Studies on selectin blockers. 5. Design, synthesis, and biological profile of sialyl Lewis x mimetics based on modified serine-glutamic acid dipeptides

Takahiro Tsukida, Yasuyuki Hiramatsu, Hideki Tsujishita, Takao Kiyoi, Masahiro Yoshida, Kiriko Kurokawa, Hideki Moriyama, Hiroshi Ohmoto, Yukihisa Wada, Tadayuki Saito, Hirosato Kondo

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Abstract

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.

Original languageEnglish
Pages (from-to)3534-3541
Number of pages8
JournalJournal of Medicinal Chemistry
Volume40
Issue number22
DOIs
Publication statusPublished - Jan 1 1997
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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    Tsukida, T., Hiramatsu, Y., Tsujishita, H., Kiyoi, T., Yoshida, M., Kurokawa, K., Moriyama, H., Ohmoto, H., Wada, Y., Saito, T., & Kondo, H. (1997). Studies on selectin blockers. 5. Design, synthesis, and biological profile of sialyl Lewis x mimetics based on modified serine-glutamic acid dipeptides. Journal of Medicinal Chemistry, 40(22), 3534-3541. https://doi.org/10.1021/jm970262k