Sulfated galactocerebrosides as potential antiinflammatory agents.
Native sulfatides, as well as many sulfated glycolipids, have been shown to avidly bind to the selectin receptors. In vivo, native sulfatides significantly block activity in selectin-dependent inflammatory responses. The fact that nonsulfated galactocerebrosides did not inhibit selectin-mediated adhesion identified a critical role for the anionic sulfate residue. We therefore initiated a program to evaluate the activity of position isomers. This study showed a binding selectivity for the positions 2 and 3 of the sulfate group on the carbohydrate ring as well as enhanced activity for the disulfated analogs. Furthermore, it was discovered that the attachment of lipophilic substituents on the carbohydrate ring was tolerated, consistent with the presence of a lipophilic pocket in the binding activity. This resulted in compounds with a 6-fold increased potency.
Marinier
A
A
Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Candiac, Quebec, Canada.
Martel
A
A
Banville
J
J
Bachand
C
C
Remillard
R
R
Lapointe
P
P
Turmel
B
B
Menard
M
M
Harte
W E
WE
Wright
J J
JJ
Todderud
G
G
Tramposch
K M
KM
Bajorath
J
J
Hollenbaugh
D
D
Aruffo
A
A
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005699:Galactosylceramides / Q000737:chemistry / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D007536:Isomerism; D008956:Models, Chemical; D019007:P-Selectin / Q000378:metabolism; D013431:Sulfates / Q000737:chemistry / Q000494:pharmacology*; D013433:Sulfoglycosphingolipids / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D005699:Galactosylceramides; D019007:P-Selectin; D013431:Sulfates; D013433:Sulfoglycosphingolipids