Novel mimics of sialyl Lewis X: design, synthesis and biological activity of a series of 2- and 3-malonate substituted galactoconjugates.
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, the 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 biological activity of this series of compounds are described. Lead compounds having a greater potency than sialyl Lewis X are identified.
Marinier
A
A
Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 100, blvd. de l'Industrie, Candiac, Canada J5 R 1J1. anne.marinier@bms.com
Martel
A
A
Bachand
C
C
Plamondon
S
S
Turmel
B
B
Daris
J P
JP
Banville
J
J
Lapointe
P
P
Ouellet
C
C
Dextraze
P
P
Menard
M
M
Wright
J J
JJ
Alford
J
J
Lee
D
D
Stanley
P
P
Nair
X
X
Todderud
G
G
Tramposch
K M
KM
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001183:Arthus Reaction / Q000188:drug therapy; D001665:Binding Sites; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006001:Glycoconjugates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008239:Lysine / Q000378:metabolism; D008314:Malonates / Q000737:chemistry; D018716:Molecular Mimicry; D009844:Oligosaccharides / Q000737:chemistry* / Q000378:metabolism; D019007:P-Selectin / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D000080506:Sialyl Lewis X Antigen; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006001:Glycoconjugates; D008314:Malonates; D009844:Oligosaccharides; D019007:P-Selectin; D000080506:Sialyl Lewis X Antigen; C030290:malonic acid; D008239:Lysine