Document Type

Dissertation

Degree

Doctor of Philosophy

Major

Chemistry, Organic

Date of Defense

12-5-2008

Graduate Advisor

Alexei Demchenko, PhD

Committee

Wesley R. Harris

Michael R. Nichols

Christopher D. Spilling

Abstract

Lipid A is a glucosamine-based phospholipid that anchors carbohydrate molecules to the outer membrane of most Gram-negative bacteria. During severe infection, this amphiphilic macromolecule invoke a strong and acute pro-inflammatory response that leads to sepsis and ultimately to septic shock, organ failure and death. Thus, following the convention that the best antidote is often a derivative of the parent agonistic molecule, researchers have actively pursued the idea of creating an analog of Lipid A that can block the cellular receptor for this molecule and thereby arrest the cascade of events that lead to sepsis. Consequently, we became interested in creating monosaccharide and disaccharide analogs of Lipid A, anticipating that our targeted design may exhibit the desired antagonistic effect without being harmful to the host cell. Since our target compounds share a structural motif prevalent in biologically relevant carbohydrates ? the presence of 1,2-trans linked residues of 2-amino-2-deoxysugars - we investigated the application of our novel thioimidoyl methodology to the synthesis of 1,2-trans glycosides of 2-amino-2-deoxysugars. We reported previously that, along with providing a flexible approach to the synthesis 2-amino-2-deoxyglucopyranosides, our method allowed for the chemoselective assembly of oligosaccharides containing multiple residues of 2-amino-2-deoxyglycoses. Herein, the application of the aforementioned thioimidoyl methodology to the selective activation approach to oligosaccharide assembly is described. More importantly, this dissertation will detail the synthesis of Lipid A analogs that contain three interesting structural features ? the aminosugar core, (R)-3-hydroxy-fatty acids, and amino acids. This unique structural configuration has never before been synthesized and tested for antagonistic activity against enteric Lipid A. Therefore, it is to be anticipated that the synthetic approaches described herein could pave the way for expanding the range of antiendotoxic compounds prepared to date.

Included in

Chemistry Commons

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