Nucleobase-Derived Nitrones: Synthesis and Antioxidant and Neuroprotective Activities in an In Vitro Model of Ischemia–Reperfusion
Herein, we report the synthesis, antioxidant, and neuroprotective properties of some nucleobase-derived nitrones named 9a–i. The neuroprotective properties of nitrones, 9a–i, were measured against an oxygen-glucose-deprivation in vitro ischemia model using human neuroblastoma SH-SY5Y cells. Our resu...
| Autores: | , , , , , , , , |
|---|---|
| Tipo de documento: | artigo |
| Data de publicação: | 2022 |
| País: | España |
| Recursos: | Universidad Complutense de Madrid (UCM) |
| Repositório: | Docta Complutense |
| Idioma: | inglês |
| OAI Identifier: | oai:docta.ucm.es:20.500.14352/72503 |
| Acesso em linha: | https://hdl.handle.net/20.500.14352/72503 |
| Access Level: | Acceso aberto |
| Palavra-chave: | antioxidants neuroprotection necrosis apoptosis oxidative stress nucleobase-derived nitrones brain ischemia Neurociencias (Medicina) Bioquímica (Biología) 2490 Neurociencias 2302 Bioquímica |
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Nucleobase-Derived Nitrones: Synthesis and Antioxidant and Neuroprotective Activities in an In Vitro Model of Ischemia–ReperfusionChamorro, BeatrizGłowacka, Iwona E.Gotkowska, JoannaGulej, RafałHadjipavlou Litina, DimitraLópez Muñoz, FranciscoMarco Contelles, José LuisPiotrowska, Dorota G.Oset Gasque, María Jesúsantioxidantsneuroprotectionnecrosisapoptosisoxidative stressnucleobase-derived nitronesbrain ischemiaNeurociencias (Medicina)Bioquímica (Biología)2490 Neurociencias2302 BioquímicaHerein, we report the synthesis, antioxidant, and neuroprotective properties of some nucleobase-derived nitrones named 9a–i. The neuroprotective properties of nitrones, 9a–i, were measured against an oxygen-glucose-deprivation in vitro ischemia model using human neuroblastoma SH-SY5Y cells. Our results indicate that nitrones, 9a–i, have better neuroprotective and antioxidant properties than α-phenyl-N-tert-butylnitrone (PBN) and are similar to N-acetyl-L-cysteine (NAC), a well-known antioxidant and neuroprotective agent. The nitrones with the highest neuroprotective capacity were those containing purine nucleobases (nitrones 9f, g, B = adenine, theophylline), followed by nitrones with pyrimidine nucleobases with H or F substituents at the C5 position (nitrones 9a, c). All of these possess EC50 values in the range of 1–6 μM and maximal activities higher than 100%. However, the introduction of a methyl substituent (nitrone 9b, B = thymine) or hard halogen substituents such as Br and Cl (nitrones 9d, e, B = 5-Br and 5-Cl uracil, respectively) worsens the neuroprotective activity of the nitrone with uracil as the nucleobase (9a). The effects on overall metabolic cell capacity were confirmed by results on the high anti-necrotic (EC50′s ≈ 2–4 μM) and antioxidant (EC50′s ≈ 0.4–3.5 μM) activities of these compounds on superoxide radical production. In general, all tested nitrones were excellent inhibitors of superoxide radical production in cultured neuroblastoma cells, as well as potent hydroxyl radical scavengers that inhibit in vitro lipid peroxidation, particularly, 9c, f, g, presenting the highest lipoxygenase inhibitory activity among the tested nitrones. Finally, the introduction of two nitrone groups at 9a and 9d (bis-nitronas 9g, i) did not show better neuroprotective effects than their precursor mono-nitrones. These results led us to propose nitrones containing purine (9f, g) and pyrimidine (9a, c) nucleobases as potential therapeutic agents for the treatment of cerebral ischemia and/or neurodegenerative diseases, leading us to further investigate their effects using in vivo models of these pathologies.MPDIUniversidad Complutense de Madrid20222022-03-2120222022-03-21journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/72503reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Atribución 3.0 Españahttps://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/725032026-06-02T12:44:21Z |
| dc.title.none.fl_str_mv |
Nucleobase-Derived Nitrones: Synthesis and Antioxidant and Neuroprotective Activities in an In Vitro Model of Ischemia–Reperfusion |
| title |
Nucleobase-Derived Nitrones: Synthesis and Antioxidant and Neuroprotective Activities in an In Vitro Model of Ischemia–Reperfusion |
| spellingShingle |
Nucleobase-Derived Nitrones: Synthesis and Antioxidant and Neuroprotective Activities in an In Vitro Model of Ischemia–Reperfusion Chamorro, Beatriz antioxidants neuroprotection necrosis apoptosis oxidative stress nucleobase-derived nitrones brain ischemia Neurociencias (Medicina) Bioquímica (Biología) 2490 Neurociencias 2302 Bioquímica |
| title_short |
Nucleobase-Derived Nitrones: Synthesis and Antioxidant and Neuroprotective Activities in an In Vitro Model of Ischemia–Reperfusion |
