Rational Design and Synthesis of Small Molecule, Non-oligosaccharide Selectin Inhibitors: (.alpha.-D-Mannopyranosyloxy)biphenyl-Substituted Carboxylic Acids

Kogan, Timothy P.; Dupre, Brian; Keller, Karin M.; Scott, Ian L.; Bui, Huong Thi; Market, Robert V.; Beck, Pamela J.; Voytus, J. A.; Revelle, B. Mitch; Scott, Dee

doi:10.1021/jm00026a004

Cited by 87 publications

(45 citation statements)

References 13 publications

(20 reference statements)

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“…4). The reference compound, sLe x , has an IC 50 of approximately 3 mM against L-selectin in this assay, consistent with values obtained in similar assays (62,63). In contrast, neoglycopolymers 8 and 9 exhibit IC 50 values of approximately 39 M (580 M saccharide residue concentration) and 35 M (520 M saccharide residue concentration), respectively.…”

Section: Synthesis Of L-selectin Ligands-supporting

confidence: 86%

Inhibition of L-selectin-mediated Leukocyte Rolling by Synthetic Glycoprotein Mimics

Sanders¹,

Gordon²,

Dwir³

et al. 1999

Journal of Biological Chemistry

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102

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Synthetic carbohydrate and glycoprotein mimics displaying sulfated saccharide residues have been assayed for their L-selectin inhibitory properties under static and flow conditions. Polymers displaying the L-selectin recognition epitopes 3,6-disulfo Lewis x(Glc) (3-O-SO 3 -Gal␤1␣4(Fuc␣1␣3)-6-O-SO 3 -Glc␤-OR) and 3,6-disulfo Lewis x(Glc) (3,6-di-O-SO 3 -Gal␤1␣4(Fuc␣1␣3)Glc␤-OR) both inhibit L-selectin binding to heparin under static, cell-free binding conditions with similar efficacies. Under conditions of shear flow, however, only the polymer displaying 3,6-disulfo Lewis x(Glc) inhibits the rolling of L-selectin-transfected cells on the glycoprotein ligand GlyCAM-1. Although it has been shown to more effective than sialyl Lewis x at blocking the L-selectin-GlyCAM-1 interaction in static binding studies, the corresponding monomer had no effect in the dynamic assay. These data indicate that multivalent ligands are far more effective inhibitors of L-selectin-mediated rolling than their monovalent counterparts and that the inhibitory activities are dependent on the specific sulfation pattern of the recognition epitope. Importantly, our results indicate the L-selectin specificity for one ligand over another found in static, cell-free binding assays is not necessarily retained under the conditions of shear flow. The results suggest that monovalent or polyvalent carbohydrate or glycoprotein mimetics that inhibit selectin binding in static assays may not block the more physiologically relevant process of selectin-mediated rolling.

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Section: Synthesis Of L-selectin Ligands-supporting

confidence: 86%

Inhibition of L-selectin-mediated Leukocyte Rolling by Synthetic Glycoprotein Mimics

Sanders¹,

Gordon²,

Dwir³

et al. 1999

Journal of Biological Chemistry

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102

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“…Molecular modeling based on the x-ray structure of E-selectin and an NMR study of the conformation of bound sLe x has led to the rational design of a series of low-molecular weight mannose-based inhibitors with structure 18 [39]. This has inspired Muller et al to synthesize the analogous derivative 19, which has an amino function that can serve as an anchor for its conjugation with paramagnetic reporter groups to form MRI CAs targeted to inflammation [40].…”

Section: Asialoglycoprotein Receptormentioning

confidence: 99%

Glycoconjugate Probes and Targets for Molecular Imaging Using Magnetic Resonance

2010

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Review Molecular recognition of sugar residues applied in molecular imagingMolecular imaging aims at probing the molecular abnormalities that are the basis of diseases rather than to image their effects [1]. An important prerequisite of this approach is the selection of appropriate markers of disease and of targeting vectors to recognize them. The latter can include low-molecular weight substrates for enzymes or high-molecular weight affinity ligands, such as monoclonal antibodies, hormone analogs and recombinant proteins. Of the three major classes of biomolecules (proteins, nucleic acids and carbohydrates), the latter class is the least exploited in molecular imaging. However, a dense layer of glyco conjugates covers all cells and carbohydrate mediated cellular recognition plays an important role in nature, both in normal and malignant processes, such as cell-cell communication, infection, inflammation, metastasis and reproduction. As carriers of information, the carbohydrates have far greater potential than proteins and nucleic acids; three different nucleotides or amino acids can generate only six distinguishable structures, while over 1000 structures can be built up from three different monosaccharides [2]. This level of complexity is probably the reason for the fact that the exploration of these compounds in molecular imaging is lagging behind [3]. Recently, significant progress has been made in glycochemistry and glycobiology; for example, automated solid-phase synthesis of oligo saccharides has become possible [4], carbohydrate-based vaccines have been developed [5] and high-throughput methods have been designed for the screening of molecular interactions [6]. The exciting new developments in glycoscience are opening way for new challenges in exploring the full potential of carbohydrates in molecular imaging. Therefore, here we give an overview of the recent literature on the use of glycoconjugates either as probes or targets in molecular imaging using MRI.MRI contrast agents (CAs) are broadly described as positive or negative, depending on whether they give rise to a brightening or a darkening effect on the MR image, respectively. The positive or brightening effect predominantly relates to the longitudinal proton relaxation time (T 1 ) and the negative or darkening effect predominantly relates to the transverse proton relaxation time (T 2 ). To date, the majority of commercially available and clinically applied positive CAs are Gd 3+ complexes of the polyaminocarboxylates diethylene triamine pentacetic acid (DTPA) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (see FiguRe 1 for some typical examples) and negative CAs are various iron oxide particles. These agents are not actively targeting. The targeted CAs for application in molecular imaging that are currently under development and described below are generally based on compounds 1 (Gd-DTPA) and 2 (Gd-DOTA), as well as iron oxide nanoparticles.Glycoconjugate probes and targets for molecular imaging using magnetic resonanceRecently...

