Abiotic Sulfhydryl Reactivity:  A Predictor of Aquatic Toxicity for Carbonyl-Containing α,β-Unsaturated Compounds

Abstract

A diverse series of aliphatic alpha,beta-unsaturated esters, ketones, and aldehydes were evaluated for reactivity with the model nucleophile sulfhydryl group in the form of the cysteine residue of the tripeptide glutathione; the reactive end point (RC50) was then related to aquatic toxicity (IGC50) assessed in the Tetrahymena pyriformis population growth impairment assay. The substructure specific to all tested reactive substances, an olefin conjugated to a carbonyl group, is inherently electrophilic and conveys the potential to act by way of Michael-type nucleophilic addition. All such unsaturated compounds are inherently acutely toxic. However, their toxicity is difficult to model with conventional descriptors since toxicity is independent of both hydrophobicity and molecular orbital electrophilicity but dependent on the specific molecular structure. While methacrylates typically did not attain an RC50 value at saturation, a linear relationship [log (IGC50(-1)) = 0.936[log (RC50(-1))] + 0.508, where n = 41, r2 = 0.846, q2 = 0.832, s = 0.35, F = 214, and Pr > F = 0.0001] was observed between aquatic toxicity and reactivity for the other carbonyl-containing alpha,beta-unsaturated chemicals.

Prediction of the reduced glutathione (GSH) reactivity of dental methacrylate monomers using NMR spectra-Relationship between toxicity and GSH reactivity

“…1). Acrylates are known to have higher electrophilic reactivity than methacrylates, and have been previously reported to have high toxicity [5][6][7] . The thiol group of glutathione (GSH) is often used as a model nucleophile, whereby the reaction rates of GSH (log K) have been used to investigate the quantitative structure-activity relationships (QSAR) of acrylates and methacrylates.…”

“…On this premise, it becomes possible to correlate the magnitude of an NMR chemical shift with the reactivity of monomers via reactions such as Michael addition 10) . Coupled with the availability of quantitative reactivity data for GSH with α, β unsaturated carbonyl compounds such as acrylates and methacrylates [5][6][7] , the magnitudes of the NMR chemical shifts of β-carbons for methacrylate monomers may thus be used to estimate their GSH reactivity.…”

Relationships between the Reduced Glutathione (GSH) Reactivity of Dental Methacrylates, Michael-reaction Acceptors and their 13C-NMR Chemical Shift of -Carbons

“…On this preface, it ends up plainly conceivable to connect the greatness of a NMR concoction move with the reactivity of monomers by means of responses, for example, Michael expansion [10]. Quantitative information on the GSH reactivity of α, β-unsaturated carbonyl mixes, for example, acrylates and methacrylates have been accounted for [5,7]. Along these lines, the greatness of the NMR concoction movements of -carbons for (meth)acylate monomers might be utilized for evaluating their GSH reactivity.…”

“…Michael expansion has been proposed as the instrument of the response of thiols with unsaturated carboxylic esters of (meth)acrylates [7], and the unsaturated β-carbon particle is the most presumably the site of assault. Spectroscopic strategies bolster synthetic advancement.…”

“…Notwithstanding log P, , −unsaturated carbonyl methacrylates utilized as tar monomers may display danger however response with tissue nucleophiles by means of Michael expansion [2][3][4][5][6] (Figure 1). Acrylates are notable to be substantially more electrophilic than methacrylates, and have been beforehand answered to have high danger [5][6][7]. Glutathione (GSH) is a nucleophile frequently utilized as a model for cell thiol gatherings.…”