Abstract:
: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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Tsukida T,Hiramatsu Y,Tsujishita H,Kiyoi T,Yoshida M,Kurokawa K,Moriyama H,Ohmoto H,Wada Y,Saito T,Kondo Hdoi
10.1021/jm970262ksubject
Has Abstractpub_date
1997-10-24 00:00:00pages
3534-41issue
22eissn
0022-2623issn
1520-4804pii
jm970262kjournal_volume
40pub_type
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