Structure-genotoxicity relationships of allylbenzenes and propenylbenzenes: a quantum chemical study.
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.
Tsai
R S
RS
Institut de Chimie Thérapeutique, Ecole de Pharmacie, Université de Lausanne, Switzerland.
Carrupt
P A
PA
Testa
B
B
Caldwell
J
J
D000081248:Allylbenzene Derivatives; D000840:Anisoles / Q000737:chemistry / Q000633:toxicity; D001593:Benzyl Compounds; D001711:Biotransformation; D004148:Dioxolanes / Q000737:chemistry / Q000633:toxicity; D005054:Eugenol / Q000031:analogs & derivatives / Q000737:chemistry / Q000633:toxicity; D005421:Flavoring Agents / Q000737:chemistry* / Q000633:toxicity*; D005609:Free Radicals; D006900:Hydroxylation; D008956:Models, Chemical; D011748:Pyrogallol / Q000031:analogs & derivatives / Q000737:chemistry / Q000633:toxicity; D012451:Safrole / Q000737:chemistry / Q000633:toxicity; D013329:Structure-Activity Relationship
D000081248:Allylbenzene Derivatives; D000840:Anisoles; D001593:Benzyl Compounds; D004148:Dioxolanes; D005421:Flavoring Agents; D005609:Free Radicals; D011748:Pyrogallol; C005246:myristicin; C005223:methyleugenol; D005054:Eugenol; C002135:elemicin; C007633:estragole; C006578:anethole; D012451:Safrole