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 language | English |
|---|---|
| Pages (from-to) | 3534-3541 |
| Number of pages | 8 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 40 |
| Issue number | 22 |
| DOIs | |
| Publication status | Published - Jan 1 1997 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Studies on selectin blockers. 5. Design, synthesis, and biological profile of sialyl Lewis x mimetics based on modified serine-glutamic acid dipeptides
AU - Tsukida, Takahiro
AU - Hiramatsu, Yasuyuki
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
PY - 1997/1/1
Y1 - 1997/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0030612363&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0030612363&partnerID=8YFLogxK
U2 - 10.1021/jm970262k
DO - 10.1021/jm970262k
M3 - Article
C2 - 9357520
AN - SCOPUS:0030612363
VL - 40
SP - 3534
EP - 3541
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 22
ER -