sterically demanding ligands remain largely underexplored as anticancer agents. In this study, we rationally designed and synthesized a series of gold(i)-NHC complexes derived from cytotoxic 1,10-phenanthroline-based NHC ligands. Comprehensive structural characterization was performed using ¹H and ¹³C NMR spectroscopy, ESI-MS, IR spectroscopy, and single-crystal X-ray diffraction. Among the synthesized complexes AuL1-AuL7, AuL4 emerged as the most active compound, exhibited potent anticancer activity, triggering mitochondrial membrane depolarization and inducing necroptosis and paraptosis in human lung adenocarcinoma (A549) cells-a mechanism distinct from conventional apoptosis-inducing gold complexes. Notably, AuL4 effectively suppressed both metastasis and clonal expansion of malignant cells, reinforcing the therapeutic potential of gold-based chemotherapeutics. These findings establish AuL4 and its analogues as promising candidates for the development of next-generation gold(i)-NHC anticancer agents, particularly for treating apoptosis-resistant lung cancers.