Syntheses of 3'-O-alpha-D-glucopyranosyl-1-beta-D-ribofuranosidoimidazole 2',3'',
4''-trisphosphate (7) and 3'-O-alpha-D-glucopyranosyl-9-beta-D-ribofuranosidopurine
2',3'',4''- trisphosphate (8), two analogues of the superpotent 1D-myo-inositol 1,4,5-trisphosphate
receptor agonist adenophostin A (2), are described. 5-O-Benzyl-1, 2-O-isopropylidene-alpha-D-ribofuranose
was prepared by an improved route from 1,2-O-isopropylidene-alpha-D-xylofuranose and
was coupled with 3,4-di-O-acetyl-2,6-di-O-benzyl-D-glucopyranosyl dimethyl phosphite
to give 3',4'-di-O-acetyl-2',5, 6'-tri-O-benzyl-3-O-alpha-D-glucopyranosyl-1, 2-O-isopropylidene-alpha-D-ribofuranose.
Removal of the isopropylidene acetal and subsequent acetylation gave the central disaccharide
1,2,3',4'-tetra-O-acetyl-2',5, 6'-tri-O-benzyl-3-O-alpha-D-glucopyranosyl-D-ribofuranose.
Vorbrüggen condensation with activated imidazole or purine gave the required beta-substituted
derivatives which were further elaborated to 7 and 8, respectively. Radioligand binding
assays to hepatic InsP(3) receptors and functional assays of Ca(2+) release from permeabilized
hepatocytes gave a rank order of potency of the ligands 2 approximately 8 > 7 approximately
Ins(1,4,5)P(3) indicating that the N(6)-amino group of 2 is of little importance for
activity and that a minimum of a two-fused-ring nucleobase is required for activity
to exceed that of Ins(1,4,5)P(3). The role of the adenine base in the activity of
the adenophostins is discussed. This general method should facilitate ready access
to nucleobase-modified adenophostin analogues for SAR studies.