Neoglycoconjugate

Biological target The 1,2,3-triazole-linked, diphenyl-substituted neoglycoconjugate 1 is a selective inhibitor of human a-l,3-fiicosyltransferase IV (Fuc-T), the enzyme catalysing the final step in the synthesis of oligosaccharides, including the leukocyte and leukaemic cell adhesion molecule, sialyl Lewis X. 

Therapeutic profile The compound has potential for the treatment of inflammation and cancer. 

Generally, mammalian Fuc-transferases have the typical structure of transmem-hrane proteins, consisting of a short N-terminal cytoplasmic tail, a transmembrane domain and a stem region followed by a large C-terminal catalytic domain [8, 9]. The substrate, GDP-fucose, binds inside this domain giving the overall structure of Fuc-T-GDP-fucose complex shown in Fig. 15.1 [8]. 

Interactions between the enzyme and diphosphate are defined by the GDP-fucose complex of Fuc-T in Fig. 15.1. Both side chains of Arg-195 (R195) and Lys-250 (K250) provide the neutralizing positive charges for the diphosphate imiL 

1 Overall structure of the Fuc-T-GDP-fucose complex stereo view showing the GDP-fucose binding site (reproduced from [8], with the permission of the American Society for Biochemistry and Molecular Biology) 

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Murata, T. and Usui, T. (2006) Enzymatic synthesis of oligosaccharides and neoglycoconjugates. Bioscience, Biotechnology, and Biochemistry, 70, 1049-1059. 

In an extensive and comprehensive survey, Chabre and Roy (Montreal) revisit the subject of neoglycoconjugates introduced three decades ago by Stowell and Lee in Volume 37 of this Series. It was then a nascent topic, and the Montreal authors now bring together in a single large article the vast new literature base that has... 

In this context, divalent presentation of this promising candidate has been investigated by the authors using the fixed cone conformation of calix[4]arene to allow introduction of the molecules onto the upper rim, and their projection into the same portion of space, thus mimicking, to some extent, a small portion of the natural cell-surface ganglioside. The synthesis of the divalent neoglycoconjugate was based on initial functionalization of the corresponding diacid with an aminated spacer and further introduction of squaric acid moieties. 

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