Date of Completion

3-9-2018

Embargo Period

2-11-2021

Keywords

Sulfatides, NKT cells, Glycosylation, N-Acylation, Sulfation, Palmostatin M, Cross Metathesis, Conjugate Addition

Major Advisor

Amy R. Howell, Ph. D.

Associate Advisor

Mark W. Peczuh, Ph. D.

Associate Advisor

Alfredo Angeles-Boza, Ph. D.

Field of Study

Chemistry

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

The two main foci herein are the preparation of sulfatides that activate a subset of type II natural killer T (NKT) cells and the synthesis and exploitation of the reactivity of unusual strained heterocycles. Chapter 1 describes the synthesis of two unnatural sulfatides. The preparation of one of these, an a-sulfatide, was motivated by the need to probe the effect of a potential a-linked sulfatide impurity in a previously synthesized b-sulfatide which had been shown to stimulate higher than expected secretion of both IFN-g and IL-4. The synthesis of the b-sulfatide was motivated by the fact that a related plakoside derivative had shown strong interaction with CD1d, an antigen presenting protein for Natural Killer T (NKT) cells. The syntheses were achieved by taking into account three different aspects: the preparation of the ceramide acceptor (sphingoid base and acyl chain), the glycosylation reaction with a suitable galactosyl donor and a regioselective sulfation reaction. These sulfatides will provide our collaborators with tools to understand the role of sulfatide-reactive type II NKT cells. The long-range goal is to develop new derivatives for biomedical applications.

Chapter 2 focuses on new syntheses of 3,4-disubstituted b-lactones, such compounds are of importance in synthetic and medicinal chemistry. Herein, the utilization of a-methylene-b-lactones in transition metal-catalyzed transformations to access 3,4-disubstituted b-lactones is described. Two successful transformationsinclude:a) olefincross metathesis(CM) of α-methylene-β-lactones scaffolds coupled with stereoselective reduction and b) rhodium-catalyzed conjugate addition of aryl boronic acids to a-methylene-b-lactones. In particular,palmostatinM inspired b-lactones were prepared as tools to investigate the Ras palmitoylation/depalmitoylation cycle, which regulates the subcellular trafficking of the N-Ras, H-Ras, and K-Ras4a isoforms, as a therapeutic target for selectively inhibiting the growth of malignancies with oncogenic N-Ras mutations. The long term goal of this project is to implement mechanistic strategies to selectively inhibit the growth of cancers with somatic Ras mutations.

Available for download on Thursday, February 11, 2021

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