Tsukida T, Moriyama H, Kurokawa K, Achiha T, Inoue Y, Kondo H
Department of Medicinal Chemistry and Biology, Kanebo, New Drug Discovery Research Laboratories, 1-5-90 Tomobuchi-Cho, Miyakojima-Ku, Osaka 534, Japan.
J Med Chem. 1998 Oct 22;41(22):4279-87. doi: 10.1021/jm980267x.
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 (sLeX, 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' beta-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' beta-turn conformation would be a comparatively tight form and would play important roles in favorable binding to E-selectin. These findings indicate that sLeX mimetics with type II and type II' beta-turn dipeptides could be a useful methodology for the design of an active selectin blocker.
我们之前发现，异手性岩藻二肽L-丝氨酸-D-谷氨酸（3a）和D-丝氨酸-L-谷氨酸（3b）在与E-选择素结合方面的效力比唾液酸化路易斯X（sLeX，1）和3'-硫酸化路易斯X类似物（2）高20至100倍。并且，通过分子动力学计算我们还提出，它们的强活性可能取决于化合物3a、b形成II型和/或II'型β-转角（筑田，T.；平松，Y.；辻下，H.；清井，T.；吉田，M.；黑川，K.；森山，H.；大本，H.；和田，Y.；斋藤，T.；近藤，H. 《药物化学杂志》1997年，40卷，3534 - 3541页）。为了阐明我们的假设，我们合成了几种3a、b化合物的类似物，并研究了它们的构效关系。结果表明，II型和/或II'型β-转角构象可能是一种相对紧密的形式，并且在与E-选择素的良好结合中起重要作用。这些发现表明，具有II型和II'型β-转角二肽的sLeX模拟物可能是设计活性选择素阻滞剂的一种有用方法。
