Microwave-assisted synthesis of arene ruthenium(II) complexes that induce S-phase arrest in cancer cells by DNA damage-mediated p53 phosphorylation.
Microwave-assisted synthesis of arene ruthenium(II) complexes that induce S-phase arrest in cancer cells by DNA damage-mediated p53 phosphorylation.
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DOI：
10.1016/j.ejmech.2013.01.037
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发表时间：
2013-05
影响因子：
6.7
通讯作者：
Qiong Wu;Cundong Fan;Tianfeng Chen;Chaoran Liu;Wenjie Mei;Sidong Chen;Baoguo Wang;Yunyun Chen;Wen-jie Zheng
中科院分区：
文献类型：
--
作者：
Qiong Wu;Cundong Fan;Tianfeng Chen;Chaoran Liu;Wenjie Mei;Sidong Chen;Baoguo Wang;Yunyun Chen;Wen-jie Zheng
菲并咪唑衍生物[（C6 H6）Ru（L）Cl]Cl·2 H2O配位的一系列芳烃钌（II）配合物在微波辐射条件下，30 min内合成了1bL = IP，2bL = p-NMe 2 PIP，3bL = p-MeOPIP，4 bL = p-HOPIP，5 bL = p-COOHPIP，6 bL = p-CF 3 PIP，7 bL = p-BrPIP，产率为89-92%，1b的晶体结构为典型的“钢琴凳”构象。用MTT法测定了配合物对多种肿瘤细胞的抗肿瘤活性，结果表明，该类配合物对所有肿瘤细胞，尤其是骨肉瘤MG-63细胞，均有较好的抑制作用，但对正常人HK-2细胞的毒性较低。其作用机制研究表明，芳烃Ru（II）配合物2b可诱导MG-63细胞周期阻滞于S期，S期细胞比例增加，cyclin A表达下调。彗星实验进一步证实2b可诱导MG-63细胞DNA损伤，并上调磷酸化p53和组蛋白的表达。体外光谱研究也表明，2b以嵌入方式与DNA分子结合，干扰肿瘤细胞的生物学功能。总之，合成的芳烃钌（II）配合物可以作为一种新的p53激活剂，在癌症化疗中具有潜在的应用。
A series of arene ruthenium(II) complexes coordinated by phenanthroimidazole derivates, [(C6H6)Ru(L)Cl]Cl·2H2O (1b L = IP, 2b L = p-NMe2PIP, 3b L = p-MeOPIP, 4b L = p-HOPIP, 5b L = p-COOHPIP, 6b L = p-CF3PIP, 7b L = p-BrPIP) have been synthesized in yields of 89–92% under microwave irradiation in 30 min, and the crystal structure of 1b by XRD gives a typical “piano stool” conformation. The antitumor activity of these complexes against various tumor cells have been evaluated by MTT assay, and the results show that this type of arene Ru(II) complexes exhibit acceptable inhibitory effect against all of these tumor cells, especially osteosarcoma MG-63 cells, but with low toxicity toward HK-2 human normal cells. Studies on the mechanism revealed that cell cycle arrest at S-phase in MG-63 cells induced by the arene Ru(II) complex 2b, which was confirmed by the increase in the percentage of cells at S-phase and down-regulator of cyclin A. The further studies by Comet assay at single cell level indicated that DNA damage in MG-63 cells was triggered by 2b, following with the up-regulation of phosphorylated p53 and histone. The studies by spectroscopy in vitro also indicate that 2b bind to DNA molecule by intercalative mode to disturb the bio-function of tumor cells. In conclusion, the synthetic arene Ru(II) complexes could serve as novel p53 activator with potential application in cancer chemotherapy.