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

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

Bioorganic & medicinal chemistry (2011-09-10)
Sayako Maruo, Isoko Kuriyama, Kouji Kuramochi, Kazunori Tsubaki, Hiromi Yoshida, Yoshiyuki Mizushina
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.

MATERIALS
Product Number
Brand
Product Description

Supelco
Acetic acid, analytical standard
Sigma-Aldrich
Hexanoic acid, purum, ≥98.0% (GC)
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Hexanoic acid, ≥98%, FCC, FG
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Stearic acid 50, tested according to Ph. Eur.
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Linolenic acid, ≥99%
Supelco
Linoleic acid, analytical standard
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Linolenic acid, analytical standard
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Acetic acid, for luminescence, BioUltra, ≥99.5% (GC)
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Acetic acid, ≥99.5%, FCC, FG
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Lauric acid, natural, ≥98%, FCC, FG
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Linoleic acid, technical, 58-74% (GC)
Supelco
Hexanoic acid, analytical standard
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Lauric acid, ≥98%, FCC, FG
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Linoleic acid, liquid, BioReagent, suitable for cell culture
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Acetic acid, natural, ≥99.5%, FG
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Acetic acid solution, suitable for HPLC
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Hexanoic acid, ≥99%
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Linoleic acid, ≥99%
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Linolenic acid, ~70% (GC)
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Acetic acid, glacial, ACS reagent, ≥99.7%
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Acetic acid, glacial, puriss., 99-100%
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Acetic acid, glacial, puriss., meets analytical specification of Ph. Eur., BP, USP, FCC, 99.8-100.5%
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Acetic acid, glacial, ReagentPlus®, ≥99%
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Acetic acid, glacial, ≥99.99% trace metals basis
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Acetic acid, glacial, puriss. p.a., ACS reagent, reag. ISO, reag. Ph. Eur., ≥99.8%
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Stearic acid, reagent grade, 95%
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Oleic acid, technical grade, 90%
Supelco
Oleic acid, analytical standard
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Dodecanoic acid, 98%
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5-Hydroxy-1,4-naphthoquinone, 97%