title: Model Suite for Predicting the Aquatic Toxicity of α,β-Unsaturated Esters Triggered by Their Chemoavailability.
abstract: For a Michael-acceptor set of 45 α,β-unsaturated esters, the 2(nd) -order rate constant of reaction with glutathione, log kGSH , was modeled through the quantum chemical reaction barrier (ΔE(≠) ) employing methane thiol as model nucleophile. Regression of their 48-h toxicity toward the ciliates Tetrahymena pyriformis (log EC50 , 50 % growth inhibition) on log Kow (octanol/water partition coefficient) and log kGSH revealed a variation in the relative weights of hydrophobicity and electrophilic reactivity as determinants of the aquatic toxicity. The difference DKk =log Kow -log kGSH turned out as a suitable means for predictively discriminating between narcosis-level (DKk >3.0) and excess-toxic (DKk <2.0) compounds. In the intermediate DKk range (2.0≤DKk ≤3.0), both narcosis-level and reactive-toxicity models are applicable for predicting aquatic toxicity. As such, DKk represents the chemoavailability of Michael-acceptor esters, characterizing their likelihood for undertaking covalent reactions with thiol sites of endogenous peptides and proteins. At the same time, DKk introduces a straightforward way for characterizing the applicability domain of QSAR (quantitative structure-activity relationship) models for predicting the toxicity of Michael-acceptor esters. The resultant model suite comprising QSARs for reactive toxicity and baseline narcosis is triggered by the compounds' chemoavailability, and yields predictions superior to existing approaches.
authors.affiliation: UFZ Department of Ecological Chemistry, Helmholtz Centre for Environmental Research, Permoserstr. 15, 04318 Leipzig, Germany tel: +49-341-235-1262, fax: +49-341-235-1785.|Institute for Organic Chemistry, Technical University Bergakademie Freiberg, Leipziger Str. 29, 09596 Freiberg, Germany.
authors.forename: Denis
authors.initials: D
authors.lastname: Mulliner
authors.affiliation: UFZ Department of Ecological Chemistry, Helmholtz Centre for Environmental Research, Permoserstr. 15, 04318 Leipzig, Germany tel: +49-341-235-1262, fax: +49-341-235-1785. gerrit.schuurmann@ufz.de.|Institute for Organic Chemistry, Technical University Bergakademie Freiberg, Leipziger Str. 29, 09596 Freiberg, Germany. gerrit.schuurmann@ufz.de.
authors.forename: Gerrit
authors.initials: G
authors.lastname: Schüürmann
keywords: Aquatic toxicity; Bioorganic chemistry; Carbonyl ester; Chemoavailability; Computational chemistry; Michael acceptor; Michael addition; Reaction barrier; Transition state