Elusive intermediates in cisplatin reaction with target amino acids: Platinum(II)-cysteine complexes assayed by IR ion spectroscopy and DFT calculations.

The reactivity of a widely used metal based antineoplastic drug, cisplatin, cis-PtCl(NH), with L-cysteine (Cys) has been investigated using a combination of electrospray ionization mass spectrometry (ESI-MS), IRMPD gas phase ion spectroscopy and DFT calculations. The cysteine lateral chain represents one of the main platination sites in proteins, which is believed to be related to the resistance mechanisms to cisplatin. The vibrational features of the mass-selected substitution product cis-[PtCl(NH)(Cys)] and the intercepted cis-[PtCl(NH)(HO)(Cys)] intermediate complex were compared to calculated IR spectra, enabling the assessment of the sampled ions structures. In cis-[PtCl(NH)(Cys)], cysteine was found to bind platinum through the sulfur atom as a thiolate zwitterion, highlighting the enhanced acidity of the cysteine thiol group upon metal coordination. The cis-[PtCl(NH)(HO)(Cys)] structure complies with the non-covalent encounter complex, formed by cis-[PtCl(NH)(HO)] and neutral cysteine. This species is able to undergo the substitution process to produce cis-[PtCl(NH)(Cys)] when activated as a mass-isolated ion suggesting its participation in the reaction mechanism of cisplatin with cysteine in solution. Finally, the DFT-calculated energy profile for the substitution reaction was correlated with the peculiar gas-phase reactivity of this non-covalent complex, resulting to be 10-fold less reactive toward substitution than the corresponding methionine complex.