Synthesis of glucopyranoside-based ligands for D-myo-inositol 1,4,5-trisphosphate receptors

Article abstract of DOI:10.1016/S0008-6215(02)00103-9

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.