Studies on selection blockers. 5. Design, synthesis, and biological profile of sialyl Lewis x mimetics based on modified serine-glutamic acid dipeptides.
We have rationally designed a sLe(x) mimetic based on molecular modeling, synthesized type II and type II' beta-turn dipeptides (3a,b), and evaluated their biological profiles both in vitro and in vivo. Against E-selectin-sLe(x) binding, the type II beta-turn dipeptide L-Ser-D-Glu 3a (IC50, 13 microM) and the type II' beta-turn dipeptide D-Ser-L-Glu 3b (IC50, 5.5 microM) were 20-100-fold more potent blockers than sLe(x) (1; IC50, 600 microM) and a 3'-sulfated Le(x) analog (2; IC50, 280 microM). On the other hand, other stereoisomers, such as L-Ser-L-Glu 3c and D-Ser-D-Glu 3d, were very weak blockers, with IC50 > 1000 microM for both 3c,d. Against the P- and L-selectins, despite much different stereochemistry of compounds 3a-d, the dipeptides 3a-d were all more potent blockers than either sLe(x) or compound 2. Interestingly, compound 3b provided significant in vivo efficacy against an immunoglobulin E-mediated skin reaction in a mouse model. These findings indicate that sLe(x) mimetics with type II and type II' beta-turn dipeptides could be useful in the design of an active selectin blocker in vitro and/or in vivo.
Tsukida
T
T
Department of Medicinal Chemistry and Biology, Kanebo, New Drug Discovery Research Laboratories, Osaka, Japan.
Hiramatsu
Y
Y
Tsujishita
H
H
Kiyoi
T
T
Yoshida
M
M
Kurokawa
K
K
Moriyama
H
H
Ohmoto
H
H
Wada
Y
Y
Saito
T
T
Kondo
H
H
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004151:Dipeptides / Q000737:chemistry*; D015195:Drug Design; D005260:Female; D007073:Immunoglobulin E / Q000009:adverse effects; D007249:Inflammation / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D009844:Oligosaccharides / Q000737:chemistry / Q000494:pharmacology*; D019087:Selectins / Q000187:drug effects*; D012694:Serine / Q000737:chemistry*; D000080506:Sialyl Lewis X Antigen; D013237:Stereoisomerism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004151:Dipeptides; D009844:Oligosaccharides; D019087:Selectins; D000080506:Sialyl Lewis X Antigen; D007073:Immunoglobulin E; C094686:glutamyl-glutamic acid; D012694:Serine