D. Charon et al., SYNTHESIS AND IN-VITRO ACTIVITIES OF A SPACER-CONTAINING GLYCOPHOSPHOLIPID LIGAND OF A LIPOPOLYSACCHARIDE RECEPTOR INVOLVED IN ENDOTOXIN TOLERANCE, Bioorganic & medicinal chemistry, 6(6), 1998, pp. 755-765
A glycophospholipid consisting in a derivative of N,N'-acylated and bi
sphosphorylated 2,3-dideoxy-2,3-diamino-D-glucose, bearing a 6-aminoca
proyl side chain as spacer arm at carbon 6 (PPDm2-B), has been synthes
ized and its effect on murine macrophages evaluated. The synthesis sta
rted from 2,3-diamino-D-glucose, which was best obtained from glucosam
ine essentially by known procedures, since attempts to use another kno
wn precursor (3-nitroglycoside) led to unexpected results. Selective N
-acylation was performed with the hydroxysuccinimide ester of (D)-3-be
nzyloxymyritic acid followed by esterification of the sole primary hyd
roxyl function by 6-azidocaproylchloride and phosphorylation of the re
sulting 1,4-diol by treatment with tetrabenzyl pyrophosphate. Hydrogen
ation on a Pd on carbon catalyst permitted the isolation of eoxy-2,3-d
i-[(R)-3-hydroxy-tetradecanamido]-alpha- D-glucopyranose 1,4-diphospha
te (PPDm2-B). In mouse macrophages, PPDm2-B enhanced the lipopolysacch
aride (LPS)-dependent secretion of tumor necrosis factor alpha (TNF-al
pha), and inhibited the LPS-induced desensitization of these cells. Th
e data suggest that PPDm2-B interacts in a serum-independent way with
an LPS receptor different froth CD14, and involved in endotoxin tolera
nce. Binding studies of a fluorescent derivative of PPDm2-B indicated
that the expression of this unknown receptor is down-regulated during
in vitro culture of the cells. Owing to its spacer arm, PPDm2-B could
thus be a promising tool for future studies of this receptor. (C) 1998
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