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“…In certain sialic acid-dependent recognition systems, determinant stringency is low. For example, selectins bind to oligosaccharides bearing truncated sialic acids (12) or appropriately placed anionic groups (sulfates, carboxylic acids) otherwise unrelated to the sialic acid structure (13)(14)(15)(16). In contrast, sialoadhesins appear to have more stringent sialic acid specificities (see "Discussion") (9).…”

mentioning

confidence: 99%

Binding Specificities of the Sialoadhesin Family of I-type Lectins

Collins¹,

Kiso²,

Hasegawa³

et al. 1997

Journal of Biological Chemistry

142

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The carbohydrate binding specificities of three sialoadhesins, a subgroup of I-type lectins (immunoglobulin superfamily lectins), were compared by measuring lectin-transfected COS cell adhesion to natural and synthetic gangliosides. The neural sialoadhesins, myelinassociated glycoprotein (MAG) and Schwann cell myelin protein (SMP), had similar and stringent binding specificities. Each required an ␣2,3-linked sialic acid on the terminal galactose of a neutral saccharide core, and they shared the following rank-order potency of binding: G Q1b␣ > > G D1a ‫؍‬ G T1b > > G M3 ‫؍‬ G M4 > > G M1 , G D1b , G D3 , G Q1b (nonbinders). In contrast, sialoadhesin had less exacting specificity, binding to gangliosides that bear either terminal ␣2,3-or ␣2,8-linked sialic acids with the following rank-order potency of binding: Sialoadhesins (1) are a structurally and functionally related family consisting of five immunoglobulin superfamily lectins (I-type lectins) (2) including myelin-associated glycoprotein (MAG), 1 Schwann cell myelin protein (SMP), CD22, CD33, and sialoadhesin. MAG and SMP are found on oligodendroglia and Schwann cells in the nervous system (3, 4), CD22 is expressed on a subset of B lymphocytes, sialoadhesin on a subset of macrophages, and CD33 on cells of myelomonocytic lineage. Sialoadhesins have been proposed to mediate cell-cell recognition, perhaps via their carbohydrate binding activities (5-7). Each sialoadhesin family member has two or more Ig-like domains: an amino-terminal V-set domain followed by one or more (up to 16) C2-set domains (8). Domain deletion and sitedirected mutagenesis of sialoadhesin and CD22 localize their carbohydrate-binding sites to the amino-terminal V-set domain, with contributions (for CD22) from the adjoining C2-set domain. These first two domains share very high amino acid sequence similarity between MAG and SMP (Ͼ70%) and significant similarity across all I-type lectins (Ͼ30% in pairwise comparisons) (2,8,9).Each I-type lectin binds to carbohydrate structures bearing a nonreducing terminal sialic acid (1,6,10). Sialic acids are a common nonreducing terminus of vertebrate glycoconjugates and appear to play uniquely important roles in recognition phenomena. Because sialic acids may be linked to Gal, GalNAc, or other sialic acid residues at various positions and because they may carry different substituents on their 9-carbon base structure, the sialic acids represent a diverse family of carbohydrate determinants (11). In certain sialic acid-dependent recognition systems, determinant stringency is low. For example, selectins bind to oligosaccharides bearing truncated sialic acids (12) or appropriately placed anionic groups (sulfates, carboxylic acids) otherwise unrelated to the sialic acid structure (13-16). In contrast, sialoadhesins appear to have more stringent sialic acid specificities (see "Discussion") (9). In this study, we used cells expressing different sialoadhesins to explore and compare the fine structural preferences of their binding to target sialylated glycoconju...

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Rational Design and Synthesis of Small Molecule, Non-oligosaccharide Selectin Inhibitors: (.alpha.-D-Mannopyranosyloxy)biphenyl-Substituted Carboxylic Acids

Cited by 87 publications

References 13 publications

Inhibition of L-selectin-mediated Leukocyte Rolling by Synthetic Glycoprotein Mimics

Inhibition of L-selectin-mediated Leukocyte Rolling by Synthetic Glycoprotein Mimics

Glycoconjugate Probes and Targets for Molecular Imaging Using Magnetic Resonance

Binding Specificities of the Sialoadhesin Family of I-type Lectins

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