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

Detalhes bibliográficos
Autor(a) principal: Schino, Ignazio
Data de Publicação: 2022
Outros Autores: Cantore, Mariangela, de Candia, Modesto, Altomare, Cosimo D., Maria, Catarina, Barros, João, Cachatra, Vasco, Calado, Patrícia, Shimizu, Karina, Freitas, Adilson A., Oliveira, Maria C., Ferreira, Maria J., Lopes, José N. C., Colabufo, Nicola A., Rauter, Amélia P.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10362/150800
Resumo: Funding Information: This research was funded by the EUROPEAN UNION project entitled “Diagnostic and Drug Discovery Initiative for Alzheimer’s Disease” (D3i4AD), FP7-PEOPLE-2013-IAPP. Publisher Copyright: © 2022 by the authors.
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spelling Exploring Mannosylpurines as Copper Chelators and Cholinesterase Inhibitors with Potential for Alzheimer’s DiseaseAlzheimer’s diseasecholinesterase inhibitorscopper chelatorspurine nucleosidesMolecular MedicinePharmaceutical ScienceDrug DiscoverySDG 3 - Good Health and Well-beingFunding Information: This research was funded by the EUROPEAN UNION project entitled “Diagnostic and Drug Discovery Initiative for Alzheimer’s Disease” (D3i4AD), FP7-PEOPLE-2013-IAPP. Publisher Copyright: © 2022 by the authors.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.DQ - Departamento de QuímicaRUNSchino, IgnazioCantore, Mariangelade Candia, ModestoAltomare, Cosimo D.Maria, CatarinaBarros, JoãoCachatra, VascoCalado, PatríciaShimizu, KarinaFreitas, Adilson A.Oliveira, Maria C.Ferreira, Maria J.Lopes, José N. C.Colabufo, Nicola A.Rauter, Amélia P.2023-03-17T22:31:13Z2022-12-302022-12-30T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article20application/pdfhttp://hdl.handle.net/10362/150800eng1424-8247PURE: 56207033https://doi.org/10.3390/ph16010054info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-03-11T05:33:14Zoai:run.unl.pt:10362/150800Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:54:19.634241Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Exploring Mannosylpurines as Copper Chelators and Cholinesterase Inhibitors with Potential for Alzheimer’s Disease
title Exploring Mannosylpurines as Copper Chelators and Cholinesterase Inhibitors with Potential for Alzheimer’s Disease
spellingShingle Exploring Mannosylpurines as Copper Chelators and Cholinesterase Inhibitors with Potential for Alzheimer’s Disease
Schino, Ignazio
Alzheimer’s disease
cholinesterase inhibitors
copper chelators
purine nucleosides
Molecular Medicine
Pharmaceutical Science
Drug Discovery
SDG 3 - Good Health and Well-being
title_short Exploring Mannosylpurines as Copper Chelators and Cholinesterase Inhibitors with Potential for Alzheimer’s Disease
title_full Exploring Mannosylpurines as Copper Chelators and Cholinesterase Inhibitors with Potential for Alzheimer’s Disease
title_fullStr Exploring Mannosylpurines as Copper Chelators and Cholinesterase Inhibitors with Potential for Alzheimer’s Disease
title_full_unstemmed Exploring Mannosylpurines as Copper Chelators and Cholinesterase Inhibitors with Potential for Alzheimer’s Disease
title_sort Exploring Mannosylpurines as Copper Chelators and Cholinesterase Inhibitors with Potential for Alzheimer’s Disease
author Schino, Ignazio
author_facet Schino, Ignazio
Cantore, Mariangela
de Candia, Modesto
Altomare, Cosimo D.
Maria, Catarina
Barros, João
Cachatra, Vasco
Calado, Patrícia
Shimizu, Karina
Freitas, Adilson A.
Oliveira, Maria C.
Ferreira, Maria J.
Lopes, José N. C.
Colabufo, Nicola A.
Rauter, Amélia P.
author_role author
author2 Cantore, Mariangela
de Candia, Modesto
Altomare, Cosimo D.
Maria, Catarina
Barros, João
Cachatra, Vasco
Calado, Patrícia
Shimizu, Karina
Freitas, Adilson A.
Oliveira, Maria C.
Ferreira, Maria J.
Lopes, José N. C.
Colabufo, Nicola A.
Rauter, Amélia P.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv DQ - Departamento de Química
RUN
dc.contributor.author.fl_str_mv Schino, Ignazio
Cantore, Mariangela
de Candia, Modesto
Altomare, Cosimo D.
Maria, Catarina
Barros, João
Cachatra, Vasco
Calado, Patrícia
Shimizu, Karina
Freitas, Adilson A.
Oliveira, Maria C.
Ferreira, Maria J.
Lopes, José N. C.
Colabufo, Nicola A.
Rauter, Amélia P.
dc.subject.por.fl_str_mv Alzheimer’s disease
cholinesterase inhibitors
copper chelators
purine nucleosides
Molecular Medicine
Pharmaceutical Science
Drug Discovery
SDG 3 - Good Health and Well-being
topic Alzheimer’s disease
cholinesterase inhibitors
copper chelators
purine nucleosides
Molecular Medicine
Pharmaceutical Science
Drug Discovery
SDG 3 - Good Health and Well-being
description Funding Information: This research was funded by the EUROPEAN UNION project entitled “Diagnostic and Drug Discovery Initiative for Alzheimer’s Disease” (D3i4AD), FP7-PEOPLE-2013-IAPP. Publisher Copyright: © 2022 by the authors.
publishDate 2022
dc.date.none.fl_str_mv 2022-12-30
2022-12-30T00:00:00Z
2023-03-17T22:31:13Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10362/150800
url http://hdl.handle.net/10362/150800
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 1424-8247
PURE: 56207033
https://doi.org/10.3390/ph16010054
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eu_rights_str_mv openAccess
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