Synthetic models related to furanocoumarin-CYP 3A4 interactions. comparison of furanocoumarin, coumarin, and benzofuran dimers as potent inhibitors of CYP3A4 activity.
Furanocoumarin derivatives (dimers and monomers) present in commercially available grapefruit juice have the capacity to inhibit the activity of human CYP3A4. Such interactions are believed to result from the mechanism-based inhibition of CYP3A4 activity in the intestine. The aim of this work was to synthesize and test a series of dimers with a view to determining the relationship between structure and inhibitory activity and determining whether they might make suitable probes of CYP3A4 activity. We prepared a series of furanocoumarin, coumarin, and benzofuran derivatives that have inhibitory effects on the activity of human CYP3A4. A synthetic benzofuran dimer, which is more accessible than furanocoumarin dimers, exhibited activity against CYP3A4 comparable to that of furanocoumarin dimers.
Oda
Kazuaki
K
Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Hokkaido, Japan. k-oda@hoku-iryo-u.ac.jp
Yamaguchi
Yuki
Y
Yoshimura
Teruki
T
Wada
Keiji
K
Nishizono
Naozumi
N
D001572:Benzofurans / Q000737:chemistry* / Q000494:pharmacology*; D001628:Beverages / Q000032:analysis; D032083:Citrus paradisi / Q000737:chemistry*; D003374:Coumarins / Q000737:chemistry* / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011564:Furocoumarins / Q000737:chemistry* / Q000494:pharmacology*; D006900:Hydroxylation; D008956:Models, Chemical; D013739:Testosterone / Q000737:chemistry / Q000378:metabolism