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Tytuł pozycji:

Derivatives of Tenuazonic Acid as Potential New Multi-Target Anti-Alzheimer's Disease Agents.

Tytuł:
Derivatives of Tenuazonic Acid as Potential New Multi-Target Anti-Alzheimer's Disease Agents.
Autorzy:
Poliseno V; Department of Pharmacy and Pharmaceutical Sciences, University of Bari 'A. Moro', via E. Orabona 4, 70125 Bari, Italy.; Centro de Química Estrutural and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal.
Chaves S; Centro de Química Estrutural and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal.
Brunetti L; Department of Pharmacy and Pharmaceutical Sciences, University of Bari 'A. Moro', via E. Orabona 4, 70125 Bari, Italy.
Loiodice F; Department of Pharmacy and Pharmaceutical Sciences, University of Bari 'A. Moro', via E. Orabona 4, 70125 Bari, Italy.
Carrieri A; Department of Pharmacy and Pharmaceutical Sciences, University of Bari 'A. Moro', via E. Orabona 4, 70125 Bari, Italy.
Laghezza A; Department of Pharmacy and Pharmaceutical Sciences, University of Bari 'A. Moro', via E. Orabona 4, 70125 Bari, Italy.
Tortorella P; Department of Pharmacy and Pharmaceutical Sciences, University of Bari 'A. Moro', via E. Orabona 4, 70125 Bari, Italy.
Magalhães JD; CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal.
Cardoso SM; CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal.; Institute of Molecular and Cell Biology, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.
Santos MA; Centro de Química Estrutural and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal.
Piemontese L; Department of Pharmacy and Pharmaceutical Sciences, University of Bari 'A. Moro', via E. Orabona 4, 70125 Bari, Italy.
Źródło:
Biomolecules [Biomolecules] 2021 Jan 15; Vol. 11 (1). Date of Electronic Publication: 2021 Jan 15.
Typ publikacji:
Journal Article; Research Support, Non-U.S. Gov't
Język:
English
Imprint Name(s):
Original Publication: Basel, Switzerland : MDPI, 2011-
MeSH Terms:
Alzheimer Disease/*drug therapy
Tenuazonic Acid/*therapeutic use
Alzheimer Disease/pathology ; Amyloid beta-Peptides/toxicity ; Cell Line, Tumor ; Cell Survival/drug effects ; Cholinesterase Inhibitors/pharmacology ; Donepezil/chemistry ; Donepezil/pharmacology ; Donepezil/therapeutic use ; Free Radical Scavengers/pharmacology ; Humans ; Hydrogen-Ion Concentration ; Metals/chemistry ; Molecular Docking Simulation ; Neuroprotection/drug effects ; Neuroprotective Agents/pharmacology ; Protein Aggregates/drug effects ; Spectrophotometry ; Tenuazonic Acid/chemistry ; Tenuazonic Acid/pharmacokinetics
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Grant Information:
UID/QUI/00100/2019 Portuguese Fundação para a Ciência e Tecnologia (FCT); POCI-01-0145-FEDER-030712 Fundação para a Ciência e Tecnologia (FCT); Contributo ordinario di supporto alla ricerca 2017-18 (Luca Piemontese) University of Bari "Aldo Moro"
Contributed Indexing:
Keywords: Alzheimer’s disease; acetylcholinesterase; amyloid; antioxidant; donepezil; metal chelation; multifunctional drugs; neurodegenerative; tenuazonic acid
Substance Nomenclature:
0 (Amyloid beta-Peptides)
0 (Cholinesterase Inhibitors)
0 (Free Radical Scavengers)
0 (Metals)
0 (Neuroprotective Agents)
0 (Protein Aggregates)
610-88-8 (Tenuazonic Acid)
8SSC91326P (Donepezil)
Entry Date(s):
Date Created: 20210120 Date Completed: 20210623 Latest Revision: 20210623
Update Code:
20240105
PubMed Central ID:
PMC7830597
DOI:
10.3390/biom11010111
PMID:
33467709
Czasopismo naukowe
Alzheimer's disease (AD) is generally recognized as a multifactorial neurodegenerative pathology with an increasing impact on society. Tenuazonic acid (TA) is a natural compound that was recently identified as a potential multitarget ligand with anti-cholinesterase, anti-amyloidogenic and antioxidant activities. Using its structure as a chemical scaffold, we synthesized and evaluated new derivatives (1-5), including tenuazonic-donepezil (TA-DNP) hybrids (4 and 5) due to the clinical importance of the anti-AD drug donepezil. These novel compounds all achieved activity in the micromolar range towards all selected targets and demonstrated to be potentially orally absorbed. Moreover, a selected compound (1) was further investigated as a chelating agent towards copper (II), zinc (II) and iron (III) and showed good chelating ability (pFe = 16.6, pCu = 11.6, pZn = 6.0 at pH 7.4). Therefore, the TA motif can be considered an interesting building block in the search for innovative multi-functional anti-neurodegenerative drugs, as exemplified by hybrid 5, a promising non-cytotoxic lead compound adequate for the early stages of AD, and capable of ameliorating the oxidative status of SH-SY5Y human neuroblastoma cells.
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