Oxazole-Based Ferroptosis Inhibitors with Promising Properties to Treat Central Nervous System Diseases

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Abstract

Ferroptosis plays an important role in the occurrence and development of many diseases, including neurodegenerative diseases. Thus, ferroptosis inhibitors able to cross the blood-brain barrier may have therapeutic potential. The best ferroptosis inhibitors so far are lipophilic radical trapping antioxidants (RTAs) that block lipid peroxidation in membranes. Several generations of ferrostatins have been synthesized, among which UAMC-3203 showed high potency in animal models with improved properties compared to ferrostatin-1. To further improve its pharmacokinetics properties, drug-likeness, and permeability, we modified UAMC-3203 by decreasing the size of the molecule and reducing its polarity by replacing the sulfonamide first by amide groups and subsequently by isosteric oxazoles. Herein, we present the design, synthesis, and biological evaluation of a novel series of oxazole RTAs with high potency, excellent oral bioavailability, and high concentrations in brain tissue.

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Ferroptosis: an iron-dependent form of nonapoptotic cell death.

Scott J. Dixon, Kathryn Lemberg, Michael Lamprecht … (2012)

Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.

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Ferroptosis: mechanisms, biology and role in disease

Xuejun Jiang, Brent Stockwell, Marcus Conrad (2021)

The research field of ferroptosis has seen exponential growth over the past few years, since the term was coined in 2012. This unique modality of cell death, driven by iron-dependent phospholipid peroxidation, is regulated by multiple cellular metabolic pathways, including redox homeostasis, iron handling, mitochondrial activity and metabolism of amino acids, lipids and sugars, in addition to various signalling pathways relevant to disease. Numerous organ injuries and degenerative pathologies are driven by ferroptosis. Intriguingly, therapy-resistant cancer cells, particularly those in the mesenchymal state and prone to metastasis, are exquisitely vulnerable to ferroptosis. As such, pharmacological modulation of ferroptosis, via both its induction and its inhibition, holds great potential for the treatment of drug-resistant cancers, ischaemic organ injuries and other degenerative diseases linked to extensive lipid peroxidation. In this Review, we provide a critical analysis of the current molecular mechanisms and regulatory networks of ferroptosis, the potential physiological functions of ferroptosis in tumour suppression and immune surveillance, and its pathological roles, together with a potential for therapeutic targeting. Importantly, as in all rapidly evolving research areas, challenges exist due to misconceptions and inappropriate experimental methods. This Review also aims to address these issues and to provide practical guidelines for enhancing reproducibility and reliability in studies of ferroptosis. Finally, we discuss important concepts and pressing questions that should be the focus of future ferroptosis research.

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ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition.

Sebastian Doll, Bettina Proneth, Yulia Tyurina … (2017)

Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches-a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines-to uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Specifically, Gpx4-Acsl4 double-knockout cells showed marked resistance to ferroptosis. Mechanistically, ACSL4 enriched cellular membranes with long polyunsaturated ω6 fatty acids. Moreover, ACSL4 was preferentially expressed in a panel of basal-like breast cancer cell lines and predicted their sensitivity to ferroptosis. Pharmacological targeting of ACSL4 with thiazolidinediones, a class of antidiabetic compound, ameliorated tissue demise in a mouse model of ferroptosis, suggesting that ACSL4 inhibition is a viable therapeutic approach to preventing ferroptosis-related diseases.

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Author and article information

Journal

Journal ID (nlm-ta): J Med Chem

Journal ID (iso-abbrev): J Med Chem

Journal ID (publisher-id): jm

Journal ID (coden): jmcmar

Title: Journal of Medicinal Chemistry

Publisher: American Chemical Society

ISSN (Print): 0022-2623

ISSN (Electronic): 1520-4804

Publication date (Electronic): 06 February 2025

Publication date Collection: 27 February 2025

Volume: 68

Issue: 4

Pages: 4908-4928

Affiliations

[1 ]Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp , Antwerp 2610, Belgium

[2 ]Cell Death Signaling Lab, Department of Biomedical Sciences, University of Antwerp , Antwerp 2610, Belgium

[3 ]Infla-Med Centre of Excellence, University of Antwerp , Antwerp 2610, Belgium

[4 ]Molecular Signalling and Cell Death Unit, VIB Center for Inflammation Research , Ghent 9052, Belgium

[5 ]Department of Biomedical Molecular Biology, Ghent University , Ghent 9000, Belgium

[6 ]Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University , Poznań 61-614, Poland

Author notes

[* ]Email: koen.augustyns@ 123456uantwerpen.be . Tel.: +3232652717.

Author information

Camilla Scarpellini https://orcid.org/0000-0002-1860-6532

Greta Klejborowska https://orcid.org/0000-0001-9365-4238

Karolina Musiałek https://orcid.org/0009-0005-0187-170X

Pieter Van der Veken https://orcid.org/0000-0003-1208-3571

Hans De Winter https://orcid.org/0000-0002-4450-7677

Koen Augustyns https://orcid.org/0000-0002-5203-4339

Article

DOI: 10.1021/acs.jmedchem.4c03149

PMC ID: 11874020

PubMed ID: 39913870

SO-VID: 4434364c-414b-4d42-856c-e898b5ea23fa

License:

Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained ( https://creativecommons.org/licenses/by/4.0/).

History

Date received : 20 December 2024

Date accepted : 28 January 2025

Date revision received : 24 January 2025

Funding

Funded by: H2020 Marie Sklodowska-Curie Actions, doi 10.13039/100010665;

Award ID: 101065370

Funded by: Universiteit Antwerpen, doi 10.13039/501100007660;

Award ID: 44874

Funded by: Fondation Charcot, doi 10.13039/501100006401;

Award ID: FAF-C/2018/1250

Funded by: Fondation Charcot, doi 10.13039/501100006401;

Award ID: F/2022/2067