Small Molecules as Structural and Functional Mimics of Sialyl Lewis X Tetrasaccharide in Selectin Inhibition:  A Remarkable Enhancement of Inhibition by Additional Negative Charge and/or Hydrophobic Group

Abstract

Several sialyl Lewis X (SLex) mimics that contain the essential functional groups for receptor interaction and a negative charge or a hydrophobic group have been developed as inhibitors of E-, P-, and L-selectins. Some of the mimics exhibit selectin inhibition activities 103−104-fold more potent than does the natural ligand tetrasaccharide, with IC50 in the low micromolar to high nanomolar range. The syntheses of these mimics are relatively simple, using TMSOTf-Ac2O mediated C-glycosylation with concurrent selective deprotection of the primary benzyl group and enzymatic aldol addition reactions as key steps.

The Proteoglycan Lectin Domain Binds Sulfated Cell Surface Glycolipids and Promotes Cell Adhesion

“…In this case, it would be necessary for the PLD to recognize more than four sugar residues to distinguish between HNK-1-reactive glycolipids and glycoproteins. This seems unlikely, because functional groups of carbohydrate determinants interacting with selectins are restricted to the three terminal sugar residues (39,40 (43)(44)(45)(46). On the other hand, neural glycoproteins that carry HNK-1 carbohydrates are not mucin-type glycoproteins, and therefore presumably are incapable of sustaining high affinity interactions.…”

Synthesis ofD-Trigalacturonic Acid Methylglycoside and Conformational Comparison with Its Sulfur Analogue

“…Glycosyl donor 9 was also synthesized from phenyl 1-thio--D-galactopyranoside (7). 10) After the C4 and C6 alcohols in 7 had been simultaneously protected in the form of p-methoxyphenylmethylidene acetal, 11) the remaining C2 and C3 alcohols were transformed into MPM ethers with MPMBr/NaH to afford 8 in 69% yield in two steps. Treatment of 8 with NBS under the aqueous condition hydrolyzed the phenylthio acetal to provide the corresponding hemiacetal, which was further converted into -trichloroacetimidate 9 according to Schmidt's protocol.…”

Selectin/Glycoconjugate Binding Assays for the Identification and Optimization of Selectin Antagonists

“…The tetrasaccharide did not block the sLe a -polymer/P-selectin and the HL-60 cell/P-selectin interaction up to 3 mM. Investigation of sLe x -related compounds including mannose-based derivatives (9,11) and fucopeptides (10,12) further proved that the sLe a -polymer-based E-, P-, and L-selectin assays are suitable for the rapid determination of the selectivity profile of selectin antagonists.…”

“…Inhibitors with IC 50 values in the low micromolar and high nanomolar range were identified (9,10). The activity profile of FM233 (Fig.…”

“…Analogous to the E-selectin assay we have developed two ELISA-type assays which quantify the binding of sLe a -polymer to immobilized P-and Lselectin. The P-selectin assay was successfully applied to identify novel P-selectin antagonists (9,10). The E-, P-, and L-selectin assays were utilized to determine the selectivity profile of sLe x and other sLe x -related compounds (9 -12).…”