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Eric Sletten Thesis Revised36.64 MB
Embargoed Access, Embargo ends: 06/26/2027
Dissertation
Nickel-catalyzed glycosylation for 1,2-cis-aminosaccharides: scope, mechanism, and application
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2018
DOI: 10.25820/etd.008028
Abstract
One of the key constituents in naturally occurring oligosaccharides and polysaccharides is α-1,2-cis-2-aminoglycosides. These α-1,2-cis-2-amino containing saccharides are essential for mediating the interactions between cells, including heparin (for anticoagulancy and heart disease), tumor-associated mucin antigens (for use as cancer vaccine therapy), and heparan sulfate (for studies of metastasis). As described in Chapter 1, there are many eloquent strategies for the synthesis of α-1,2-cis-2-aminoglycosides; however, many of them have limitations including: scalability, use of stoichiometric amount of activator, and unpredictable stereoselectivity. These limitations were overcome by the Nguyen Group who merged the stereoselective control of transition metal catalysis with carbohydrate chemistry to afford α-1,2-cis-2-aminosaccharides effectively. A thorough review of this work can be found in Section 1.4.
Yet, there were still some optimization of the methodology that needed to be preformed, primarily with the ligated nickel catalyst. The first generation catalyst needed to be ligated immediately prior to glycosylation, which provided variability in the yield and stereoselectivity of the glycosylation reaction. Bearing from the hypothesis that the ligands were interfering with the chelation of the metal center and the sugar motif, I decided to attempt the glycosylation reaction with the commercially available, nickel triflate. As illustrated in Section 1.5, the unligated catalyst was able to provide saccharides bearing these α-1,2-cis-2-aminosaccharides in excellent yields and high α-selectivity under operationally simple and mild reaction conditions.
Even upon simplification of the catalyst, the mechanism of the glycosylation event was still unknown. In the literature, there were several discrepancies on the true role of metal triflate catalysts in glycosylation reactions. As a consequence, in Section 1.6 I systematically designed the experiments to study the role of nickel triflate. Experimental evidence from control reactions and 19F NMR spectroscopy were obtained for the first time to confirm and quantify the triflic acid that was released from nickel triflate. This is significant because the released triflic acid is paramount in achieving a stereoselective α-1,2-cis-2-amino glycosidic bond by way of a transient anomeric triflate.
With the ability to straightforwardly synthesize α-1,2-cis-2-aminosaccharides under the established nickel triflate conditions, in Chapter 2, I demonstrated how attachment of the well-defined sulfated saccharide can inhibit the carbohydrate-processing enzyme, heparanase. Heparanase is regarded as a regulator of aggressive tumor behavior as clinical studies have shown that raised heparanase levels correlated with increased tumor size, amplified angiogenesis, enhanced metastasis, and inflammation. As such, heparanase is a leading target for the treatment of cancers and other diseases.
The preliminary studies on the strength of inhibition of heparanase by sulfated 2-aminosugar functionalized polymers was examined in three areas: length of polymer, the display of the saccharides, and the sulfation pattern of the saccharide. From these studies it was found that the optimal display for inhibition of heparanase was by a diantennary glycopolymer of 12 repeating units containing a GlcNS(6S)α(1,4)GlcA disaccharide. This glycopolymer was capable of inhibiting heparanase degradation of natural HS polysaccharide with an IC50 = 0.10 ± 0.04 nM.
Once potent inhibition of heparanase was established glycopolymer inhibitor of heparanase was examined for cross-bioactivity, with other HS-binding proteins (growth factors, platelet factor 4, P-selectin, and antithromobin III) which are responsible for mediating angiogenic activity, antibody-induced thrombocytopenia, cell metastasis, and anticoagulancy. In comparison to natural heparin, the synthetic glycopolymer had low affinity for these HS-binding proteins. In addition, the glycopolymer possessed antiproliferative properties towards human umbilical endothelial cells (HUVEC) and a potent antimetastatic effect against 4T1 mouse breast carcinoma cells.
Details
- Title: Subtitle
- Nickel-catalyzed glycosylation for 1,2-cis-aminosaccharides: scope, mechanism, and application
- Creators
- Eric Thomas Sletten
- Contributors
- Hien M Nguyen (Advisor)Christopher Pigge (Advisor)Sara Mason (Committee Member)Leonard MacGillivray (Committee Member)Gary Small (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Chemistry
- Date degree season
- Autumn 2018
- DOI
- 10.25820/etd.008028
- Publisher
- University of Iowa
- Number of pages
- xliii, 613 pages
- Copyright
- Copyright 2018 Eric Thomas Sletten
- Language
- English
- Date submitted
- 11/28/2018
- Description illustrations
- illustrations, graphs
- Description bibliographic
- Includes bibliographical references (pages 601-613).
- Public Abstract (ETD)
- The assembly of sugar chains containing 2-aminosugars can be quite challenging under previously developed procedures. To overcome these limitations, the use of transition-metal catalysis was merged with carbohydrate chemistry for the formation of 2-aminosugar-containing molecules. Importantly, the new methodology provided the desired 2-aminosugars in the correct arrangement. After optimizing these conditions using a commercially available nickel catalyst, the scope of different substrates and the mechanism of the reaction were then studied. Following their construction, these well-defined 2-aminosugars were then attached onto a polymer backbone in a repetitive fashion to imitate naturally ocurring heparan sulfate polysaccharides. These synthetic polymers were then utilized to strongly prevent the enzyme, heparanase, from promoting tumor growth and the spreading of cancer throughout the body.
- Academic Unit
- Chemistry
- Record Identifier
- 9984830730202771
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