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
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DOI：
10.1016/j.bmc.2011.08.023
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发表时间：
2011-10-01
影响因子：
3.5
通讯作者：
Mizushina, Yoshiyuki
中科院分区：
文献类型：
--
作者：
Maruo, Sayako;Kuriyama, Isoko;Mizushina, Yoshiyuki
我们之前发现维生素K(3)（甲萘醌，2-甲基-1,4-萘醌）抑制人类线粒体DNA聚合酶γ (pol γ)的活性。本研究以1,4-萘醌衍生物核桃酮（5-羟基-1,4-萘醌）为研究对象，化学合成了与C2:0 - C22:6脂肪酸偶联的新型核桃酮（5- o -酰基核桃酮）。化学修饰的核桃酮增强了哺乳动物的pol抑制作用及其细胞毒和抗炎活性。在10种合成的5- o -酰基核桃酮中，油酸偶联核桃酮（c18:1-酰基核桃酮）对DNA复制pol - α活性和人结肠癌（HCT116）细胞生长的抑制作用最强。c12:0-酰基核桃酮是DNA修复相关的pot - lambda的最强抑制剂，也是对脂多糖（LPS）诱导的肿瘤坏死因子(TNF)- α产生的最强抑制。此外，该化合物最大程度地减少了12- o -十四烷醇-13-醋酸酯（TPA）诱导的小鼠耳急性炎症。C12:0-和c18:1-酰基核桃酮选择性抑制哺乳动物pol的活性，但不影响其他pol和DNA代谢酶的活性。这些数据表明，新的5- o -酰基核桃苷类药物是基于哺乳动物的锅抑制作用靶向抗癌和/或抗炎药物的。此外，研究结果表明，核桃酮的酰化是一种有效的化学修饰，可以提高维生素K(3)衍生物如核桃酮的抗癌和抗炎作用。(C) 2011 Elsevier Ltd.版权所有。
We previously found that vitamin K(3) (menadione, 2-methyl-1,4-naphthoquinone) inhibits the activity of human mitochondrial DNA polymerase gamma (pol gamma). 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 alpha 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 pot lambda, as well as the strongest suppression of the production of tumor necrosis factor (TNF)-alpha 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 pot 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. (C) 2011 Elsevier Ltd. All rights reserved.