Among the broad range of antineoplastic agents present in therapy, cisplatin represents a fortunate example of the potential attached to metal complexes in medicine. Its use for solid tumors has been pivotal for 40 years and it is still considered a first-choice drug for several tumors. The use of cisplatin, however, has shown several inconveniences and severe adverse effects believed to be mediated by the interaction with proteins. With the aim of obtaining a better comprehension of the binding motifs of cisplatin with aminoacid residues, we have undertaken an exploration of the structural and vibrational features of the primary complexes of cisplatin with target aminoacids, such as methionine and histidine (cis-[PtCl(NH3)2(AA)]+) using mass spectrometry and IR ion spectroscopy. Intriguingly, mass spectra show the presence of formally penta-coordinated cisplatin-derived complexes, which present the aminoacid together with the former water ligand (cis-[PtCl(NH3)2(AA)(H2O)]+) in a similar fashion as what we already observed with small models of biological ligands. These species, characterized by IR ion spectroscopy, represent the first step for the substitution reaction in solution of the aqua complex of cisplatin with the incoming aminoacid, namely the encounter complex (Figure 1) along the reaction coordinate of the bimolecular reaction. In this contribution, a novel way of interpreting the interaction of cisplatin with aminoacids will be presented, based on the characterization and activation of the encounter complex as an isolated species together with quantum-mechanics calculations, to gain insights not only about the features of the substitution products, but also on the reaction mechanism and energetics.

Cisplatin ligand substitution by aminoacids: Structure and reactivity of isolated encounter complexes

ACS Spring Meeting 2021

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