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Alza, N.P.; Richmond, V.; Baier, C.J.; Freire, E.; Baggio, R.; Murray, A.P. "Synthesis and cholinesterase inhibition of cativic acid derivatives" (2014) Bioorganic and Medicinal Chemistry. 22(15):3838-3849
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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 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.

Registro:

Documento: Artículo
Título:Synthesis and cholinesterase inhibition of cativic acid derivatives
Autor:Alza, N.P.; Richmond, V.; Baier, C.J.; Freire, E.; Baggio, R.; Murray, A.P.
Filiación:INQUISUR-CONICET, Departamento de Química, Universidad Nacional Del sur, Av. Alem 1253, B8000CPB Bahía Blanca, Argentina
UMYMFOR (CONICET-UBA), Departamento de Química Orgánica, Universidad de Buenos Aires, 1428 Buenos Aires, Argentina
INIBIBB-CONICET, Instituto de Investigaciones Bioquímicas de Bahía Blanca, Camino La Carrindanga km. 7, B8000FWB Bahía Blanca, Argentina
Gerencia de Investigación y Aplicaciones, Centro Atómico Constituyentes, Comisión Nacional de Energía Atómica, Av. Gral. Paz 1499, 1650 San-Martin, Buenos Aires, Argentina
Escuela de Ciencia y Tecnología, Universidad Nacional General San Martín, Martín de Irigoyen 3100, 1650 San-Martín, Buenos Aires, Argentina
Palabras clave: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
Año:2014
Volumen:22
Número:15
Página de inicio:3838
Página de fin:3849
DOI: http://dx.doi.org/10.1016/j.bmc.2014.06.030
Título revista:Bioorganic and Medicinal Chemistry
Título revista abreviado:Bioorg. Med. Chem.
ISSN:09680896
CODEN:BMECE
CAS:1,2 dibromoethane, 106-93-4; cholinesterase, 9001-08-5; diethylamine, 109-89-7, 660-68-4; morpholine, 110-91-8; piperidine, 110-89-4, 6091-44-7; acetylcholinesterase, 9000-81-1; 17-hydroxycativic acid; Acetylcholinesterase; Butyrylcholinesterase; Cholinesterase Inhibitors; Diterpenes
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09680896_v22_n15_p3838_Alza

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Citas:

---------- APA ----------
Alza, N.P., Richmond, V., Baier, C.J., Freire, E., Baggio, R. & Murray, A.P. (2014) . Synthesis and cholinesterase inhibition of cativic acid derivatives. Bioorganic and Medicinal Chemistry, 22(15), 3838-3849.
http://dx.doi.org/10.1016/j.bmc.2014.06.030
---------- CHICAGO ----------
Alza, N.P., Richmond, V., Baier, C.J., Freire, E., Baggio, R., Murray, A.P. "Synthesis and cholinesterase inhibition of cativic acid derivatives" . Bioorganic and Medicinal Chemistry 22, no. 15 (2014) : 3838-3849.
http://dx.doi.org/10.1016/j.bmc.2014.06.030
---------- MLA ----------
Alza, N.P., Richmond, V., Baier, C.J., Freire, E., Baggio, R., Murray, A.P. "Synthesis and cholinesterase inhibition of cativic acid derivatives" . Bioorganic and Medicinal Chemistry, vol. 22, no. 15, 2014, pp. 3838-3849.
http://dx.doi.org/10.1016/j.bmc.2014.06.030
---------- VANCOUVER ----------
Alza, N.P., Richmond, V., Baier, C.J., Freire, E., Baggio, R., Murray, A.P. Synthesis and cholinesterase inhibition of cativic acid derivatives. Bioorg. Med. Chem. 2014;22(15):3838-3849.
http://dx.doi.org/10.1016/j.bmc.2014.06.030