Mechanistic Fingerprints from Chloride to Iodide: Halide vs. Ammonia Release in Platinum Anticancer Complexes.

Platinum-based drugs play a pivotal role in contemporary cancer treatment, but their therapeutic utility is often limited by acquired resistance. The diiodido analog, cis-[PtI2(NH3)2] is a promising derivative that has demonstrated the ability to overcome cisplatin resistance in vitro. To establish the molecular basis for this superior activity, we integrated experimental (NMR) spectroscopy with computational density functional theory (DFT) methods to precisely and comparatively understand the drug activation mechanisms. Comparative 14N NMR experiments elucidated the initial ligand substitution step, confirming halide displacement and a markedly higher tendency for ammonia release from cis-[PtI2(NH3)2], particularly when reacting with sulfur-containing amino acids. Complementary DFT calculations determined the substitution energy values, revealing that the superior leaving-group ability of iodide results in a thermodynamically more favorable activation. Conceptual DFT parameters (softness, hardness, and Fukui indices) further demonstrated that initial substitution induces a strong trans effect, leading to the electronic sensitization of the remaining iodide ligand. This strong agreement between computational predictions and experimental data establishes a coherent molecular activation mechanism for cis-[PtI2(NH3)2], demonstrating that iodide substitution promotes both thermodynamic and electronic activation of the platinum center, which is the key to its distinct pharmacological profile and ability to circumvent resistance.