Studies on Selectin Blockers. 4. Structure−Function Relationships of Sulfated Sialyl Lewis X Hexasaccharide Ceramides toward E-, P-, and L-Selectin Binding

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Abstract
In order to clarify the real ligand structure of L-selectin proposed by Rosen et al., we first synthesized 6-sulfated sLex hexasaccharide ceramide 1, 6‘-sulfated sLex hexasaccharide ceramide 2, and 6,6‘-disulfated sLex hexasaccharide ceramide 3 and examined their binding avidities for L-selectin. As a result, we found that the 6‘-sulfated sLex hexasaccharide ceramides 1−3 have similar binding avidities to L-selectin and their binding to L-selectin appeared somewhat stronger than that of sLex. For P-selectin, the sulfated sLex derivatives 1 − 3 showed a similar avidity to sLex. On the other hand, 6-sulfated sLex2 was recognized to E-selectin and the binding avidity was apparently weak as compared to that of sLex hexasaccharide ceramide. Surprisingly, 6‘-sulfated and 6,6‘-disulfated sLexs 1 and 3 did not bind to E-selectin at all. We constructed the E-selectin−sLex complex model and investigated the binding mode. Namely, the galactose 6‘-position was directed toward the negatively charged residues, Glu80 and Asp100. Our results with E-selectin indicate that the replacement of 6‘-OH position from anionic charged group to cationic charged one, e.g., amino groups, could have a marked affect on E-selectin recognition. These results could provide useful information for the drug design of selectin blockers.