Rational design of gold(i)-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.