Inhibition of insect juvenile hormone epoxide hydrolase: asymmetric synthesis and assay of glycidol-ester and epoxy-ester inhibitors of trichoplusia ni epoxide hydrolase.
Juvenile hormone (JH) undergoes metabolic degradation by two major pathways involving JH esterase and JH epoxide hydrolase (EH). While considerable effort has been focussed on the study of JH esterase and the development of inhibitors for this enzyme, much less has been reported on the study of JH-EH. In this work, the asymmetric synthesis of two classes of inhibitors of recombinant JH-EH from Trichoplusia ni, a glycidol-ester series and an epoxy-ester series is reported. The most effective glycidol-ester inhibitor, compound 1, exhibited an I(50) of 1.2x10(-8) M, and the most effective epoxy-ester inhibitor, compound 11, exhibited an I(50) of 9.4x10(-8) M. The potency of the inhibitors was found to be dependent on the absolute configuration of the epoxide. In both series of inhibitors, the C-10 R-configuration was found to be significantly more potent that the corresponding C-10 S-configuration. A mechanism for epoxide hydration catalyzed by insect EH is also presented.
Linderman
R J
RJ
Department of Chemistry, North Carolina State University, Raleigh, NC 27695, USA. russell_linderman@ncsu.edu
Roe
R M
RM
Harris
S V
SV
Thompson
D M
DM
D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D004852:Epoxy Compounds / Q000138:chemical synthesis*; D015394:Molecular Structure; D009036:Moths / Q000201:enzymology*; D020005:Propanols / Q000138:chemical synthesis*; D018411:Spodoptera / Q000166:cytology
D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D020005:Propanols; D004851:Epoxide Hydrolases; C055698:juvenile hormone epoxide hydrolase; C004312:glycidol