Title

Synthesis of Cyclic Enolphosphonates and Enolphosphates as Inhibitors of Serine Hydrolases

Document Type

Dissertation

Degree

Doctor of Philosophy

Major

Chemistry

Date of Defense

8-4-2016

Graduate Advisor

Christopher D. Spilling, PhD

Committee

Bier, Melinda

Alexei Demchenko

Janet Braddock-Wilking

Cynthia Dupureur

Abstract

Cyclophostin is a potent naturally occurring inhibitor of acetylcholinesterase with a novel bicyclic enolphosphate structure. The cyclipostins are a family of potent hormone-sensitive lipase inhibitors which share the same bicyclic enolphosphate core structure with cyclophostin which but differ primarily in that they are long-chain alkyl phosphate esters whereas cyclophostin is a methyl phosphate ester. Due to the novelty of the inhibitor structure, potency, and ability to select between two serine hydrolase enzymes with a simple change in the ester substituent, the ongoing structure activity relationship investigation of this family of inhibitors was continued. Methods of transesterification were investigated in order to prepare new analogs of the cyclipostins. An α,α-difluorophosphonate monocyclic analog was prepared to investigate the possibility of enhancing the potency of these inhibitors. A monocyclic phosphate analog was prepared in order to provide, in conjunction with a previously synthesized phosphonate analog, a first recorded direct comparison of α,α-difluorophosphonate esters, phosphate esters, and phosphonate esters as inhibitors of serine hydrolases. Finally, approaches to the synthesis of a fluorescent analog of an existing phosphonate inhibitor were investigated in order to probe the mechanism by which these compounds inhibit the growth of Mycobacterium tuberculosis.

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