Discovery of Chromenes As Inhibitors of Macrophage Migration Inhibitory Factor

Overview

Journal Bioorg Med Chem

Specialties Biochemistry
Chemistry

Date 2018 Feb 12

PMID 29428527

Citations 4

Authors

Tjie Kok

Hannah Wapenaar

Kan Wang

Constantinos G Neochoritis

Tryfon Zarganes-Tzitzikas

Giordano Proietti

Nikolaos Eleftheriadis

Katarzyna Kurpiewska

Justyna Kalinowska-Tluscik

Robbert H Cool

Gerrit J Poelarends

Alexander Domling

Frank J Dekker

Affiliations

Soon will be listed here.

Abstract

Macrophage migration inhibitory factor (MIF) is an essential signaling cytokine with a key role in the immune system. Binding of MIF to its molecular targets such as, among others, the cluster of differentiation 74 (CD74) receptor plays a key role in inflammatory diseases and cancer. Therefore, the identification of MIF binding compounds gained importance in drug discovery. In this study, we aimed to discover novel MIF binding compounds by screening of a focused compound collection for inhibition of its tautomerase enzyme activity. Inspired by the known chromen-4-one inhibitor Orita-13, a focused collection of compounds with a chromene scaffold was screened for MIF binding. The library was synthesized using versatile cyanoacetamide chemistry to provide diversely substituted chromenes. The screening provided inhibitors with IC's in the low micromolar range. Kinetic evaluation suggested that the inhibitors were reversible and did not bind in the binding pocket of the substrate. Thus, we discovered novel inhibitors of the MIF tautomerase activity, which may ultimately support the development of novel therapeutic agents against diseases in which MIF is involved.

Citing Articles

Heteroannulations of cyanoacetamide-based MCR scaffolds utilizing formamide.

Zingiridis M, Papachristodoulou D, Menegaki D, Froudas K, Neochoritis C Beilstein J Org Chem. 2025; 21:217-225.

PMID: 39877861 PMC: 11773184. DOI: 10.3762/bjoc.21.13.

Knoevenagel-IMHDA and -IMSDA sequences for the synthesis of chiral condensed O,N-, S,N- and N-heterocycles.

Kajtar M, Kiraly S, Benyei A, Kiss-Szikszai A, Konya-Abraham A, Horvath L RSC Adv. 2025; 15(2):1230-1248.

PMID: 39816179 PMC: 11733422. DOI: 10.1039/d4ra08353a.

The Chromenopyridine Scaffold: A Privileged Platform in Drug Design.

Pedroso de Lima F, Costa M, Sousa A, Proenca M Molecules. 2024; 29(13).

PMID: 38998955 PMC: 11243271. DOI: 10.3390/molecules29133004.

Highly Selective MIF Ketonase Inhibitor KRP-6 Diminishes M1 Macrophage Polarization and Metabolic Reprogramming.

Vamos E, Kalman N, Sturm E, Nayak B, Teppan J, Vantus V Antioxidants (Basel). 2023; 12(10).

PMID: 37891870 PMC: 10604361. DOI: 10.3390/antiox12101790.

Allosteric Inhibitors of Macrophage Migration Inhibitory Factor (MIF) Interfere with Apoptosis-Inducing Factor (AIF) Co-Localization to Prevent Parthanatos.

Chen D, Osipyan A, Adriana J, Kader M, Gureev M, Knol C J Med Chem. 2023; 66(13):8767-8781.

PMID: 37352470 PMC: 10350922. DOI: 10.1021/acs.jmedchem.3c00397.

References

Lubetsky J, Swope M, Dealwis C, Blake P, Lolis E . Pro-1 of macrophage migration inhibitory factor functions as a catalytic base in the phenylpyruvate tautomerase activity. Biochemistry. 1999; 38(22):7346-54. DOI: 10.1021/bi990306m. View

Shimizu T, Abe R, Nakamura H, Ohkawara A, Suzuki M, Nishihira J . High expression of macrophage migration inhibitory factor in human melanoma cells and its role in tumor cell growth and angiogenesis. Biochem Biophys Res Commun. 1999; 264(3):751-8. DOI: 10.1006/bbrc.1999.1584. View

Orita M, Yamamoto S, Katayama N, Aoki M, Takayama K, Yamagiwa Y . Coumarin and chromen-4-one analogues as tautomerase inhibitors of macrophage migration inhibitory factor: discovery and X-ray crystallography. J Med Chem. 2001; 44(4):540-7. DOI: 10.1021/jm000386o. View

de Jong Y, Abadia-Molina A, Satoskar A, Clarke K, Rietdijk S, Faubion W . Development of chronic colitis is dependent on the cytokine MIF. Nat Immunol. 2001; 2(11):1061-6. DOI: 10.1038/ni720. View

