Stereoselective ecotoxicity and environmental stability of the anticancer drug duvelisib in aquatic systems

The environmental presence of anticancer drugs is of increasing concern due to their high biological activity, persistence, and potential effects on non-target organisms. However, information on the ecotoxicity of many recently introduced compounds remains scarce, particularly regarding stereoselective effects. In this study, the aquatic ecotoxicity of duvelisib, a chiral PI3K inhibitor, was evaluated for the first time using the marine bacterium Vibrio fischeri and the freshwater microalga Raphidocelis subcapitata. A chiral Electrokinetic Chromatography (EKC) method enabled enantiomer-specific quantification and verification of actual exposure concentrations. Stability studies confirmed that both enantiomers and the racemate remained unchanged under the tested conditions. Ecotoxicological results revealed a clear difference in sensitivity between organisms, with R. subcapitata showing higher susceptibility (EC₅₀ = 2.1-4.9 mg L^-1) than V. fischeri (EC₅₀ = 13.1-21.9 mg L^-1). According to EU Directive 93/67/EEC, duvelisib can be classified as toxic to green algae and harmful to marine bacteria. Based primarily on EC₅₀ values, S-duvelisib exhibited higher toxicity than R-duvelisib in both aquatic bioassay systems, whereas EC₂₀ values showed more complex low-effect responses. The racemate exhibited organism-dependent concentration-response behavior, indicating that mixture effects may differ from those of the individual enantiomers. Screening-level QSAR predictions obtained with ECOSAR and VERA were broadly consistent with algal toxicity in terms of order of magnitude but were less suitable for bacterial bioluminescence inhibition and stereoselective interpretation. Overall, this study provides the first integrated assessment of duvelisib in aquatic systems and highlights the importance of stereochemistry and experimental validation in environmental hazard characterization of chiral anticancer drugs.