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pK(a)-Determination and Conformational Studies by NMR Spectroscopy of D-Altrose-Containing and other Pseudodisaccharides as Glycosidase Inhibitor Candidates
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
2012 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 1, 74-84 p.Article in journal (Refereed) Published
Abstract [en]

The pK(a) values of six amine-linked pseudodisaccharides have been determined by using an NMR-based titration method. The pK(a) varies significantly depending on the linkage position and is inversely correlated with the number of electronegative groups in the beta-position to the amino group. Four of the pseudodisaccharides contain alpha-altroside moieties, the conformations of which were determined in the protonated and neutral states, again by using NMR techniques. In the neutral state, 2-amino-2-deoxyaltrosides and 3-amino-3-deoxyaltrosides were both found to occupy C-4(1) and S-O(2) conformations. On protonation, little change in the population distribution was seen for the 3-amino-3-deoxyaltrosides, but for the 2-amino-2-deoxyaltrosides, a shift in equilibrium position towards the skew conformer (more than 80% populated) takes place, and also a small amount of the other chair conformer (i.e., C-1(4), approximately 10% populated) was observed. 3-Amino-3-deoxyaltrosides have been shown to act as glycosidase inhibitors and insights into conformational equilibria as a function of protonation state should facilitate the design of better glycosidase inhibitors based on flexible monosaccharide amines.

Place, publisher, year, edition, pages
2012. no 1, 74-84 p.
Keyword [en]
Carbohydrates, Conformation analysis, NMR spectroscopy, Protonation, Inhibitors, Enzymes
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-76752DOI: 10.1002/ejoc.201101385ISI: 000299294000010OAI: oai:DiVA.org:su-76752DiVA: diva2:527200
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Note
4Available from: 2012-05-18 Created: 2012-05-16 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Structure, dynamics and reactivity of carbohydrates: NMR spectroscopic studies
Open this publication in new window or tab >>Structure, dynamics and reactivity of carbohydrates: NMR spectroscopic studies
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The main focus of this thesis is on the ring conformations of carbohydrate molecules; how the conformational equilibria and the rates of the associated interconversions are affected by the molecular constitution and their surroundings.

The conformational equilibria of a group of amine linked pseudodisaccharides, designed as potential glycosidase inhibitors, comprising α-D-altrosides are described in Chapter 3. The OS2 conformation was largely populated, and the ring conformation was found to depend on the charge of the amine functionality.

The conformations of β-D-xylopyranoside derivatives with naphthyl-based aglycones, which are potential anti-cancer agents, are described in chapter 4. Solvent dependent flexibility was observed. Intramolecular hydrogen bonds were concluded to be involved in the stabilization of 1C4 conformers in non-hydrogen bonding solvents of low polarity.

Chapter 5 describes the first measurements of the conformational exchange rates of mannuronic acid ester derivatives between the 4C1 and 1C4 conformations, through DNMR measurements. The relative reactivity of glycosyl triflates as electrophiles in glycosylation reactions were investigated with NMR-based competition experiments.

In Chapter 6, investigations of ruthenium-catalyzed epimerizations of the allylic alcohols of glycal derivatives, and stereoselective synthesis of esters through a DYKAT protocol, are described. The kinetics of the epimerizations were elaborated through different NMR-spectroscopic methods.

Chapter 7 describes additions of NMR chemical shift data of mono- and oligosaccharides to database of the computer program CASPER, and applications thereof.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University, 2013. 67 p.
Keyword
Carbohydrates, Conformation, NMR spectroscopy, Hydrogen bond
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-92408 (URN)978-91-7447-730-6 (ISBN)
Public defence
2013-09-20, Magnélisalen, Kemiska Övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 4: Submitted. Paper 5: Manuscript.

Available from: 2013-08-29 Created: 2013-08-02 Last updated: 2016-04-11Bibliographically approved

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