Design, synthesis and evaluation of furanocoumarin monomers as inhibitors of CYP3A4.

A number of furanocoumarins isolated from grapefruit juice have been found to inhibit CYP3A4 activity in vitro. In this study, we have designed and synthesised a range of analogues based on bergamottin to investigate the relationship between chemical structure and inhibition of CYP3A4 activity. Studies were performed using human liver microsomes and human intestinal S9 fraction, with testosterone as the marker substrate. With the exception of the coumarin and phenolic furanocoumarin derivatives, which were inactive, the alkyloxy-furanocoumarin analogues were found to inhibit CYP3A4 activity in a dose dependent manner, with observed IC50 values ranging from 0.13 +/- 0.03 to 49.3 +/- 1.9 microM. The unsaturated furan derivatives were found to exhibit time-dependent inhibition, showing a 2-, 4- and 14-fold increase in potency for 6',7'-epoxybergamottin, 6',7'-dihydroxybergamottin and bergamottin, respectively after a preincubation period of ten minutes. Reduction of the furan moiety resulted in an 11-fold decrease in inhibitory potency, suggesting that this functional group is key to the interaction between these compounds and CYP3A4.

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.