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

The synthesis of a series of tetrahydrofuranyl α- and β-xylopyranoside trisphosphates, designed by excision of three motifs of adenophostin A is reported. The synthetic route features improved preparations of allyl α-d-xylopyranoside and its 2-O-benzyl ether, and gives access to four diastereoisomeric trisphosphates, which show a range of abilities to mobilise Ca2+ from the intracellular stores of hepatocytes. A comparison of the potencies of the four trisphosphates provides useful information relating to the effects of stereochemical variation on the recognition of carbohydrate-based trisphosphates by d-myo-inositol 1,4,5-trisphosphate receptors. 1-O-[(3′S,4′R)-3-hydroxytetrahydrofuran-4-yl] α-d-xylopyranoside 3,4,3′-trisphosphate (8) is the most active member of the series with a potency close to Ins(1,4,5)P3; a β-linked analogue, 1-O-[(3′R,4′S)-3-hydroxytetrahydrofuran-4-yl] β-d-xylopyranoside 3,4,3′-trisphosphate, is ca. 20-fold weaker than Ins(1,4,5)P3, and the other compounds are much less active. While no compound attained a potency close to that of adenophostin A, we believe that 8 represents the minimal structure for potent Ca2+-releasing activity in this type of carbohydrate-based analogue.