5-O-Acyl plumbagins inhibit DNA polymerase activity and suppress the inflammatory response.
We previously found that vitamin K3 (menadione, 2-methyl-1,4-naphthoquinone) inhibits the activity of human mitochondrial DNA polymerase (pol) γ. In this study, we focused on plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), and chemically synthesized novel plumbagins conjugated with C2:0 to C22:6 fatty acids (5-O-acyl plumbagins). These chemically modified plumbagins displayed enhanced mammalian pol inhibition, with plumbagin conjugated to docosahexaenoic acid (C22:6-acyl plumbagin) exhibiting the strongest inhibition of pol λ among the ten 5-O-acyl plumbagins synthesized. C22:6-acyl plumbagin selectively inhibited the activities of mammalian pol species, but did not influence the activities of other pols or DNA metabolic enzymes tested. The inhibition of pol λ, a DNA repair/recombination pol, by these compounds was significantly correlated with both their suppression of lipopolysaccharide (LPS) induced tumor necrosis factor-α (TNF-α) production by mouse RAW264.7 macrophages and the reduction of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation in the mouse ear. These data indicate that 5-O-acyl plumbagins act as anti-inflammatory agents by inhibiting mammalian pol λ. These results further suggest that C22:6-acyl plumbagin is a promising anti-inflammatory candidate and that acylation could be an effective chemical modification to improve the anti-inflammatory activity of vitamin K3 derivatives, such as plumbagin.
Laboratory of Food & Nutritional Sciences, Faculty of Nutrition, Kobe Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Japan; Cooperative Research Center of Life Sciences, Kobe Gakuin University, Chuo-ku, Kobe, Hyogo 651-8586, Japan.
Takefumi
T
Onodera
Laboratory of Food & Nutritional Sciences, Faculty of Nutrition, Kobe Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Japan.
Isoko
I
Kuriyama
Laboratory of Food & Nutritional Sciences, Faculty of Nutrition, Kobe Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Japan.
Yuka
Y
Sakamoto
Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto 606-8522, Japan.
Moe
M
Kawamura
Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto 606-8522, Japan.
Kouji
K
Kuramochi
Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto 606-8522, Japan.
Kazunori
K
Tsubaki
Cooperative Research Center of Life Sciences, Kobe Gakuin University, Chuo-ku, Kobe, Hyogo 651-8586, Japan; Department of Biological Science and Technology, Life System, Institute of Technology and Science, The University of Tokushima Graduate School, Minami-Josanjima-cho, Tokushima 770-8506, Japan.
Atsushi
A
Tabata
Cooperative Research Center of Life Sciences, Kobe Gakuin University, Chuo-ku, Kobe, Hyogo 651-8586, Japan; Department of Biological Science and Technology, Life System, Institute of Technology and Science, The University of Tokushima Graduate School, Minami-Josanjima-cho, Tokushima 770-8506, Japan.
Hideaki
H
Naganune
Cooperative Research Center of Life Sciences, Kobe Gakuin University, Chuo-ku, Kobe, Hyogo 651-8586, Japan; Graduate School of Agriculture, Shinshu University, Minamiminowa-mura, Kamiina-gun, Nagano 399-4598, Japan. Electronic address: mizushina@shinshu-u.ac.jp.
Yoshiyuki
Y
Mizushina
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D005227:Fatty Acids / Q000737:chemistry; D055785:Gene Knockdown Techniques; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009285:Naphthoquinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010940:Plant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D051381:Rats; D013755:Tetradecanoylphorbol Acetate; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000893:Anti-Inflammatory Agents; D029968:Escherichia coli Proteins; D005227:Fatty Acids; D008070:Lipopolysaccharides; D009285:Naphthoquinones; D010940:Plant Proteins; D014409:Tumor Necrosis Factor-alpha; C415367:DNA polymerase beta2; D019951:DNA Polymerase beta; D013755:Tetradecanoylphorbol Acetate; C014758:plumbagin
5-O-Acyl plumbagins; Anti-inflammation; C22:6-acyl plumbagin; DNA polymerase λ; Enzyme inhibitor