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Synthesis of Donor-based Analogues as Inhibitors of Mycobacterial Glycosyltransferases

  • Author / Creator
    Li, Jing
  • 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.

  • Subjects / Keywords
  • Graduation date
    2010-06
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3K954
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Department of Chemistry
  • Supervisor / co-supervisor and their department(s)
    • Lowary, Todd L. (Chemistry)
  • Examining committee members and their departments
    • Stryker, Jeffrey M. (Chemistry)
    • Bergens, Steven H. (Chemistry)
    • O’Doherty, George (Chemistry, West Virginia University)
    • West, Frederick G. (Chemistry)
    • Glover, Mark (Biochemistry)