Inhibition of epoxide metabolism by α,β-epoxyketones and isosteric analogs

Chalcone oxides and several isosteric compounds have been prepared to examine the importance of the α,β-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 hyhydrogen-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.