Novel PD-L1-Targeted Phenyl-Pyrazolone Derivatives with Antioxidant Properties - Université de Lille Accéder directement au contenu
Article Dans Une Revue Molecules Année : 2023

Novel PD-L1-Targeted Phenyl-Pyrazolone Derivatives with Antioxidant Properties


Orally-active anticancer small molecules targeting the PD-1/PD-L1 immune checkpoint are actively searched. Phenyl-pyrazolone derivatives with a high affinity for PD-L1 have been designed and characterized. In addition, the phenyl-pyrazolone unit acts as a scavenger of oxygen free radicals, providing antioxidant effects. The mechanism is known for the drug edaravone (1) which is also an aldehyde-reactive molecule. The present study reports the synthesis and functional characterization of new molecules (2–5) with an improved anti-PD-L1 activity. The leading fluorinated molecule 5 emerges as a potent checkpoint inhibitor, avidly binding to PD-L1, inducing its dimerization, blocking PD-1/PD-L1 signaling mediated by phosphatase SHP-2 and reactivating the proliferation of CTLL-2 cells in the presence of PD-L1. In parallel, the compound maintains a significant antioxidant activity, characterized using electron paramagnetic resonance (EPR)-based free radical scavenging assays with the probes DPPH and DMPO. The aldehyde reactivity of the molecules was investigated using 4-hydroxynonenal (4-HNE), which is a major lipid peroxidation product. The formation of drug-HNE adducts, monitored by high resolution mass spectrometry (HRMS), was clearly identified and compared for each compound. The study leads to the selection of compound 5 and the dichlorophenyl-pyrazolone unit as a scaffold for the design of small molecule PD-L1 inhibitors endowed with antioxidant properties.
Fichier principal
Vignette du fichier
molecules-28-03491.pdf (3.69 Mo) Télécharger le fichier
Origine Fichiers éditeurs autorisés sur une archive ouverte

Dates et versions

hal-04139041 , version 1 (23-06-2023)




Romain Regnault, Frédérique Klupsch, Hassiba El-Bouazzati, Romain Magnez, Raphaël Le Biannic, et al.. Novel PD-L1-Targeted Phenyl-Pyrazolone Derivatives with Antioxidant Properties. Molecules, 2023, 28 (8), pp.3491. ⟨10.3390/molecules28083491⟩. ⟨hal-04139041⟩
19 Consultations
10 Téléchargements



Gmail Mastodon Facebook X LinkedIn More