Enantioselective Synthesis and Pharmacological Evaluation of Aza-CGP37157–Lipoic Acid Hybrids for the Treatment of Alzheimer’s Disease
Hybrids based on an aza-analogue of CGP37157, a mitochondrial Na+/Ca2+ exchanger antagonist, and lipoic acid were obtained in order to combine in a single molecule the antioxidant and NRF2 induction properties of lipoic acid and the neuroprotective activity of CGP37157. The four possible enantiomers...
| Autores: | , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Universidad Complutense de Madrid (UCM) |
| Repositorio: | Docta Complutense |
| Idioma: | inglés |
| OAI Identifier: | oai:docta.ucm.es:20.500.14352/72079 |
| Acceso en línea: | https://hdl.handle.net/20.500.14352/72079 |
| Access Level: | acceso abierto |
| Palabra clave: | CGP37157 lipoic acid neuroprotection NRF2 induction Neurociencias (Medicina) Química farmaceútica 2490 Neurociencias 2390 Química Farmacéutica |
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Enantioselective Synthesis and Pharmacological Evaluation of Aza-CGP37157–Lipoic Acid Hybrids for the Treatment of Alzheimer’s DiseaseCores Esperón, ÁngelMichalska Dziama, PatrycjaPérez Moreno, José MiguelCrisman Vigil, EnriqueGómez Serrano, ClaraVillacampa Sanz, MercedesMenéndez Ramos, José CarlosLeón Martínez, RafaelCGP37157lipoic acidneuroprotectionNRF2 inductionNeurociencias (Medicina)Química farmaceútica2490 Neurociencias2390 Química FarmacéuticaHybrids based on an aza-analogue of CGP37157, a mitochondrial Na+/Ca2+ exchanger antagonist, and lipoic acid were obtained in order to combine in a single molecule the antioxidant and NRF2 induction properties of lipoic acid and the neuroprotective activity of CGP37157. The four possible enantiomers of the hybrid structure were synthesized by using as the key step a fully diastereoselective reduction induced by Ellman’s chiral auxiliary. After computational druggability studies that predicted good ADME profiles and blood–brain permeation for all compounds, the DPPH assay showed moderate oxidant scavenger capacity. Following a cytotoxicity evaluation that proved the compounds to be non-neurotoxic at the concentrations tested, they were assayed for NRF2 induction capacity and for anti-inflammatory properties and measured by their ability to inhibit nitrite production in the lipopolysaccharide-stimulated BV2 microglial cell model. Moreover, the compounds were studied for their neuroprotective effect in a model of oxidative stress achieved by treatment of SH-SY5Y neuroblastoma cells with the rotenone–oligomycin combination and also in a model of hyperphosphorylation induced by treatment with okadaic acid. The stereocenter configuration showed a critical influence in NRF2 induction properties, and also in the neuroprotection against oxidative stress experiment, leading to the identification of the compound with S and R configuration as an interesting hit with a good neuroprotective profile against oxidative stress and hyperphosphorylation, together with a relevant anti-neuroinflammatory activity. This interesting multitarget profile will be further characterized in future work.MPDIUniversidad Complutense de Madrid20222022-01-0420222022-01-04journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/72079reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)InglésengRTI2018-097662-B-I00 Not available Not availablePI17 01700 Not availablePI20 00433B2017 BMD-3813PI20 00433 Not availablePI20 00433B2017 BMD-3827open accesshttp://purl.org/coar/access_right/c_abf2Atributtion 4.0 Internationalhttps://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/720792026-06-02T12:44:21Z |
| dc.title.none.fl_str_mv |
Enantioselective Synthesis and Pharmacological Evaluation of Aza-CGP37157–Lipoic Acid Hybrids for the Treatment of Alzheimer’s Disease |
| title |
Enantioselective Synthesis and Pharmacological Evaluation of Aza-CGP37157–Lipoic Acid Hybrids for the Treatment of Alzheimer’s Disease |
| spellingShingle |
Enantioselective Synthesis and Pharmacological Evaluation of Aza-CGP37157–Lipoic Acid Hybrids for the Treatment of Alzheimer’s Disease Cores Esperón, Ángel CGP37157 lipoic acid neuroprotection NRF2 induction Neurociencias (Medicina) Química farmaceútica 2490 Neurociencias 2390 Química Farmacéutica |
| title_short |
Enantioselective Synthesis and Pharmacological Evaluation of Aza-CGP37157–Lipoic Acid Hybrids for the Treatment of Alzheimer’s Disease |
| title_full |
Enantioselective Synthesis and Pharmacological Evaluation of Aza-CGP37157–Lipoic Acid Hybrids for the Treatment of Alzheimer’s Disease |
| title_fullStr |
