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Antioxidant Properties and Aldehyde Reactivity of PD-L1 Targeted Aryl-Pyrazolone Anticancer Agents

Small molecules targeting the PD-1/PD-L1 checkpoint are actively searched to complement the anticancer arsenal. Different molecular scaffolds have been reported, including phenyl-pyrazolone derivatives which potently inhibit binding of PD-L1 to PD-1. These molecules are structurally close to antioxi...

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Autores principales: Leleu-Chavain, Natascha, Regnault, Romain, Ahouari, Hania, Le Biannic, Raphaël, Kouach, Mostafa, Klupsch, Frédérique, Magnez, Romain, Vezin, Hervé, Thuru, Xavier, Bailly, Christian, Goossens, Jean-François, Millet, Régis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9143004/
https://www.ncbi.nlm.nih.gov/pubmed/35630791
http://dx.doi.org/10.3390/molecules27103316
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author Leleu-Chavain, Natascha
Regnault, Romain
Ahouari, Hania
Le Biannic, Raphaël
Kouach, Mostafa
Klupsch, Frédérique
Magnez, Romain
Vezin, Hervé
Thuru, Xavier
Bailly, Christian
Goossens, Jean-François
Millet, Régis
author_facet Leleu-Chavain, Natascha
Regnault, Romain
Ahouari, Hania
Le Biannic, Raphaël
Kouach, Mostafa
Klupsch, Frédérique
Magnez, Romain
Vezin, Hervé
Thuru, Xavier
Bailly, Christian
Goossens, Jean-François
Millet, Régis
author_sort Leleu-Chavain, Natascha
collection PubMed
description Small molecules targeting the PD-1/PD-L1 checkpoint are actively searched to complement the anticancer arsenal. Different molecular scaffolds have been reported, including phenyl-pyrazolone derivatives which potently inhibit binding of PD-L1 to PD-1. These molecules are structurally close to antioxidant drug edaravone (EDA) used to treat amyotrophic lateral sclerosis. For this reason, we investigated the capacity of five PD-L1-binding phenyl-pyrazolone compounds (1–5) to scavenge the formation of oxygen free radicals using electron spin resonance spectroscopy with DPPH/DMPO probes. In addition, the reactivity of the compounds toward the oxidized base 5-formyluracil (5fU) was assessed using chromatography coupled to mass spectrometry and photodiode array detectors. The data revealed that the phenyl-pyrazolone derivatives display antioxidant properties and exhibit a variable reactivity toward 5fU. Compound 2 with a N-dichlorophenyl-pyrazolone moiety cumulates the three properties, being a potent PD-L1 binder, a robust antioxidant and an aldehyde-reactive compound. On the opposite, the adamantane derivative 5 is a potent PD-L1 binding with a reduced antioxidant potential and no aldehyde reactivity. The nature of the substituent on the phenyl-pyrazolone core modulates the antioxidant capacity and reactivity toward aromatic aldehydes. The molecular signature of the compound can be adapted at will, to confer additional properties to these PD-L1 binders.
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spelling pubmed-91430042022-05-29 Antioxidant Properties and Aldehyde Reactivity of PD-L1 Targeted Aryl-Pyrazolone Anticancer Agents Leleu-Chavain, Natascha Regnault, Romain Ahouari, Hania Le Biannic, Raphaël Kouach, Mostafa Klupsch, Frédérique Magnez, Romain Vezin, Hervé Thuru, Xavier Bailly, Christian Goossens, Jean-François Millet, Régis Molecules Article Small molecules targeting the PD-1/PD-L1 checkpoint are actively searched to complement the anticancer arsenal. Different molecular scaffolds have been reported, including phenyl-pyrazolone derivatives which potently inhibit binding of PD-L1 to PD-1. These molecules are structurally close to antioxidant drug edaravone (EDA) used to treat amyotrophic lateral sclerosis. For this reason, we investigated the capacity of five PD-L1-binding phenyl-pyrazolone compounds (1–5) to scavenge the formation of oxygen free radicals using electron spin resonance spectroscopy with DPPH/DMPO probes. In addition, the reactivity of the compounds toward the oxidized base 5-formyluracil (5fU) was assessed using chromatography coupled to mass spectrometry and photodiode array detectors. The data revealed that the phenyl-pyrazolone derivatives display antioxidant properties and exhibit a variable reactivity toward 5fU. Compound 2 with a N-dichlorophenyl-pyrazolone moiety cumulates the three properties, being a potent PD-L1 binder, a robust antioxidant and an aldehyde-reactive compound. On the opposite, the adamantane derivative 5 is a potent PD-L1 binding with a reduced antioxidant potential and no aldehyde reactivity. The nature of the substituent on the phenyl-pyrazolone core modulates the antioxidant capacity and reactivity toward aromatic aldehydes. The molecular signature of the compound can be adapted at will, to confer additional properties to these PD-L1 binders. MDPI 2022-05-21 /pmc/articles/PMC9143004/ /pubmed/35630791 http://dx.doi.org/10.3390/molecules27103316 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Leleu-Chavain, Natascha
Regnault, Romain
Ahouari, Hania
Le Biannic, Raphaël
Kouach, Mostafa
Klupsch, Frédérique
Magnez, Romain
Vezin, Hervé
Thuru, Xavier
Bailly, Christian
Goossens, Jean-François
Millet, Régis
Antioxidant Properties and Aldehyde Reactivity of PD-L1 Targeted Aryl-Pyrazolone Anticancer Agents
title Antioxidant Properties and Aldehyde Reactivity of PD-L1 Targeted Aryl-Pyrazolone Anticancer Agents
title_full Antioxidant Properties and Aldehyde Reactivity of PD-L1 Targeted Aryl-Pyrazolone Anticancer Agents
title_fullStr Antioxidant Properties and Aldehyde Reactivity of PD-L1 Targeted Aryl-Pyrazolone Anticancer Agents
title_full_unstemmed Antioxidant Properties and Aldehyde Reactivity of PD-L1 Targeted Aryl-Pyrazolone Anticancer Agents
title_short Antioxidant Properties and Aldehyde Reactivity of PD-L1 Targeted Aryl-Pyrazolone Anticancer Agents
title_sort antioxidant properties and aldehyde reactivity of pd-l1 targeted aryl-pyrazolone anticancer agents
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9143004/
https://www.ncbi.nlm.nih.gov/pubmed/35630791
http://dx.doi.org/10.3390/molecules27103316
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