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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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info:eu-repo/semantics/restrictedAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Atribución-NoComercial-SinDerivadas 2.5 Argentina (CC BY-NC-ND 2.5 AR)