Inhibitory effects of vitamin K3 derivatives on DNA polymerase and inflammatory activity

Previously, we reported that vitamin K, (menadione, 2-methyl-1,4-naphthoquinone) (compound 2) inhibits the activity of human mitochondria] DNA polymerase gamma (pol gamma). In this study, we investigated the inhibitory effects (IEs) of vitamin K-3 and its derivatives, such as 1,4-naphthoquinone (compound 1) and 1,2-dimethyl-1,4-naphthoquinone (compound 3), on the activity of mammalian pols. Among compounds 1-3 (10 mu M for each), compound I was the strongest inhibitor of mammalian pols alpha and gimel, which belong to the B and X pol families, respectively, whereas compound 2 was the strongest inhibitor of human pol gamma, a family A pol. However, these compounds did not affect the activity of human pol kappa, a family Y pol. As we previously found a positive relationship between pol gimel inhibition and anti-inflammatory action, we examined whether these vitamin K-3 derivatives are able to inhibit inflammatory responses. Among the three compounds tested, compound I caused the greatest reduction in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced acute inflammation in mouse ears. In addition, in a cell culture system using RAW264.7 mouse macrophages, compound 1 displayed the strongest suppression of tumor necrosis factor (TNF)-alpha production induced by lipopolysaccharide (LPS). In an in vivo mouse model of LPS-evoked acute inflammation, the intraperitoneal injection of compound 1 into mice suppressed TNF-alpha production in their peritoneal macrophages and serum. In an in vivo colitis mouse model induced using dextran sulfate sodium (DSS), the vitamin K-3 derivatives markedly suppressed DSS-evoked colitis. In conclusion, this study has identified several vitamin K-3 derivatives, such as compound 1, that are promising anti-inflammatory candidates.