Synthesis and Inhibitory Properties of Pheromone Analogues for the Epoxide Hydrolase of the Gypsy Moth

Article abstract of DOI:10.1021/jo00090a012

A series of analogues of disparlure, the gypsy moth (Lymantria dispar) sex attractant, was synthesized, and the potency of these inhibitors in suppressing the metabolism of disparlure by the L. dispar epoxide hydrolase (EH) was determined.The analogues substituted at the 6-position (6-hydroxy-, 6-oxo-, and 6,6-difluorodisparlure; (+/-)-threo,cis-11, (+/-)-13, and (+/-)-17, respectively), along with 9,9-difluorodisparlure <(+/-)-26>, were the most potent inhibitors (IC 50 values of 4-9 μM).Two other 9-substituted analogues, 9-hydroxydisparlure <(+/-)-threo,cis-21> and 9-oxodisparlure <(+/-)-22>, were slightly less potent (IC 50 values of 18 and 30 μM, respectively).Analogues substituted at both the 6- and 9-positions (threo,erythro-6,9-dihydroxy-, threo,threo-6,9-dihydroxy-, and 6,9-dioxodisparlure; (+/-)-threo,erythro-32, (+/-)-threo,threo-32, and (+/-)-33, respectively) were generally the least potent inhibitors (IC 50 values of 27-200 μM).On the basis of a model of the EH active site, a hypothesis is advanced to rationalize the higher potencies of the 6-substituted analogues.Pheromone metabolism plays a key role in pheromone perception, and the potential consequences of inhibition of pheromone metabolism are discussed.