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

Area of Science:

• Inorganic Chemistry
• Medicinal Chemistry
• Computational Chemistry

Background:

• Platinum(IV) complexes are explored as next-generation chemotherapy agents, offering potential for reduced side effects and oral administration.
• Activation of platinum(IV) drugs typically involves reduction, but ligand protonation and hydrolysis can interfere, especially in acidic conditions.
• Understanding protonation behavior is crucial for optimizing platinum(IV) complex efficacy and predicting their behavior in vivo.

Purpose of the Study:

• To investigate the protonation sites and behavior of platinum(IV) complexes relevant to cisplatin and carboplatin.
• To elucidate the influence of axial and equatorial ligands on the protonation equilibria of platinum(IV) complexes.
• To understand how ligand structure affects the stability and activation pathways of platinum(IV) anticancer agents.

Main Methods:

• Utilized mass spectrometry techniques, including collision-induced dissociation (CID) and infrared multiple photon dissociation (IRMPD) spectroscopy.
• Employed density functional theory (DFT) calculations to support experimental structural characterization.
• Synthesized and analyzed protonated platinum(IV) complexes with varying axial hydroxido and acetato ligands.

Main Results:

• Protonation generally favors carboxylato ligands in the investigated platinum(IV) complexes.
• The carboplatin-derived complex showed a mixture of protonation sites (protomers), indicating complex protonation equilibria.
• Ligand type and positional arrangement critically influence where protonation occurs on platinum(IV) complexes.

Conclusions:

• Protonation site preference in platinum(IV) complexes is dictated by both axial and equatorial ligand environments.
• The observed protonation patterns are essential for understanding the activation mechanisms and potential hydrolysis side reactions of platinum(IV) drugs.
• This study provides fundamental insights into the solution chemistry of platinum(IV) complexes, informing future drug design.