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

Overview

Journal J Med Chem

Publisher American Chemical Society

Date 2025 Feb 6

PMID 39913870

Authors

Camilla Scarpellini

Greta Klejborowska

Caroline Lanthier

Ariane Toye

Karolina Musialek

Emily Van San

Magali Walravens

Maya Berg

Behrouz Hassannia

Pieter Van der Veken

Hans De Winter

Tom Vanden Berghe

Koen Augustyns

Affiliations

Soon will be listed here.

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 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 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.

References

Lu Y, Shen Z, Xu Y, Lin H, Shen L, Jin Y . Discovery of New Phenyltetrazolium Derivatives as Ferroptosis Inhibitors for Treating Ischemic Stroke: An Example Development from Free Radical Scavengers. J Med Chem. 2024; 67(14):11712-11731. DOI: 10.1021/acs.jmedchem.4c00211. View

Xavier da Silva T, Friedmann Angeli J, Ingold I . GPX4: old lessons, new features. Biochem Soc Trans. 2022; 50(3):1205-1213. DOI: 10.1042/BST20220682. View

Seibt T, Proneth B, Conrad M . Role of GPX4 in ferroptosis and its pharmacological implication. Free Radic Biol Med. 2018; 133:144-152. DOI: 10.1016/j.freeradbiomed.2018.09.014. View

Zhang H, Zhao Z, Zhou C . Recent advance in oxazole-based medicinal chemistry. Eur J Med Chem. 2017; 144:444-492. DOI: 10.1016/j.ejmech.2017.12.044. View

Jin T, He Q, Cheng C, Li H, Liang L, Zhang G . UAMC-3203 or/and Deferoxamine Improve Post-Resuscitation Myocardial Dysfunction Through Suppressing Ferroptosis in a Rat Model of Cardiac Arrest. Shock. 2021; 57(3):344-350. PMC: 8868183. DOI: 10.1097/SHK.0000000000001869. View

Tonnus W, Meyer C, Steinebach C, Belavgeni A, von Massenhausen A, Zamora Gonzalez N . Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury. Nat Commun. 2021; 12(1):4402. PMC: 8292346. DOI: 10.1038/s41467-021-24712-6. View

Gaschler M, Stockwell B . Lipid peroxidation in cell death. Biochem Biophys Res Commun. 2017; 482(3):419-425. PMC: 5319403. DOI: 10.1016/j.bbrc.2016.10.086. View

Pope L, Dixon S . Regulation of ferroptosis by lipid metabolism. Trends Cell Biol. 2023; 33(12):1077-1087. PMC: 10733748. DOI: 10.1016/j.tcb.2023.05.003. View

Scarpellini C, Klejborowska G, Lanthier C, Hassannia B, Vanden Berghe T, Augustyns K . Beyond ferrostatin-1: a comprehensive review of ferroptosis inhibitors. Trends Pharmacol Sci. 2023; 44(12):902-916. DOI: 10.1016/j.tips.2023.08.012. View

10.

Balla A, Tran B, Valtari A, Steven P, Scarpellini C, Augustyns K . A Novel Ferroptosis Inhibitor UAMC-3203, a Potential Treatment for Corneal Epithelial Wound. Pharmaceutics. 2023; 15(1). PMC: 9863691. DOI: 10.3390/pharmaceutics15010118. View

11.

Hofmans S, Vanden Berghe T, Devisscher L, Hassannia B, Lyssens S, Joossens J . Novel Ferroptosis Inhibitors with Improved Potency and ADME Properties. J Med Chem. 2015; 59(5):2041-53. DOI: 10.1021/acs.jmedchem.5b01641. View

12.

Kagan V, Mao G, Qu F, Friedmann Angeli J, Doll S, St Croix C . Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol. 2016; 13(1):81-90. PMC: 5506843. DOI: 10.1038/nchembio.2238. View

13.

Van Coillie S, Van San E, Goetschalckx I, Wiernicki B, Mukhopadhyay B, Tonnus W . Targeting ferroptosis protects against experimental (multi)organ dysfunction and death. Nat Commun. 2022; 13(1):1046. PMC: 8873468. DOI: 10.1038/s41467-022-28718-6. View

14.

Agmon E, Solon J, Bassereau P, Stockwell B . Modeling the effects of lipid peroxidation during ferroptosis on membrane properties. Sci Rep. 2018; 8(1):5155. PMC: 5979948. DOI: 10.1038/s41598-018-23408-0. View

15.

Chen X, Comish P, Tang D, Kang R . Characteristics and Biomarkers of Ferroptosis. Front Cell Dev Biol. 2021; 9:637162. PMC: 7859349. DOI: 10.3389/fcell.2021.637162. View

16.

Dixon S, Lemberg K, Lamprecht M, Skouta R, Zaitsev E, Gleason C . Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012; 149(5):1060-72. PMC: 3367386. DOI: 10.1016/j.cell.2012.03.042. View

17.

Stockwell B . Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell. 2022; 185(14):2401-2421. PMC: 9273022. DOI: 10.1016/j.cell.2022.06.003. View

18.

Ji H, Zhang Y, Zhang N, Wang K, Meng N, Zhang J . Design, synthesis, and evaluation of formylpiperazine analogs of Ferrostatin-1 as novel improved ferroptosis inhibitors. Bioorg Med Chem. 2024; 105:117716. DOI: 10.1016/j.bmc.2024.117716. View

19.

Lee J, Kim W, Bae K, Lee S, Lee E . Lipid Metabolism and Ferroptosis. Biology (Basel). 2021; 10(3). PMC: 8000263. DOI: 10.3390/biology10030184. View

20.

Linkermann A, Skouta R, Himmerkus N, Mulay S, Dewitz C, De Zen F . Synchronized renal tubular cell death involves ferroptosis. Proc Natl Acad Sci U S A. 2014; 111(47):16836-41. PMC: 4250130. DOI: 10.1073/pnas.1415518111. View