Synthesis and Analysis of Mechanism Based Inhibitors of Juvenile Hormone Epoxide Hydrolase from Insect Trichoplusia ni

Abstract

The research presented here entails a multi-disciplinary advance at understanding the role of juvenile hormone epoxide hydrolase in the metabolism of juvenile hormone in last stadium Trichoplusia ni. The work combines synthetic organic chemistry and biochemistry. A series of juvenile hormone analogs have been synthesized and their effectiveness to inhibit insect JHEH has been ascertained. Some of the key elements in the synthetic sequence for the fluorinated compounds include chemoselective oxidation of a primary alcohol in the presence of an alpha-fluorinated alcohol, introduction of a geminal difluoro group via a Reformatsky reaction or use of the DAST reagent, and selective nucleophilic and electrophilic epoxidation reactions. The synthesis of some of the non-fluorinated compounds employed regio-selective opening of an epoxide, Sonogashira palladium catalyzed cross coupling, nucleophilic epoxidation, and a variety of protecting group manipulations. Of all the inhibitors tested, the alkene 10 was the most effective alternative substrate with an I50 of 4.29 mM, slightly more potent than the benchmark MEMD. We also found that the introduction of fluorine increased the potency of the inhibitors compared to the non-fluorinated analogs. Lastly, inhibitor 5 provided insight to support a novel mechanism based inhibition of juvenile hormone epoxide hydrolase by formation of a tetrahydrofuran intermediate.