Studies on selectin blockers. 6. Discovery of homologous fucose sugar unit necessary for E-selectin binding.
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.
Hiramatsu
Y
Y
Department of Medicinal Chemistry, Kanebo, New Drug Discovery Research Laboratories, 1-5-90 Tomobuchi-Cho, Miyakojima-Ku, Osaka 534, Japan.
Moriyama
H
H
Kiyoi
T
T
Tsukida
T
T
Inoue
Y
Y
Kondo
H
H
D002240:Carbohydrate Sequence; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D019040:E-Selectin / Q000737:chemistry / Q000378:metabolism*; D005643:Fucose / Q000737:chemistry* / Q000378:metabolism; D006027:Glycosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation
C112864:(N-(2-tetradecylhexadecanoyl)-O-furofuranosylseryl)glutamic acid 1-methylamide; D004151:Dipeptides; D019040:E-Selectin; D006027:Glycosides; D008024:Ligands; D005643:Fucose