All Platinum(II) Ions Are Equal, but Some React Differently: Insights Into the Biomolecular Reactivity of Platinum(II)-Based Anticancer Agents.

Platinum-based anticancer agents are widely used in cancer therapy due to their efficacy in killing cancer cells through interactions with the DNA. However, their clinical application is limited by severe side effects and the development of drug resistance, which have been related to their lack of specificity and mechanism of action. To overcome these challenges, novel platinum(II) complexes, K[Pt(Butene-ASA)Cl3] (Compound 1) and [Pt(L-Ala)(Butene-ASA)Cl] (Compound 2), were previously synthesized and characterized. Particularly, Compound 2 showed cytotoxic activity comparable to that of cisplatin (DDP) against all tested cancer cell lines in a previous study. The current investigation employed electrospray ionization mass spectrometry (ESI-MS) to analyze the interactions of these complexes with model biomolecules, including an oligonucleotide (8mer), peptide (Angiotensin I, AT1), and protein (Cytochrome c, CytC). DDP and oxaliplatin (OxPt) were used as reference substances. Tandem mass spectrometry (MS/MS) and UV-Vis spectroscopy enabled the identification of the platination sites on the model biomolecules. Compound 2 demonstrated lower reactivity toward DNA than DDP, while both compounds 1 and 2 exhibited a significant shift in reactivity toward peptides and proteins, particularly compared to DDP and OxPt. The results suggest that Zeise's salt derivatives may preferentially target peptides and proteins rather than DNA, which could provide a novel mechanism of action for platinum-based anticancer agents. These findings expand the understanding of platinum(II) complex reactivity and highlight their potential for developing alternative therapeutic strategies aimed at overcoming the limitations of traditional platinum-based drugs.