Ebselen Analogues with Dual Human Neutrophil Elastase (HNE) Inhibitory and Antiradical Activity

Overview

Journal RSC Med Chem

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2024 Apr 26

PMID 38665832

Authors

Letizia Crocetti

Francesca Catarzi

Maria Paola Giovannoni

Claudia Vergelli

Gianluca Bartolucci

Marco Pallecchi

Paola Paoli

Patrizia Rossi

Martina Lippi

Igor A Schepetkin

Mark T Quinn

Gabriella Guerrini

Affiliations

Soon will be listed here.

Abstract

Human neutrophil elastase (HNE) plays an essential role in host defense against bacteria but is also involved in several respiratory diseases. Recent reports suggest that compounds exhibiting a combination of HNE inhibitory activity with antiradical properties may be therapeutically beneficial for the treatment of respiratory diseases involving inflammation and oxidative stress. We report here the synthesis and biological evaluation of novel ebselen analogues exhibiting HNE inhibitory and antiradical activities. HNE inhibition was evaluated in an enzymatic system using human HNE, whereas antiradical activity was evaluated in a cell-based assay system using phorbol 12-myristate 13-acetate (PMA)-stimulated murine bone marrow leukocytes as the source of reactive oxygen species (ROS). HNE inhibition was due to the N-CO group targeting Ser195-OH at position 2 of the scaffold, while antiradical activity was due to the presence of the selenium atom. The most active compounds 4d, 4f, and 4j exhibited a good balance between anti-HNE (IC = 0.9-1.4 μM) and antiradical activity (IC = 0.05-0.7 μM). Additionally, the solid-state structure of 4d was determined and compared to that of the similar compound -propionyl-1,2-benzisoselenazol-3(2)-one.

References

Cantini N, Khlebnikov A, Crocetti L, Schepetkin I, Floresta G, Guerrini G . Exploration of nitrogen heterocycle scaffolds for the development of potent human neutrophil elastase inhibitors. Bioorg Med Chem. 2020; 29:115836. PMC: 8848500. DOI: 10.1016/j.bmc.2020.115836. View

Krishnan K, Ziniel P, Li H, Huang X, Hupalo D, Gombakomba N . Torin 2 Derivative, NCATS-SM3710, Has Potent Multistage Antimalarial Activity through Inhibition of Phosphatidylinositol 4-Kinase ( PI4KIIIβ). ACS Pharmacol Transl Sci. 2020; 3(5):948-964. PMC: 7551716. DOI: 10.1021/acsptsci.0c00078. View

Crocetti L, Giovannoni M, Cantini N, Guerrini G, Vergelli C, Schepetkin I . Novel Sulfonamide Analogs of Sivelestat as Potent Human Neutrophil Elastase Inhibitors. Front Chem. 2020; 8:795. PMC: 7491426. DOI: 10.3389/fchem.2020.00795. View

Li X, Shi B, Teng Y, Cheng Y, Yang H, Li J . Design, synthesis and biological evaluation of novel 2-phenyl pyrimidine derivatives as potent Bruton's tyrosine kinase (BTK) inhibitors. Medchemcomm. 2019; 10(2):294-299. PMC: 6390688. DOI: 10.1039/c8md00413g. View

Zhang L, Zhou L, Du J, Li M, Qian C, Cheng Y . Induction of apoptosis in human multiple myeloma cell lines by ebselen via enhancing the endogenous reactive oxygen species production. Biomed Res Int. 2014; 2014:696107. PMC: 3921973. DOI: 10.1155/2014/696107. View

Azeredo J, Penteado F, Nascimento V, Sancineto L, Braga A, Joao Lenardao E . "Green Is the Color": An Update on Ecofriendly Aspects of Organoselenium Chemistry. Molecules. 2022; 27(5). PMC: 8911681. DOI: 10.3390/molecules27051597. View

Guerin P, Gauthier E . Induction of cellular necrosis by the glutathione peroxidase mimetic ebselen. J Cell Biochem. 2003; 89(1):203-11. DOI: 10.1002/jcb.10500. View

