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-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 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] 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)P3; 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)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.
Rosenberg
H J
HJ
Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, UK.
Riley
A M
AM
Marwood
R D
RD
Correa
V
V
Taylor
C W
CW
Potter BVL
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels; D002463:Cell Membrane Permeability; D015544:Inositol 1,4,5-Trisphosphate / Q000737:chemistry; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007527:Isoenzymes / Q000737:chemistry; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008968:Molecular Conformation; D054803:Phospholipase C delta; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D010738:Type C Phospholipases / Q000737:chemistry; D014994:Xylose / Q000031:analogs & derivatives*
D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007527:Isoenzymes; D018160:Receptors, Cytoplasmic and Nuclear; D015544:Inositol 1,4,5-Trisphosphate; D014994:Xylose; D010738:Type C Phospholipases; D054803:Phospholipase C delta; D002118:Calcium