Synthesis of N-Acetyllactosamine Derivatives with Variation in the Aglycon Moiety for the Study of Inhibition of Sialyl Lewis x Expression

Graphical Abstract

Nicking the sugar: N-Acetyllactosamine derivatives with hydrophobic aglycon moieties such as 1 have been found to be effective inhibitors of cell-surface expression of sialyl Lewis x (sLe^x) on U937 human cells. These high-affinity acceptor decoys of fucosyltransferase divert the fucose moiety from endogenous glycoconjugates, thereby inhibiting sLe^x expression.

Abstract

Herein we describe an inhibition study of the sialyl Lewis x (sLe^x) expression on a human monocytic cell line (U937), using a series of peracetylated N-Acetyllactosamine (LacNAc) analogues with variation at the aglycon moiety. It was found that the extent of inhibition was related to the hydrophobicity and structure of the aglycon. In general, peracetylated LacNAc analogues with a naphthyl or biphenyl aglycon (3, 4, 6, and 7) were better in suppression of sLe^xexpression than a benzyl derivative (2). Steady-state kinetic experiments with humanα-1,3-fucosyltransferases IV and VI (FucT IV and VI, EC 2.4.1.65) revealed that the deacetylated LacNAc-aglycons with naphthyl (18, 19, and 20) or biphenyl (17) moieties exhibited higher affinity to the fucosyltransferases than aglycon moieties with smaller hydrophobic groups (14, 15, and 16). These results are in agreement with the findings of the U937 cell-based experiments, and suggest that the higher enzyme affinity LacNAc-aglycons make better acceptor decoys and, hence, the observed differences in LacNAc-aglycon inhihitory effects on sLe^xexpression.