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

摘要

The synthesis of a series of tetrahydrofuranyl #alpha#- and #beta#-xylopyranoside trisphosphates,designed by excision of three motifs of adenophostin A is reported.The synthetic route features improved preparations of allyl #alpha#-D-xylopyranoside and its 2-O-benzyl ether, and gives access to four diastereoisomeric trisphosphates, which show a range of abilities to mobilise Ca~(2+) 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-hydroxytetra-hydrofuran-4-yl] #alpha#-D-xylopyranoside 3,4,3'-trisphosphate (8) is the most active member of the series with a potency close to Ins(1,4,5)P_3; a #beta#-linked analogue, 1-O-[(3'R,4'S)-3-hydroxytetrahydrofuran-4-yl] #beta#-D-xylopyranoside 3,4,3'-trisphosphate, is ca. 20-fold weaker than Ins(1,4,5)P_3, 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 Ca~(2+) -releasing activity in this type of carbohydrate-based analogue.