5-O-Acyl plumbagins inhibit DNA polymerase activity and suppress the inflammatory response
5-O-Acyl plumbagins inhibit DNA polymerase activity and suppress the inflammatory response
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5-O-酰基白花丹素抑制 DNA 聚合酶活性并抑制炎症反应
DOI：
10.1016/j.abb.2015.02.032
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
H.Nagamune and *Y.Mizushina
中科院分区：
文献类型：
--
作者：
T.Onodera; I.Kuriyama; Y.Sakamoto; M.Kawamura; K.Kuramochi; K.Tsubaki A.Tabata; H.Nagamune and *Y.Mizushina
我们以前发现维生素K3（甲萘醌，2-甲基-1，4-萘醌）抑制人线粒体DNA聚合酶（pol）γ的活性。本研究以5-羟基-2-甲基-1，4-萘醌（5-hydroxy-2-methyl-1，4-naphthoquinone，5-O-acyl plumbagins）为研究对象，通过化学方法合成了一种新型的与C2：0 ~ C22：6脂肪酸共轭的5-O-酰基白花丹素（5-O-acyl plumbagins）。这些化学修饰的白花丹素显示出增强的哺乳动物pol抑制，其中与二十二碳六烯酸（C22：6-酰基白花丹素）缀合的白花丹素在合成的10种5-O-酰基白花丹素中表现出对pol λ的最强抑制。C22：6-酰基白花丹醌选择性抑制哺乳动物pol种类的活性，但不影响其他pol或DNA代谢酶的活性。这些化合物对pol λ（一种DNA修复/重组pol）的抑制作用与其抑制脂多糖（LPS）诱导的小鼠RAW264.7巨噬细胞产生肿瘤坏死因子-α（TNF-α）和减少12-O-十四烷酰佛波醇-13-乙酸酯（TPA）诱导的小鼠耳炎显著相关。这些数据表明，5-O-酰基白花丹素通过抑制哺乳动物pol λ作为抗炎剂。这些结果进一步表明，C22：6-酰基白花丹素是一种有前途的抗炎候选物，酰化可能是一种有效的化学修饰，以提高维生素K3衍生物，如白花丹素的抗炎活性。
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 K3derivatives, such as plumbagin.