Krasowska D, Iraci N, Santi C, Drabowicz J, Cieslak M, Kazmierczak-Baranska J . Diselenides and Benzisoselenazolones as Antiproliferative Agents and Glutathione-S-Transferase Inhibitors. Molecules. 2019; 24(16). PMC: 6721112. DOI: 10.3390/molecules24162914. View

Groom C, Bruno I, Lightfoot M, Ward S . The Cambridge Structural Database. Acta Crystallogr B Struct Sci Cryst Eng Mater. 2016; 72(Pt 2):171-9. PMC: 4822653. DOI: 10.1107/S2052520616003954. View

10.

Quinn M, Gauss K . Structure and regulation of the neutrophil respiratory burst oxidase: comparison with nonphagocyte oxidases. J Leukoc Biol. 2004; 76(4):760-81. DOI: 10.1189/jlb.0404216. View

11.

Schepetkin I, Khlebnikov A, Quinn M . N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase. J Med Chem. 2007; 50(20):4928-38. DOI: 10.1021/jm070600+. View

12.

Yang C, Shen H, Ong C . Ebselen induces apoptosis in HepG(2) cells through rapid depletion of intracellular thiols. Arch Biochem Biophys. 2000; 374(2):142-52. DOI: 10.1006/abbi.1999.1574. View

13.

Nakayama Y, Odagaki Y, Fujita S, Matsuoka S, Hamanaka N, Nakai H . Clarification of mechanism of human sputum elastase inhibition by a new inhibitor, ONO-5046, using electrospray ionization mass spectrometry. Bioorg Med Chem Lett. 2002; 12(17):2349-53. DOI: 10.1016/s0960-894x(02)00393-1. View

14.

Abouzaki N, Christopher S, Trankle C, Wallace Van Tassell B, Carbone S, Mauro A . Inhibiting the Inflammatory Injury After Myocardial Ischemia Reperfusion With Plasma-Derived Alpha-1 Antitrypsin: A Post Hoc Analysis of the VCU-α1RT Study. J Cardiovasc Pharmacol. 2018; 71(6):375-379. PMC: 6501048. DOI: 10.1097/FJC.0000000000000583. View

15.

Muller A, Cadenas E, Graf P, Sies H . A novel biologically active seleno-organic compound--I. Glutathione peroxidase-like activity in vitro and antioxidant capacity of PZ 51 (Ebselen). Biochem Pharmacol. 1984; 33(20):3235-9. DOI: 10.1016/0006-2952(84)90083-2. View

16.

He J, Li D, Xiong K, Ge Y, Jin H, Zhang G . Inhibition of thioredoxin reductase by a novel series of bis-1,2-benzisoselenazol-3(2H)-ones: Organoselenium compounds for cancer therapy. Bioorg Med Chem. 2012; 20(12):3816-27. DOI: 10.1016/j.bmc.2012.04.033. View

17.

Al-Kuraishy H, Al-Gareeb A, Al-Hussaniy H, Al-Harcan N, Alexiou A, El-Saber Batiha G . Neutrophil Extracellular Traps (NETs) and Covid-19: A new frontiers for therapeutic modality. Int Immunopharmacol. 2022; 104:108516. PMC: 8733219. DOI: 10.1016/j.intimp.2021.108516. View

18.

Andrews P, Babior B . Endogenous protein phosphorylation by resting and activated human neutrophils. Blood. 1983; 61(2):333-40. View

19.

Crocetti L, Quinn M, Schepetkin I, Giovannoni M . A patenting perspective on human neutrophil elastase (HNE) inhibitors (2014-2018) and their therapeutic applications. Expert Opin Ther Pat. 2019; 29(7):555-578. PMC: 9642779. DOI: 10.1080/13543776.2019.1630379. View

20.

Singh V, Poon J, Yan J, Lu X, Karlsson Ott M, Butcher R . Nitro-, Azo-, and Amino Derivatives of Ebselen: Synthesis, Structure, and Cytoprotective Effects. J Org Chem. 2016; 82(1):313-321. DOI: 10.1021/acs.joc.6b02418. View