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β-Mannosidase and β-hexosaminidase inhibitors: synthesis of 1,2-bis-epi-valienamine and 1-epi-2-acetamido-2-deoxy-valienamine from D-mannose
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Department of Biochemistry, Lund University.
Stockholm University, Faculty of Science, Department of Physical, Inorganic and Structural Chemistry, Structural Chemistry.
Department of Biochemistry, Lund University.
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2009 (English)In: Tetrahedron: asymmetry, ISSN 0957-4166, E-ISSN 1362-511X, Vol. 20, no 6-8, 795-807 p.Article in journal (Refereed) Published
Abstract [en]

A partially protected C-5C-5a unsaturated carbasugar with α-lyxo configuration is synthesised in five steps and 26% overall yield from a known mannose-derived hemiacetal, using ring-closing metathesis as a key step. This carbasugar is converted into valienamine derivatives with β-lyxo (i.e., corresponding to β-manno at C-1–C-4), α-lyxo (i.e., corresponding to α-manno at C-1–C-4) and β-2-acetamido-2-deoxy-xylo (i.e., corresponding to β-GlcNAc at C-1–C-4) configurations. This is the first report of the synthesis of the β-lyxo compound, 1,2-bis-epi-valienamine, which was found to inhibit Cellulomonas fimi β-mannosidase (CfMan2A) with Ki 140 μM. We report the crystal structures of three protected C-5C-5a unsaturated carbasugars with lyxo configuration.

Place, publisher, year, edition, pages
Elsevier Ltd. , 2009. Vol. 20, no 6-8, 795-807 p.
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-28978DOI: 10.1016/j.tetasy.2009.02.016ISI: 000266735500018OAI: oai:DiVA.org:su-28978DiVA: diva2:228356
Available from: 2009-07-29 Created: 2009-07-29 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Synthesis of Carbohydrate Mimics and Development of a Carbohydrate Epimerisation Method
Open this publication in new window or tab >>Synthesis of Carbohydrate Mimics and Development of a Carbohydrate Epimerisation Method
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis the synthesis of several hydrolytically stable carbohydrate mimics with the potential to function as glycosidase or lectin inhibitors are described. This work is presented in Chapters 2-5.

Chapters 2 and 3 describe synthetic efforts for producing carbasugars, and include the first synthesis of 1,2-bis-epi-valienamine and the preparation of two previously known aminocarbasugars. All three compounds were synthesised starting from D-mannose, using ring-closing metathesis as the key step. 1,2-Bis-epi-valienamine was found to inhibit Cellulomonas fimi β-mannosidase with a Ki value of 140 mM. Also included is the development of a novel synthetic route from cheap D-fructose to three mannose-mimicking carbasugars using a ring-closing metathesis strategy. Two of the compounds are potential inhibitors of the FimH adhesin.

In Chapters 4 and 5 the synthesis of a number of pseudodisaccharides are presented; valienamine- and epi-valienamine-containing pseudodisaccharides and a small library of S-linked pseudodisaccharides were prepared. Various synthetic strategies were explored, including an alkylation strategy, Mitsunobu couplings, and sulfonate displacements. This is the first report on the synthesis of a valienamine pseudodisaccharide with β-lyxo-configuration. Two of the S-linked pseudodisaccharides were found to bind to Concanavalin A with high affinity.

The final chapter (Chapter 6) of this thesis focuses on the development of a carbohydrate epimerisation method using transition metal catalysis. Two equilibrium constants involving gluco/manno- and gluco/allo-alcohols were determined via this method.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University, 2010. 92 p.
Keyword
Carbohydrate Mimic, Ring-closing Metathesis, Carbohydrate Chemistry, Carbasugar, Aminocarbasugar, Pseudodisaccharide, Glycosidase and Lectin Inhibitors
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-45855 (URN)978-91-7447-170-0 (ISBN)
Public defence
2010-12-15, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 13:00 (English)
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Supervisors
Note
At the time od doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Submitted. Paper 3: Manuscript. Paper 5: Manuscript.Available from: 2010-11-23 Created: 2010-11-15 Last updated: 2010-12-06Bibliographically approved

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