Synthesis, characterization, DNA binding, topoisomerase inhibition, and apoptosis induction studies of a novel cobalt(III) complex with a thiosemicarbazone ligand

In this study, 9-anthraldehyde-N(4)-methylthiosemicarbazone (MeATSC) 1 and [Co(phen)(2)(O(2)CO)]Cl·6H(2)O 2 (where phen = 1,10-phenanthroline) were synthesized. [Co(phen)(2)(O(2)CO)]Cl·6H(2)O 2 was used to produce anhydrous [Co(phen)(2)(H(2)O)(2)](NO(3))(3) 3. Subsequently, anhydrous [Co(phen)(2)(H(2)O)(2)](NO(3))(3) 3 was reacted with MeATSC 1 to produce [Co(phen)(2)(MeATSC)](NO(3))(3)·1.5H(2)O·C(2)H(5)OH 4. The ligand, MeATSC 1 and all complexes were characterized by elemental analysis, FT IR, UV–visible, and multinuclear NMR ((1)H, (13)C, and (59)Co) spectroscopy, along with HRMS, and conductivity measurements, where appropriate. Interactions of MeATSC 1 and complex 4 with calf thymus DNA (ctDNA) were investigated by carrying out UV–visible spectrophotometric studies. UV–visible spectrophotometric studies revealed weak interactions between ctDNA and the analytes, MeATSC 1 and complex 4 (K(b) = 8.1 × 10(5) and 1.6 × 10(4) M(−1), respectively). Topoisomerase inhibition assays and cleavage studies proved that complex 4 was an efficient catalytic inhibitor of human topoisomerases I and IIα. Based upon the results obtained from the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay on 4T1-luc metastatic mammary breast cancer cells (IC(50) = 34.4 ± 5.2 μM when compared to IC(50) = 13.75 ± 1.08 μM for the control, cisplatin), further investigations into the molecular events initiated by exposure to complex 4 were investigated. Studies have shown that complex 4 activated both the apoptotic and autophagic signaling pathways in addition to causing dissipation of the mitochondrial membrane potential (ΔΨ(m)). Furthermore, activation of cysteine-aspartic proteases3 (caspase 3) in a time- and concentration-dependent manner coupled with the ΔΨ(m), studies implicated the intrinsic apoptotic pathway as the major regulator of cell death mechanism.