Studies on selectin blockers. 6. Discovery of homologous fucose sugar unit necessary for E-selectin binding

Journal of Medicinal Chemistry
Y HiramatsuH Kondo

Abstract

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.

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Citations

Oct 9, 2002·Medicinal Research Reviews·Neelu Kaila, Bert E Thomas
Jun 7, 2005·Bioorganic & Medicinal Chemistry Letters·Christian GirardDaniel Scherman
Dec 2, 1999·Biochimica Et Biophysica Acta·E StaudacherL März
Sep 2, 2000·Bioorganic & Medicinal Chemistry Letters·K KurokawaH Kondo
Nov 29, 2001·British Journal of Pharmacology·A Ikegami-KuzuharaT Saito
Nov 15, 2001·Advances in Anatomic Pathology·J J ListinskyG P Siegal
Oct 26, 2001·The Journal of Surgical Research·T YoshimuraH Wada
Dec 22, 2005·Immunology Letters·Isaac P Witz
Mar 8, 2008·International Journal of Cancer. Journal International Du Cancer·Tegest AychekIsaac P Witz
Jan 20, 2021·Nature Reviews. Drug Discovery·Benjamin A H Smith, Carolyn R Bertozzi
Feb 17, 2007·Journal of Medicinal Chemistry·Remo KranichEwald M Aydt
May 26, 2004·Archives of Biochemistry and Biophysics·John L Magnani

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