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Eur J Med Chem. 2015 Apr 13;94:132-9. doi: 10.1016/j.ejmech.2015.02.042. Epub 2015 Feb 24.

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

Author information

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.

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

PMID:
25765759
DOI:
10.1016/j.ejmech.2015.02.042
[Indexed for MEDLINE]

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