Organometallic Iridium(III) complex interacts with DNA and exhibits anticancer potential: Insights from biophysical, cell-based and computational studies.

Organometallic iridium (III) complexes have garnered significant interest in anticancer research due to their potent efficacy against a wide range of cancers. This study investigates an Ir(III) complex as a targeted DNA-binding agent for advanced cancer therapy using biophysical, cellular, and in silico approaches. Intercalative binding with calf thymus DNA was confirmed through multiple techniques: UV-visible spectroscopy showed a 73.8% hyperchromic shift at 260 nm; the absence Ir(III/IV) oxidation peak at 1.45 V in DNA-Ir-complex vs. free Ir-complex in cyclic voltammetry studies, indicating bulky Ir-DNA adduct formation, viscosity of DNA increased by 28%, competitive fluorescence quenching, circular dichroism perturbations at 245 and 275 nm, and 65% dye displacement validated classical intercalation via minor-groove access and base-stacking interactions. Raman spectroscopy shifts (e.g., 494 → 483 cm-1 for PO2- backbone vibrations, indicating conformational alterations in the phosphodiester framework, 1703 → 1696 cm-1 corresponding to base carbonyl stretching, suggesting perturbation of hydrogen bonding and base stacking interactions) revealed a ligand-induced structural modification of DNA, possibly reflecting a transition toward an A-like conformation. Molecular docking predicted a binding free energy (ΔG) of -11.17 kJ mol-1, with preferential interaction at GC-rich regions. Furthermore, the complex induced photoactivated plasmid DNA strand breakage and exhibited potent cytotoxicity (IC50 = 8.46 μM) in MIA PaCa-2 pancreatic carcinoma cells, with comet assay confirming significant DNA damage. Network pharmacology analysis identified 114 high-confidence protein targets involved in key cancer-related pathways. These integrated findings highlight the promising anticancer potential of the Ir(III) complex and paving the way for rational metallodrug design.