Date of Completion

8-24-2015

Embargo Period

8-22-2020

Keywords

Sulfatides, Glycosylation, Sulfation, Natural killer T cell, β-Lactones, α-Alkylidine-β-lactones, α-Methylene-β-lactones, Activity-based protein profiling (ABPP)

Major Advisor

Amy R. Howell

Associate Advisor

Mark W. Peczuh

Associate Advisor

Christian Brückner

Field of Study

Chemistry

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Sulfatides are innate glycosphingolipids shown to activate a subpopulation of type II NKT cells. Their activation has been reported to sometimes have antagonistic roles to those of type I NKT cells in some disease models. This has sparked a lot of interest in the synthesis of natural and unnatural sulfatides for an examination of their influence on NKT cell responses. The design, synthesis and evaluation of type II NKT cell activation of several sulfatide ligands are described in this thesis.

A two-step methodology has been developed for the rapid assembly of disubstituted β-lactones. The first step is olefin cross metathesis (CM) of a-methylene-β-lactones with various alkene cross partners to furnish a-alkylidine-β-lactones. These are subsequently diastereoselectively reduced. A diverse library of β-lactones, including (±)-nocardiolactone has been prepared. Combining this approach with competitive activity-based protein profiling (ABPP) identified lead β-lactone inhibitors for several serine hydrolases, including disease-associated enzymes and enzymes of uncharacterized function.

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