# Protonation of Pt(IV) Anticancer Complexes Assayed by Vibrational Ion Spectroscopy

## TL;DR

This study investigates how protonation affects Pt(IV) anticancer complexes, revealing how ligand types influence protonation and reactivity.

## Contribution

The paper introduces new insights into protonation preferences and protomer populations in Pt(IV) complexes using IR ion spectroscopy and DFT.

## Key findings

- Protonation is generally favored on carboxylato ligands in Pt(IV) complexes.
- The carboplatin-derived complex showed mixed protomer populations.
- Axial and equatorial ligand configurations significantly influence prototropic equilibria.

## Abstract

Platinum(IV) complexes are being studied as potential alternatives to traditional platinum(II)‐based chemotherapy drugs. They promise reduced side effects and potential for oral administration. In fact, a preliminary reduction in the cellular medium is recognized as a crucial step for activation. However, a deeper understanding of the protonation sites and substitution behavior of Pt(IV) complexes is needed, considering that ligand hydrolysis may compete with reduction‐mediated activation, particularly in acidic environments such as the stomach. In this study, we investigated protonated Pt(IV) complexes with equatorial ligands common to widely used Pt(II) drugs containing square planar geometry, such as cisplatin and carboplatin. The additional axial substituents in the octahedral coordination sphere of Pt(IV) include different combinations of hydroxido and acetato ligands. Mass spectrometry‐based methods, including collision‐induced dissociation (CID) and infrared multiple photon dissociation (IRMPD) spectroscopy, supported by density functional theory (DFT) calculations, were employed. Structural characterization revealed that protonation preferences are influenced by the type and position of the ligands. Notably, protonation is generally favored on the carboxylato ligands; however, the carboplatin‐derived complex exhibited a mixed population of protomers, highlighting the significance of both axial and equatorial ligand configurations in shaping the prototropic equilibria happening in solution.

Protonated Pt(IV) complexes with various equatorial and axial ligands were characterized by IR ion spectroscopy and DFT. Protonation typically occurs at carboxylato ligands, eventually increasing their substitution propensity. However, the carboplatin‐derived complex showed mixed protomer populations, highlighting the significance of ligand selection to mitigate undesired reactivity.