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In this study, 9-anthraldehyde-N(4)-methylthiosemicarbazone (MeATSC) 1 and [Co(phen)(OCO)]Cl·6HO 2 (where phen = 1,10-phenanthroline) were synthesized. [Co(phen)(OCO)]Cl·6HO 2 was used to produce anhydrous [Co(phen)(HO)](NO)3. Subsequently, anhydrous [Co(phen)(HO)](NO)3 was reacted with MeATSC 1 to produce [Co(phen)(MeATSC)](NO)·1.5HO·CHOH 4. The ligand, MeATSC 1 and all complexes were characterized by elemental analysis, FT IR, UV-visible, and multinuclear NMR (H, C, and 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 = 8.1 × 10 and 1.6 × 10 M, 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 = 34.4 ± 5.2 μM when compared to IC = 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). Furthermore, activation of cysteine-aspartic proteases3 (caspase 3) in a time- and concentration-dependent manner coupled with the ΔΨ, studies implicated the intrinsic apoptotic pathway as the major regulator of cell death mechanism.
Beebe SJ, Celestine MJ, Bullock JL, Sandhaus S, Arca JF, Cropek DM, Ludvig TA, Foster SR, Clark JS, Beckford FA, Tano CM, Tonsel-White EA, Gurung RK, Stankavich CE, Tse-Dinh YC, Jarrett WL, Holder AA. Synthesis, characterization, DNA binding, topoisomerase inhibition, and apoptosis induction studies of a novel cobalt(III) complex with a thiosemicarbazone ligand. J Inorg Biochem. 2020 Feb;203:110907. doi: 10.1016/j.jinorgbio.2019.110907. Epub 2019 Nov 2. PMID: 31715377; PMCID: PMC7053658.
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