Targeting Breast Cancer: Synthesis and Biological Evaluation of Novel D-Fructose Based Molecular Imaging Agents And Cytotoxic Noscapine Analogues

• Author / Creator

  Ghaly, Peter EKG

• Among the characteristic hallmarks of cancer cells is their high replicative potential, which in turn leads to the overexpression of the facilitative hexose transporters (GLUTs) to provide the energy required for cell growth and proliferation. Interestingly, in 1996 the major D-fructose transporter (GLUT5) was identified to be overexpressed in breast cancer cells compared to their healthy counterparts. The first part of this thesis describes the synthesis and biological evaluation of four C-2 fluorescently labeled D-fructose derivatives that were developed to target GLUT5. Based on the findings with the fluorescently labeled compounds, an optimized synthetic pathway was developed for the synthesis of the corresponding C-2 modified D-fructose derivatives bearing a fluorinated side chain. This pathway can be applied for the synthesis of [18F] PET imaging agents. The second part of this thesis describes the design and synthesis of novel noscapine analogues as cytotoxic agents targeting microtubules. Nine new compounds have been successfully synthesized and biologically evaluated as potential antiproliferative agents. Interestingly, one of the developed analogues showed superior cytotoxic activity over the parent noscapine molecule. Computational data suggest binding of these compounds to both colchicine and noscapine binding sites; however, a higher affinity to the colchicine site.

• Subjects / Keywords

  • noscapine
  • D-fructose
  • tubulin
  • breast cancer

• Graduation date

  Fall 2017

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3XP6VK68

• 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.