In Vitro and in Vivo Anticancer Activity of Copper Bis(thiosemicarbazone) Complexes

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) (GTSCH2) 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 IIα inhibition unlike that for Cu­(GTSC). In vivo administration of Cu­(GTSC) significantly inhibits tumor growth in HCT116 xenografts in nude mice.