Inhibition of rat liver microsomal lipid peroxidation elicited by 2,2-dimethylchromenes and chromans containing fluorinated moieties resistant to cytochrome P-450 metabolism.
2,2-Dimethylchromenes and chromans containing cytochrome P-450 resistant 2,2,2-trifluoroethoxy aryl substituents were synthesized and their activity as lipid peroxidation inhibitors evaluated and compared with that exhibited by the corresponding non-fluorinated derivatives. Lipid peroxidation was stimulated in rat liver microsomes by addition of Fe-ascorbate or NADPH, and determined with the TBARS (thiobarbituric acid reactive substances) test. In assays using Fe-ascorbate stimulation, only those derivatives with a OH group at C6 (i.e. 6 and 12) elicited good inhibitory activities (IC50 = 6.0 and 5.3 microM, respectively). In respect to the NADPH dependent incubations, inhibitory activity of compound 11 (IC50 = 6.0 microM) was the highest found within the 6,7-dialkoxy derivatives tested. Results on metabolism assays with this compound showed the generation of phenol 12 (i.e. the putative active antioxidant species); on the other hand, no metabolite resulting from dealkylation at C7 was detected, thus confirming the resistance conferred by the CF3CH2O group to the cytochrome P-450 promoted cleavage. Finally, in assays where incubations in the presence of NADPH were prolonged up to three hours, inhibitory activity of the non-fluorinated 6,7-dialkoxychroman 8 remained constant, thus suggesting that a continued release of the species responsible for the inhibitory activity was produced. However, inhibition elicited by the fluorinated analog 11 showed a small decrease during the third hour of incubation. This decrease could be attributed to the slight inhibition of the cytochrome P-450 metabolism exerted by substrates bearing the CF3CH2O substituent, which would decelerate the generation of the active phenol species.(ABSTRACT TRUNCATED AT 250 WORDS)
Irurre
J
J
Department of Biological Organic Chemistry, C.I.D. (C.S.I.C.), Barcelona, Spain.
Casas
J
J
Ramos
I
I
Messeguer
A
A
D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D002839:Chromans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002867:Chromones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005461:Fluorine; D066298:In Vitro Techniques; D007501:Iron / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D009249:NADP / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D002839:Chromans; D002867:Chromones; D017392:Thiobarbituric Acid Reactive Substances; D005461:Fluorine; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D007501:Iron; D001205:Ascorbic Acid