Xylopyranoside-based agonists of D-myo-inositol 1,4,5-trisphosphate receptors: synthesis and effect of stereochemistry on biological activity

The synthesis of a series of tetrahydrofuranyl alpha- and beta -xylopyranos ide trisphosphates, designed by excision of three motifs of adenophostin A is reported. The synthetic route features improved preparations of allyl al pha -D-xylopyranoside and its 2-O-benzyl ether, and gives access to four di astereoisomeric trisphosphates, which show a range of abilities to mobilise Ca2+ from the intracellular stores of hepatocytes. A comparison of the pot encies of the four trisphosphates provides useful information relating to t he effects of stereochemical variation on the recognition of carbohydrate-b ased trisphosphates by D-myo-inositol 1,4,5-trisphosphate receptors. 1-O-[( 3 'S,4 'R)-3-hydroxytetrahydrofuran-4-yl] alpha -D-xylopyranoside 3,4,3 ' - trisphosphate (8) is the most active member of the series with a potency cl ose to Ins(1,4,5)P-3; a beta -linked analogue, 1-O-[(3 'R,4 'S)-3-hydroxyte trahydrofuran-4-yl] beta -D-xylopranoside 3,4,3 ' -trisphosphate, is ca. 20 -fold weaker than Ins(1,4,5)P-3, and the other compounds are much less acti ve. While no compound attained a potency close to that of adenophostin A, w e believe that 8 represents the minimal structure for potent Ca2+-releasing activity in this type of carbohydrate-based analogue. (C) 2001 Elsevier Sc ience I,td. All rights reserved.