Synthesis of Allylic Hydroperoxides and EPR Spin-Trapping Studies on the Formation of Radicals in Iron Systems as Potential Initiators of the Sensitizing Pathway

Abstract

Many terpenes used as fragrance compounds autoxidize when exposed to air, forming allylic hydroperoxides that have the potential to be skin contact allergens. To trigger the immunotoxicity process that characterizes contact allergy, these hydroperoxides are supposed to bind covalently to proteins in the skin via radical pathways. We investigated the formation of reactive radical intermediates from 7-hydroperoxy-3,7-dimethylocta-1,5-dien-3-ol and 2-hydroperoxylimonene, responsible for the sensitizing potential acquired by autoxidized linalool and limonene. Both compounds were synthesized through new short and reproducible synthetic pathways. The hydroperoxide decomposition catalyzed by Fe(II)/Fe(III) redox systems, playing a key role in degradating peroxides in vivo, was examined by spin-trapping-EPR spectroscopy. Alkoxyl and carbon-centered free radicals derived from the hydroperoxides were successfully trapped by the spin-trap 5,5-dimethyl-1-pyrroline N-oxide, whereas peroxyl radicals were characterized by spin-trapping studies with 5-diethoxyphosphoryl-5-methyl-1-pyrroline N-oxide. Using liquid chromatography combined with mass spectrometry, we demonstrated the formation of adducts, via radical mechanisms induced by Fe(II)/Fe(III), between the hydroperoxides and N-acetylhistidine methyl ester, a model amino acid that is prone to radical reactions. Free radicals derived from these hydroperoxides can thus induce amino acid chemical modifications via radical mechanisms. The study of these mechanisms will help to understand the sensitizing potential of hydroperoxides.

Sensitization potential and potency of terpene hydroperoxides in the cocultured activation test method

“…29,30 For the mixture Citr-6/7-OOH, we used exactly the same procedure as described for Lin-6/7-OOH, and obtained, for both mixtures, an isomer ratio of 6:4. 30 Cyc-hex-OOH was also synthesized with a method described in the literature. 31 All synthesized compounds were pure according to the 1 H and 13 C nuclear magnetic resonance F I G U R E 1 Chemical structures of terpene hydroperoxides included in this study: limonene-1-hydroperoxide (1), limonene-2hydroperoxide (2), linalool-6-hydroperoxide (3), linalool-7hydroperoxide (4), citronellol-6-hydroperoxide (5), citronellol-7hydroperoxide (6), cumene hydroperoxide (7), and 1-(1-hydroperoxy-1-methylethyl)cyclohexene (8) characterizations, in agreement with the literature.…”

Iodide reaction times of peroxyhemiacetals (PHAs) in the peroxide value titration; implications for the testing of citrus oils

“…A mixture of linalool hydroperoxide isomers was obtained by synthesis using the method of Kao et al as previously reported …”

“…Preparations of purified limonene hydroperoxide isomers and linalool hydroperoxide isomers have been previously reported, so the corresponding PHAs should be obtained in situ by simply mixing them with a relevant aldehyde in a nonpolar solvent. The aldehydes endogenous to citrus oils, such as octanal and/or decanal, are relevant aldehydes for the purpose herein.…”

An HPLC method for the detection of hydro peroxides derived from linalyl acetate in citrus oils, using post‐column luminol‐mediated chemiluminescence detection

“…Skold et al had prepared a mixture of II and III via a Rose Bengal photosensitized oxidation of linalyl acetate, and characterized the hydroperoxide products by 1H and 13C NMR . Using their characterization data for structural confirmation purposes, we attempted to prepare a mixture of II and III via a chemical oxidation reported by Kao et al that had worked for linalool oxidation.…”

“…Starting from linalyl acetate, we duplicated the Kao et al synthetic procedure to obtain linalyl acetate hydroperoxide (Figure ). We expected a product mixture containing two positional isomers as reported for linalool, but hoped that the corresponding acetates (II and III) would be separable by column chromatography.…”