Mechanistic Proposal for the Formation of Specific Immunogenic Complexes via a Radical Pathway: A Key Step in Allergic Contact Dermatitis to Olefinic Hydroperoxides

Abstract

The widespread use of scented products causes an increase of allergic contact dermatitis to fragrance compounds in Western countries today. Many fragrance compounds are prone to autoxidation, forming hydroperoxides as their primary oxidation products. Hydroperoxides are known to be strong allergens and to form specific immunogenic complexes. However, the mechanisms for the formation of the immunogenic complexes are largely unknown. We have investigated this mechanism for (5R)-5-isopropenyl-2-methyl-2-cyclohexene-1-hydroperoxide (Lim-2-OOH) by studying the formation of adducts in the reaction between this hydroperoxide and 5,10,15,20-tetraphenyl-21H,23H-porphine iron(III) chloride (Fe(III)TPPCl) in the presence of protected cysteine (NAc-Cys-OMe) or glutathione (GSH). Isolated adducts originate from the addition of the thiol group of NAc-Cys-OMe over the carbon-carbon double bonds of carvone. Furthermore, adducts between NAc-Cys-OMe and carveol as well as between GSH and carvone have been identified. The formation of these adducts most likely proceeds via the radical thiol-ene mechanism. The addition of a terpene moiety to cysteine offers an explanation of the specificity of the immune response to structurally different hydroperoxides. These results also explain the lack of cross-reactivity between carvone and Lim-2-OOH. In conclusion, we propose that immunogenic complexes of olefinic hydroperoxides can be formed via the radical thiol-ene mechanism. These complexes will be specific for the individual olefinic hydroperoxides due to the inclusion of a terpene moiety derived from the hydroperoxide.

Mechanistic studies on the reactivity of sensitizing allylic hydroperoxides: investigation of the covalent modification of amino acids by carbon-radical intermediates

“…Previously, the reactivity of 3 with N-Ac-Cys-OMe in the presence of 5,10,15,20-tetraphenyl-21H,23H-porphyrin iron (III) chloride was studied by LC-MS. Adducts different from the ones we report here were described. 23 The authors observed also LC-MS peaks with m/z 328 and 344. They showed that 3 evolves easily to the formation of carvone in the presence of iron, 14 and proved thus accurately the formation of adducts by addition of the thiol group of cysteine either to the endocyclic bond of carvone or to the double bond of its isoprenyl group through a 2-electron reaction pathway, adducts having m/z 328.…”

Determination of the Absolute Configuration of (−)‐Hydroxynitrilaphos and Related Biosynthetic Questions

“…Chlorotrimethylsilane (2.00 g, 18.4 mmol, 2.34 mL) was added dropwise and stirring was continued for 45 min at 0 °C, followed by 1 h at room temperature. All volatiles were removed in vacuo and the residue was purified by flash chromatography, R f =0.48 (EtOAc), to give the desired methyl ester 14 (1.22 g, 6.9 mmol, 56 %) as colorless solid; all recorded spectra were identical to those reported in the literature …”

“…All volatiles were removed in vacuo and the residue was purified by flash chromatography, R f = 0.48 (EtOAc), to give the desired methyl ester 14 (1.22 g, 6.9 mmol, 56 %) as colorless solid;a ll recorded spectra were identical to those reported in the literature. [42] Methyl N-acetyl-S-(2-diethoxyphosphoryl-1-hydroxyiminoethyl)cysteinate (15): [22] Chloro-oxime 12 (525 mg, 2.3 mmol) was dissolved in dry CH 2 Cl 2 (10 mL) at 0 8Cb efore addition of (R)-methyl N-acetyl cysteinate [(R)-14,4 05 mg, 2.3 mmol] in CH 2 Cl 2 (5 mL). Et 3 N( 233 mg, 2.3 mmol, 0.32 mL) was added dropwise and stirring was continued for 90 min at 0 8C, followed by 2hat room temperature.…”

Tryptophan-based fluorophores for studying protein conformational changes

“…Compounds 40 and 42 were prepared from intermediates 17 and 22 , respectively, which were acetylated using Ac 2 O; 34 tosyl group removal was effected using cesium carbonate. 32 Compounds 43 and 44 were synthesized by acetylating intermediates 29 and 8 , respectively (Scheme 5 of the Supplementary data).…”