Studies on selectin 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' β-turn dipeptides (3a,b), and evaluated their biological profiles both in vitro and in vivo. Against E- selectin-sLe(x) binding, the type II β-turn dipeptide L-Ser-D-Glu 3a (IC₅₀, 13 μM) and the type II' β-turn dipeptide D-Ser-L-Glu 3b (IC₅₀, 5.5 μM) were 20-100-fold more potent blockers than sLe(x) (1; IC₅₀, 600 μM) and a 3'-sulfated Le(x) analog (2; IC₅₀, 280 μM). 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 μM 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' β-turn dipeptides could be useful in the design of an active selection blocker in vitro and/or in vivo.