In Vitro and in Vivo Anticancer Activity of Copper Bis(thiosemicarbazone) Complexes
In Vitro and in Vivo Anticancer Activity of Copper Bis(thiosemicarbazone) Complexes
复制标题
DOI：
10.1021/jm300938r
复制
发表时间：
2013-02-14
影响因子：
7.3
通讯作者：
Samuelson, Ashoka G.
中科院分区：
文献类型：
--
作者：
Palanimuthu, Duraippandi;Shinde, Sridevi Vijay;Samuelson, Ashoka G.
合成了在配体的二酮骨架上带有甲基、苯基和氢的中性和阳离子铜双缩氨基硫脲配合物。所有这些都进行了表征，光谱方法，并在三种情况下，通过X射线晶体学。体外细胞毒性研究表明，它们具有细胞毒性，不像相应的锌络合物。由甘氨酰-双（4-甲基-4-苯基-3-氨基硫脲）（GTSCH（2））衍生的铜配合物Cu（GTSC）和Cu（GTSCHCl）是对多种人类癌细胞系最具细胞毒性的配合物，具有与抗癌药物阿霉素相似的效力，并且比相应的锌配合物高高达1000倍。氚标记的胸腺嘧啶核苷掺入实验表明，Cu（GTSC）和Cu（GTSCHCl）明显抑制DNA合成。细胞周期分析表明，Cu（GTSC）和Cu（GTSCHCl）诱导HCT 116细胞凋亡。Cu（GTSCHCl）络合物引起明显的DNA切割和Topo II α抑制，这与Cu（GTSC）不同。体内施用Cu（GTSC）显著抑制裸鼠中HCT 116异种移植物中的肿瘤生长。
Neutral and cationic copper bis(thiosemicarbazone) complexes bearing methyl, phenyl, and hydrogen, on the diketo-backbone of the ligand have been synthesized. All of them were characterized by spectroscopic methods and in three cases by X-ray crystallography. In vitro cytotoxicity studies revealed that they are cytotoxic unlike the corresponding zinc complexes. Copper complexes Cu(GTSC) and Cu(GTSCHCl) derived from glyoxal-bis(4-methyl-4-phenyl-3-thiosemicarbazone) (GTSCH(2)) are the most cytotoxic complexes against various human cancer cell lines, with a potency similar to that of the anticancer drug adriamycin and up to 1000 fold higher than that of the corresponding zinc complex. Tritiated thymidine incorporation assay revealed that Cu(GTSC) and Cu(GTSCHCl) inhibit DNA synthesis substantially. Cell cycle analyses showed that Cu(GTSC) and Cu(GTSCHCl) induce apoptosis in HCT116 cells. The Cu(GTSCHCl) complex caused distinct DNA cleavage and Topo II alpha inhibition unlike that for Cu(GTSC). In vivo administration of Cu(GTSC) significantly inhibits tumor growth in HCT116 xenografts in nude mice.