Corinti Davide, Gabano Elisabetta, Chiavarino Barbara, Crestoni Maria Elisa, Osella Domenico, Fornarini Simonetta
Dipartimento di Chimica e Tecnologie del Farmaco, Università di Roma "La Sapienza", P. le A. Moro 5, I-00185, Roma, Italy.
Dipartimento per lo Sviluppo Sostenibile e la Transizione Ecologica, Università del Piemonte Orientale, Piazza S. Eusebio 5, 13100, Vercelli, Italy.
Chempluschem. 2025 Jun;90(6):e202400754. doi: 10.1002/cplu.202400754. Epub 2025 Apr 3.
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.
铂（IV）配合物正在作为传统铂（II）基化疗药物的潜在替代品进行研究。它们有望减少副作用并具有口服给药的潜力。事实上，细胞培养基中的初步还原被认为是激活的关键步骤。然而，考虑到配体水解可能与还原介导的激活竞争，特别是在胃等酸性环境中，需要更深入地了解铂（IV）配合物的质子化位点和取代行为。在本研究中，我们研究了具有广泛使用的含平面正方形几何结构的铂（II）药物（如顺铂和卡铂）常见的赤道配体的质子化铂（IV）配合物。铂（IV）八面体配位球中的额外轴向取代基包括羟基和乙酸根配体的不同组合。采用了基于质谱的方法，包括碰撞诱导解离（CID）和红外多光子解离（IRMPD）光谱，并辅以密度泛函理论（DFT）计算。结构表征表明，质子化偏好受配体类型和位置的影响。值得注意的是，质子化通常倾向于在羧酸根配体上；然而，卡铂衍生的配合物表现出多种质子异构体，突出了轴向和赤道配体构型在塑造溶液中质子转移平衡方面的重要性。
