{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T14:24:52Z","timestamp":1788272692617,"version":"build-2803163510"},"reference-count":57,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,15]],"date-time":"2023-04-15T00:00:00Z","timestamp":1681516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Contrat de Plan Etat R\u00e9gion CPER Cancer 2015\u20132020"},{"name":"SATT Nord and Inserm-Transfert"},{"name":"Start-AIRR from the R\u00e9gion Hauts-de-France\/BPI"},{"name":"public utility foundation Institut pour la Recherche sur le Cancer de Lille (IRCL)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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\u20135) 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.<\/jats:p>","DOI":"10.3390\/molecules28083491","type":"journal-article","created":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T02:02:59Z","timestamp":1681696979000},"page":"3491","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Novel PD-L1-Targeted Phenyl-Pyrazolone Derivatives with Antioxidant Properties"],"prefix":"10.3390","volume":"28","author":[{"given":"Romain","family":"Regnault","sequence":"first","affiliation":[{"name":"ULR 7365\u2014GRITA\u2014Groupe de Recherche sur les formes Injectables et les Technologies Associ\u00e9es, CHU Lille, University Lille, F-59000 Lille, 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