Lubetsky J, Dios A, Han J, Aljabari B, Ruzsicska B, Mitchell R . The tautomerase active site of macrophage migration inhibitory factor is a potential target for discovery of novel anti-inflammatory agents. J Biol Chem. 2002; 277(28):24976-82. DOI: 10.1074/jbc.M203220200. View

Munaut C, Boniver J, Foidart J, Deprez M . Macrophage migration inhibitory factor (MIF) expression in human glioblastomas correlates with vascular endothelial growth factor (VEGF) expression. Neuropathol Appl Neurobiol. 2002; 28(6):452-60. DOI: 10.1046/j.1365-2990.2002.00416.x. View

Tomiyasu M, Yoshino I, Suemitsu R, Okamoto T, Sugimachi K . Quantification of macrophage migration inhibitory factor mRNA expression in non-small cell lung cancer tissues and its clinical significance. Clin Cancer Res. 2002; 8(12):3755-60. View

Leng L, Metz C, Fang Y, Xu J, Donnelly S, Baugh J . MIF signal transduction initiated by binding to CD74. J Exp Med. 2003; 197(11):1467-76. PMC: 2193907. DOI: 10.1084/jem.20030286. View

Calandra T, Roger T . Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol. 2003; 3(10):791-800. PMC: 7097468. DOI: 10.1038/nri1200. View

10.

Al-Abed Y, Dabideen D, Aljabari B, Valster A, Messmer D, Ochani M . ISO-1 binding to the tautomerase active site of MIF inhibits its pro-inflammatory activity and increases survival in severe sepsis. J Biol Chem. 2005; 280(44):36541-4. DOI: 10.1074/jbc.C500243200. View

11.

Shi X, Leng L, Wang T, Wang W, Du X, Li J . CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex. Immunity. 2006; 25(4):595-606. PMC: 3707630. DOI: 10.1016/j.immuni.2006.08.020. View

12.

Bernhagen J, Krohn R, Lue H, Gregory J, Zernecke A, Koenen R . MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med. 2007; 13(5):587-96. DOI: 10.1038/nm1567. View

13.

Xu X, Wang B, Ye C, Yao C, Lin Y, Huang X . Overexpression of macrophage migration inhibitory factor induces angiogenesis in human breast cancer. Cancer Lett. 2008; 261(2):147-57. DOI: 10.1016/j.canlet.2007.11.028. View

14.

Wang K, Nguyen K, Huang Y, Domling A . Cyanoacetamide multicomponent reaction (I): Parallel synthesis of cyanoacetamides. J Comb Chem. 2009; 11(5):920-7. DOI: 10.1021/cc9000778. View

15.

Wang K, Kim D, Domling A . Cyanoacetamide MCR (III): three-component Gewald reactions revisited. J Comb Chem. 2009; 12(1):111-8. PMC: 3721980. DOI: 10.1021/cc9001586. View

16.

Jorgensen W, Gandavadi S, Du X, Hare A, Trofimov A, Leng L . Receptor agonists of macrophage migration inhibitory factor. Bioorg Med Chem Lett. 2010; 20(23):7033-6. PMC: 2989669. DOI: 10.1016/j.bmcl.2010.09.118. View

17.

Balachandran S, Gadekar P, Parkale S, Yadav V, Kamath D, Ramaswamy S . Synthesis and biological activity of novel MIF antagonists. Bioorg Med Chem Lett. 2011; 21(5):1508-11. DOI: 10.1016/j.bmcl.2010.12.127. View

18.

Wang K, Herdtweck E, Domling A . One-pot synthesis of 2-amino-indole-3-carboxamide and analogous. ACS Comb Sci. 2011; 13(2):140-6. PMC: 3124116. DOI: 10.1021/co100040z. View

19.

Al-Abed Y, Vanpatten S . MIF as a disease target: ISO-1 as a proof-of-concept therapeutic. Future Med Chem. 2011; 3(1):45-63. DOI: 10.4155/fmc.10.281. View

20.

Alam A, Pal C, Goyal M, Kundu M, Kumar R, Iqbal M . Synthesis and bio-evaluation of human macrophage migration inhibitory factor inhibitor to develop anti-inflammatory agent. Bioorg Med Chem. 2011; 19(24):7365-73. DOI: 10.1016/j.bmc.2011.10.056. View