Design and synthesis of C-linked fucosides as inhibitors of E-selectin.
Two series of C-linked fucosides as mimetics for the tetrasaccharide sialyl Lewis X have been synthesized and tested as inhibitors of E-Selectin. The fucopeptides have been prepared from three key intermediates, including alpha-C-allyl fucose, natural and unnatural amino acids bearing hydroxyl groups and an alpha, omega-diacid moiety for the imitation of the essential three parts of SLex, i.e., the Fuc, Gal, and NeuAc. The nature and distance of the linkage of the fucose moiety to the amino acids as well as the distance between the amino acids and the terminal carboxylic acid group turned out to be crucial for the biological activity. In addition the necessity of both OH groups (4- and 6-OH) in the Gal part could be confirmed. Conformational NMR study of the most active mimetic supports the structure-activity relationship. A second series of mimetics was prepared, where Fuc and Gal moieties were purely C-linked. In the synthesis of beta-C-allyl galactose an intramolecular 1,2-hydride shift led to an interesting side product. However, the substituted glycosidic oxygens led to a substantial loss of conformational constrain, which could not be compensated and resulted in low activity.
Uchiyama
T
T
Frontier Research Program on Glycotechnology, Institute of Physical & Chemical Research (RIKEN), Saitama, Japan.
Woltering
T J
TJ
Wong
W
W
Lin
C C
CC
Kajimoto
T
T
Takebayashi
M
M
Weitz-Schmidt
G
G
Asakura
T
T
Noda
M
M
Wong
C H
CH
D019040:E-Selectin / Q000378:metabolism*; D006027:Glycosides / Q000138:chemical synthesis* / Q000737:chemistry; D007983:Lewis Blood Group Antigens / Q000737:chemistry; D016256:Lewis X Antigen / Q000737:chemistry; D008958:Models, Molecular; D009844:Oligosaccharides / Q000737:chemistry; D000080506:Sialyl Lewis X Antigen
D019040:E-Selectin; D006027:Glycosides; D007983:Lewis Blood Group Antigens; D016256:Lewis X Antigen; D009844:Oligosaccharides; D000080506:Sialyl Lewis X Antigen