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.

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