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New Nonhydrolyzable Mimetics of Sialyl Lewis X and Their Binding Affinity to P‐Selectin
Author(s) -
Carrel Frédéric,
Giraud Sylvain,
Spertini Olivier,
Vogel Pierre
Publication year - 2004
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.200490096
Subject(s) - chemistry , pyran , hydroxymethyl , stereochemistry , acetic acid , wittig reaction , methyl iodide , medicinal chemistry , organic chemistry
Wittig olefination of (2 S ,3 R ,5 S ,6 R )‐5‐(acetyloxy)‐tetrahydro‐6‐[(methoxymethoxy)methyl]‐3‐(phenylthio)‐ 2 H ‐pyran‐2‐acetaldehyde ((+)‐ 10 ) with {2‐[(2 S ,3 R ,4 R ,5 R ,6 S )‐tetrahydro‐3,4,5‐tris(methoxymethoxy)‐6‐methyl‐ 2 H ‐pyran‐2‐yl]ethyl}triphenylphosphonium iodide ((−)‐ 11 ) gave a ( Z )‐alkene derivative (+)‐ 12 that was converted into ( αR ,2 R ,3 S ,4 R ,5 R ,6 S )‐tetrahydro‐ α ,3‐dihydroxy‐2‐(hydroxymethyl)‐5‐(phenylthio)‐6‐{(2 Z )‐4‐[(2 S ,3 S ,4 R ,5 S ,6 S )‐tetrahydro‐3,4,5‐trihydroxy‐6‐methyl‐2 H ‐pyran‐2‐yl]but‐2‐enyl}2 H ‐pyran‐4‐acetic acid ( 8 ), ( αR ,2 R ,3 S ,4 R ,6 S )‐tetrahydro‐ α ,3‐dihydroxy‐2‐(hydroxymethyl)‐6‐{4‐[(2 S ,3 S ,4 R ,5 S ,6 S )‐tetrahydro‐3,4,5‐trihydroxy‐6‐methyl‐2 H ‐pyran‐2‐yl]butyl}‐2 H ‐pyran‐4‐acetic acid ( 9 ), and simpler analogues without the hydroxyacetic side chain such as (2 S ,3 S ,4 R ,5 S ,6 S )‐tetrahydro‐6‐methyl‐2‐{(2 Z )‐4‐[(2 S ,3 R ,5 S ,6 R )‐tetrahydro‐5‐hydroxy‐6‐(hydroxymethyl)‐3‐(phenylthio)‐2 H ‐pyran‐2‐yl]but‐2‐enyl}‐2 H ‐pyran‐3,4,5‐triol ( 30 ), (2 S ,3 S ,4 R ,5 S ,6 S )‐tetrahydro‐6‐methyl‐2‐{[(2 S ,5 S ,6 R )‐tetrahydro‐5‐hydroxy‐6‐(hydroxymethyl)‐2 H ‐pyran‐2‐yl]butyl}‐2 H ‐pyran‐3,4,5‐ triol ((−)‐ 41 ) and (2 S ,3 S ,4 R ,5 S ,6 S )‐tetrahydro‐6‐methyl‐2‐{(2 Z / E ))‐4‐[(2 R ,5 S ,6 R )‐tetrahydro‐5‐hydroxy‐6‐(hydroxymethyl)‐2 H ‐pyran‐2‐yl]but‐2‐enyl}‐2 H ‐pyran‐3,4,5‐triol ( 43 ). The key intermediates (+)‐ 10 and (−)‐ 11 were derived from isolevoglucosenone and from L ‐fucose, respectively. The following IC 50 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 m M , respectively.