Bis(thiosemicarbazone) Complexes of Cobalt(III). Synthesis, Characterization, and Anticancer Potential

Nine bis(thiosemicarbazone) (BTSC) cobalt(III) complexes of the general formula [Co(BTSC)(L)(2)]NO3 were synthesized, where BTSC = diacetyl bis(thiosemicarbazone) (ATS), pyruvaldehyde bis(thiosemicarbazone) (PTS), or glyoxal bis(thiosemicarbazone) (GTS) and L = ammonia, imidazole (Im), or benzylamine (BnA). These compounds were characterized by multinuclear NMR spectroscopy, mass spectrometry, cyclic voltammetry, and X-ray crystallography. Their stability in phosphate-buffered saline was investigated, and found to be highly dependent on the nature of the axial ligand, L. These studies revealed that complex stability is primarily dictated by the axial ligand following the sequence NH3 > Im > BnA. The cellular uptake and cytotoxicity in cancer cells were also determined. Both the cellular uptake and cytotoxicity were significantly affected by the nature of the equatorial BTSC. Complexes of ATS were taken up much more effectively than those of PTS and GTS. The cytotoxicity of the complexes was correlated to that of the free ligand. Cell uptake and cytotoxicity were also determined under hypoxic conditions. Only minor differences in the hypoxia activity and uptake were observed. Treatment of the cancer cells with the copper-depleting agent tetrathiomolybdate decreased the cytotoxic potency of the complexes, indicating that they may operate via a copper-dependent mechanism. These results provide a structure-activity relationship for this class of compounds, which may be applied for the rational design of new cobalt(III) anticancer agents.