Anticancer activity of salinomycin quaternary phosphonium salts

• Published in: European journal of medicinal chemistry 2025-01, Vol.282, p.117055, Article 117055
• Main Authors: Jędrzejczyk, Marta, Sulik, Michał, Mielczarek-Puta, Magdalena, Lim, Gwan Yong, Podsiad, Małgorzata, Hoser, Jakub, Bednarczyk, Piotr, Struga, Marta, Huczyński, Adam
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Anticancer; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Ionophores; Membrane Potential, Mitochondrial - drug effects; Microbial Sensitivity Tests; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria-targeting; Molecular Structure; Organophosphorus Compounds - chemical synthesis; Organophosphorus Compounds - chemistry; Organophosphorus Compounds - pharmacology; Polyether Polyketides; Pyrans - chemical synthesis; Pyrans - chemistry; Pyrans - pharmacology; Reactive Oxygen Species - metabolism; Salts - chemical synthesis; Salts - chemistry; Salts - pharmacology; Structure-Activity Relationship; TPP cation; Triphenylphosphine
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.117055

In recent years salinomycin has emerged as a promising anticancer drug. Many literature reports have proved its remarkable antiproliferative activity. Moreover, chemical modifications of salinomycin lead to analogues with even higher cytotoxicity against cancer cell lines and a better selectivity index for malignant cells than those of the unmodified compound or a standard anticancer drug such as doxorubicin. In this paper we report the synthesis of a series of twelve novel salinomycin conjugates and their characterization by spectroscopic and spectrometric methods. Salinomycin was conjugated with different triphenylphosphonium cations in order to find out whether the conjugation with mitochondrial targeting vectors would have a beneficial impact on biological properties. Salinomycin and its novel conjugates were tested to determine their in vitro antiproliferative and antimicrobial activity. Taking into account the presence of triphenylphosphonium moiety, the impact of the obtained analogues on mitochondria activity was evaluated by MitoTrackers dyes, furthermore their apoptosis effect and cell cycle arrest were assessed. In addition, the changes in the mitochondrial membrane potential were measured and the ability to generate reactive oxygen species was assessed. Finally, we conducted biophysical studies to investigate the impact of the obtained salinomycin analogues on mitochondrial respiration rates and their electrophysiological properties. Results of this study have proved that conjugation of salinomycin with phosphonium cations leads to promising results in the search for promising anticancer agents. [Display omitted] •A series of new salinomycin triphenylphosphonium (TPP+) conjugates were synthesized.•Salinomcyin – TPP+ conjugates were more active than unmodified salinomycin.•The activity of several salinomcyin – TPP+ conjugates surpasses that of the commonly used cytostatic drugs.•Significant selectivity of action of salinomcyin – TPP+ conjugates is proved.•The effects of TPP + conjugates on mitochondria were stronger than that of salinomycin.