BIBLIOS

Document type
Journal articles

Document subtype
Full paper

Title
Exploring Mannosylpurines as Copper Chelators and Cholinesterase Inhibitors with Potential for Alzheimer’s Disease

Participants in the publication
Ignazio Schino (Author)
Mariangela Cantore (Author)
Modesto de Candia (Author)
Cosimo D. Altomare (Author)
Catarina Maria (Author)
FACULDADE DE CIÊNCIAS DA UNIVERSIDADE DE LISBOA
João Barros (Author)
FACULDADE DE CIÊNCIAS DA UNIVERSIDADE DE LISBOA
Vasco Cachatra (Author)
FACULDADE DE CIÊNCIAS DA UNIVERSIDADE DE LISBOA
Dep. Química e Bioquímica
Patrícia Calado (Author)
FACULDADE DE CIÊNCIAS DA UNIVERSIDADE DE LISBOA
Karina Shimizu (Author)
Adilson A. Freitas (Author)
Maria C. Oliveira (Author)
Maria J. Ferreira (Author)
José N. C. Lopes (Author)
Nicola A. Colabufo (Author)
Amélia P. Rauter (Author)
FACULDADE DE CIÊNCIAS DA UNIVERSIDADE DE LISBOA

Summary
Alzheimer’s Disease (AD) is characterized by a progressive cholinergic neurotransmission imbalance, with a decrease of acetylcholinesterase (AChE) activity followed by a significant increase of butyrylcholinesterase (BChE) in the later AD stages. BChE activity is also crucial for the development of Aβ plaques, the main hallmarks of this pathology. Moreover, systemic copper dyshomeostasis alters neurotransmission leading to AD. In the search for structures targeting both events, a set of novel 6-benzamide purine nucleosides was synthesized, differing in glycone configuration and N7/N9 linkage to the purine. Their AChE/BChE inhibitory activity and metal ion chelating properties were evaluated. Selectivity for human BChE inhibition required N9-linked 6-deoxy-α-d-mannosylpurine structure, while all three tested β-d-derivatives appeared as non-selective inhibitors. The N9-linked l-nucleosides were cholinesterase inhibitors except the one embodying either the acetylated sugar or the N-benzyl-protected nucleobase. These findings highlight that sugar-enriched molecular entities can tune bioactivity and selectivity against cholinesterases. In addition, selective copper chelating properties over zinc, aluminum, and iron were found for the benzyl and acetyl-protected 6-deoxy-α-l-mannosyl N9-linked purine nucleosides. Computational studies highlight molecular conformations and the chelating molecular site. The first dual target compounds were disclosed with the perspective of generating drug candidates by improving water solubility.


Where published
Pharmaceuticals

Publication Identifiers
ISSN - 1424-8247

Publisher
MDPI AG



Document Identifiers
DOI - https://doi.org/10.3390/ph16010054
URL - http://dx.doi.org/10.3390/ph16010054