Synthesis and cholinesterase inhibition of cativic acid derivatives

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 et...

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Publicado:	2014
Materias:	Alzheimer's disease Cholinesterase inhibitors Diterpenoids Labdane Molecular modeling SH-SY5Y neuroblastoma cells 1,2 dibromoethane 1,3 dibromopropane 1,4 dibromobutane 1,5 dibromopentane 1,6 dibromohexane 17 hydroxycativic acid cativic acid derivative cholinesterase diethylamine diterpenoid morpholine piperidine plant extract pyrrolidine tertiary amine unclassified drug 17-hydroxycativic acid acetylcholinesterase cholinesterase inhibitor diterpene article catalysis controlled study drug structure drug synthesis enzyme active site enzyme inhibition enzyme kinetics Grindelia Grindelia ventanensis human human cell IC 50 in vitro study molecular docking neuroblastoma cell nonhuman structure activity relation toxicity testing animal binding site chemistry conformation kinetics metabolism synthesis tumor cell line X ray crystallography Acetylcholinesterase Animals Binding Sites Butyrylcholinesterase Catalytic Domain Cell Line, Tumor Cholinesterase Inhibitors Crystallography, X-Ray Diterpenes Humans Kinetics Molecular Conformation Molecular Docking Simulation
Acceso en línea:	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09680896_v22_n15_p3838_Alza http://hdl.handle.net/20.500.12110/paper_09680896_v22_n15_p3838_Alza
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

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spelling	paper:paper_09680896_v22_n15_p3838_Alza2023-06-08T15:58:56Z Synthesis and cholinesterase inhibition of cativic acid derivatives Alzheimer's disease Cholinesterase inhibitors Diterpenoids Labdane Molecular modeling SH-SY5Y neuroblastoma cells 1,2 dibromoethane 1,3 dibromopropane 1,4 dibromobutane 1,5 dibromopentane 1,6 dibromohexane 17 hydroxycativic acid cativic acid derivative cholinesterase diethylamine diterpenoid morpholine piperidine plant extract pyrrolidine tertiary amine unclassified drug 17-hydroxycativic acid acetylcholinesterase cholinesterase cholinesterase inhibitor diterpene article catalysis controlled study drug structure drug synthesis enzyme active site enzyme inhibition enzyme kinetics Grindelia Grindelia ventanensis human human cell IC 50 in vitro study molecular docking neuroblastoma cell nonhuman structure activity relation toxicity testing animal binding site chemistry conformation kinetics metabolism synthesis tumor cell line X ray crystallography Acetylcholinesterase Animals Binding Sites Butyrylcholinesterase Catalytic Domain Cell Line, Tumor Cholinesterase Inhibitors Crystallography, X-Ray Diterpenes Grindelia Humans Kinetics Molecular Conformation Molecular Docking Simulation 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 μM), selectivity over butyrylcholinesterase (BChE) (IC50 = 171.1 μM) 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 μM 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 non-cytotoxic. © 2014 Elsevier Ltd. All rights reserved. 2014 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09680896_v22_n15_p3838_Alza http://hdl.handle.net/20.500.12110/paper_09680896_v22_n15_p3838_Alza
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	Alzheimer's disease Cholinesterase inhibitors Diterpenoids Labdane Molecular modeling SH-SY5Y neuroblastoma cells 1,2 dibromoethane 1,3 dibromopropane 1,4 dibromobutane 1,5 dibromopentane 1,6 dibromohexane 17 hydroxycativic acid cativic acid derivative cholinesterase diethylamine diterpenoid morpholine piperidine plant extract pyrrolidine tertiary amine unclassified drug 17-hydroxycativic acid acetylcholinesterase cholinesterase cholinesterase inhibitor diterpene article catalysis controlled study drug structure drug synthesis enzyme active site enzyme inhibition enzyme kinetics Grindelia Grindelia ventanensis human human cell IC 50 in vitro study molecular docking neuroblastoma cell nonhuman structure activity relation toxicity testing animal binding site chemistry conformation kinetics metabolism synthesis tumor cell line X ray crystallography Acetylcholinesterase Animals Binding Sites Butyrylcholinesterase Catalytic Domain Cell Line, Tumor Cholinesterase Inhibitors Crystallography, X-Ray Diterpenes Grindelia Humans Kinetics Molecular Conformation Molecular Docking Simulation
spellingShingle	Alzheimer's disease Cholinesterase inhibitors Diterpenoids Labdane Molecular modeling SH-SY5Y neuroblastoma cells 1,2 dibromoethane 1,3 dibromopropane 1,4 dibromobutane 1,5 dibromopentane 1,6 dibromohexane 17 hydroxycativic acid cativic acid derivative cholinesterase diethylamine diterpenoid morpholine piperidine plant extract pyrrolidine tertiary amine unclassified drug 17-hydroxycativic acid acetylcholinesterase cholinesterase cholinesterase inhibitor diterpene article catalysis controlled study drug structure drug synthesis enzyme active site enzyme inhibition enzyme kinetics Grindelia Grindelia ventanensis human human cell IC 50 in vitro study molecular docking neuroblastoma cell nonhuman structure activity relation toxicity testing animal binding site chemistry conformation kinetics metabolism synthesis tumor cell line X ray crystallography Acetylcholinesterase Animals Binding Sites Butyrylcholinesterase Catalytic Domain Cell Line, Tumor Cholinesterase Inhibitors Crystallography, X-Ray Diterpenes Grindelia Humans Kinetics Molecular Conformation Molecular Docking Simulation Synthesis and cholinesterase inhibition of cativic acid derivatives
topic_facet	Alzheimer's disease Cholinesterase inhibitors Diterpenoids Labdane Molecular modeling SH-SY5Y neuroblastoma cells 1,2 dibromoethane 1,3 dibromopropane 1,4 dibromobutane 1,5 dibromopentane 1,6 dibromohexane 17 hydroxycativic acid cativic acid derivative cholinesterase diethylamine diterpenoid morpholine piperidine plant extract pyrrolidine tertiary amine unclassified drug 17-hydroxycativic acid acetylcholinesterase cholinesterase cholinesterase inhibitor diterpene article catalysis controlled study drug structure drug synthesis enzyme active site enzyme inhibition enzyme kinetics Grindelia Grindelia ventanensis human human cell IC 50 in vitro study molecular docking neuroblastoma cell nonhuman structure activity relation toxicity testing animal binding site chemistry conformation kinetics metabolism synthesis tumor cell line X ray crystallography Acetylcholinesterase Animals Binding Sites Butyrylcholinesterase Catalytic Domain Cell Line, Tumor Cholinesterase Inhibitors Crystallography, X-Ray Diterpenes Grindelia Humans Kinetics Molecular Conformation Molecular Docking Simulation
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 μM), selectivity over butyrylcholinesterase (BChE) (IC50 = 171.1 μM) 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 μM 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 non-cytotoxic. © 2014 Elsevier Ltd. All rights reserved.
title	Synthesis and cholinesterase inhibition of cativic acid derivatives
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
publishDate	2014
url	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09680896_v22_n15_p3838_Alza http://hdl.handle.net/20.500.12110/paper_09680896_v22_n15_p3838_Alza
_version_	1768544558544584704

Synthesis and cholinesterase inhibition of cativic acid derivatives

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