Predicting Michael-acceptor reactivity and toxicity through quantum chemical transition-state calculations

Abstract

The electrophilic reactivity of Michael acceptors is an important determinant of their toxicity. For a set of 35 α,β-unsaturated aldehydes, ketones and esters with experimental rate constants of their reaction with glutathione (GSH), k(GSH), quantum chemical transition-state calculations of the corresponding Michael addition of the model nucleophile methane thiol (CH(3)SH) have been performed at the B3LYP/6-31G** level, focusing on the 1,2-olefin addition pathway without and with initial protonation. Inclusion of Boltzmann-weighting of conformational flexibility yields intrinsic reaction barriers ΔE(‡) that for the case of initial protonation correctly reflect the structural variation of k(GSH) across all three compound classes, except that they fail to account for a systematic (essentially incremental) decrease in reactivity upon α-substitution. By contrast, the reduction in k(GSH) through β-substitution is well captured by ΔE(‡). Empirical correction for the α-substitution effect yields a high squared correlation coefficient (r(2) = 0.96) for the quantum chemical prediction of log k(GSH), thus enabling an in silico screening of the toxicity-relevant electrophilicity of α,β-unsaturated carbonyls. The latter is demonstrated through application of the calculation scheme for a larger set of 46 Michael-acceptor aldehydes, ketones and esters with experimental values for their toxicity toward the ciliates Tetrahymena pyriformis in terms of 50% growth inhibition values after 48 h exposure (EC(50)). The developed approach may add in the predictive hazard evaluation of α,β-unsaturated carbonyls such as for the European REACH (Registration, Evaluation, Authorization and Restriction of Chemicals) Directive, enabling in particular an early identification of toxicity-relevant Michael-acceptor reactivity.

2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells

“…The GSH reactivity of the acrylamide moiety, which is present in the FDAapproved anticancer drugs ibrutinib and canertinib, is seven times less reactive than PK11000 (23). Considering the clear correlation of compound-GSH reactivity with toxicity (22,24,25), the reactivity of the PK11000 is close to the level of therapeutically applied thiol reactive agents.…”

Automated computational screening of the thiol reactivity of substituted alkenes

“…The second step is a Michael-type addition reaction, where the nucleophilic thiolate attacks the more electrophilic carbon of the olefin (Scheme 2) [10]. Conjugated addition then proceeds through formation of a carbanion at the intermediate a-carbon.…”

“…Several studies have correlated calculated molecular descriptors of electrophiles to toxicological or pharmacological properties [1,10,16]. Descriptors calculated from natural bond orbital (NBO) theory, such as electrophilicity, steric accessibility, and energy levels of olefin have been successfully correlated to the rates of thiol additions of electrophiles [16].…”

Computational insights into the suicide inhibition of Plasmodium falciparum Fk506-binding protein 35

“…Considering the electrophile, a derivative of the chosen Michael acceptor (3-buten-2-one) has been shown to have greater reactivity than its aldehyde or ester equivalents, with a predicted log K of 3.51 when reacted with glutathione. 59 This structure also has a log EC of À4.51 for Tetrahymena pyriformis after 48 h exposure, indicating this Michael acceptor has a comparatively smaller toxicity than other similar Michael acceptors (1-penten-3-one, 1-hexen-3-one, and 1-octen-3-one have comparable log K and log EC values). 59 This Michael acceptor would also be anchored to a large natural product, limiting its ability to react in tight protein pockets.…”