Design and Mechanistic Investigation of Novel Metallodrugs: From Structure-Activity Relationships to Selective Cancer Cell Targeting

The relentless pursuit of alternatives to conventional platinum-based chemotherapeutics, hampered by severe side effects and drug resistance, defines a critical frontier in oncology drug discovery. This review consolidates and highlights the significance of our recent advances in designing novel metallodrugs based on pyridine-2,6-dicarboxylate derivatives coordinated with various metal ions (Ga(III), Ce(IV), Zn(II), Cu(II), Ni(II), Sr(II)). Through systematic synthesis and evaluation, we establish how strategic structural modifications dictate cytotoxicity, cellular uptake, and mechanistic pathways. Our comprehensive in vitro profiling across a panel of human cancer cell lines (including A431, SW480, BEL-7404) revealed potent anticancer activity, with IC50 values as low as 0.56 μM, coupled with remarkable selectivity over normal cell lines (IC50 > 500 μM). Mechanistic investigations, employing flow cytometry, western blotting, and fluorescence microscopy, demonstrated that these complexes induce cell death via metal-dependent pathways, including apoptosis (intrinsic and extrinsic), autophagy, and cell cycle arrest, often accompanied by significant reactive oxygen species (ROS) generation. The distorted octahedral geometry prevalent in the most active complexes correlates with enhanced cellular uptake and target interaction. This work underscores the profound impact of rational design in metallodrug development, offering a robust platform for creating next-generation anticancer agents with superior efficacy, selectivity, and multi-mechanistic profiles to overcome the limitations of current therapies.