1,2,3-Triazole-Dithiocarbamate Hybrids, a Group of Novel Cell Active SIRT1 Inhibitors
1,2,3-Triazole-Dithiocarbamate Hybrids, a Group of Novel Cell Active SIRT1 Inhibitors
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1,2,3-三唑-二硫代氨基甲酸酯杂化物，一组新型细胞活性 SIRT1 抑制剂。
DOI：
10.1159/000438620
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发表时间：
2016-01
影响因子：
--
通讯作者：
Liu Hong Min
中科院分区：
文献类型：
--
作者：
Zheng Yi Chao;Wang Long Zhen;Zhao Li Jie;Zhao Li Juan;Zhan Qian Na;Ma Jin Lian;Zhang Bin;Wang Meng Meng;Wang Zhi Ru;Li Jin Feng;Liu Ying;Chen Zhe Sheng;Shen Dan Dan;Liu Xue Qi;Ren Meng;Lv Wen Lei;Zhao Wen;Duan Ying Chao;Liu Hong Min
背景/目的：据报道，人类SIRT1参与肿瘤发生，主要是由于其通过赖氨酸382去乙酰化对p53的调节作用。SIRT1抑制剂大量应用于化疗研究，但很少应用于临床试验。方法与结果：本研究通过分子对接和生化评价，鉴定了一系列具有1,4-双哌嗪碳二硫酸甲酯支架的新型化合物对SIRT1具有抑制效力。进一步的细胞水平研究表明，最有效的SIRT1抑制剂之一化合物3a具有细胞活性。它可以通过积累p53的K382乙酰化来上调p53的数量，从而导致人胃癌细胞系MGC-803细胞中p53的稳定。同时，我们还发现化合物3a可以灭活细胞中的SIRT2，这表明该化合物是一种非选择性SIRT抑制剂。结论：化合物3a是一种有效的、可逆的、具有细胞活性的SIRT1抑制剂，值得进一步研究作为抗癌药物或生物学工具。
Background/Aims: Human SIRT1 is reported to be involved in tumorgenesis, mainly due to its modulating effect on p53 by deacetylation on lysine382. A large quantity of SIRT1 inhibitors was applied in chemotherapeutic study, but few of them were applied into clinical trials. Methods and Results: In the current study, a novel series of compounds with 1,4-bispiperazinecarbodithioic acid methyl esters scaffold were characterized to have inhibitory potency to SIRT1 by molecular docking and biochemical evaluation. Further cell level study revealed that one of the most potent SIRT1 inhibitors, compound 3a, is cell active. It can upregulate the amount of p53 by accumulating the K382 acetylation of p53, which lead to the stabilization of p53 in human gastric cancer cell line MGC-803 cells. Meanwhile, we also found compound 3a can inactivate SIRT2 in cells, which suggests the compound as a non-selective SIRT inhibitor. Conclusion: All these findings indicate that compound 3a is a potent, reversible and cell active SIRT1 inhibitor and deserves further investigation as an anticancer agent or a biological tool.
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影响因子：
3.2
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Schwienhorst, A