Hiramatsu Y, Moriyama H, Kiyoi T, Tsukida T, Inoue Y, Kondo H
Department of Medicinal Chemistry, Kanebo, New Drug Discovery Research Laboratories, 1-5-90 Tomobuchi-Cho, Miyakojima-Ku, Osaka 534, Japan.
J Med Chem. 1998 Jun 18;41(13):2302-7. doi: 10.1021/jm9707481.
We describe a mimic of the sugar unit of the E-selectin ligand, sialyl Lewis X (sLeX). 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 sLeX mimetics and developed a potent E-selectin blocker characterized by beta-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-Ser-L-Glu derivatives 3a,b showed 65-90-fold more potent inhibitory activities than the sulfated LeX 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.
我们描述了一种E-选择素配体唾液酸化路易斯X（sLeX）糖单元的模拟物。随着对结构-功能关系的理解不断加深，碳水化合物正进入合理药物设计的领域。我们研究了一种制备sLeX模拟物的新方法，并开发了一种以β-转角二肽为特征的强效E-选择素阻滞剂。这种E-选择素阻滞剂的另一个特点是六元岩藻糖环被五元岩藻糖环取代。有趣的是，发现五元岩藻糖环也能与E-选择素上的钙离子结合，这可能是六元岩藻糖环的一个重要作用。特别是，L-Ser-D-Glu和D-Ser-L-Glu衍生物3a、b的抑制活性比硫酸化LeX类似物1高65至90倍。此外，分子动力学（MD）研究表明，六元岩藻糖环中对钙离子结合至关重要的2-和3-羟基与五元岩藻糖环的2-和3-羟基很好地重叠。这些新发现可能有助于新型选择素阻滞剂的设计。
