Contribution of the adenine base to the activity of adenophostin A investigated using a base replacement strategy

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-ribo furanosidopurine 2',3",4"-trisphosphate (8), two analogues of the superpote nt 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 p repared by an improved route from 1,2-O-isopropylidene-alpha -D-xylofuranos e and was coupled with 3,4-di-O-acetyl-2,6-di-O-benzyl-D-glucopyranosyl dim ethyl phosphite to give 3',4'-di-O-acetyl-2',5,6'-tri-O-benzyl-3-O-alpha -D -glucopyranosyl- 1,2-O-isopropylidene-a-D-ribofuranose. Removal of the isop ropylidene acetal and subsequent acetylation gave the central disaccharide 1,2,3',4'-tetra-O-acetylQ-2',5,6'-tri-O-benzyl-3-O-alpha -D-glucopyranosyl- D-ribofuranose. Vorbruggen condensation with activated imidazole or purine gave the required P-substituted derivatives which were further elaborated t o 7 and 8, respectively. Radioligand binding assays to hepatic InsP(3) rece ptors and functional assays of Ca2+ release from permeabilized hepatocytes gave a rank order of potency of the ligands 2 approximate to 8 > 7 approxim ate to 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 i s required for activity to exceed that of Ins(1,4,5)P-3. The role of the ad enine base in the activity of the adenophostins is discussed. This general method should facilitate ready access to nucleobase-modified adenophostin a nalogues for SAR studies.