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 analogue, cis-PtI2(NH3)2 is a promising derivative that has demonstrated the ability to overcome cis-platin resistance in vitro. To establish the molecular basis for this superior activity, we in-tegrated experimental 14N Nuclear Magnetic Resonance (NMR) spectroscopy with com-putational density functional theory (DFT) methods to precisely and comparatively un-derstand the drug activation mechanisms. Comparative 14N NMR experiments elucidated the initial ligand substitution step, confirming halide displacement and a markedly high-er tendency for ammonia release from cis-PtI2(NH3)2, particularly when reacting with sul-fur-containing amino acids. Complementary DFT calculations determined the substitu-tion 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 estab-lishes a coherent molecular activation mechanism for cis-PtI2(NH3)2 demonstrating that iodide substitution promotes both thermodynamic and electronic activation of the plati-num center, which is the key to its distinct pharmacological profile and ability to circum-vent resistance.