Synthesis of 8-geranyloxypsoralen analogues and their evaluation as inhibitors of CYP3A4.
Furanocoumarins have been shown to inhibit CYP3A4 in vitro with varying degrees of potency. In this study, we report the effects of a series of novel furanocoumarins based on the naturally occurring derivative 8-geranylepoxypsoralen which has been shown to be a more potent inhibitor of CYP3A4 than its 5-position-substituted counterpart bergamottin. Compounds were designed, synthesised and tested for their ability to inhibit CYP3A4 activity in human liver microsomes using testosterone as the marker substrate. Both the saturated and unsaturated phenolic furanocoumarin derivatives were found to be inactive. However, the 8-alkyloxy-furanocoumarin analogues were shown to inhibit CYP3A4 activity in a dose dependent manner, with IC(50) values ranging from 0.78+/-0.11 to 3.93+/-0.53 microM. The reduced furan derivative dihydro-8-geranyloxypsoralen showed a 4-fold decrease in inhibitory potency, suggesting that the furan moiety plays a role in the interaction between these compounds and CYP3A4.
Academic Unit of Clinical Pharmacology, The University of Sheffield, Royal Hallamshire Hospital, Sheffield, UK.
E C
EC
Row
S A
SA
Brown
A V
AV
Stachulski
M S
MS
Lennard
D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011564:Furocoumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D008099:Liver / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011564:Furocoumarins; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C068337:bergamottin