2. Academic Validation
  3. Novel series of benzoquinones with high potency against 5-lipoxygenase in human polymorphonuclear leukocytes

Novel series of benzoquinones with high potency against 5-lipoxygenase in human polymorphonuclear leukocytes

  • Eur J Med Chem. 2015 Apr 13:94:132-9. doi: 10.1016/j.ejmech.2015.02.042.
Rosanna Filosa 1,  Antonella Peduto 2,  Anja M Schaible 3,  Verena Krauth 3,  Christina Weinigel 4,  Dagmar Barz 4,  Carmen Petronzi 5,  Ferdinando Bruno 5,  Fiorentina Roviezzo 6,  Giuseppe Spaziano 5,  Bruno D'Agostino 5,  Mario De Rosa 5,  Oliver Werz 7
Affiliations

Affiliations

  • 1 Department of Experimental Medicine, University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy. Electronic address: rosanna.filosa@unina2.it.
  • 2 Department of Experimental Medicine, University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy; Dermofarma, Via Cortenocera, 82030 S. Salvatore Telesino, BN, Italy.
  • 3 Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University, Philosophenweg 14, 07743 Jena, Germany.
  • 4 Institute of Transfusion Medicine, University Hospital Jena, 07743 Jena, Germany.
  • 5 Department of Experimental Medicine, University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy.
  • 6 Department of Experimental Pharmacology, University Federico II of Naples, Naples, Italy.
  • 7 Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University, Philosophenweg 14, 07743 Jena, Germany. Electronic address: oliver.werz@uni-jena.de.
PMID: 25765759 DOI: 10.1016/j.ejmech.2015.02.042
Abstract

5-Lipoxygenase (5-LO) is a potential target for pharmacological intervention with various inflammatory and allergic diseases. Starting from the natural dual 5-LO/microsomal prostaglandin E2 synthase (mPGES)-1 inhibitor embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone, 2) that suppresses 5-LO activity in human primary leukocytes with IC50 = 0.8-2 μM, we synthesized 48 systematically modified derivatives of 2. We modified the 1,4-quinone to 1,2-quinone, mono- or bimethylated the hydroxyl groups, and varied the C11-n-alkyl residue (C4- to C16-n-alkyl or prenyl) of 2. Biological evaluation yields potent analogues being superior over 2 and obvious structure-activity relationships (SAR) for inhibition of 5-LO. Interestingly, conversion to 1,2-benzoquinone and bimethylation of the hydroxyl moieties strongly improves 5-LO inhibition in polymorphonuclear leukocytes versus 2 up to 60-fold, exemplified by the C12-n-alkyl derivative 22c (4,5-dimethoxy-3-dodecyl-1,2-benzoquinone) with IC50 = 29 nM. Regarding inhibition of mPGES-1, none of the novel benzoquinones could outperform the parental compound 2 (IC50 = 0.21 μM), and only modest suppressive effects on 12- and 15-LOs were evident. Together, our detailed SAR study reveals 22c as highly potent 5-LO-selective lead compound in intact cells that warrants further preclinical evaluation as anti-inflammatory agent.

Keywords

5-Lipoxygenase; Arachidonic acid; Benzoquinone; Inflammation; Microsomal prostaglandin E(2) synthase-1.

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