| title_full |
Nucleobase-Derived Nitrones: Synthesis and Antioxidant and Neuroprotective Activities in an In Vitro Model of Ischemia–Reperfusion |
| title_fullStr |
Nucleobase-Derived Nitrones: Synthesis and Antioxidant and Neuroprotective Activities in an In Vitro Model of Ischemia–Reperfusion |
| title_full_unstemmed |
Nucleobase-Derived Nitrones: Synthesis and Antioxidant and Neuroprotective Activities in an In Vitro Model of Ischemia–Reperfusion |
| title_sort |
Nucleobase-Derived Nitrones: Synthesis and Antioxidant and Neuroprotective Activities in an In Vitro Model of Ischemia–Reperfusion |
| dc.creator.none.fl_str_mv |
Chamorro, Beatriz Głowacka, Iwona E. Gotkowska, Joanna Gulej, Rafał Hadjipavlou Litina, Dimitra López Muñoz, Francisco Marco Contelles, José Luis Piotrowska, Dorota G. Oset Gasque, María Jesús |
| author |
Chamorro, Beatriz |
| author_facet |
Chamorro, Beatriz Głowacka, Iwona E. Gotkowska, Joanna Gulej, Rafał Hadjipavlou Litina, Dimitra López Muñoz, Francisco Marco Contelles, José Luis Piotrowska, Dorota G. Oset Gasque, María Jesús |
| author_role |
author |
| author2 |
Głowacka, Iwona E. Gotkowska, Joanna Gulej, Rafał Hadjipavlou Litina, Dimitra López Muñoz, Francisco Marco Contelles, José Luis Piotrowska, Dorota G. Oset Gasque, María Jesús |
| author2_role |
author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Universidad Complutense de Madrid |
| dc.subject.none.fl_str_mv |
antioxidants neuroprotection necrosis apoptosis oxidative stress nucleobase-derived nitrones brain ischemia Neurociencias (Medicina) Bioquímica (Biología) 2490 Neurociencias 2302 Bioquímica |
| topic |
antioxidants neuroprotection necrosis apoptosis oxidative stress nucleobase-derived nitrones brain ischemia Neurociencias (Medicina) Bioquímica (Biología) 2490 Neurociencias 2302 Bioquímica |
| description |
Herein, we report the synthesis, antioxidant, and neuroprotective properties of some nucleobase-derived nitrones named 9a–i. The neuroprotective properties of nitrones, 9a–i, were measured against an oxygen-glucose-deprivation in vitro ischemia model using human neuroblastoma SH-SY5Y cells. Our results indicate that nitrones, 9a–i, have better neuroprotective and antioxidant properties than α-phenyl-N-tert-butylnitrone (PBN) and are similar to N-acetyl-L-cysteine (NAC), a well-known antioxidant and neuroprotective agent. The nitrones with the highest neuroprotective capacity were those containing purine nucleobases (nitrones 9f, g, B = adenine, theophylline), followed by nitrones with pyrimidine nucleobases with H or F substituents at the C5 position (nitrones 9a, c). All of these possess EC50 values in the range of 1–6 μM and maximal activities higher than 100%. However, the introduction of a methyl substituent (nitrone 9b, B = thymine) or hard halogen substituents such as Br and Cl (nitrones 9d, e, B = 5-Br and 5-Cl uracil, respectively) worsens the neuroprotective activity of the nitrone with uracil as the nucleobase (9a). The effects on overall metabolic cell capacity were confirmed by results on the high anti-necrotic (EC50′s ≈ 2–4 μM) and antioxidant (EC50′s ≈ 0.4–3.5 μM) activities of these compounds on superoxide radical production. In general, all tested nitrones were excellent inhibitors of superoxide radical production in cultured neuroblastoma cells, as well as potent hydroxyl radical scavengers that inhibit in vitro lipid peroxidation, particularly, 9c, f, g, presenting the highest lipoxygenase inhibitory activity among the tested nitrones. Finally, the introduction of two nitrone groups at 9a and 9d (bis-nitronas 9g, i) did not show better neuroprotective effects than their precursor mono-nitrones. These results led us to propose nitrones containing purine (9f, g) and pyrimidine (9a, c) nucleobases as potential therapeutic agents for the treatment of cerebral ischemia and/or neurodegenerative diseases, leading us to further investigate their effects using in vivo models of these pathologies. |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2022 2022-03-21 2022 2022-03-21 |
| 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/20.500.14352/72503 |
| url |
https://hdl.handle.net/20.500.14352/72503 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 Atribución 3.0 España https://creativecommons.org/licenses/by/3.0/es/ |
| dc.rights.openaire.fl_str_mv |
info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 Atribución 3.0 España https://creativecommons.org/licenses/by/3.0/es/ |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
application/pdf |
| dc.publisher.none.fl_str_mv |
MPDI |
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MPDI |
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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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