Cytotoxic and oxidative stress-related effects of N2O2-type Ni(II)-thiosemicarbazone complexes: Experimental and computational studies

New thiosemicarbazone-based Ni(II) complexes, [Ni(L1-3)] (1-3), were synthesized, structurally characterized, and evaluated for their cytotoxic potential in a panel of human cervical (HeLa), lung (A549), breast (MDA-MB231), and pancreatic (PANC-1) cancer cells, along with a non-cancerous human embryonic kidney (HEK-293) cell line. The complexes exhibited selective cytotoxic effects, with HeLa cells showing the highest sensitivity. Among them, complex 2 demonstrated the most pronounced antiproliferative activity and selectivity compared to complexes 1 and 3. Cellular studies in HeLa cells revealed increased oxidative stress markers, mitochondrial dysfunction, and apoptosis-related alterations accompanying the observed cytotoxicity. Chemical antioxidant assays indicated higher radical-scavenging activity for the free ligand, whereas complex 2 displayed the highest TEAC value among the metal complexes. To support the experimental findings, computational studies including quantum chemical calculations, molecular docking, molecular dynamics simulations, and MM/GBSA analyses were performed, revealing favourable electronic properties and stable interactions of the complexes with the PI3K alpha/mTOR kinase. Overall, the combined experimental and computational results highlight complex 2 as a promising Ni(II)-thiosemicarbazone scaffold with selective cytotoxic activity associated with altered oxidative stress parameters.