Bnn. Rao et al., SIALYL-LEWIS-X MIMICS DERIVED FROM A PHARMACOPHORE SEARCH ARE SELECTIN INHIBITORS WITH ANTIINFLAMMATORY ACTIVITY, The Journal of biological chemistry, 269(31), 1994, pp. 19663-19666
The selectins, a family of adhesion receptors involved in leukocyte ex
travasation, recognize sialyl Lewis X (sLe(x); NeuAc alpha 2-3Gal beta
1-4(Fuc alpha 1-3)GlcNAc) and related oligosaccharides. We used confo
rmational energy computations, high field NMR, and structure-function
studies to define distance parameters of critical functional groups of
sLe(x). This sLe(x) pharmacophore was used to search a three dimensio
nal data base of chemical structures. Compounds that had a similar spa
tial relationship of functional groups were tested as inhibitors of se
lectin binding. Glycyrrhizin, a triterpene glycoside, was identified a
nd found to block selectin binding to sLe(x) in vitro. We substituted
different sugars for the glucuronic acids of glycyrrhizin and found th
e L-fucose derivative to be the most active in vitro and in vivo. A C-
fucoside derivative, synthesized on a linker designed for stability an
d to more closely approximate the original sLe(x) pharmacophore, resul
ted in an easily synthesized, effective selectin blocker with anti-inf
lammatory activity,