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

Research output: Contribution to journalArticle

31 Citations (Scopus)

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

Fingerprint

Selectins
Dipeptides
Serine
Inhibitory Concentration 50
Glutamic Acid
L-Selectin
Stereoisomerism
P-Selectin
E-Selectin
Immunoglobulin E
5-acetylneuraminyl-(2-3)-galactosyl-(1-4)-(fucopyranosyl-(1-3))-N-acetylglucosamine
Skin
serine containing aminolipid

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Studies on selectin blockers. 5. Design, synthesis, and biological profile of sialyl Lewis x mimetics based on modified serine-glutamic acid dipeptides. / Tsukida, Takahiro; Hiramatsu, Yasuyuki; Tsujishita, Hideki; Kiyoi, Takao; Yoshida, Masahiro; Kurokawa, Kiriko; Moriyama, Hideki; Ohmoto, Hiroshi; Wada, Yukihisa; Saito, Tadayuki; Kondo, Hirosato.

In: Journal of Medicinal Chemistry, Vol. 40, No. 22, 01.01.1997, p. 3534-3541.

Research output: Contribution to journalArticle

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, vol. 40, no. 22, pp. 3534-3541. https://doi.org/10.1021/jm970262k
Tsukida, Takahiro ; Hiramatsu, Yasuyuki ; Tsujishita, Hideki ; Kiyoi, Takao ; Yoshida, Masahiro ; Kurokawa, Kiriko ; Moriyama, Hideki ; Ohmoto, Hiroshi ; Wada, Yukihisa ; Saito, Tadayuki ; Kondo, Hirosato. / Studies on selectin blockers. 5. Design, synthesis, and biological profile of sialyl Lewis x mimetics based on modified serine-glutamic acid dipeptides. In: Journal of Medicinal Chemistry. 1997 ; Vol. 40, No. 22. pp. 3534-3541.
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AU - Tsujishita, Hideki

AU - Kiyoi, Takao

AU - Yoshida, Masahiro

AU - Kurokawa, Kiriko

AU - Moriyama, Hideki

AU - Ohmoto, Hiroshi

AU - Wada, Yukihisa

AU - Saito, Tadayuki

AU - Kondo, Hirosato

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