Synthesis of glucopyranoside-based ligands for d-myo-inositol 1,4,5-trisphosphate receptors Original Research Article

Adenophostins A and B are naturally occurring glyconucleotides that interact potently with receptors for d-myo-inositol 1,4,5-trisphosphate, an important second messenger molecule in most cell types. Here we describe the design and synthesis of glucopyranoside-based analogues of adenophostin A lacking the adenine component. The key synthetic strategy involves glycosylation of selectively protected alcohols, derived from methyl β-d-ribofuranoside or 1,4-anhydroerythritol, using glycosyl donors synthesised from 2,6-di-O-benzyl-d-glucopyranose derivatives. Further elaboration and deprotection of the coupled products gave two trisphosphate analogues; methyl 3-O-α-d-glucopyranosyl-β-d-ribofuranoside 2,3′,4′-trisphosphate (“ribophostin”) and (3′S,4′R)-3′-hydroxytetrahydrofuran-4′-yl α-d-glucopyranoside 3,4,3′-trisphosphosphate (“furanophostin”). The route to furanophostin was further modified to give (3′S,4′R)-3′-hydroxytetrahydrofuran-4′-yl α-d-glucopyranoside 3′-phosphate 3,4-bisphosphorothioate, the first phosphorothioate-containing adenophostin analogue.