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Direct STD NMR Identification of beta-Galactosidase Inhibitors from a Virtual Dynamic Hemithioacetal System
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
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2010 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 49, no 3, 589-593 p.Article in journal (Refereed) Published
Abstract [en]

 The formation of a dynamic hemithioacetal system and its application toward the discovery of ß-galactosidase inhibitors were successfully investigated. The designed dynamic system, which has a virtual character in neutral aqueous media, was subjected to a direct in situ identification of the best inhibitors by 1H STD NMR spectroscopy (ONPC : o-nitrophenyl-β-galactopyranoside).

Place, publisher, year, edition, pages
2010. Vol. 49, no 3, 589-593 p.
Keyword [en]
National Category
Chemical Sciences
URN: urn:nbn:se:kth:diva-12442DOI: 10.1002/anie.200903920ISI: 000274262800023ScopusID: 2-s2.0-74549200492OAI: diva2:311714
Swedish Research Council
QC 20100908Available from: 2010-04-22 Created: 2010-04-22 Last updated: 2011-01-24Bibliographically approved
In thesis
1. Dynamic Sulfur Chemistry: Screening, Evaluation and Catalysis
Open this publication in new window or tab >>Dynamic Sulfur Chemistry: Screening, Evaluation and Catalysis
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis deals with the design, formation and evaluation of dynamic systems constructed by means of sulfur-containing reversible reactions, in organic and aqueous media and under mild conditions.

In a first part, the synthesis of thioglycoside derivatives, constituting the biologically relevant starting components of the dynamic systems, is described. In addition, the pD-profile of the mutarotation process in aqueous media for a series of 1-thioaldoses is reported and revealed an astonishing beta-anomeric preference for all the carbohydrate analogs under acidic or neutral conditions.

In a second part, the phosphine-catalyzed or -mediated disulfide metathesis for dynamic system generation in organic or aqueous media is presented, respectively. The direct in situ 1H STD-NMR resolution of a dynamic carbohydrate system in the presence of a target protein (Concanavalin A) proved the suitability and compatibility of such disulfide metathesis protocols for the discovery of biologically relevant ligands.

In a third part, hemithioacetal formation is demonstrated as a new and efficient reversible reaction for the spontaneous generation of a dynamic system, despite a virtual character of the component associations in basic aqueous media. The direct in situ 1H STD-NMR identification of the best dynamic beta-galactosidase inhibitors from the dynamic HTA system was performed and the results were confirmed by inhibition studies. Thus, the HTA product formed from the reaction between 1-thiogalactopyranose and a pyridine carboxaldehyde derivative provided the best dynamic inhibitor.

In a fourth and final part, a dynamic drug design strategy, where the best inhibitors from the aforementioned dynamic HTA system were used as model for the design of non-dynamic (or “static”) beta-galactosidase inhibitors, is depicted. Inhibition studies disclosed potent leads among the set of ligands.

Place, publisher, year, edition, pages
Stockholm: KTH, 2010. 84 p.
Trita-CHE-Report, ISSN 1654-1081 ; 2010:14
Dynamic combinatorial chemistry; dynamic sulfur chemistry; thioglycoside; mutarotation; disulfide metathesis; hemithioacetal formation; 1H STD-NMR; inhibition; phosphine; Concanavalin A; beta-galactosidase; dynamic drug discovery.
National Category
Chemical Sciences Organic Chemistry Organic Chemistry
urn:nbn:se:kth:diva-12414 (URN)978-91-7415-618-8 (ISBN)
Public defence
2010-05-12, F3, Lindstedtsvägen 26, KTH, Stockholm, 10:00 (English)
QC 20100621Available from: 2010-04-22 Created: 2010-04-20 Last updated: 2010-11-29Bibliographically approved

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