title: Inhibitory effect of novel 5-O-acyl juglones on mammalian DNA polymerase activity, cancer cell growth and inflammatory response.
abstract: 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.
authors: Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto 606-8522, Japan.
authors: Sayako
authors: S
authors: Maruo
authors: Isoko
authors: I
authors: Kuriyama
authors: Kouji
authors: K
authors: Kuramochi
authors: Kazunori
authors: K
authors: Tsubaki
authors: Hiromi
authors: H
authors: Yoshida
authors: Yoshiyuki
authors: Y
authors: Mizushina
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D009285:Naphthoquinones / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D009285:Naphthoquinones; D014409:Tumor Necrosis Factor-alpha; C415367:DNA polymerase beta2; D019951:DNA Polymerase beta; D013755:Tetradecanoylphorbol Acetate; C005134:juglone