Nucleophilicity of Glutathione: A Link to Michael Acceptor Reactivities

Abstract

Deprotonated glutathione is among the most potent biological nucleophiles and plays an important physiological role in cellular detoxification by forming covalent conjugates with Michael acceptors. The electrophilicity E of various Michael acceptors was characterized recently according to the Patz–Mayr relation lg k 2=s N(N+E). We now determined the nucleophilic reactivity (N, s N) of glutathione (GSH) in aqueous solution at 20 °C to connect published GSH reactivities (k GSH) with Mayr's electrophilicity scale (E). In this way, electrophilicities E of more than 70 Michael acceptors could be estimated, which can now be used to systematically predict novel reactions with the multitude of nucleophiles whose nucleophilicity parameters N/s N are known.

Nucleophilicity Prediction via Multivariate Linear Regression Analysis

“…However, Michael acceptors did not follow the same trend and were shown to correlate with their methyl anion affinities instead. 8a , 11 Similarly, nucleophiles provided fair correlations with the highest occupied molecular orbital (HOMO) energy only when divided in structurally similar subsets over a relatively small range of N values. A general correlation accounting for different types of nucleophiles could not be found so far.…”

MetaTREE, a Novel Database Focused on Metabolic Trees, Predicts an Important Detoxification Mechanism: The Glutathione Conjugation

“…Quantitative Structure-Activity Relationship (QSAR) analyses, mostly based on quantum mechanical descriptors, have been also proposed. However, they involve quite limited learning sets and have restricted applicability domains, so they are amenable only to predicting the reactivity of close congeners [14].…”

Towards the Inhibition of Protein–Protein Interactions (PPIs) in STAT3: Insights into a New Class of Benzothiadiazole Derivatives

“…The absence of reactivity at the acidic pH can be explained on one hand by the pH-dependent nucleophilicity of GSH [ 32 ] and on the other hand by the deprotonation of compound 1 occurring at a neutral/basic pH (pKa = 6.88 ± 0.03) [ 22 ], which can lead to structure rearrangements that possibly contribute to an increased reactivity towards GSH. However, the methyl groups seem fundamental for the covalent reaction, since no adducts were detectable upon incubation of GSH with compound 1d , which was the second most active compound according to the results reported in Table 2 .…”

“…At a neutral pH ( Figure 4C), a single adduct was detectable at the reaction endpoint (504.12121 m/z), whereas at a basic pH ( Figure 4D), three signals at 502.10569, 504.12120, and 520.11607 m/z were detected along with the complete oxidation of GSH to its dimer GSSG (i.e., the conversion of the singly charged GSH ion at 308.09106 m/z to the doubly charged GSSG ion at 307.08332 m/z). The absence of reactivity at the acidic pH can be explained on one hand by the pH-dependent nucleophilicity of GSH [32] and on the other hand by the deprotonation of compound 1 occurring at a neutral/basic pH (pKa = 6.88 ± 0.03) [22], which can lead to structure rearrangements that possibly contribute to an increased reactivity towards GSH. However, the methyl groups seem fundamental for the covalent reaction, since no adducts were detectable upon incubation of GSH with compound 1d, which was the second most active compound according to the results reported in Table 2.…”