Prediction of Michael-Type Acceptor Reactivity toward Glutathione

Abstract

A model has been developed to predict the kinetic rate constants (k(GSH)) of α,β-unsaturated Michael acceptor compounds for their reaction with glutathione (GSH). The model uses the local charge-limited electrophilicity index ω(q) [Wondrousch, D., et al. (2010) J. Phys. Chem. Lett. 1, 1605-1610] at the β-carbon atom as a descriptor of reactivity, a descriptor for resonance stabilization of the transition state, and one for steric hindrance at the reaction sites involved. Overall, the Michael addition model performs well (r² = 0.91; rms = 0.34). It includes various classes of compounds with double and triple bonds, linear and cyclic systems, and compounds with and without substituents in the α-position. Comparison of experimental and predicted rate constants demonstrates even better performance of the model for individual classes of compounds (e.g., for aldehydes, r² = 0.97 and rms = 0.15; for ketones, r² = 0.95 and rms = 0.35). The model also allows for the prediction of the RC₅₀ values from the Schultz chemoassay, the accuracy being close to the interlaboratory experimental error. Furthermore, k(GSH) and associated RC₅₀ values can be predicted in cases where experimental measurements are not possible or restricted, for example, because of low solubility or high volatility. The model has the potential to provide information to assist in the assessment and categorization of toxicants and in the application of integrated testing strategies.

Chemical reactivity and biological activity of dihydro-1,4-dithiin tetraoxides

“…The first four descriptors, obtained using the semiempirical AM1 methods, are molecular properties known to be useful for predicting electrophilic reactivity. [22][23][24]32,33 However, none of these molecular descriptors correlated with the k values for the dithiin−GSH reactions in a statistically significant manner (p > 0.05), suggesting that they are not suitable for the prediction of dithiin electrophilicity.…”

“…Single point energies in water were calculated for these conformers using AM1 Hamiltonian and restricted Hartree-Fock formalism on TSAR version 3.3 software (Oxford Molecular, Oxford, UK). The respective values of E HOMO and E LUMO were then used to compute the absolute difference between E HOMO and E LUMO (|E HOMO [22][23][24] Calculation of electrostatic atomic charges Q of the dithiins was performed on optimized geometries using the semi-empirical AM1 Hamiltonian method on Spartan software. Taft's polar substituent constants * obtained from the literature 25 were used for appropriate substituents of the dithiins.…”

“…To identify the chemical descriptors that may be useful for predicting the nucleophilic susceptibility of dithiins, various molecular, fragment, and atomic descriptors were calculated computationally or obtained from the literature and then correlated 24 However, for 2 and 3, the * values for their corresponding R and R= were unavailable, and thus the value of CH 2 CH 3 was used as a substitute.…”

Modelagem in chemico: as bases mecanísticas entre a reatividade e a toxicidade

“…Essas ligações não são específicas, mas podem desencadear uma série de reações no organismo, ocasionando irritação e sensibilização da pele e trato respiratório, disfunção no sistema imune, toxicidade à reprodução, mutagenicidade, carcinogenicidade, entre outros efeitos adversos (Schultz et al, 2006 (Schwöbel et al, 2010). Os métodos in chemico são elaborados a partir de dados de estudos prévios da toxicidade das substâncias e de estudos epidemiológicos para a comparação dos resultados obtidos quimicamente e verificação da exatidão do método proposto.…”

Global and Local Reactivity Descriptors Based on Quadratic and Linear Energy Models for α,β-Unsaturated Organic Compounds

“…In this study we used different energy models to obtain global and local reactivity descriptors for α, β -unsaturated thioester, ester and amides able to provide alternative substrates for enzymatic CO 2 fixation. The capacity of these descriptors to describe the reactivity of these compounds was priorly validated with experimentally reported rate constants of α, β -unsaturated ketones with gluthatione in aqueous solution [28].…”