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 modeli ng, 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-Gl u 3a (IC50, 13 mu M) and the type II' beta-turn dipeptide D-Ser-L-Glu 3b (IC50, 5.5 mu M) were 20-100-fold more potent blockers than sLe(x) (1; IC50, 600 mu M) and a 3'-sulfated Le(x) analog (2; IC50, 280 mu M) . On the other hand, other stereoisomers, such as L-Ser-L-Glu 3e and D -Ser-D-Glu 3d, were very weak blockers, with IC50 > 1000 mu M for both 3c,d. Against the P- and L-selectins, despite much different stereoch emistry of compounds 3a-d, the dipeptides 3a-d were all more potent bl ockers than either sLe(x) or compound 2. Interestingly, compound 3b pr ovided significant in. vivo efficacy against an immunoglobulin E-media ted skin reaction in a mouse model. These findings indicate that sLe(x ) mimetics with type II and type II' beta-turn dipeptides could be use ful in the design of an active selectin blocker in vitro and/or in viv o.