Selectin Antagonists Research Articles

Synthesis of benzylated (R)- and as conformationally restricted building blocks for the preparation of E- and P-selectin antagonists

A straightforward synthesis for the aminoethyl-C-α-d-mannosides (R)-1 and (S)-1 has been developed. The conformationally restricted mannosides serve as building blocks for the synthesis of a new class of selectin antagonists of type A.

Novel synthetic inhibitors of selectin-mediated cell adhesion: synthesis of 1,6-bis[3-(3-carboxymethylphenyl)-4-(2-alpha-D- mannopyranosyloxy)phenyl]hexane (TBC1269).

Reports of a high-affinity ligand for E-selectin, sialyl di-Lewis(x) (sLe(x)Le(x), 1), motivated us to incorporate modifications to previously reported biphenyl-based inhibitors that would provide additional interactions with the protein. These compounds were assayed for the ability to inhibit the binding of sialyl Lewis(x) (sLe(x), 2) bearing HL-60 cells to E-, P-, and L-selectin fusion proteins. We report that dimeric or trimeric compounds containing multiple components of simple nonoligosaccharide selectin antagonists inhibit sLe(x)-dependent binding with significantly enhanced potency over the monomeric compound. The enhanced potency is consistent with additional binding interactions within a single selectin lectin domain; however, multivalent interaction with multiple lectin domains as a possible alternative cannot be ruled out. Compound 15e (TBC1269) showed optimal in vitro activity from this class of antagonists and is currently under development for use in the treatment of asthma.

セレクチン阻害薬の開発における効率的グリコシル化反応の設計と展開

Current progress on glycobiology and glycotechnology urge the development of various new drugs. As an example of the applicable studies based on the carbohydrate chemistry, there is the drug design of selectin antagonists which block the interaction between the selectin and its natural ligand, sialyl Lewis X (sLeX). The highly effective synthesis of sLeX is one of the important things for the investigation of selectin antagonists, for example, to establish a high-throughput screening (HTS) of active compounds. As a result, we succeeded the highly practical synthesis of sLeX pentasaccharide and discovered a potent selectin antagonist, GSC-150, using the HTS. In addition, in order to establish a large scale synthesis of GSC-150, a one-pot glycosylation characterized by “Armed-Disarmed Coupling” was developed. This glycosylation was an applicable method for the synthesis of various LeX analogs.

Chemoenzymatic synthesis of dendritic sialyl Lewis x

Traditional structure activity relationship studies (SAR) have led to the development of numerous sialyl Lewis x analogs in the search for potential antiinflammatory agents. However, these methods do not take into account cluster or multivalent effects. Reported herein is the chemoenzymatic synthesis of di-, tetra-, and octa-valent sLe x ligands scaffolded on dendrimers. Hypervalent l-lysine cores with covalently attached 2-acetamido-2-deoxy- d-glucose ( N-acetylglucosamine, GlcNAc) residues were chemically prepared and enzymatically transformed into sLe x-containing dendrimers so that multivalency, and its role in selectin-sLe x interactions may be evaluated. This work constitutes another successful enzymatic synthesis of sLe x and represents the first example of GlcNAc elongation on a synthetic dendrimer scaffold. These sLe x dendrimers are currently being investigated as selectin antagonists.

Development of Tools for the Design of Selectin Antagonists

AbstractA molecular modeling tool for the rational design of E‐selectin antagonists based on the lead structure sialyl Lewisx has been developed. The binding affinity to the receptor is considerably influenced by the entropy and consequently by the antagonist's ability to place its pharmacophores in an optimal spatial arrangement, i.e., by its preorganization for binding. The computational model assesses the preorganization of a potential selectin antagonist with the aid of Monte Carlo (jumping between wells)/stochastic dynamics [MC(JBW)/SD] simulations. The model has been validated by correlating preorganization and bioactivity of several selectin antagonists. The results suggest that only preorganized compounds are likely to bind to E‐selectin.

An ELISA for selectins based on binding to a physiological ligand

Members of the selectin family of adhesion receptors, consisting of L-, P- and E-selectin, mediate the initial interaction between leukocytes and endothelium during leukocyte trafficking from the blood into tissue sites. These receptors have attracted great attention in recent years due to their participation in a number of acute and chronic inflammatory diseases. We describe here a new ELISA that measures the binding between selectin–IgG chimeras and a physiological ligand for L-selectin and can be used to screen selectin inhibitors. The ligand used is a mucin-like glycoprotein known as GlyCAM-1, which is derived from high endothelial venules in secondary lymphoid organs. We demonstrate binding of all three selectins to GlyCAM-1 and demonstrate that the binding interactions satisfy a number of important criteria. The advantage of this ELISA over previous assays is that a macromolecular physiological ligand is employed, rather than a fortuitous or simplified carbohydrate ligand. Thus, the protein–carbohydrate interactions, as well as other interactions contributing to ligand recognition, can be investigated. The assay is suitable for high-throughput screening of compounds and may find use in the identification of selectin antagonists with anti-inflammatory potential.

