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dc.contributor.author
Alza, Natalia Paola
dc.contributor.author
Richmond, Victoria
dc.contributor.author
Baier, Carlos Javier
dc.contributor.author
Freire Espeleta, Eleonora
dc.contributor.author
Baggio, Ricardo Fortunato
dc.contributor.author
Murray, Ana Paula
dc.date.available
2017-12-06T20:45:05Z
dc.date.issued
2014-06
dc.identifier.citation
Alza, Natalia Paola; Richmond, Victoria; Baier, Carlos Javier; Freire Espeleta, Eleonora; Baggio, Ricardo Fortunato; et al.; Synthesis and cholinesterase inhibition of cativic acid derivatives; Elsevier; Bioorganic & Medicinal Chemistry; 22; 15; 6-2014; 3838-3849
dc.identifier.issn
0968-0896
dc.identifier.uri
http://hdl.handle.net/11336/29888
dc.description.abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder associated with memory impairment and cognitive deficit. Most of the drugs currently available for the treatment of AD are acetylcholinesterase (AChE) inhibitors. In a preliminary study, significant AChE inhibition was observed for the ethanolic extract of Grindelia ventanensis (IC50 = 0.79 mg/mL). This result prompted us to isolate the active constituent, a normal labdane diterpenoid identified as 17-hydroxycativic acid (1), through a bioassay guided fractionation. Taking into account that 1 showed moderate inhibition of AChE (IC50 = 21.1 lM), selectivity over butyrylcholinesterase (BChE) (IC50 = 171.1 lM) and that it was easily obtained from the plant extract in a very good yield (0.15% w/w), we decided to prepare semisynthetic derivatives of this natural diterpenoid through simple structural modifications. A set of twenty new cativic acid derivatives (3–6) was prepared from 1 through transformations on the carboxylic group at C-15, introducing a C2–C6 linker and a tertiary amine group. They were tested for their inhibitory activity against AChE and BChE and some structure–activity relationships were outlined. The most active derivative was compound 3c, with an IC50 value of 3.2 lM for AChE. Enzyme kinetic studies and docking modeling revealed that this inhibitor targeted both the catalytic active site and the peripheral anionic site of this enzyme. Furthermore, 3c showed significant inhibition of AChE activity in SH-SY5Y human neuroblastoma cells, and was noncytotoxic.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Elsevier
dc.rights
info:eu-repo/semantics/restrictedAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.subject
Alzheimers Disease
dc.subject
Cholinesterase Inhibitors
dc.subject
Diterpenoids
dc.subject
Labdane
dc.subject
Sh-Sy5y Neuroblastoma Cells
dc.subject
Molecular Modeling
dc.subject.classification
Otras Ciencias Químicas
dc.subject.classification
Ciencias Químicas
dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
dc.title
Synthesis and cholinesterase inhibition of cativic acid derivatives
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2017-12-06T16:48:48Z
dc.journal.volume
22
dc.journal.number
15
dc.journal.pagination
3838-3849
dc.journal.pais
Países Bajos
dc.journal.ciudad
Amsterdam
dc.description.fil
Fil: Alza, Natalia Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
dc.description.fil
Fil: Richmond, Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina
dc.description.fil
Fil: Baier, Carlos Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
dc.description.fil
Fil: Freire Espeleta, Eleonora. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.description.fil
Fil: Baggio, Ricardo Fortunato. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.description.fil
Fil: Murray, Ana Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
dc.journal.title
Bioorganic & Medicinal Chemistry
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1016/j.bmc.2014.06.030
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0968089614004763


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