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Investigation of the Synthesis, Reactivity and Biological Properties of Various 6-Substituted D-Fructose Derivatives Open Access


Other title
Type of item
Degree grantor
University of Alberta
Author or creator
Scully, Thomas W
Supervisor and department
West, Frederick G (Chemisrty)
Examining committee member and department
Carruthers, Anthony (Biochemistry and Molecular Pharmacology)
Cairo, Christopher, W (Chemisrty)
Clive, Derrick L J (Chemistry)
West, Frederick G (Chemistry)
Vederas, John C (Chemistry)
Department of Chemistry

Date accepted
Graduation date
2017-11:Fall 2017
Doctor of Philosophy
Degree level
The detection of small tumors growing in complex organs, including breast tissue, is a challenge in modern medical imaging. The use of positron emission tomography (PET) and tracer molecules containing radionuclei such as 18F have been of significant value to detect small tumors. The commonly used PET tracer [18F]-2-fluoro-2-deoxy-D-glucose ([18F]-FDG) is widely used but it suffers from several important limitations. [18F]-FDG provides false positives in PET scans and has a very short half-life resulting from the rapid decay of the 18F nucleus. This short half-life requires that the 18F is produced immediately before it is incorporated into the tracer molecule and that the tracer is used very soon after it is produced. The specialized facilities needed to produce 18F for medical purposes limits the number of scans that can be performed as only a small number of these facilities exist. Tissue specific transport of tracer molecules is dictated by what type of biomolecule they are intended to mimic, and how well they are recognized by the transport machinery of the cell. [18F]-FDG is transported through the hexose transporter (GLUT) pathway as it is a D-glucose mimic. There are 14 known members of the GLUT family each with a different substrate specificity and/or tissue distribution. For example, GLUT1 is a ubiquitously expressed D-glucose transporter while GLUT5 is a D-fructose transporter which is only expressed in a small number of tissues, including breast tumor tissue. To date no GLUT5 specific tracer molecule that can be used for medical imaging exists. Creation of a tracer molecule with the desired properties must begin with the creation of a scaffold that is recognized as D-fructose by GLUT5 but can carry with it an observable moiety. To circumvent the limitations of the PET imaging modality a fluorescent tag could be appended to a D-fructose scaffold allowing for real time imaging without the short half-life of 18F. Chapter 1 on this thesis outlines a broad introduction to the body of knowledge around the GLUT transporters, their structure, substrate binding, tissue distribution, and mechanism of transport. Further, an overview of small molecules which have been shown to be transported by the GLUT transporters is included. Chapter 2 outlines the initial studies towards the selective functionalization of D-fructose at the C6 position in order attach a fluorescent dye to D-fructose via this carbon. Chapter 3 outlines a second strategy employed to functionalize the C6 position of D-fructose by incorporation of an iodine atom to C6. This intermediate was used as a precursor for many metal mediated transformations. Further, Chapter 3 outlines the use of the alkyl iodide as a radical precursor for intramolecular cyclization reactions as well as reduction to produce the natural product 6-deoxy-D-fructose. In Chapter 4, a set of four 6-amino-6-deoxy-hexose derivatives which are attached to the NBD fluorophore were evaluated for their biological properties with EMT6 and MCF7 breast cancer cell lines. The ability of these compounds to be taken up by these cell lines, the pathway by which the compounds were transported, and their efflux profiles were evaluated by flow cytometry.
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. 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.
Citation for previous publication
O-M. Soueidan, T. W. Scully, J. Kaur, R. Panigrhi, A, Belovodskiy, V. Do, C. D. Matier, M. J. Lemieux, F. Wuest, C. Cheeseman, and F. G. West. ACS Chem. Bio. 2017, 12, 1087-1094

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