Studies on selectin blockers. 6. Discovery of homologous fucose sugar unit necessary for E-selectin binding

Yasuyuki Hiramatsu, Hideki Moriyama, Takao Kiyoi, Takahiro Tsukida, Yoshimasa Inoue, Hirosato Kondo

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

We describe a mimic of the sugar unit of the E-selectin ligand, sialyl Lewis X (sLe(X)). Carbohydrates are entering the realm of rational drug design, aided by the growing understanding of the structure-function relationships. We investigated a new methodology of preparing sLe(X) mimetics and developed a potent E-selectin blocker characterized by β-turn dipeptides. Another characteristic point of this E-selectin blocker is that the six-membered fucose ring was replaced with a five-membered fucose ring. Interestingly, it was found that the five-membered fucose ring could also bind to a calcium ion on the E-selectin, which could be an important role of the six-membered fucose ring. Especially, the L-Ser-D-Glu and D-SerL-Glu derivatives 3a,b showed 65-90-fold more potent inhibitory activities than the sulfated Le(x) analogue 1. In addition, molecular dynamics (MD) studies indicated that the 2- and 3-OH groups of the six-membered fucose ring, which were necessary for the calcium binding, overlapped well with the 2- and 3-OH groups of the five-membered fucose ring. These new findings could be useful for the design of new types of selectin blockers.

Original languageEnglish
Pages (from-to)2302-2307
Number of pages6
JournalJournal of Medicinal Chemistry
Volume41
Issue number13
DOIs
Publication statusPublished - Jun 18 1998
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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