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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-05-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/10/3316 |
| _version_ | 1797497413219385344 |
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| author | Natascha Leleu-Chavain Romain Regnault Hania Ahouari Raphaël Le Biannic Mostafa Kouach Frédérique Klupsch Romain Magnez Hervé Vezin Xavier Thuru Christian Bailly Jean-François Goossens Régis Millet |
| author_facet | Natascha Leleu-Chavain Romain Regnault Hania Ahouari Raphaël Le Biannic Mostafa Kouach Frédérique Klupsch Romain Magnez Hervé Vezin Xavier Thuru Christian Bailly Jean-François Goossens Régis Millet |
| author_sort | Natascha Leleu-Chavain |
| collection | DOAJ |
| 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 (<b>1</b>–<b>5</b>) 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 <b>2</b> with a <i>N</i>-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 <b>5</b> 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. |
| first_indexed | 2024-03-10T03:18:11Z |
| format | Article |
| id | doaj.art-2213cf7b7fe44b0d864af0447bcfb049 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T03:18:11Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-2213cf7b7fe44b0d864af0447bcfb0492023-11-23T12:24:29ZengMDPI AGMolecules1420-30492022-05-012710331610.3390/molecules27103316Antioxidant Properties and Aldehyde Reactivity of PD-L1 Targeted Aryl-Pyrazolone Anticancer AgentsNatascha Leleu-Chavain0Romain Regnault1Hania Ahouari2Raphaël Le Biannic3Mostafa Kouach4Frédérique Klupsch5Romain Magnez6Hervé Vezin7Xavier Thuru8Christian Bailly9Jean-François Goossens10Régis Millet11Univ. Lille, Inserm, CHU Lille, U1286—INFINITE—Lille Inflammation Research International Center, ICPAL, 3 Rue du Professeur Laguesse, 59000 Lille, FranceUniv. Lille, CHU Lille, ULR 7365—GRITA—Groupe de Recherche sur les Formes Injectables et les Technologies Associées, 59000 Lille, FranceLASIRE Laboratoire Avancé de Spectroscopie pour les Intéractions la Réactivité et l′Environnement, 59655 Villeneuve d′Ascq, FranceUniv. Lille, Inserm, CHU Lille, U1286—INFINITE—Lille Inflammation Research International Center, ICPAL, 3 Rue du Professeur Laguesse, 59000 Lille, FranceUniv. Lille, CHU Lille, ULR 7365—GRITA—Groupe de Recherche sur les Formes Injectables et les Technologies Associées, 59000 Lille, FranceUniv. Lille, Inserm, CHU Lille, U1286—INFINITE—Lille Inflammation Research International Center, ICPAL, 3 Rue du Professeur Laguesse, 59000 Lille, FranceUniv. Lille, CHU Lille, CNRS, Inserm, UMR9020—UMR1277—Canther—Cancer Heterogeneity, Plasticity and Resistance to Therapies, 59000 Lille, FranceLASIRE Laboratoire Avancé de Spectroscopie pour les Intéractions la Réactivité et l′Environnement, 59655 Villeneuve d′Ascq, FranceUniv. Lille, CHU Lille, CNRS, Inserm, UMR9020—UMR1277—Canther—Cancer Heterogeneity, Plasticity and Resistance to Therapies, 59000 Lille, FranceOncowitan, Scientific Consulting Office, 59290 Lille, FranceUniv. Lille, CHU Lille, ULR 7365—GRITA—Groupe de Recherche sur les Formes Injectables et les Technologies Associées, 59000 Lille, FranceUniv. Lille, Inserm, CHU Lille, U1286—INFINITE—Lille Inflammation Research International Center, ICPAL, 3 Rue du Professeur Laguesse, 59000 Lille, FranceSmall 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 (<b>1</b>–<b>5</b>) 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 <b>2</b> with a <i>N</i>-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 <b>5</b> 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.https://www.mdpi.com/1420-3049/27/10/3316aldehyde reactivityantioxidantcancerdrug adductsedaravonePD-L1 |
| spellingShingle | Natascha Leleu-Chavain Romain Regnault Hania Ahouari Raphaël Le Biannic Mostafa Kouach Frédérique Klupsch Romain Magnez Hervé Vezin Xavier Thuru Christian Bailly Jean-François Goossens Régis Millet Antioxidant Properties and Aldehyde Reactivity of PD-L1 Targeted Aryl-Pyrazolone Anticancer Agents Molecules aldehyde reactivity antioxidant cancer drug adducts edaravone PD-L1 |
| 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 | aldehyde reactivity antioxidant cancer drug adducts edaravone PD-L1 |
| url | https://www.mdpi.com/1420-3049/27/10/3316 |
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