Early cellular and molecular changes in ischemia/reperfusion injury: Inhibition by a selectin antagonist, P-selectin glycoprotein ligand-1

Early cellular and molecular changes in ischemia/reperfusion injury: Inhibition by a selectin antagonist, P-selectin glycoprotein ligand-1

Pitfalls in the synthesis and biological evaluation of sialyl-Lewis X mimetics as potential selectin antagonists

The lower molecular weight analog 12 of sialyl Lewis X was prepared and effected equal binding affinity to E- and P-selectin compared to the parent tetrasaccharide. If 12 was prepared using acidic ion exchange resins, false positive test were produced, especially binding to P-selectin seemed to be considerably enhanced. Traces of polyanions released from the resins which are difficult to detect by routine analysis were identified to be highly potent selectin inhibitors, probably by their action on a non-carbohydrate binding site.

Recent progresses in the glycodrug area

Abstract

C-Fucopeptides as selectin antagonists: Attachment of lipid moieties enhances the activity

The biological activity of a potent selectin antagonist could be 40-fold enhanced by attachment of a lipid moiety. Also an enantioselective synthesis of β,ω-dihydroxyamino acids by Sharpless asymmetric dihydroxylation (AD-reaction) allowed general access to this important class of compounds.

Nitric oxide decreases lung injury after intestinal ischemia.

After injury to a primary organ, mediators are released into the circulation and may initiate inflammation of remote organs. We hypothesized that the local production of nitric oxide (NO) may act to limit the spread of inflammation to secondarily targeted organs. In anesthetized rats, 30 min of intestinal ischemia followed by 2 h of reperfusion (I/R) did not increase lung albumin leak. However, after treatment with NG-nitro-L-arginine methyl ester (L-NAME), intestinal I/R led to increased lung leak, suggesting a protective effect of endogenous NO. The site of action of NO appeared to be the lung and not the gut because 1) after treatment with L-NAME, local delivery of NO to the lung by inhalation abolished the increase in intestinal I/R-induced lung leak; 2) L-NAME had no effect on epithelial permeability (51Cr-labeled EDTA clearance) of reperfused small bowel; and 3) after treatment with L-NAME, local delivery of NO to the gut by luminal perfusion did not improve epithelial permeability of reperfused intestines. Furthermore, L-NAME increased, and inhaled NO decreased, the density of lung neutrophils in rats subjected to intestinal I/R, and treatment with the selectin antagonist fucoidan abolished L-NAME-induced lung leak in rats subjected to intestinal I/R. We conclude that endogenous lung NO limits secondary lung injury after intestinal I/R by decreasing pulmonary neutrophil retention.

Combined glycomimetic and multivalent strategies for the design of potent selectin antagonists

Stepwise large scale synthesis of 3′-sulfo-Lewis x-Glc mimetic of the lead anti-inflammatory agent sialyl Lewis x in a form suitable for copolymerization with acrylamide has been achieved. The resulting watersoluble copolyacrylamide showed inhibition of binding of both L-and E-selectins in the μMolar range.

ChemInform Abstract: Synthesis of Deoxy Sialyl Lewisx Analogues, Potential Selectin Antagonists.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of Deoxy Sialyl Lewisx Analogues, Potential Selectin Antagonists

Synthesis of Deoxy Sialyl Lewis^x Analogues, Potential Selectin Antagonists

Characterization of E-selectin-deficient mice: Demonstration of overlapping function of the endothelial selectins

The Initial rolling interaction of leukocytes with the blood vessel wall during leukocyte trafficking has been postulated to rely on members of the selectin family of adhesion molecules. Two selectins, E-selectin and P-selectin, have been identified that are expressed on activated endothelial cells. Mice deficient in E-selectin expression have been produced in order to examine the role of this selectin in leukocyte trafficking. Mice homozygous for an E-selectin null mutation were viable and exhibited no obvious developmental alterations. E-selectin-deficient mice displayed no significant change in the trafficking of neutrophils in several models of inflammation. However, blocking both endothelial selectins by treatment of the E-selectin-deficient animals with an anti-murine P-selectin antibody, 5H1, significantly inhibited neutrophil emigration in two distinct models of inflammation. While neutrophil accumulation at early times during thloglycollate-induced peritonitis was dependent on P-selectin, neutrophil accumulation at later time points was blocked by 5H1 only in E-selectin-deficient mice but not in wild-type mice. Similarly, edema as well as leukocyte accumulation in a model of delayed-type hypersensitivity in the skin was almost completely prevented by blockade of P-selectin function with 5H1 in the E-selectin-deficient mice while the same treatment had no effect In wild-type mice. These data demonstrate that the majority of neutrophil migration in both models requires an endothellal selectin but that E-selectin and P-selectin are functionally redundant. These data have Important implications in the use of selectin antagonists in the treatment of inflammatory disease.

Inhibition of Immune Complex-Induced Inflammation by A small Molecular Weight Selectin Antagonist

The anti-inflammatory effect of a small molecular weight antagonist of P- and E-selectin-dependent cell adhesion was examined. The glycolipid sulphatide was shown to block the adherence of thrombin-activated rat platelets to HL-60 cells. This interaction is known to be dependent on P-selectin. The rat dermal reverse passive Arthus reaction was used to assess the effect of sulphatide on a neutrophil dependent inflammatory response. Sulphatide dosedependently blocked both the vascular permeability increase and cell infiltration after intraperitoneal administration. These results show that a small molecular weight compound which blocks P- and E-selectin dependent adhesion in vitro can effectively block the inflammation due to immune complex deposition. A compound with this type of profile may have therapeutic potential in the treatment of immune complex mediated diseases.