Synthesis of glucopyranos-6′-yl purine and pyrimidine isonucleosides as potential cholinesterase inhibitors. Access to pyrimidine-linked pseudodisaccharides through Mitsunobu reaction

Abstract

AbstractThe synthesis of new isonucleosides comprising purine and pyrimidine-derived systems linked to methyl glucopyranosidyl units at C-6 and evaluation of their cholinesterase inhibitory profiles is reported. Their access was based on the Mitsunobu coupling of partially acetylated and benzylated methyl glucopyranosides with purine and pyrimidine derivatives. While the reactions with purines and theobromine proceeded with complete regioselectivity, affording exclusively N9- or N1-linked 6′-isonucleosides, respectively, the use of pyrimidine nucleobases led to N1 and/or N3-glucopyranosid-6′-yl pyrimidines and/or to N1,N3/2-O,4-O-pyrimidine-linked pseudodisaccharides through bis-coupling, depending on the substitution pattern of the sugar precursor and on the nature of the nucleobase. From this series of compounds, four were shown to be effective and selective inhibitors of acetylcholinesterase with inhibition constants in the micromolar concentration range. A tri-O-acetylated N1-glucopyranosid-6′-yl theobromine and a benzylated N1,N3-bis-glucopyranosid-6-yl thymine were the most active molecules with Ki values of 4 μM. A tri-O-benzylated glucopyranosid-6′-yl uracil displayed good and selective inhibition of butyrylcholinesterase (Ki=8.4±1.0 μM), similar to that exhibited by the standard galantamine. Molecular docking simulations, performed with the two most effective acetylcholinesterase inhibitors, showed interactions with key amino acid residues located at the enzyme’s active site gorge, which explain the competitive component of their inhibitory activities.