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.

Effects of cationic head group structure on cytotoxicity and mitochondrial actions of amphiphilic ionic liquids.

Ionic liquids (ILs) are a class of low melting point salts with physicochemical properties that make them suitable for a range of industrial applications. Accumulating evidence suggests that certain ILs are cytotoxic and potential environmental pollutants, thus understanding the structural features that promote IL cytotoxicity is important. Amphiphilic ionic liquids (AmILs), a class of ILs with lipophilic N-alkyl chains, containing aromatic head groups are generally more cytotoxic than their aliphatic counterparts, however the impact of other head group properties are less clear. This study therefore sought to provide new structure activity relationship (SAR) insights regarding the role of the cationic head group on AmIL cytotoxicity. A series of AmILs bearing a range of structurally diverse aromatic cations varying in size, charge, and lipophilicity was synthesised and screened against human MDA-MB-231 breast cancer cells. It was found that larger and more lipophilic head groups increased cytotoxicity, although the magnitude of the changes were modest. The mitochondrial effects of representative ILs were assessed. The AmILs induced mitochondrial dysfunction in MDA-MB-231 cells at cytotoxic concentrations, suggesting that they target mitochondria. The new SAR information from this study may assist in the design of AmILs with controlled cytotoxicity.

Protonophoric and mitochondrial uncoupling activity of aryl-carbamate substituted fatty acids.

Aryl-urea substituted fatty acids are protonophores and mitochondrial uncouplers that utilise a urea-based synthetic anion transport moiety to carry out the protonophoric cycle. Herein we show that replacement of the urea group with carbamate, a functional group not previously reported to possess anion transport activity, produces analogues that retain the activity of their urea counterparts. Thus, the aryl-carbamate substituted fatty acids uncouple oxidative phosphorylation and inhibit ATP production by collapsing the mitochondrial proton gradient. Proton transport proceeds via self-assembly of the deprotonated aryl-carbamates into membrane permeable dimeric species, formed by intermolecular binding of the carboxylate group to the carbamate moiety. These results highlight the anion transport capacity of the carbamate functional group.

Expansion of the structure-activity relationship of branched chain fatty acids: Effect of unsaturation and branching group size on anticancer activity.

Branched chain fatty acids (BCFAs) are a class of fatty acid with promising anticancer activity. The BCFA 13-methyltetradecanoic acid (13-MTD) inhibits tumour growth in vivo without toxicity but efficacy is limited by moderate potency, a property shared by all known BCFAs. The mechanism of action of BCFAs has not been fully elucidated, and in the absence of a clearly defined target optimisation of BCFA potency must rely on structure-activity relationships. Our current understanding of the structural features that promote BCFA anticancer activity is limited by the low structural diversity of reported BCFAs.The aim of this study was to examine the effects of two new structural modifications- unsaturation and branching group size- on BCFA activity. Thus, homologous series of saturated and cis-Δ11 unsaturated BCFAs were synthesised bearing methyl, ethyl, propyl and butyl branching groups, and were screened in vitro for activity against three human cancer cell lines. Potencies of the new BCFAs were compared to 13-MTD and an unbranched monounstaurated fatty acid (MUFA) bearing a cis-Δ11 double bond. The principal findings to emerge were that the anticancer activity of BCFAs was adversly affected by larger branching groups but significantly improved by incorporation of a cis-Δ11 double bond into the BCFA alkyl chain. This study provides new structure-activity relationship insights that may be used to develop BCFAs with improved potency and therapeutic potential.