Add time:09/02/2019         Source:sciencedirect.com

A total of 51 natural and synthetic simple coumarins, furanocoumarins, chromanones, furanochromanones and some structurally related compounds were tested for their antimutagenic potencies with respect to IQ in Salmonella typhimurium TA 98. Antimutagenic potencies were quantified by the inhibitory dose for 50% reduction of mutagenic activity (ID50) and by the remaining mutagenic activity at the highest dose tested. Antimutagenic activities of the parent compounds were weak (ID50: 500–750 nmol/plate) but increased in the coumarin series with introduction of hydroxy, methoxy and (or) methyl groups at carbons 4, 5, 6 and 7 (ID50: 70–400 nmol/plate). However, the antimutagenicity of compounds with hydroxy or methoxy substituents at C-5, C-6 and C-7 all together was low. Moreover, a hydroxy or methoxy function at C-8 greatly reduced antimutagenic potency. This was in part also true for substituents at C-3. Coumarin glycosides and glucuronides of antimutagenic aglycones were, however, inactive. Introduction of a carboxyl function rendered the respective coumarin inactive. Surprisingly, some synthetic coumarins with a bromo or iodo substituent at C-8 or a benzyloxy function at C-5 were found to be very potent antimutagens (ID50: 9.3–14.5 nmol/plate), whereas analogues possessing a bromo or formyl function at C-5 were less effective (ID50: 176 and 395 nmol/plate). Furanocoumarins and furanochromanones were very potent antimutagens (ID50: 5.1–26.5 nmol/plate). In enzyme kinetic experiments with Salmonella the inhibition mechanisms of xanthotoxin and visnagin were concentration dependent, being non-competitive at low concentrations. Reduction of the activity of 7-ethoxy- and 7-methoxyresorufin-O-dealkylases with IC50 values of 1.2–11.7 μM indicated strong inhibition of cytochrome P-450 1A1 and 1A2 dependent monooxygenases by some of the furanocoumarines and -chromanones. The mutagenic activity of N-hydroxy-IQ in Salmonella, however, was not reduced by any of these compounds. In various experiments designed for modulation of the mutagenic response inhibition of activation of IQ to N-OH-IQ was found to be the only relevant mechanism of antimutagenesis of psoralen, angelicin and khellin.

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