Synthesis of New Purine Nucleosides as potential Metal Chelators and Anticholinesterase Agents ^†

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by multiple factors, such as the progressive decline in the levels of the neurotransmitter acetylcholine, and the deregulation of the homeostasis of bio-metals, such as copper, zinc and iron. Acetylcholine is hydrolyzed by acetylcholinesterase and butyrylcholinesterase and the current therapeutic strategies are based on the treatment of AD patients with these enzymes’ inhibitors. Although these strategies are focused on symptomatic relief of the disease, recent studies have shown that the long-term use of these drugs may lead to disease-modifying benefits. The deregulation of the bio-metals’ homeostasis has been related to oxidative stress and to the induction of Ab aggregation and tau hyperphosphorylation and aggregation. Since AD is a multifactorial disease, discovering a multi-target drug could be an interesting challenge, leading to a disease-modifying therapy. In this context, mannosylpurines synthesized by our group have already shown potent butyrylcholinesterase (BChE) inhibition. Aiming at the discovery of multitarget drug candidates, we have synthesized a new series of mannosyl and rhamnosylpurines and evaluated copper chelation and cholinesterase inhibition. The results obtained will be presented and discussed.