Chemistry of Isoeugenol and Its Oxidation Products: Mechanism and Kinetics of Isoeugenol as a Skin Sensitizer

Ahn, J, Avonto, C, Pandey, P, Khan, S, Khan, IA, Roberts, D ORCID: 0000-0001-6112-5868 and Chittiboyina, AG (2023) Chemistry of Isoeugenol and Its Oxidation Products: Mechanism and Kinetics of Isoeugenol as a Skin Sensitizer. Chemical Research in Toxicology, 36 (5). pp. 747-756. ISSN 0893-228X

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Abstract

Structurally similar phytochemical compounds may elicit markedly different skin sensitization responses. Eugenol and isoeugenol are natural phenylpropanoids found in various essential oils are frequently used as fragrance ingredients in consumer products due to their pleasing aromatic properties. Both compounds are also skin sensitizers with isoeugenol being a stronger sensitizer than eugenol. The most commonly accepted mechanisms for haptenation by eugenol involve formation of a quinone methide or an ortho-quinone intermediate. The mechanism for the increased skin response to isoeugenol remains elusive, although quinone methide intermediates have been proposed. The recent identification of diastereomeric 7,4′-oxyneolignans as electrophilic, thiol-depleting isoeugenol derivatives has revived interest in the possible role of elusive reactive intermediates associated with the isoeugenol’s haptenation process. In the present work, integrated non-animal skin sensitization methods were performed to determine the ability of syn-7,4′-oxyneolignan to promote haptenation and activation of further molecular pathways in keratinocytes and dendritic cells, confirming it as a candidate skin sensitizer. Kinetic NMR spectroscopic studies using dansyl cysteamine (DCYA) confirmed the first ordered nature of the nucleophilic addition for the syn-7,4′-oxyneolignan. Computational studies reaffirmed the “syn” stereochemistry of the isolated 7,4′-oxyneolignans along with that of their corresponding DCYA adducts and provided evidence for the preferential stereoselectivity. A plausible rationale for isoeugenol’s strong skin sensitization is proposed based on the formation of a hydroxy quinone methide as a reactive intermediate rather than the previously assumed quinone methide.

Item Type:	Article
Additional Information:	This document is the Accepted Manuscript version of a Published Work that appeared in final form in Chemical Research in Toxicology, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.chemrestox.2c00407
Uncontrolled Keywords:	Skin; Eugenol; Indolequinones; Eugenol; Skin; Indolequinones; 3405 Organic Chemistry; 34 Chemical Sciences; Eugenol; Skin; Indolequinones; 0302 Inorganic Chemistry; 0304 Medicinal and Biomolecular Chemistry; 0305 Organic Chemistry; Toxicology; 3214 Pharmacology and pharmaceutical sciences; 3404 Medicinal and biomolecular chemistry; 3405 Organic chemistry
Subjects:	Q Science > QD Chemistry R Medicine > RS Pharmacy and materia medica
Divisions:	Pharmacy and Biomolecular Sciences
Publisher:	American Chemical Society
Date of acceptance:	25 March 2023
Date of first compliant Open Access:	6 February 2026
Date Deposited:	06 Feb 2026 10:23
Last Modified:	06 Feb 2026 10:23
DOI or ID number:	10.1021/acs.chemrestox.2c00407
Editors:	Dai, J
URI:	https://researchonline.ljmu.ac.uk/id/eprint/28066

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