Substituent-Controlled Double Orthometalation and Anticancer Activity in Half-Sandwich Ir(III) Complexes Bearing C^∧N...

Platinum-based chemotherapeutic agents remain among the most widely used anticancer drugs; however, they show two main limitations: intrinsic or acquired resistance and severe side effects. To address these limitations, the design of alternative metal-based complexes with tunable properties is of growing interest. In this work, we report the rational design and synthesis of five novel half-sandwich Ir-(III) complexes incorporating benzo-[h]-imidazoquinoline ligands with an aryl ring. Two strategic structural modifications were introduced into the ligand: (i) alkylation of the imidazole nitrogen (H or 4-ethylmorpholine) and (ii) variation of the aryl substituent (OMe or CN), which not only induced the formation of a dinuclear complex but also modulated key physicochemical properties, including lipophilicity, cytotoxicity, or stability. The new complexes exhibited cytotoxicity toward different cancer cell lines, with IC₅₀ values in the low micromolar range, which are within the same order of magnitude as cisplatin, though operating through a distinct mechanism. Notably, the complexes induced mitochondrial dysfunction, even when morpholine-containing ligands, typically associated with lysosomal targeting, were employed. Additional studies revealed interactions of the complexes with cellular molecules such as NADH and glutathione (GSH), disrupting redox homeostasis and increasing ROS (reactive oxygen species) levels. Furthermore, the complexes exhibited moderate binding affinity for bovine serum albumin (BSA), with molecular docking analyses suggesting a specific interaction near tryptophan residue 134. These Ir-(III) complexes are promising candidates for further development as anticancer agents with distinct mechanisms of action capable of overcoming drug resistance.