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. Epub 2015 Feb 24.

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.

MeSH terms

  • Arachidonate 12-Lipoxygenase / metabolism
  • Arachidonate 15-Lipoxygenase / metabolism
  • Benzoquinones / chemistry*
  • Chemistry Techniques, Synthetic
  • Drug Evaluation, Preclinical / methods
  • Humans
  • Inhibitory Concentration 50
  • Intramolecular Oxidoreductases / metabolism
  • Lipoxygenase Inhibitors / chemical synthesis
  • Lipoxygenase Inhibitors / chemistry*
  • Lipoxygenase Inhibitors / pharmacology*
  • Neutrophils / drug effects*
  • Neutrophils / enzymology
  • Prostaglandin-E Synthases
  • Structure-Activity Relationship

Substances

  • Benzoquinones
  • Lipoxygenase Inhibitors
  • quinone
  • Arachidonate 12-Lipoxygenase
  • ALOX15 protein, human
  • Arachidonate 15-Lipoxygenase
  • Intramolecular Oxidoreductases
  • PTGES protein, human
  • Prostaglandin-E Synthases