Ligand Recognition by E- and P-Selectin: Chemoenzymatic Synthesis and Inhibitory Activity of Bivalent Sialyl Lewis x Derivatives and Sialyl Lewis x Carboxylic Acids
1998; American Chemical Society; Volume: 63; Issue: 15 Linguagem: Inglês
10.1021/jo980350s
ISSN1520-6904
AutoresValentin Wittmann, Shuichi Takayama, Ke Wei Gong, Gabriele Weitz‐Schmidt, Chi‐Huey Wong,
Tópico(s)Peptidase Inhibition and Analysis
ResumoDescribed is the preparation of five sLex dimers and five sLex carboxylic acids by coupling chemoenzymatically synthesized amino-substituted sialyl Lewis x (sLex) derivative 4 to homobifunctional cross-linkers 20−24 of varying chain length. 20−24 were obtained by alkylating low-molecular-weight oligoethylene glycols with tert-butyl bromoacetate and subsequent transformation of the di-tert-butyl esters into disuccinimide esters. The products were assayed for inhibition against binding of a sLea-polymer to immobilized E- and P-selectin. In the E-selectin assay all dimers had lower IC50 values than the sLex monomer. The results show that comparable binding enhancements can be obtained with linkers of completely different length and rigidity. In the P-selectin assay four of the five sLex carboxylic acids displayed significantly improved inhibitory potency. The lowest IC50 value was observed for the compound with the shortest spacer between the sLex moiety and the additional carboxylate, being ca. 20−40 times more potent than unmodified sLex. These findings should be of importance for the design of new multivalent forms of sLex as well as sLex mimetics as high-affinity selectin ligands.
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