Structure-Potency Relationships for Epoxides in Allergic Contact Dermatitis

Epoxides are known or proposed to be involved in skin sensitization in various ways. Some are encountered directly, and others have been shown to be formed abiotically and metabolically from various unsaturated chemicals. They can react as S(N)2 electrophiles. To date no quantitative mechanistic models (QMMs) are known for skin sensitization potency of this subcategory of S(N)2 electrophiles. Here we have considered the reaction mechanistic chemistry of epoxides and combined published experimental kinetic data (rate constants k for reaction with a cysteine-based peptide) together with calculated hydrophobicity data (logP) to derive a QMM correlating potency in the local lymph node assay (LLNA), expressed as EC3, with a relative alkylation index (RAI, calculated as logk + 0.4 logP). The QMM equation, pEC3 = 2.42(+/- 0.26) RAI + 4.04 (+/- 0.25), n = 9, R-2 = 0.928, R-2(adj) = 0.917, F = 90, s = 0.18, fits the data well, with one positive outlier. The outlier can be rationalized by its exhibiting an alert for oxidation of an amine moiety to give, in this case, the highly reactive glycidaldehyde. The epoxide QMM predicts the potency of a nonepoxide S(N)2 electrophile (predicted EC3, 0.48%; observed EC3, 0.5%), which suggests that it could form the basis for a more general H-polar SN2 QMM that could be a valuable tool in skin sensitization risk assessment for this quite extensive and structurally diverse reaction mechanistic domain.