Reactions of cisplatin and cis-[PtI2(NH3)2] with molecular models of relevant protein sidechains: A comparative analysis

Quite surprisingly, cisplatin and cis-[PtI2(NH3)2] were found to manifest significant differences in their reactions with the model protein lysozyme. We decided to explore whether these differences recur when reacting these two Pt compounds with other proteins. Notably, ESI-MS measurements carried out on cytochrome c nicely confirmed the reaction pattern observed for lysozyme. This prompted us to exploit a computational DFT approach to disclose the molecular basis of such behavior. We analyzed comparatively the reactions of cis-[PtCl2(NH3)2] and cis-[PtI2(NH3)2] with appropriate molecular models (Ls) of the sidechains of relevant aminoacids. We found that when Pt(II) complexes are reacted with sulfur ligands both quickly lose their halide ligands and then the resulting cis-[Pt(L)2(NH3)2] species loses ammonia upon reaction with a ligand excess. In the case of imidazole, again cis-[PtCl2(NH3)2] and cis-[PtI2(NH3)2] quickly lose their halide ligands but the resulting cis-[Pt(L)2(NH3)2] species does not lose ammonia by reaction with excess imidazole. These results imply that the two platinum complexes manifest a significantly different behavior in their reaction with representative small molecules in agreement with what observed in the case of model proteins. It follows that the protein itself must play a crucial role in triggering the peculiar reactivity of cis-[PtI2(NH3)2] and in governing the nature of the formed protein adducts. The probable reasons for the observed behavior are critically commented and discussed. While cisplatin show high barriers for ammine substitution – 26-28 kcal mol−1 – and vanishingly slow reactions rates, the iodido analogue cis-[PtI2(NH3)2] species show accessible barriers for ammine substitution – 23-24 kcal mol−1 – and low but observable rates. [Display omitted] •Iodido analogue of cisplatin displays strong antiproliferative properties in vitro.•ESI-MS identified binding sites preferentially occupied by the two complexes.•DFT calculations predicted their reactivity toward protein targets.•Both iodide and ammonia exchange are involved in iodoplatin-protein reaction.•Thermodynamic control imposes targeted protein sites in the trend His>Met>Cys.