Organic synthesis and bioassay of novel inhibitors of JH III epoxide hydrolase activity from fifth stadium cabbage loopers, Trichoplusia ni

A series of novel methyl esters with a quaternary ammonium salt, sulfoxide, amine N-oxide, difluorocyclopropane, fluorohydrin, episulfide or epoxide were prepared from undecylenic acid as potential inhibitors of JH III epoxide hydrolase activity from last stadium, wandering cabbage loopers, Trichoplusia ni. Among the non-epoxides examined, the fluorohydrin and sulfoxide (at 100 μM of inhibitor) demonstrated the highest percent inhibition of the insoluble epoxide hydrolase activity while the quaternary ammonium salt, the difluorocyclopropane, and the sulfoxide demonstrated the highest inhibitory activity against the solubilized JH epoxide hydrolase activity. These differences in inhibition between insoluble and solubilized enzyme were in some cases pronounced. For example, the quaternary amine demonstrated no inhibitory activity toward the insoluble enzyme but inhibited 33% of the solubilized JH epoxide hydrolase activity. The incorporation of a cationic character in the amine N-oxide and ammonium salt produced lower inhibitory activity as compared to the sulfoxide, episulfide, difluorocyclopropane, and fluorohydrin for the insoluble epoxide hydrolase, and activity was similar for the solubilized enzyme. Comparing the most potent non-epoxide to the epoxide inhibitors, the fluorohydrin produced 24% inhibition as compared to 85% for the corresponding epoxide and 42% for the epoxide with a shorter backbone chain length for the insoluble epoxide hydrolase activity. For the solubilized epoxide hydrolase activity, difluorocyclopropane demonstrated 34% inhibition as compared to 21% inhibition for the corresponding epoxide. The difluorocyclopropane appeared to be acting as a competitive inhibitor of JH III epoxide hydrolase activity. The I50s were greater than 100 μM for all compounds synthesized for both the soluble and solubilized enzymes; the only exceptions were the C11 and C12 epoxides against the insoluble epoxide hydrolase activity (I50s = 0.1 and 0.8 μM, respectively). The importance of JH mimicry in epoxide hydrolase inhibition is discussed.