Novel 15-Lipoxygenase-1 Inhibitor Protects Macrophages from Lipopolysaccharide-Induced Cytotoxicity

  • J Med Chem. 2019 May 9;62(9):4624-4637. doi: 10.1021/acs.jmedchem.9b00212.
Hao Guo ,  Iris C Verhoek ,  Gerian G H Prins ,  Ramon van der Vlag  1 ,  Petra E van der Wouden ,  Ronald van Merkerk ,  Wim J Quax ,  Peter Olinga ,  Anna K H Hirsch  1  2  3 ,  Frank J Dekker
Affiliations
  • 1. Department of Chemical Biology 2, Stratingh Institute for Chemistry , University of Groningen , Nijenborgh 7 , 9747 AG Groningen , The Netherlands.
  • 2. Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)-Helmholtz Centre for Infection Research (HZI) , Department of Drug Design and Optimization , Campus Building E8.1 , 66123 Saarbrücken , Germany.
  • 3. Department of Pharmacy , Saarland University , 66123 Saarbrücken , Germany.
PMID: 30964295 DOI: 10.1021/acs.jmedchem.9b00212
Abstract

Various mechanisms for regulated cell death include the formation of oxidative mediators such as lipid peroxides and nitric oxide (NO). In this respect, 15-lipoxygenase-1 (15-LOX-1) is a key enzyme that catalyzes the formation of lipid peroxides. The actions of these peroxides are interconnected with nuclear factor-κB signaling and NO production. Inhibition of 15-LOX-1 holds promise to interfere with regulated cell death in inflammatory conditions. In this study, a novel potent 15-LOX-1 inhibitor, 9c (i472), was developed and structure-activity relationships were explored. In vitro, this inhibitor protected cells from lipopolysaccharide-induced cell death, inhibiting NO formation and lipid peroxidation. Thus, we provide a novel 15-LOX-1 inhibitor that inhibits cellular NO production and lipid peroxidation, which set the stage for further exploration of these mechanisms.

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