Anti-tumor effects of novel 5-O-acyl plumbagins based on the inhibition of mammalian DNA replicative polymerase activity.
Anti-tumor effects of novel 5-O-acyl plumbagins based on the inhibition of mammalian DNA replicative polymerase activity.
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DOI：
10.1371/journal.pone.0088736
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Mizushina Y
中科院分区：
文献类型：
--
作者：
Kawamura M;Kuriyama I;Maruo S;Kuramochi K;Tsubaki K;Yoshida H;Mizushina Y
我们先前发现维生素K3(甲萘二酮，2-甲基-1，4-萘醌)能抑制人线粒体γ聚合酶γ的活性。本研究以5-羟基-2-甲基-1，4-萘醌为研究对象，化学合成了与C2：0~C22：6脂肪酸偶联的新型化合物(5-O-酰基白花素)。这些经过化学修饰的白花蛇抗菌素增强了对哺乳动物Pol的抑制和它们的细胞毒活性。与C18以上不饱和脂肪酸组成的链结合，可强烈抑制小牛POLα和人POLγ的活性。在合成的10种5-O-酰基白花丹中，与油酸(C18：1-酰基白花丹)偶联的白花丹对人结肠癌(HCT116)细胞增殖的抑制作用最强。这些化合物对PolDNA复制型POLα的抑制活性与其对癌细胞增殖的抑制活性具有高度的相关性。C18：1-酰化铅选择性地抑制哺乳动物POL的活性，但不影响所测试的其他POL和DNA代谢酶的活性。该化合物对多种人癌细胞株的增殖有抑制作用，是9种细胞株中对HT-29结肠癌细胞(LD50 = 2.9µM)抑制作用最强的一种细胞毒抑制剂。在裸鼠体内的抗肿瘤实验中，C18：1-酰基白花黄素被证明是一种很有前途的肿瘤抑制药物。这些数据表明，新的5-O-酰基白花素是基于对哺乳动物α复制的抑制而发挥抗癌作用的。此外，实验结果表明，白花蛇舌草素的酰化反应是一种有效的化学修饰，可以提高维生素K3衍生物的抗癌活性。
We previously found that vitamin K3 (menadione, 2-methyl-1,4-naphthoquinone) inhibits the activity of human mitochondrial DNA polymerase γ (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 enhanced mammalian pol inhibition and their cytotoxic activity. Plumbagin conjugated with chains consisting of more than C18-unsaturated fatty acids strongly inhibited the activities of calf pol α and human pol γ. Plumbagin conjugated with oleic acid (C18:1-acyl plumbagin) showed the strongest suppression of human colon carcinoma (HCT116) cell proliferation among the ten synthesized 5-O-acyl plumbagins. The inhibitory activity on pol α, a DNA replicative pol, by these compounds showed high correlation with their cancer cell proliferation suppressive activity. C18:1-Acyl plumbagin selectively inhibited the activities of mammalian pol species, but did not influence the activities of other pols and DNA metabolic enzymes tested. This compound inhibited the proliferation of various human cancer cell lines, and was the cytotoxic inhibitor showing strongest inhibition towards HT-29 colon cancer cells (LD50 = 2.9 µM) among the nine cell lines tested. In an in vivo anti-tumor assay conducted on nude mice bearing solid tumors of HT-29 cells, C18:1-acyl plumbagin was shown to be a promising tumor suppressor. These data indicate that novel 5-O-acyl plumbagins act as anti-cancer agents based on mammalian DNA replicative pol α inhibition. Moreover, the results suggest that acylation of plumbagin is an effective chemical modification to improve the anti-cancer activity of vitamin K3 derivatives, such as plumbagin.
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影响因子：
3.8
作者：
MONKS, TJ;HANZLIK, RP;GRAHAM, DG
通讯作者：
GRAHAM, DG
影响因子：
3.5
作者：
Maruo, Sayako;Kuriyama, Isoko;Mizushina, Yoshiyuki
通讯作者：
Mizushina, Yoshiyuki
DOI：
10.1016/0167-4781(96)00121-2
发表时间：
1996-09-11
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION
影响因子：
--
作者：
Mizushina, Y;Tanaka, N;Sakaguchi, K
通讯作者：
Sakaguchi, K
影响因子：
2.1
作者：
Kusumoto, R;Masutani, C;Hanaoka, F
通讯作者：
Hanaoka, F
影响因子：
4.8
作者：
Mizushina, Y;Kamisuki, S;Sakaguchi, K
通讯作者：
Sakaguchi, K