New nonhydrolyzable mimetics of sialyl Lewis x and their binding affinity to P-selectin

Wittig olefination of (2S,3R,5S,6R)-5-(acetyloxy)-tetrahydro-6-[(methoxymethoxy)methyl]-3-(phe nylthio)2H-pyran-2-acetaldehyde ((+)-10) with {2-[(2S,3R,4R,5R,6S)-tetrahydro-3,4,5-tris(methoxymethoxy)-6-methyl-2H-p yran-2-yl]ethyl}triphenylphosphonium iodide ((-)-11) gave a (Z)-alkene derivative (+)-12 that was converted into (alphaR,2R,3S,4R,5R,6S)-tetrahydro-alpha,3-dihydroxy-2-(hydroxymethyl)-5 -(phenylthio)-6-{(2Z)-4-[(2S,3S,4R,5S,6S)-tetrahydro-3,4,5-trihydroxy-6- methyl-2H-pyran-2-yl]but-2-enyl}2H-pyran-4-acetic acid (8), (alphaR,2R,3S,4R,6S)-tetrahydro-alpha,3-dihydroxy-2-(hydroxymethyl)-6-{4 -[(2S,3S,4R,5S,6S)-tetrahydro-3,4,5-trihydroxy-6-methyl-2H-pyran-2-yl]bu tyl}-2H-pyran-4-acetic acid (9), and simpler analogues without the hydroxyacetic side chain such as (2S,3S,4R,5S,6S)-tetrahydro-6-methyl-2-{(2Z)-4-[(2S,3R,5S,6R)-tetrahydro -5-hydroxy-6-(hydroxymethyl)-3-(phenylthio)-2H-pyran-2-yl]but-2-enyl}-2H -pyran-3,4,5-triol (30), (2S,3S,4R,5S,6S)-tetrahydro-6-methyl-2-{[(2S,5S,6R)-tetrahydro-5-hydroxy -6-(hydroxymethyl)-2H-pyran-2-yl]butyl}-2H-pyran-3,4,5-triol ((-)-41) and (2S,3S,4R,5S,6S)-tetrahydro-6-methyl-2-{(2Z/E))-4-[(2R,5S,6R)-tetrahydro -5-hydroxy-6-(hydroxymethyl)-2H-pyran-2-yl]but-2-enyl}-2H-pyran-3,4,5-tr iol (43). The key intermediates (+)-10 and (-)-11 were derived from isolevoglucosenone and from L-fucose, respectively. The following IC50 values were measured in a ELISA test for the affinities of sialyl Lewis x tetrasaccharide, 8, 9. 30, (-)-41, and 43 toward P-selectin: 0.7, 2.5-2.8, 7.3-8.0, 5.3-5.9, 5.0-5.2, and 3.4-4.1 mM, respectively.