Skin sensitization to linalyl hydroperoxide: support for radical intermediates.

Abstract

In order to better understand the skin sensitization mechanism of allylic hydroperoxides, linalyl hydroperoxide (1) and several of its potential rearrangement products-epoxylinalool (2), epoxynerol (3), epoxygeraniol (4), and furan (5) and pyran (6) derivatives-were synthesized. The sensitizing properties of these molecules have been screened on mice using the local lymph node assay (LLNA) and further evaluated on guinea pigs using the Freund's complete adjuvant test (FCAT). Linalyl hydroperoxide (1) and linalyl epoxide (2) were found to be sensitizers, while the other compounds were classified as mild sensitizers or nonsensitizers. In the guinea pigs, no cross-reactions were observed between skin sensitizers 1 and 2. Radical-trapping experiments were carried out on linalyl hydroperoxide (1) using TTBP as trapping agent and Fe(3+)-TPP as radical inducer. The major reaction taking place is the formation of a furan ring by intramolecular reaction of the oxygen-centered radical with the isoprenyl double bond with the formation of a tertiary radical. Reaction of this intermediate with radicals derived from TTBP gave compounds 10a,b in 25% yield. The second important reaction, accounting for 14%, is taking place on the allylic double bond with the formation of a less stable primary radical which is not trapped by a TTBP-derived radical but by a hydroxy radical to give a mixture of epoxides 3 and 4. These results are in favor of the formation of a carbon-centered reactive radical as intermediate in the skin sensitization to linalyl hydroperoxide.