دانلود رایگان مقاله توپوایزومراز انسانی IB هدف تیوزمیکاربازون مس پیچیده

Abstract

The human topoisomerase IB inhibition and the antiproliferative activity of 3-(4-bromophenyl)-1-pyridin-2-ylprop-2-en-1-one thiosemicarbazone HPyCT4BrPh alone and its copper(II) complex [Cu(PyCT4BrPh)Cl] was investigated. [Cu(PyCT4BrPh)Cl] inhibits both the DNA cleavage and religation step of the enzyme, whilst the ligand alone does not display any effect. In addition we show that coordination to copper(II) improves the cytotoxicity of HPyCT4BrPh against THP-1 leukemia and MCF-7 breast cancer cells. The data indicate that the copper(II) thiosemicarbazone complex may hit human topoisomerase IB and that metal coordination can be useful to improve cytotoxicity of this versatile class of compounds.

4. Conclusions

HPyCT4BrPh and its copper(II) complex [Cu(PyCT4BrPh)Cl] (1), already known to be cytotoxic agents against HL60 leukemia cells, MDA-MB 231 and HCT-116 tumor cells, are shown to have cytotoxic effect also against THP-1 and MCF-7 cells. Coordination of the thiosemicarbazone to copper(II) improves the effect, making complex (1) more efficient than the parental compound (Table 1). In fact the ligand HPyCT4BrPh shows some cytotoxic activity, but upon coordination to copper(II) to form complex (1) the cytotoxic effect increases 6-fold against THP-1 leukemia cells and 8-fold against MCF- 7 solid tumor cells (Table 1). This effect is due to complex (1) since addition of CuCl2 does not induce any toxicity. Thiosemicarbazones have been suggested to exert their antineoplastic activity through several mechanisms such as Fe chelation, in this way being responsible for the iron impoverishment of the biological systems. They may also act through the redox cycling properties of the resulting FeII-thiosemicarbazones complex, inhibiting essential enzymes such as ribonucleotide reductase [42]. Other mechanisms are also described, such as inhibition of topoisomerase IIa, for which the binding of thiosemicarbazone to the ATP hydrolysis domain was shown to be responsible for enzyme inhibition [18].