Electrophilic reactivity and skin sensitization potency of SNAr electrophiles

We published in 2011 a quantitative mechanistic model (QMM) for skin sensitization potency of SNAr electrophiles in the mouse local lymph node assay (LLNA). In this model, potency was correlated with a combination of σ* for the leaving group and the total σ(-) values of the other substituents in the aromatic ring. Shortly afterward Natsch et al. published a kinetic study in which rate constants were determined for reactions of SNAr electrophiles with the cysteine-based peptide Ac-RFAACAA (Cys-peptide) that is used in the direct peptide reactivity assay (DPRA), and correlations were sought between these rate constants and sensitization potency in the LLNA. These two publications together have enabled the present study, aiming to develop a linear free energy relationship (LFER) correlating Cys-peptide reactivity with a reactivity parameter (RP) based on a combination of σ* and σ(-) substituent constants and, by analyzing differences between the QMM based on RP and the QMM based on Cys-peptide rate constants, to gain further insights into the underlying chemistry of skin sensitization. For the 2,4-dinitro-X-subsituted benzenes (DNXB), the rate constants of Natsch et al. are well correlated with the reactivity parameter used in our earlier work, with two outliers. These are the compounds with X = F and X = SCN, which are both substantially more reactive toward Cys-peptide than predicted from comparison of their RP values with those of the other DNXB compounds. These two compounds are both negative outliers from a correlation of sensitization potency with experimental rate constants, but fit well to the correlation of sensitization potency with RP values. With these two compounds excluded, sensitization potency is well correlated with the experimental rate constants for the DNXB compounds (X = SO3(-), I, Br, Cl) together with 2,4-dichloro-1-nitrobenzene and 1,3,4,5-tetrachloro-2,6-dicyanobenzene. The regression equation is pEC3 = 0.88 log k + 4.03, R(2) = 0.966. The implication of DNFB being an outlier is that the model Cys-peptide nucleophile is substantially more sterically hindered than the cutaneous nucleophile(s) involved in the sensitization process. The pattern seen with 2,4-dinitrothiocyanatobenzene suggests that this compound reacts as an SNAr electrophile in the sensitization process, but by a different pathway, acting as a CN transfer agent, with the model Cys-peptide. For two further compounds, 2,4,6-trinitrochlorobenzene and 2,4,6-trinitrobenzenesulfonate, the Cys-peptide rate constants are well predicted by the reactivity parameter based on displacement of the Cl or SO3(-) substituent, but their sensitization potency is underestimated by both the Cys-peptide rate constant and this reactivity parameter. However, potency of these two compounds is well predicted by a reactivity parameter calculated on the basis of displacement of the 2-nitro group. This is interpreted as a case of sensitization being driven by the thermodynamically favored rather than the kinetically favored reaction product.