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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.

Type

Journal

J Med Chem

Publication Date

02/11/2000

Volume

43

Pages

4278 - 4287

Keywords

Adenine, Adenosine, Animals, Calcium, Calcium Channel Agonists, Calcium Channels, In Vitro Techniques, Inositol 1,4,5-Trisphosphate, Inositol 1,4,5-Trisphosphate Receptors, Liver, Magnetic Resonance Spectroscopy, Membranes, Radioligand Assay, Rats, Receptors, Cytoplasmic and Nuclear, Spectrometry, Mass, Fast Atom Bombardment, Structure-Activity Relationship