Identification of 2,4-Dinitro-Biphenyl-Based Compounds as MAPEG Inhibitors.

Abstract

We identified 2,4-dinitro-biphenyl-based compounds as new inhibitors of leukotriene C4 synthase (LTC4 S) and 5-lipoxygenase-activating protein (FLAP), both members of the "Membrane Associated Proteins in Eicosanoid and Glutathione metabolism" (MAPEG) family involved in the biosynthesis of pro-inflammatory eicosanoids. By molecular docking we evaluated the putative binding against the targets of interest, and by applying cell-free and cell-based assays we assessed the inhibition of LTC4 S and FLAP by the small molecules at low micromolar concentrations. The present results integrate the previously observed inhibitory profile of the tested compounds against another MAPEG member, i. e., microsomal prostaglandin E2 synthase (mPGES)-1, suggesting that the 2,4-dinitro-biphenyl scaffold is a suitable molecular platform for a multitargeting approach to modulate pro-inflammatory mediators in inflammation and cancer treatment.

• Authors: Simone Di Micco, Stefania Terracciano, Martina Pierri, Vincenza Cantone, Stefanie Liening, Stefanie König, Ulrike Garscha, Robert Klaus Hofstetter, Andreas Koeberle, Oliver Werz, Ines Bruno, Giuseppe Bifulco
• Journal: ChemMedChem (ChemMedChem) Vol. 17 Issue 22 Pg. e202200327 (11 18 2022) ISSN: 1860-7187 [Electronic] Germany
• PMID: 36111583 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. ChemMedChem published by Wiley-VCH GmbH.

Chemical References

• diphenyl
• Glutathione Transferase
• 5-Lipoxygenase-Activating Proteins
• Biphenyl Compounds
• Prostaglandin-E Synthases

Topics

• Molecular Docking Simulation
• Glutathione Transferase
• 5-Lipoxygenase-Activating Proteins
• Biphenyl Compounds (pharmacology)
• Prostaglandin-E Synthases (metabolism)