Access Type
Open Access Dissertation
Date of Award
January 2024
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Chemistry
First Advisor
Hien M. Nguyen
Abstract
Cancer remains a formidable challenge in modern medicine, demanding innovative approaches and treatments. Among the emerging strategies, inhibiting heparanase and fibroblast growth factor 2 (FGF2) has garnered considerable attention in recent years. This dissertation presents a novel approach to designing and synthesizing a diverse library of heparan sulfate (HS) mimetics derived from aminoglycosides to study their binding to two heparin-binding proteins involved in cancer development and metastasis. Heparanase cleaves HS polysaccharide chains in the extracellular matrix (ECM) and is a regulator of aggressive tumor behavior. Clinical studies have illustrated that aberrant heparanase expression correlates with increased tumor size, amplified tumor angiogenesis, and enhanced metastasis. Heparanase cleaves GlcAβ(1,4)GlcNS bonds of HS, releasing sequestered pools of HS oligosaccharide-binding growth factors, thereby promoting tumor angiogenesis and growth. Cleavage of HS chains degrades the structural integrity of the ECM, allowing the migration of malignant cells into the bloodstream and promoting cancer metastasis. Thus, heparanase is a viable target for cancer therapeutics. Although small molecules, saccharides, and antibodies have been developed, only four sugar molecules have advanced to clinical trials. While these molecules were successful in mouse models, adverse side effects terminated or halted their clinical advancement in humans. To date, anti-heparanase-based therapy has not yet been implemented in the clinic. In the first section, we report cost-effective strategies for the expedient and scalable synthesis of selective heparanase inhibitors from aminoglycosides (7-12 steps). This strategy significantly reduces the number of synthetic steps compared to the traditional synthesis of HS oligosaccharide mimetics (24-32 steps) prepared from selectively protected monosaccharides. Structure-activity relationship studies indicated that N-sulfated tobramycin derivatives are better inhibitors compared to kanamycin and apramycin, as well as their corresponding O-sulfated derivatives. Interestingly, incorporating a lipophilic scaffold onto specific regions of the designed inhibitors further enhanced their potency. The lead compounds exhibit high inhibition (IC50: 50 200 nM) against heparanase and are highly selective for this enzyme. Unlike natural heparan sulfate/heparin, these compounds show little or no off-target effects toward heparin-binding proteins. The second section builds on our results from the first project, recognizing the interplay between heparanase activity and the release of HS-bound growth factors. This section includes screening our ligand library and designing new ligands to improve binding to FGF2 and its primary receptor, FGFR1. Overall, both heparanase and FGF2 require a balance of structural and functional modifications of the ligands to achieve greater binding activity.
Recommended Citation
Wakpal, Joseph, "Design And Synthesis Of Aminoglycoside-Based Heparan Sulfate Mimetics For Structure-Activity Relationship Studies Of Heparan-Binding Proteins" (2024). Wayne State University Dissertations. 4127.
https://digitalcommons.wayne.edu/oa_dissertations/4127