title: Microwave-assisted synthesis of novel purine nucleosides as selective cholinesterase inhibitors.
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 N(7)-ligation. Some of the nucleosides were far more potent than the drug galantamine, and the most promising competitive and selective BChE inhibitor, the N(7)-linked 2-acetamido-α-D-mannosylpurine, showed a Ki of 50 nM and a selectivity factor of 340 fold for BChE over AChE.
authors.affiliation: Centro de Química e Bioquímica/Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, Ed. C8, Piso 5, 1749-016 Lisboa, Portugal. aprauter@fc.ul.pt.
authors.forename: S
authors.initials: S
authors.lastname: Schwarz
authors.forename: R
authors.initials: R
authors.lastname: Csuk
authors.forename: A P
authors.initials: AP
authors.lastname: Rauter
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004593:Electrophorus; D008872:Microwaves; D011684:Purine Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D002800:Cholinesterase Inhibitors; D011684:Purine Nucleosides; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase