Inhibition of epoxide metabolism by alpha,beta-epoxyketones and isosteric analogs.
Chalcone oxides and several isosteric compounds have been prepared to examine the importance of the alpha,beta-epoxyketone moiety in the inhibition of the hydrolysis of [3H]-trans-stilbene oxide to its meso-diol by mouse liver cytosolic epoxide hydrolase (cEH). Inhibition of microsomal EH and glutathione S-transferase were also examined. For cEH, replacement of the carbonyl by methylidene reduces inhibitor potency by a factor of 44, while replacement of the epoxide ring with a cyclopropyl ring reduces inhibition by a factor of 450. A 2'-hydroxyl also reduces cEH inhibition by 100 times. These observations are consistent with a model of the active site in which the carbonyl is hy-hydrogen-bonded to an acidic site presumed to be involved in initiating epoxide hydrolysis. The chalcone oxides thus bind tightly but are not readily turned over as substrates.
D000818:Animals; D001665:Binding Sites; D002599:Chalcone / Q000031:analogs & derivatives / Q000494:pharmacology; D047188:Chalcones; D003600:Cytosol / Q000201:enzymology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors; D004852:Epoxy Compounds / Q000378:metabolism*; D004988:Ethers, Cyclic / Q000378:metabolism*; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors; D008099:Liver / Q000201:enzymology; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D013267:Stilbenes / Q000378:metabolism; D013329:Structure-Activity Relationship
D047188:Chalcones; D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D013267:Stilbenes; C028770:chalcone epoxide; D002599:Chalcone; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases; C025906:stilbene oxide