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Dr. Alessia Bertamino

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Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, SA, Italy
Interests: design, synthesis and biological characterization of pharmacologically actives small molecules, peptidomimetics e peptides (antitumoral agents, antiviral compounds and ionic channel modulators); study of new reaction mechanisms and synthetic strategy optimization

Dr. Tania Ciaglia

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Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, SA, Italy
Interests: novel target; anticancer; small molecules; biological evaluation; synthesis; activity assay; molecular modeling

Special Issue Information

Dear Colleagues,

Anticancer therapy represents an open challenge in the research field, mainly due to off-target toxicity and the development of chemoresistance phenomena. The recent advances in molecular biology have opened the way for the recognition of novel molecular targets that previously have not been explored and analyzed for cancer treatment. In this context, a design that is supported by molecular modeling methodologies, synthesis, and pharmacological characterization of small molecules active against these new targets plays a key role in the medicinal chemistry field, representing a focal point for the future development of more effective treatments.

Dr. Alessia Bertamino
Dr. Tania Ciaglia
Guest Editors

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Keywords

novel target
anticancer
small molecules
biological evaluation
synthesis
activity assay
molecular modeling

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Research

17 pages, 3856 KiB

Open AccessArticle

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

by Romain Regnault, Frédérique Klupsch, Hassiba El-Bouazzati, Romain Magnez, Raphaël Le Biannic, Natascha Leleu-Chavain, Hania Ahouari, Hervé Vezin, Régis Millet, Jean-François Goossens, Xavier Thuru and Christian Bailly

Molecules 2023, 28(8), 3491; https://doi.org/10.3390/molecules28083491 - 15 Apr 2023

Viewed by 1761

Abstract

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. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Activity of Novel Antitumor Drugs)

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