Biosafety-inspired structural optimization of triazolium ionic liquids based on structure-toxicity relationships.

Ionic liquids (ILs), owing to their low vapor pressure and excellent solvating ability, are being increasingly applied in various industries to replace highly toxic organic solvents. They mainly pollute aquatic environment and soils, directly endangering eco-environment and human health. Therefore, it is critical to understand and optimize structural motifs of ILs with reduced toxicity. Considering human oral exposure is the major route, our investigations employed a human cell panel (modeling oral exposures) including human stomach (GES-1), intestinal (FHC), liver (HepG2) and kidney (HEK293) cells using a series of experimental and computational approaches to explore the cytotoxicity and molecular mechanism of ILs. We discovered that the cytotoxicity of triazolium and imidazolium ILs was human cell line-dependent with cytotoxicity in an order of FHC > GES-1 > HepG2 > HEK293. For this reason, a toxicity assay using a single cell line was highly inappropriate. Compared to anions (Br, OTs, OTMBS) we tested, the cation of ILs played a major role in causing cytotoxicity. Ionic liquids with cations having longer hydrophobic sidechains (IL09 vs. IL01) readily insert into cell membranes with enhanced membrane and lipidomic perturbations, induce cytotoxicity by triggering cell cycle arrest and apoptosis. Reducing sidechain length and incorporating three nitrogen atoms (triazolium) instead of two (imidazolium) in the cation core alleviated cytotoxicity by reducing cell membrane perturbations and cell function interference. These findings provide important guiding principles for the design of the next-generation of "green" and safe ILs.