Publication Type Journal Article
Title Synthesis of glucopyranos-6 -yl purine and pyrimidine isonucleosides as potential cholinesterase inhibitors. Access to pyrimidine-linked pseudodisaccharides through Mitsunobu reaction
Authors Daniela Batista Stefan Schwarz Anne Loesche Rene Csuk Paulo J. Costa M. Conceição Oliveira Nuno Manuel Xavier
Groups BioMol HC
Journal PURE AND APPLIED CHEMISTRY
Year 2016
Month April
Volume 88
Number 4
Pages 363-379
Abstract The 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, af(f)ording exclusively N-9-or N-1-linked 6 -isonucleosides, respectively, the use of pyrimidine nucleobases led to N-1 and/or N-3-glucopyranosid-6 -yl pyrimidines and/or to N-1, N-3/2-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 N-1-glucopyranosid-6 -yl theobromine and a benzylated N-1, N-3-bis-glucopyranosid-6-yl thymine were the most active molecules with K-i values of 4 mu M. A tri-O-benzylated glucopyranosid-6 -yl uracil displayed good and selective inhibition of butyrylcholinesterase (K-i = 8.4 +/- 1.0 mu M), 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.
DOI http://dx.doi.org/10.1515/pac-2016-0102
ISBN
Publisher WALTER DE GRUYTER GMBH
Book Title
ISSN 0033-4545
EISSN 1365-3075
Conference Name
Bibtex ID ISI:000377216400007
Observations
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