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.

Synthesis of Novel Thiopurine Pyranonucleosides: Evaluation of Their Bioactivity

“…It is generally accepted that N-9 nucleosides are thermodynamically favored over their N-7 isomers. Starting from the same substrate, regioselective synthesis of both N-7 and N-9 pyranosylguanine nucleosides has been achieved by application of kinetic and thermodynamic control reaction conditions respectively [36,37] In the present study, the structural differentiation of the purine base affects probably the stability of the intermediate transition state resulting in the case of thio purines more easily the thermodynamically favored N-9 isomers. …”

New antitumor 6-chloropurine nucleosides inducing apoptosis and G2/M cell cycle arrest

“…All four isomers (α/β, N 7 /N 9 ) could be detected using these reaction conditions [19]. Nevertheless, only the β-anomers were subjected to biological testings, in as much as they were the predominant species when introducing the glycosyl or galactosyl moieties and the α-anomers appeared in very low amount.…”

Continuous Flow and Microwave‐Assisted Vorbrüggen Glycosylations: Historical Perspective to High‐Throughput Strategies

“…Very recently, Rauter and co-workers [51] accomplished the synthesis and examined the anticholinesterase activity of 6-chloropurine (CP) or 2-acetamido-6-chloropurine (ACP) with d-glucosyl, d-galactosyl, and d-mannosyl subunits in which microwave-assisted Vorbrüggen glycosylation was studied. Persilylated purine 51 or 52 and sugar coupling partner 53 were heated with BSA (1.5 equiv.)…”