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- Title page_Table of contents
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- Chapter 1 Introduction and outline
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- Chapter 2
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- Chapter 3
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- Chapter 5
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- Chapter 8 Conclusion and future prospects
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- Summary in Dutch
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- List of publications_Curriculum Vitae
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Cyclophellitol analogues for profiling of exo- and endo-glycosidases
To this day, all cyclophellitol-based inhibitors and ABPs have been close analogues of their natural substrate counterparts. As a result, these probes showed high selectivity towards their target glycosidases. While such probes are of high value for studying these specific enzyme classes, they impede the simultaneous profiling of glycosidases that process different substrate configurations with a single probe. This Thesis focusses on structural derivatization of cyclophellitol-based probes with the aim of enabling inter-class labelling of glycosidases. The synthesis of cyclophellitol-based inhibitors and probes is described, which either lack the hydroxymethylene functionality at C2, C4 and C5, or are furanose-based cyclitol aziridines. Their labelling is biochemically evaluated on complex biological samples. The synthesis of a novel reversible inhibitor, gluco-1H-imidazole, is described in Chapter 5. In the last Chapters of...
Show moreTo this day, all cyclophellitol-based inhibitors and ABPs have been close analogues of their natural substrate counterparts. As a result, these probes showed high selectivity towards their target glycosidases. While such probes are of high value for studying these specific enzyme classes, they impede the simultaneous profiling of glycosidases that process different substrate configurations with a single probe. This Thesis focusses on structural derivatization of cyclophellitol-based probes with the aim of enabling inter-class labelling of glycosidases. The synthesis of cyclophellitol-based inhibitors and probes is described, which either lack the hydroxymethylene functionality at C2, C4 and C5, or are furanose-based cyclitol aziridines. Their labelling is biochemically evaluated on complex biological samples. The synthesis of a novel reversible inhibitor, gluco-1H-imidazole, is described in Chapter 5. In the last Chapters of this Thesis, synthetic methodologies for the construction of endo-glycosidase probes are described. Chapter 6 reports on the introduction of a spiro-epoxide warhead onto a disaccharide moiety for the purpose of constructing probes for GH99 endo-α-mannosidases, while the construction of xylobiose-cyclophellitol probes from xylo-cyclophellitol acceptors via direct glycosylation is described in Chapter 7. Finally, Chapter 8 provides a summary of this Thesis, followed by future prospects.
Show less- All authors
- Schröder, S.P.
- Supervisor
- Overkleeft, H.S.; Marel, G.A. van der
- Co-supervisor
- Codée, J.D.C.
- Committee
- Stelt, M. van der; Aerts, J.M.F.G.; Artola, M.; Minnaard, A.J.; Davies, G.J.; Williams, S.J.
- Qualification
- Doctor (dr.)
- Awarding Institution
- Leiden Institute of Chemistry (LIC) , Science , Leiden University
- Date
- 2018-05-17
- ISBN
- 9789462999640