A. Marinier et al., Novel mimics of sialyl Lewis X: Design, synthesis and biological activity of a series of 2-and 3-malonate substituted galactoconjugates, BIO MED CH, 9(6), 2001, pp. 1395-1427
A series of potent inhibitors of P-selectin as potential anti-inflammatory
agents is reported. These compounds are derivatives of galactocerebrosides
bearing a malonate side chain in positions 2 and 3 of the galactose moiety.
Based on the binding mode of sialyl Lewis X, the two acidic groups of the
malonate are designed to form ionic interactions with two important lysines
in the active site of P-selectin, Lys113 and Lys111. On the other hand, th
e 4- and 6-hydroxy groups on the galactose ring are arranged to chelate the
calcium ion in the P-selectin active site. The synthesis and the biologica
l activity of this series of compounds are described. Lead compounds having
a greater potency than sialyl Lewis X are identified. (C) 2001 Elsevier Sc
ience Ltd. All rights reserved.