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Design and synthesis of inhibitors for the human neuraminidase 3 enzyme

  • Author / Creator
    Zou, Yao
  • Sialidase enzymes play an important role in regulation of cellular activities by hydrolyzing the terminal, non-reducing sialic acids attached to various glycolipids, glycoproteins, and gangliosides. The family of human sialidase enzymes, NEU1, NEU2, NEU3, and NEU4 contribute specifically to different cellular processes. In particular, the plasma membrane associated sialidase NEU3 was studied by our group due to its specificity for glycolipids and its proposed role in cell signaling. This thesis describes the design and synthesis of sialidase inhibitors based on the 2,3-didehydro-N-acetyl neuraminic acid scaffold. Specific inhibitors of these enzymes will allow us to explore their function in vivo. In Chapter 2 we describe a series of C9 and N5Ac modified analogs of DANA (2,3-Didehydro-2-deoxy-N-acetylneuraminic acid) which were designed, synthesized and biologically evaluated. Molecular docking experiments revealed NEU3 can tolerate large hydrophobic groups at the C9 position, however, N5Ac derivatives failed to inhibit NEU3. This result suggested that glycerol side-chain modified derivatives of DANA could prove to be potent inhibitors of the enzyme. In Chapter 3 we develop a synthetic route to generate a series of C7-modified DANA derivatives. We isolated several C7-hydrazone derivatives that will be tested against human neuraminidase enzymes as inhibitors. The results from these studies provided valuable insight regarding the interaction of small molecule inhibitors with the active site of the human NEU3 enzyme, and have improved synthetic strategies towards DANA derivatives that may take advantage of the unique active site topology of NEU3.

  • Subjects / Keywords
  • Graduation date
    2011-11
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/R3QX3T
  • 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
    Master's
  • Department
    • Department of Chemistry
  • Supervisor / co-supervisor and their department(s)
    • Cairo, Christopher W. (Chemistry)
  • Examining committee members and their departments
    • Schieber, Andreas (Agricultural, Food & Nutritional Science)
    • Hall, Dennis G. (Chemistry)