Cyclopropyl oxiranes: reversible inhibitors of cytosolic and microsomal epoxide hydrolases

A series of aryl- and alkyl-substituted cyclopropyl oxiranes were synthesized as potential suicide inhibitors of mouse liver epoxide hydrolase (EH). The inhibitory potency of each compound and its corresponding alkene precursor was determined with mouse liver EHs using [3H]-cis-stilbene oxide as substrate for microsomal EH (mEH) and for glutathione-S-transferase, and using [3H]-trans-stilbene oxide for cytosolic EH (cEH). The cyclopropyl oxiranes all showed low (26-60% at 5 X 10(-4) M) inhibition of glutathione transferase and moderate inhibition (I50 = 5 X 10(-4) to 6 X 10(-6) M) for cEH and mEH. cis-Phenylcyclopropyl oxirane had an I50 for mEH near that for a commonly used inhibitor, 1,1,1-trichloropropene oxide. Inhibition appeared competitive and reversible, and the cyclopropyl oxiranes appeared to function as alternate substrates. Absence of irreversible inhibition is evidence against a strongly electrophilic epoxide-opening mechanism involving a cyclopropyl carbinyl-homoallyl cation rearrangement. Instead, a concerted mechanism is favored, in which electrophilic opening and hydroxide attack occur in a concerted fashion.