Studies on selection blockers. 5. Design, synthesis, and biological profile of sialyl Lewis x mimetics based on modified serine-glutamic acid dipeptides.
Studies on selection blockers. 5. Design, synthesis, and biological profile of sialyl Lewis x mimetics based on modified serine-glutamic acid dipeptides.
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选择阻滞剂的研究。
DOI：
10.1021/jm970262k
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发表时间：
1997
影响因子：
7.3
通讯作者：
H. Kondo
中科院分区：
文献类型：
--
作者：
T. Tsukida;Y. Hiramatsu;H. Tsujishita;T. Kiyoi;M. Yoshida;K. Kurokawa;H. Moriyama;H. Ohmoto;Y. Wada;T. Saito;H. Kondo
我们基于分子模型合理设计了sLe(x)模拟物，合成了II型和II'型β转角二肽(3a,b)，并评估了它们的体外和体内生物学特征。针对 E-选择素-sLe(x) 结合，II 型 β 转角二肽 L-Ser-D-Glu 3a (IC50, 13 microM) 和 II' 型 β 转角二肽 D-Ser-L-Glu 3b (IC50, 5.5 microM) 是比 sLe(x) (1; IC50, 600 microM) 强 20-100 倍的阻断剂3'-硫酸化 Le(x) 类似物（2；IC50，280 microM）。另一方面，其他立体异构体，例如 L-Ser-L-Glu 3c 和 D-Ser-D-Glu 3d，是非常弱的阻断剂，3c、d 的 IC50 > 1000 microM。针对 P-和 L-选择素，尽管化合物 3a-d 的立体化学有很大不同，但二肽 3a-d 都是比 sLe(x) 或化合物 2 更有效的阻断剂。有趣的是，化合物 3b 在小鼠模型中针对免疫球蛋白 E 介导的皮肤反应提供了显着的体内功效。这些发现表明，具有II型和II'型β-转角二肽的sLe(x)模拟物可用于体外和/或体内活性选择素阻断剂的设计。
We have rationally designed a sLe(x) mimetic based on molecular modeling, synthesized type II and type II' beta-turn dipeptides (3a,b), and evaluated their biological profiles both in vitro and in vivo. Against E-selectin-sLe(x) binding, the type II beta-turn dipeptide L-Ser-D-Glu 3a (IC50, 13 microM) and the type II' beta-turn dipeptide D-Ser-L-Glu 3b (IC50, 5.5 microM) were 20-100-fold more potent blockers than sLe(x) (1; IC50, 600 microM) and a 3'-sulfated Le(x) analog (2; IC50, 280 microM). 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 microM 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' beta-turn dipeptides could be useful in the design of an active selectin blocker in vitro and/or in vivo.