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E-selectin and the natural tetrasaccharide ligand sialyl Lewis*. the importance of pharmacophore pre-organization in glyco-mimetics

Titz, Alexander. E-selectin and the natural tetrasaccharide ligand sialyl Lewis*. the importance of pharmacophore pre-organization in glyco-mimetics. 2008, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_8336

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Abstract

The selectins play a key role in the inflammatory cascade. The initial tethering and rolling of the leukocytes on the vascular endothelial cells, mediated by the selectins, is an essential mechanism of the host immune defense. Excessive infiltration of leukocytes into inflamed tissue can, however, lead to severe pathological consequences as observed in various diseases (e.g. rheumatoid arthritis, stroke or reperfusion injury). Therefore, blocking of the selectins is a valuable pharmaceutical approach. The tetrasaccharide sialyl Lewisx (sLex) is the natural binding epitope common to all selectin ligands, and consequently served as a lead compound in selectin antagonist research. As observed for many carbohydrate-protein interactions, the affinity of sLex towards the selectins is in the low millimolar range. Its bio-active conformation has been determined by trNOE-NMR experiments and X-ray crystallography in complex with the selectins. Because binding of the selectins to their ligands occurs under shear stress conditions, the stabilization of the pharmacophores in sLex mimetics in the bio-active conformation is a pre-requisite for binding. In this PhD thesis, the importance of pre-organization of the acid orientation in sLex mimetics, but also the correct orientation of the core were studied. The stabilization of the acid orientation was studied by a non-covalent approach, using (R)- and (S)-adamantyllactic acid as replacements for the Nacetyl neuraminic acid in sLex (chapter 2.1). Then, a ‘click chemistry’ library, directed towards the exploration of additional enthalpic contributions to binding, based on a pre-organized triazololactate was investigated (chapter 2.2). The results obtained from these studies finally led to the project where the acid orientation is covalently locked in the bio-active orientation (chapter 2.3). The core conformation of sLex and mimetics thereof was studied and found to be stabilized via a lipophilic interresidue interaction between fucose and galactose (chapter 2.4).
Advisors:Ernst, Beat
Committee Members:Nicotra, Francesco
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molekulare Pharmazie (Ernst)
UniBasel Contributors:Ernst, Beat
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:8336
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:200
Language:English
Identification Number:
Last Modified:22 Jan 2018 15:51
Deposited On:08 Jan 2010 11:04

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