Structure-genotoxicity relationships of allylbenzenes and propenylbenzenes: A quantum chemical study

Abstract

Quantum mechanical calculations at the semiempirical level (AM1 method) were conducted for estragole (1), methyleugenol (2), safrole (3), alpha-asarone (4), beta-asarone (5), elemicin (6), allylbenzene (7), eugenol (8), trans-anethole (9), isosafrole (10), and myristicin (11), and the results compared with the known genotoxicity of 1-6 and the absence of genotoxicity of 7-11 (unscheduled DNA synthesis assay). The various compounds showed no significant differences in the relative stability of the radical species formed as intermediates in C-sp3 hydroxylation (delta HR(radical)) and in the corresponding enthalpy of activation (delta H++). In contrast, the carbonium ions of the genotoxic congeners 1-6 were shown to be comparatively more stable than those of the inactive compounds 7-11, with the exception of eugenol (8). The inactivity of this compound could be due to a very rapid stabilization of the carbonium ion by deprotonation to form a quinone methide, as suggested by quantum chemical calculations. The relative stability of the carbonium ion thus appears to be one of the key factors in the genotoxicity of allylbenzenes and propenylbenzenes.

Predicting Rates of Cytochrome-P450-Mediated Bioactivation and Its Application to the Design of Safer Chemicals

“…An example of the failure of the PNR model was recendy published by Testa and coworkers (44). These workers found that the genotoxicity of allylbenzenes and propenylbenzenes did not correlate with the PNR derived enthalpy of activation.…”

General Principles for the Design of Safer Chemicals: Toxicological Considerations for Chemists

“…As with allyl alcoholic substituents, propargyl alcoholic substituents (CsC-C-OH) that contain at least one hydrogen on the alcoholic carbon are also known to undergo enzymatic oxidation to the corresponding a,6-unsaturated carbonyl metabolites and are quite toxic (46)(47)(48). In addition, propargyl alcohols that contain an aromatic substituent on the alcoholic carbon may undergo Phase-n sulfate conjugation reactions to yield electrophilic species analogous to 10 (49). It is advisable that chemists either avoid propargyl alcoholic moieties altogether during the design of a chemical substance or, if this moiety is necessary, incorporate the same structural modifications described above for allyl alcoholic moieties to prevent or reduce bioactivation to electrophilic metabolites.…”

Dual dispersive liquid–liquid microextraction for determination of phenylpropenes in oils by gas chromatography–mass spectrometry

“…In terms of chemical constituents, plant-based volatile oils can be categorized as terpenoids and phenylpropanoids that contain phenylpropenes, which are the major components of various essential oils. Phenylpropenes can be chemically classified as propenylbenzenes (e.g., anethole), which have a 1,2-double bond and are non-genotoxic, and allylbenzenes (e.g., safrole), which have a 2,3-double bond and are carcinogenic according to rodent studies [8]. Although the latter are nonreactive, their metabolites (allylbenzenes-2,3-oxide) develop toxicity when they undergo cytochrome P450-metiated 1-hydroylation followed by sulfation.…”