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Synthesis of Donor-based Analogues as Inhibitors of Mycobacterial Glycosyltransferases Open Access


Other title
Analogues, Inhibitors, Glycosyltransferases, Bicyclo[3.1.0]hexane, Sulfonium ion
Type of item
Degree grantor
University of Alberta
Author or creator
Li, Jing
Supervisor and department
Lowary, Todd L. (Chemistry)
Examining committee member and department
O’Doherty, George (Chemistry, West Virginia University)
West, Frederick G. (Chemistry)
Stryker, Jeffrey M. (Chemistry)
Glover, Mark (Biochemistry)
Bergens, Steven H. (Chemistry)
Department of Chemistry

Date accepted
Graduation date
Doctor of Philosophy
Degree level
Tuberculosis (TB) is the disease arising from infection by Mycobacterial tuberculosis and kills millions of people every year. Difficulties in the treatment of TB and the emergence of multiple-drug resistant and extreme-drug resistant M. tuberculosis strains have increased interest in finding new antimycobacterial agents. The cell wall of mycobacteria is essential for the survival of these bacteria and enzymes involved in its assembly are key targets for anti-mycobacterial chemotherapy. One of the largest components of the cell wall is the arabinogalactan, which is composed of arabinofuranose (Araf) and galactofuranose (Galf) residues. These monosaccharides are incorporated into the polysaccharide by arabinosyltransferases and galactosyltransferases that employ decaprenolphophoarabinose (DPA) and uridine diphospho-galactofuranose (UDP-Galf) as the donor substrate, respectively. The synthesis of analogues of DPA and UDP-Galf as potential inhibitors of mycobacterial glycosyltransferases is presented in the thesis. Carbohydrate mimics of Araf and Galf that have a bicyclo[3.1.0]hexane at the core were prepared. Key steps involved the formation of bicyclo[3.1.0]hexane system via an intramolecular displacement reaction followed by a separation by converting a mixture of enantiomers into diastereomers. The absolute configuration of these species was confirmed by X-ray analysis of a crystalline derivative of the Araf analogue. The bicyclo[3.1.0]hexane based mimics were then alkylated with various aldehydes through reductive amination to form the DPA and UDP-Galf analogues. The synthesis of the sulfonium ion analogs of Galf was also carried out. The precursor of these compounds, a cyclic sulfide, was synthesized in nine steps from D-arabinitol. The key step is a conversion of an olefin into hydroxymethyl group thus establishing a stereogenic centre that is essential in forming a molecule that is a mimic of the galactofuranose ring. This sulfide was then coupled with alkyl halides to form sulfonium ion compounds in good yields. All of the DPA and UDP-Galf analogues were tested for their ability to inhibit GlfT2, a key galactofuranosyltransferase involved in the synthesis of the galactan portion of the mycobacterial arabinogalactan. Most of the compounds showed weak inhibition of the enzyme; however, a few were moderately active and are the mode of inhibition of these analogues is currently being studied.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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