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Issue 15, 2014
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Microwave-assisted synthesis of novel purine nucleosides as selective cholinesterase inhibitors

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Abstract

Alzheimer's disease (AD), the most common form of senile dementia, is characterized by high butyrylcholinesterase (BChE) levels in the brain in later AD stages, for which no treatment is available. Pursuing our studies on selective BChE inhibitors, that may contribute to understand the role of this enzyme in disease progression, we present now microwave-assisted synthesis and anticholinesterase activity of a new nucleoside series embodying 6-chloropurine or 2-acetamido-6-chloropurine linked to D-glucosyl, D-galactosyl and D-mannosyl residues. It was designed to assess the contribution of sugar stereochemistry, purine structure and linkage to the sugar for cholinesterase inhibition efficiency and selectivity. Compounds were subjected to Ellman's assay and their inhibition constants determined. The α-anomers were the most active compounds, while selectivity for BChE or acetylcholinesterase (AChE) inhibition could be tuned by the purine base, by the glycosyl moiety and by N7-ligation. Some of the nucleosides were far more potent than the drug galantamine, and the most promising competitive and selective BChE inhibitor, the N7-linked 2-acetamido-α-D-mannosylpurine, showed a Ki of 50 nM and a selectivity factor of 340 fold for BChE over AChE.

Graphical abstract: Microwave-assisted synthesis of novel purine nucleosides as selective cholinesterase inhibitors

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Publication details

The article was received on 19 Jan 2014, accepted on 07 Feb 2014 and first published on 11 Feb 2014


Article type: Paper
DOI: 10.1039/C4OB00142G
Author version available: Download Author version (PDF)
Citation: Org. Biomol. Chem., 2014,12, 2446-2456
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    Microwave-assisted synthesis of novel purine nucleosides as selective cholinesterase inhibitors

    S. Schwarz, R. Csuk and A. P. Rauter, Org. Biomol. Chem., 2014, 12, 2446
    DOI: 10.1039/C4OB00142G

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