Cytotoxicity of acridinium-based ionic liquids: Structure-activity relationship and mechanistic studies

Ionic liquids (ILs) are a class of low melting point salts with physicochemical properties suitable for a range of industrial applications such as chemical processing and battery design. Major challenges to the wide-scale adoption of ILs in industry include their eco- and cytotoxic effects, however, this opens up the possibility of the use of ILs use as novel anticancer agents. Understanding the structural features that promote IL cytotoxicity is therefore important. Key structural features that can impact IL cytotoxicity include size and lipophilicity of the cationic head group. In this study, the cytotoxic effects of acridinium-based ILs containing relatively large tri- and tetracyclic cations were evaluated. It was found that 9-phenylacridinium-based ILs are potent cytotoxic agents that reduce the viability of human MDA-MB-231 breast cancer cells with IC₅₀ concentrations in the nanomolar range. In mechanistic studies, it was found that unlike the pyridinium-based analogue, [C₁₆Py][I], acridinium-based ILs did not inhibit oxidative phosphorylation or induce reactive oxygen species formation, and may instead target other mitochondrial processes or components such as mitochondrial DNA.