Studies on selectin blockers. 7. Structure-activity relationships of sialyl Lewis X mimetics based on modified ser-glu dipeptides

Takahiro Tsukida, Hideki Moriyama, Kiriko Kurokawa, Toshio Achiha, Yoshimasa Inoue, Hirosato Kondo

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26 Citations (Scopus)

Abstract

We have previously found that heterochiral fucodipeptides, L-Ser-D-Glu (3a) and D-Ser-L-Glu (3b), exhibited up to 20-100 times more potency than a sialyl Lewis X (sLe(X), 1) and a 3'sulfated Lewis X analogue (2) toward E- selectin binding and have also proposed, from molecular dynamics calculation, that their strong activities would depend on a possible formation of the type II and/or type II' β-turn of compounds 3a,b (Tsukida, T.; Hiramatsu, Y.; Tsujishita, H.; Kiyoi, T.; Yoshida, M.; Kurokawa, K.; Moriyama, H.; Ohmoto, H.; Wada, Y.; Saito, T.; Kondo, H. J. Med. Chem. 1997, 40, 3534-3541). To clarify our hypothesis, we synthesized several analogues of compounds 3a,b and investigated their structure-activity relationships. As a result, it was indicated that the type II and/or type II' β-turn conformation would be a comparatively tight form and would play important roles in favorable binding to E-selectin. These findings indicate that sLe(X) mimetics with type II and type II' β-turn dipeptides could be a useful methodology for the design of an active selectin blocker.

Original languageEnglish
Pages (from-to)4279-4287
Number of pages9
JournalJournal of Medicinal Chemistry
Volume41
Issue number22
DOIs
Publication statusPublished - Oct 23 1998
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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