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

Abstract

In this study, 9-anthraldehyde-N(4)-methylthiosemicarbazone (MeATSC) 1 and [Co(phen)2(O2CO)]Cl·6H2O 2 (where phen = 1,10-phenanthroline) were synthesized. [Co(phen)2(O2CO)]Cl·6H2O 2 was used to produce anhydrous [Co(phen)2(H2O)2](NO3)33. Subsequently, anhydrous [Co(phen)2(H2O)2](NO3)33 was reacted with MeATSC 1 to produce [Co(phen)2(MeATSC)](NO3)3·1.5H2O·C2H5OH 4. The ligand, MeATSC 1 and all complexes were characterized by elemental analysis, FT IR, UV-visible, and multinuclear NMR (1H, 13C, and 59Co) 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 (Kb = 8.1 × 105 and 1.6 × 104 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 (IC50 = 34.4 ± 5.2 μM when compared to IC50 = 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 (ΔΨm). Furthermore, activation of cysteine-aspartic proteases3 (caspase 3) in a time- and concentration-dependent manner coupled with the ΔΨm, studies implicated the intrinsic apoptotic pathway as the major regulator of cell death mechanism.

• Authors: Stephen J Beebe, Michael J Celestine, Jimmie L Bullock, Shayna Sandhaus, Jessa Faye Arca, Donald M Cropek, Tekettay A Ludvig, Sydney R Foster, Jasmine S Clark, Floyd A Beckford, Criszcele M Tano, Elizabeth A Tonsel-White, Raj K Gurung, Courtney E Stankavich, Yuk-Ching Tse-Dinh, William L Jarrett, Alvin A Holder
• Journal: Journal of inorganic biochemistry (J Inorg Biochem) Vol. 203 Pg. 110907 (02 2020) ISSN: 1873-3344 [Electronic] United States
• PMID: 31715377 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Coordination Complexes
• Organometallic Compounds
• Thiosemicarbazones
• Topoisomerase Inhibitors
• Cobalt
• DNA
• DNA Topoisomerases, Type I
• DNA Topoisomerases, Type II

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cobalt (chemistry)
• Coordination Complexes (chemical synthesis, pharmacology)
• DNA (chemistry)
• DNA Topoisomerases, Type I (chemistry, metabolism)
• DNA Topoisomerases, Type II (chemistry, metabolism)
• Humans
• Mice
• Organometallic Compounds (chemical synthesis, pharmacology)
• Thiosemicarbazones (chemistry)
• Topoisomerase Inhibitors (chemical synthesis, pharmacology)