Inhibitory effect of novel 5-O-acyl juglones on mammalian DNA polymerase activity, cancer cell growth and inflammatory response

Bioorg Med Chem. 2011 Oct 1;19(19):5803-12. doi: 10.1016/j.bmc.2011.08.023. Epub 2011 Aug 18.


We previously found that vitamin K(3) (menadione, 2-methyl-1,4-naphthoquinone) inhibits the activity of human mitochondrial DNA polymerase γ (pol γ). In this study, we focused on juglone (5-hydroxy-1,4-naphthoquinone), which is a 1,4-naphthoquinone derivative, and chemically synthesized novel juglones conjugated with C2:0 to C22:6 fatty acid (5-O-acyl juglones). The chemically modified juglones enhanced mammalian pol inhibition and their cytotoxic and anti-inflammatory activities. The juglone conjugated with oleic acid (C18:1-acyl juglone) showed the strongest inhibition of DNA replicative pol α activity and human colon carcinoma (HCT116) cell growth in 10 synthesized 5-O-acyl juglones. C12:0-Acyl juglone was the strongest inhibitor of DNA repair-related pol λ, as well as the strongest suppression of the production of tumor necrosis factor (TNF)-α production induced by lipopolysaccharide (LPS) in the compounds tested. Moreover, this compound caused the greatest reduction in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced acute inflammation in mouse ears. C12:0- and C18:1-Acyl juglones selectively inhibited the activities of mammalian pol species, but did not influence the activities of other pols and DNA metabolic enzymes tested. These data indicate that the novel 5-O-acyl juglones target anti-cancer and/or anti-inflammatory agents based on mammalian pol inhibition. Moreover, the results suggest that acylation of juglone is an effective chemical modification to improve the anti-cancer and anti-inflammation of vitamin K(3) derivatives, such as juglone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemistry*
  • Anti-Inflammatory Agents / therapeutic use
  • Anti-Inflammatory Agents / toxicity
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / toxicity
  • Cell Line, Tumor
  • DNA Polymerase beta / antagonists & inhibitors*
  • DNA Polymerase beta / metabolism
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / therapeutic use
  • Enzyme Inhibitors / toxicity
  • Humans
  • Inflammation / chemically induced
  • Inflammation / drug therapy
  • Lipopolysaccharides / toxicity
  • Mice
  • Naphthoquinones / chemistry*
  • Naphthoquinones / therapeutic use
  • Naphthoquinones / toxicity
  • Tetradecanoylphorbol Acetate / toxicity
  • Tumor Necrosis Factor-alpha / metabolism


  • Anti-Inflammatory Agents
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Lipopolysaccharides
  • Naphthoquinones
  • Tumor Necrosis Factor-alpha
  • DNA polymerase beta2
  • DNA Polymerase beta
  • Tetradecanoylphorbol Acetate
  • juglone