Synthesis and cholinesterase inhibition of cativic acid derivatives

Autores
Alza, Natalia Paola; Richmond, Victoria; Baier, Carlos Javier; Freire Espeleta, Eleonora; Baggio, Ricardo Fortunato; Murray, Ana Paula
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
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
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
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
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
Fil: Baggio, Ricardo Fortunato. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
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
Materia
Alzheimers Disease
Cholinesterase Inhibitors
Diterpenoids
Labdane
Sh-Sy5y Neuroblastoma Cells
Molecular Modeling
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/29888
Acceder
id CONICETDig_ea118a66697a145d47b57e5683c62355
oai_identifier_str oai:ri.conicet.gov.ar:11336/29888
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Synthesis and cholinesterase inhibition of cativic acid derivativesAlza, Natalia PaolaRichmond, VictoriaBaier, Carlos JavierFreire Espeleta, EleonoraBaggio, Ricardo FortunatoMurray, Ana PaulaAlzheimers DiseaseCholinesterase InhibitorsDiterpenoidsLabdaneSh-Sy5y Neuroblastoma CellsMolecular Modelinghttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Alzheimer’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.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; ArgentinaFil: 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; ArgentinaFil: 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; ArgentinaFil: 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; ArgentinaFil: Baggio, Ricardo Fortunato. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: 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; ArgentinaElsevier2014-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/29888Alza, 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; 3838-38490968-0896CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.bmc.2014.06.030info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0968089614004763info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:45:18Zoai:ri.conicet.gov.ar:11336/29888instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:45:18.558CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Synthesis and cholinesterase inhibition of cativic acid derivatives
title Synthesis and cholinesterase inhibition of cativic acid derivatives
spellingShingle Synthesis and cholinesterase inhibition of cativic acid derivatives
Alza, Natalia Paola
Alzheimers Disease
Cholinesterase Inhibitors
Diterpenoids
Labdane
Sh-Sy5y Neuroblastoma Cells
Molecular Modeling
title_short Synthesis and cholinesterase inhibition of cativic acid derivatives
title_full Synthesis and cholinesterase inhibition of cativic acid derivatives
title_fullStr Synthesis and cholinesterase inhibition of cativic acid derivatives
title_full_unstemmed Synthesis and cholinesterase inhibition of cativic acid derivatives
title_sort Synthesis and cholinesterase inhibition of cativic acid derivatives
dc.creator.none.fl_str_mv Alza, Natalia Paola
Richmond, Victoria
Baier, Carlos Javier
Freire Espeleta, Eleonora
Baggio, Ricardo Fortunato
Murray, Ana Paula
author Alza, Natalia Paola
author_facet Alza, Natalia Paola
Richmond, Victoria
Baier, Carlos Javier
Freire Espeleta, Eleonora
Baggio, Ricardo Fortunato
Murray, Ana Paula
author_role author
author2 Richmond, Victoria
Baier, Carlos Javier
Freire Espeleta, Eleonora
Baggio, Ricardo Fortunato
Murray, Ana Paula
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Alzheimers Disease
Cholinesterase Inhibitors
Diterpenoids
Labdane
Sh-Sy5y Neuroblastoma Cells
Molecular Modeling
topic Alzheimers Disease
Cholinesterase Inhibitors
Diterpenoids
Labdane
Sh-Sy5y Neuroblastoma Cells
Molecular Modeling
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 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.
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
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
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
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
Fil: Baggio, Ricardo Fortunato. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
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
description 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.
publishDate 2014
dc.date.none.fl_str_mv 2014-06
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/29888
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
0968-0896
CONICET Digital
CONICET
url http://hdl.handle.net/11336/29888
identifier_str_mv 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
0968-0896
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0968089614004763
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
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application/pdf
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dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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