Enantioselective Synthesis and Pharmacological Evaluation of Aza-CGP37157–Lipoic Acid Hybrids for the Treatment of Alzheimer’s Disease |
| title_full_unstemmed |
Enantioselective Synthesis and Pharmacological Evaluation of Aza-CGP37157–Lipoic Acid Hybrids for the Treatment of Alzheimer’s Disease |
| title_sort |
Enantioselective Synthesis and Pharmacological Evaluation of Aza-CGP37157–Lipoic Acid Hybrids for the Treatment of Alzheimer’s Disease |
| dc.creator.none.fl_str_mv |
Cores Esperón, Ángel Michalska Dziama, Patrycja Pérez Moreno, José Miguel Crisman Vigil, Enrique Gómez Serrano, Clara Villacampa Sanz, Mercedes Menéndez Ramos, José Carlos León Martínez, Rafael |
| author |
Cores Esperón, Ángel |
| author_facet |
Cores Esperón, Ángel Michalska Dziama, Patrycja Pérez Moreno, José Miguel Crisman Vigil, Enrique Gómez Serrano, Clara Villacampa Sanz, Mercedes Menéndez Ramos, José Carlos León Martínez, Rafael |
| author_role |
author |
| author2 |
Michalska Dziama, Patrycja Pérez Moreno, José Miguel Crisman Vigil, Enrique Gómez Serrano, Clara Villacampa Sanz, Mercedes Menéndez Ramos, José Carlos León Martínez, Rafael |
| author2_role |
author author author author author author author |
| dc.contributor.none.fl_str_mv |
Universidad Complutense de Madrid |
| dc.subject.none.fl_str_mv |
CGP37157 lipoic acid neuroprotection NRF2 induction Neurociencias (Medicina) Química farmaceútica 2490 Neurociencias 2390 Química Farmacéutica |
| topic |
CGP37157 lipoic acid neuroprotection NRF2 induction Neurociencias (Medicina) Química farmaceútica 2490 Neurociencias 2390 Química Farmacéutica |
| description |
Hybrids based on an aza-analogue of CGP37157, a mitochondrial Na+/Ca2+ exchanger antagonist, and lipoic acid were obtained in order to combine in a single molecule the antioxidant and NRF2 induction properties of lipoic acid and the neuroprotective activity of CGP37157. The four possible enantiomers of the hybrid structure were synthesized by using as the key step a fully diastereoselective reduction induced by Ellman’s chiral auxiliary. After computational druggability studies that predicted good ADME profiles and blood–brain permeation for all compounds, the DPPH assay showed moderate oxidant scavenger capacity. Following a cytotoxicity evaluation that proved the compounds to be non-neurotoxic at the concentrations tested, they were assayed for NRF2 induction capacity and for anti-inflammatory properties and measured by their ability to inhibit nitrite production in the lipopolysaccharide-stimulated BV2 microglial cell model. Moreover, the compounds were studied for their neuroprotective effect in a model of oxidative stress achieved by treatment of SH-SY5Y neuroblastoma cells with the rotenone–oligomycin combination and also in a model of hyperphosphorylation induced by treatment with okadaic acid. The stereocenter configuration showed a critical influence in NRF2 induction properties, and also in the neuroprotection against oxidative stress experiment, leading to the identification of the compound with S and R configuration as an interesting hit with a good neuroprotective profile against oxidative stress and hyperphosphorylation, together with a relevant anti-neuroinflammatory activity. This interesting multitarget profile will be further characterized in future work. |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2022 2022-01-04 2022 2022-01-04 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/20.500.14352/72079 |
| url |
https://hdl.handle.net/20.500.14352/72079 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.relation.none.fl_str_mv |
RTI2018-097662-B-I00 Not available Not available PI17 01700 Not available PI20 00433B2017 BMD-3813 PI20 00433 Not available PI20 00433B2017 BMD-3827 |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 Atributtion 4.0 International https://creativecommons.org/licenses/by/4.0/ |
| dc.rights.openaire.fl_str_mv |
info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
open access http://purl.org/coar/access_right/c_abf2 Atributtion 4.0 International https://creativecommons.org/licenses/by/4.0/ |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
application/pdf |
| dc.publisher.none.fl_str_mv |
MPDI |
| publisher.none.fl_str_mv |
MPDI |
| dc.source.none.fl_str_mv |
reponame:Docta Complutense instname:Universidad Complutense de Madrid (UCM) |
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Universidad Complutense de Madrid (UCM) |
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Docta Complutense |
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Docta Complutense |
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