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Pre-organization of the core structure of E-selectin antagonists

Schwizer, Daniel and Patton, John T. and Cutting, Brian and Smiesko, Martin and Wagner, Beatrice and Kato, Ako and Weckerle, Céline and Binder, Florian P. C. and Rabbani, Said and Schwardt, Oliver and Magnani, John L. and Ernst, Beat. (2012) Pre-organization of the core structure of E-selectin antagonists. Chemistry - A European Journal, 18 (5). pp. 1342-1351.

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Official URL: http://edoc.unibas.ch/dok/A6070808

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Abstract

A new class of N-acetyl-D-glucosamine (GlcNAc) mimics for E-selectin antagonists was designed and synthesized. The mimic consists of a cyclohexane ring substituted with alkyl substituents adjacent to the linking position of the fucose moiety. Incorporation into E-selectin antagonists led to the test compounds 8 and the 2'-benzoylated analogues 21, which exhibit affinities in the low micromolar range. By using saturation transfer difference (STD)-NMR it could be shown that the increase in affinity does not result from an additional hydrophobic contact of the alkyl substituent with the target protein E-selectin, but rather from a steric effect stabilizing the antagonist in its bioactive conformation. The loss of affinity found for antagonists 10 and 35 containing a methyl substituent in a remote position (and therefore unable to support to the stabilization of the core) further supports this hypothesis. Finally, when a GlcNAc mimetic containing two methyl substituents (52 and 53) was used, in which one methyl was positioned adjacent to the fucose linking position and the other was in a remote position, the affinity was regained.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Ehemalige Einheiten Pharmazie > Molecular Modeling (Vedani)
05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molekulare Pharmazie (Ernst)
UniBasel Contributors:Cutting, Brian and Smiesko, Martin and Wagner, Beatrice and Weckerle, Celine and Binder, Florian and Rabbani, Said and Schwardt, Oliver and Ernst, Beat
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Wiley
ISSN:0947-6539
e-ISSN:1521-3765
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:28 Nov 2017 11:06
Deposited On:01 Mar 2013 11:07

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