Design and synthesis of a new Sialyl Lewis X Mimetic: How selective are the selectin receptors?

Vleeschauwer, Marc De; Vaillancourt, Marc; Goudreau, Nathalie; Guindon, Yvan; Gravel, Denis

doi:10.1016/s0960-894x(01)00130-5

Cited by 22 publications

(10 citation statements)

References 27 publications

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“…Furthermore, no interaction with the selectins was noted for the GlcNAc moiety, confirming its role as a tether holding in space the fucose and galactose. Similar conclusions were reached independently through the synthesis of sLe x analogues. − The pharmacophores of sLe x being identified, the modification of the GlcNAc, and the addition of supplementary binding sites on the galactose and the fucose were considered by us and others.…”

supporting

confidence: 53%

A New Approach to Explore the Binding Space of Polysaccharide-Based Ligands: Selectin Antagonists

Calosso¹,

Charpentier²,

Vaillancourt³

et al. 2012

ACS Med. Chem. Lett.

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The discovery of molecules that interfere with the binding of a ligand to a receptor remains a topic of great interest in medicinal chemistry. Herein, we report that a monosaccharide unit of a polysaccharide ligand can be replaced advantageously by a conformationally locked acyclic molecular entity. A cyclic component of the selectin ligand Sialyl Lewis(x), GlcNAc, is replaced by an acyclic tether, tartaric esters, which link two saccharide units. The conformational bias of this acyclic tether originates from the minimization of intramolecular dipole-dipole interaction and the gauche effect. The evaluation of the binding of these derivatives to P-selectin was measured by surface plasmon resonance spectroscopy. The results obtained in our pilot study suggest that the discovery of tunable tethers could facilitate the exploration of the carbohydrate recognition domain of various receptors.

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supporting

confidence: 53%

A New Approach to Explore the Binding Space of Polysaccharide-Based Ligands: Selectin Antagonists

Calosso¹,

Charpentier²,

Vaillancourt³

et al. 2012

ACS Med. Chem. Lett.

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“…While these structures are most often associated with O-glycans, it is their prominent role as ligands to the endothelial cell selectins that make them relevant in the current discussion. Many biochemical, in vitro and in vivo studies have confirmed that sLe x is a selectin ligand (Phillips et al 1990;Walz et al 1990) and based on this, a role for sialic acid in leukocyte trafficking has been extensively investigated with interference of selectin/sLe x interactions being a focus for therapeutic development for multiple diseases (Norman et al 1998;De Vleeschauwer et al 2001). However, a natural variant of E-selectin exists as S128R which cannot recognize sLe x motifs (Rao et al 2002).…”

Section: Dw Scott and Rp Patelmentioning

confidence: 99%

Endothelial heterogeneity and adhesion molecules N-glycosylation: Implications in leukocyte trafficking in inflammation

Scott

Patel

2013

Glycobiology

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Inflammation is a major contributing element to a host of diseases with the interaction between leukocytes and the endothelium being key in this process. Much is understood about the nature of the adhesion molecule proteins expressed on any given leukocyte and endothelial cell that modulates adhesive interactions. Although it is appreciated that these proteins are heavily glycosylated, relatively little is known about the roles of these posttranslational modifications and whether they are regulated, and if so how during inflammation. Herein, we suggest that a paucity in this understanding is one major reason for the lack of successful therapies to date for modulating leukocyte-endothelial interactions in human inflammatory disease and discuss developing paradigms of (i) how endothelial adhesion molecule glycosylation (with a focus on N-glycosylation) maybe a critical element in understanding endothelial heterogeneity between different vascular beds and species, (ii) how adhesion molecule N-glycosylation may be under distinct, and as yet, unknown modes of regulation during inflammatory stress to affect the inflammatory response in a vascular bed- and disease-specific manner (analogous to a "zip code" for inflammation) and finally (iii) to underscore the concept that a fuller appreciation of the role of adhesion molecule glycoforms is needed to provide foundations for disease and tissue-specific targeting of inflammation.

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“…These molecules are structurally complex and possess many stereocenters with different functionalities that complicate the identification of the pharmacophores involved in the binding to the receptor. Sialyl Lewis X ( 1 , sLe X ), a sialylated and fucosylated tetrasaccharide, represents a particularly interesting target for the development of novel pharmaceutical agents and has not surprisingly been the subject of numerous medicinal studies (Figure ). − A sLe X antagonist (GMI-1070, 2 ) was recently shown to reverse vascular occlusions in sickle cell animal model and in preliminary clinical trials, when given intravenously (Figure ) …”

mentioning

confidence: 99%

Acyclic Tethers Mimicking Subunits of Polysaccharide Ligands: Selectin Antagonists

Calosso

Tambutet

Charpentier

et al. 2014

ACS Med. Chem. Lett.

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We report on the design and synthesis of molecules having E- and P-selectins blocking activity both in vitro and in vivo. The GlcNAc component of the selectin ligand sialyl Lewis(X) was replaced by an acyclic tether that links two saccharide units. The minimization of intramolecular dipole-dipole interactions and the gauche effect would be at the origin of the conformational bias imposed by this acyclic tether. The stereoselective synthesis of these molecules, their biochemical and biological evaluations using surface plasmon resonance spectroscopy (SPR), and in vivo assays are described. Because the structure of our analogues differs from the most potent E-selectin antagonists reported, our acyclic analogues offer new opportunities for chemical diversity.

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Design and synthesis of a new Sialyl Lewis X Mimetic: How selective are the selectin receptors?

Cited by 22 publications

References 27 publications

A New Approach to Explore the Binding Space of Polysaccharide-Based Ligands: Selectin Antagonists

A New Approach to Explore the Binding Space of Polysaccharide-Based Ligands: Selectin Antagonists

Endothelial heterogeneity and adhesion molecules N-glycosylation: Implications in leukocyte trafficking in inflammation

Acyclic Tethers Mimicking Subunits of Polysaccharide Ligands: Selectin Antagonists

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