Effects of quinone derivatives, such as 1,4-naphthoquinone, on DNA polymerase inhibition and anti-inflammatory action.

Abstract

Previously, we reported that vitamin K(3), which consists of a quinone component, inhibits the activity of human DNA polymerase γ (pol γ). In this study, we investigated the inhibitory effects of 4 quinone derivatives (1,4-benzoquinone (BQ), 1,4-naphthoquinone (NQ), 9,10-anthraquinone (AQ) and 5,12-naphthacenequinone (NCQ)) on the activity of mammalian pols. BQ and NQ potently inhibited the activity of all the pol species: pols α, β, γ, δ, ε and λ, and NQ was a stronger pol inhibitor than BQ. Because we previously found a positive relationship between pol l inhibition and anti-inflammatory action, we examined whether these quinone derivatives could inhibit inflammatory responses. BQ and NQ caused a marked reduction in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced acute inflammation in mouse ear, although AQ and NCQ did not. In a cell culture system using mouse macrophages, NQ displayed the strongest suppression in the production of tumor necrosis factor (TNF)-α induced by lipopolysaccharide (LPS) among the quinone derivatives tested. Moreover, NQ was found to inhibit the action of nuclear factor (NF)-κ. In an in vivo mouse model of LPS-evoked acute inflammation, intraperitoneal injection of BQ and NQ to mice led to suppression of TNF-α production in serum. These anti-inflammatory responses of NQ were more potent than those of BQ. In conclusion, this study has identified several quinone derivatives, such as NQ, that are promising anti-inflammatory candidates.

• Authors: Kazuki Kobayashi, Shin Nishiumi, Masayuki Nishida, Midori Hirai, Takeshi Azuma, Hiromi Yoshida, Yoshiyuki Mizushina, Masaru Yoshida
• Journal: Medicinal chemistry (Shariqah (United Arab Emirates)) (Med Chem) Vol. 7 Issue 1 Pg. 37-44 (Jan 2011) ISSN: 1875-6638 [Electronic] Netherlands
• PMID: 21235518 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anthraquinones
• Anti-Inflammatory Agents, Non-Steroidal
• Antifibrinolytic Agents
• Enzyme Inhibitors
• Naphthoquinones
• Nucleic Acid Synthesis Inhibitors
• Vitamin K 3
• DNA-Directed DNA Polymerase
• 1,4-naphthoquinone

Topics

• Animals
• Anthraquinones (pharmacology)
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Antifibrinolytic Agents (pharmacology)
• Cattle
• Cell Line
• DNA-Directed DNA Polymerase (metabolism)
• Enzyme Inhibitors (pharmacology)
• Female
• Genes, pol
• Humans
• Inflammation (chemically induced, drug therapy)
• Macrophages (drug effects)
• Mice
• Mice, Inbred C57BL
• Naphthoquinones (pharmacology)
• Nucleic Acid Synthesis Inhibitors
• Rats
• Vitamin K 3 (pharmacology)