A β-carboline derivative-based nickel(ii) complex as a potential antitumor agent: synthesis, characterization, and cytotoxicity.
A β-carboline derivative-based nickel(ii) complex as a potential antitumor agent: synthesis, characterization, and cytotoxicity.
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DOI：
10.1039/c7md00428a
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发表时间：
2018-01
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通讯作者：
Jing-Mei Yang;Yanyi Zhu;Sheng Chen;Xing Lu;Yi-ming Wu;Feng'e Ma;Liangyao Li;Yang Yang-Yang;Zhenhao Shi;K. Huang;Xue Hong;P. Jiang;Yan Peng
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作者：
Jing-Mei Yang;Yanyi Zhu;Sheng Chen;Xing Lu;Yi-ming Wu;Feng'e Ma;Liangyao Li;Yang Yang-Yang;Zhenhao Shi;K. Huang;Xue Hong;P. Jiang;Yan Peng
合成并表征了6-甲氧基-1-吡啶-β-咔啉(4a)镍(II)配合物。以人正常肝细胞株HL-7702为研究对象，研究了该化合物对6种肿瘤细胞株MGC-803、Hep G2、T24、OS-RC-2、NCI-H460、SK-OV-3的细胞毒作用。MGC-803、HEP G2、T24、OS-RC-2、NCI-H460和SK-OV-3的IC50值一般在微摩尔范围内(3.77-15.10μM)，低于配体4和顺铂。此外，4a(6μM)显著诱导细胞周期停滞于S期，并使p-Akt、Cyclin E、Cyclin A和CDK2表达下调，p27表达上调。各种实验表明，4a可诱导MGC-803细胞凋亡，激活caspase-3，增加细胞内ROS水平，提高细胞内[Ca~(2+)]_c水平。此外，包括细胞色素c和APAF-1在内的内在凋亡蛋白的表达增加。进一步的内源性细胞凋亡是通过执行分子caspase-9和caspase-3触发的。总之，4a的细胞毒作用主要是通过诱导细胞周期停滞在S期和诱导细胞内源性凋亡来实现的。
A novel nickel(ii) complex of 6-methoxy-1-pyridine-β-carboline (4a) was synthesized and characterized. The cytotoxicities of the complex towards six cancer cell lines, including MGC-803, Hep G2, T24, OS-RC-2, NCI-H460, and SK-OV-3, and human normal liver cell line HL-7702 were investigated. The IC50 values for MGC-803, Hep G2, T24, OS-RC-2, NCI-H460 and SK-OV-3 were generally in the micromolar range (3.77-15.10 μM), lower than those of ligand 4 and cisplatin. Furthermore, 4a (6 μM) significantly induced cell cycle arrest at the S phase, and caused the down-regulation of p-AKT, cyclin E, cyclin A and CDK2 and the up-regulation of p27. Various experiments showed that 4a induced apoptosis, activated caspase-3, increased the levels of reactive oxygen species (ROS) and enhanced the intracellular [Ca2+]c levels in MGC-803. In addition, the expression of intrinsic apoptotic proteins, including cytochrome c and apaf-1, increased. Further intrinsic apoptosis was triggered via executive molecular caspase-9 and caspase-3. In short, 4a exerted its cytotoxic activity primarily through inducing cell cycle arrest at the S phase and intrinsic apoptosis.