From Preassociation to Chelation: A Survey of Cisplatin Interaction with Methionine at Molecular Level by IR Ion Spectroscopy and Computations

[Image: see text] Methionine (Met) plays an important role in the metabolism of cisplatin anticancer drug. Yet, methionine platination in aqueous solution presents a highly complex pattern of interconnected paths and intermediates. This study reports on the reaction of methionine with the active aqua form of cisplatin, cis-[PtCl(NH(3))(2)(H(2)O)](+), isolating the encounter complex of the reactant pair, {cis-[PtCl(NH(3))(2)(H(2)O)](+)·Met}, by electrospray ionization. In the unsolvated state, charged intermediates are characterized for their structure and photofragmentation behavior by IR ion spectroscopy combined with quantum-chemical calculations, obtaining an outline of the cisplatin–methionine reaction at a molecular level. To summarize the major findings: (i) the {cis-[PtCl(NH(3))(2)(H(2)O)](+)·Met} encounter complex, lying on the reaction coordinate of the Eigen-Wilkins preassociation mechanism for ligand substitution, is delivered in the gas phase and characterized by IR ion spectroscopy; (ii) upon vibrational excitation, ligand exchange occurs within {cis-[PtCl(NH(3))(2)(H(2)O)](+)·Met}, releasing water and cis-[PtCl(NH(3))(2)(Met)](+), along the calculated energy profile; (iii) activated cis-[PtCl(NH(3))(2)(Met)](+) ions undergo NH(3) departure, forming a chelate complex, [PtCl(NH(3))(Met)](+), whose structure is congruent with overwhelming S-Met ligation as the primary coordination step. The latter process involving ammonia loss marks a difference with the prevailing chloride replacement in protic solvent, pointing to the effect of a low-polarity environment.