Synthesis, Characterization, DNA Binding, Topoisomerase Inhibition, and Apoptosis Induction Studies of a Novel Cobalt(III) Complex With a Thiosemicarbazone Ligand

Authors

Stephen J. Beebe, Old Dominion University
Michael J. Celestine, Old Dominion University
Jimmie L. Bullock, Old Dominion University
Shayna Sandhaus, Florida International University
Jessa Faye Arca, University of Southern MississippiFollow
Donald M. Cropek, US Army Construction Engineering Research LabFollow
Tekettay A. Ludvig, Old Dominion University
Sydney R. Foster, Old Dominion University
Jasmine S. Clark, Old Dominion University
Floyd A. Beckford, University of Virginia
Criszcele M. Tano, Old Dominion University
Elizabeth A. Tonsel-White, Old Dominion University
Raj K. Gurung, Old Dominion UniversityFollow
Courtney E. Stankavich, Old Dominion University
Yuk Ching Tse-Dinh, Florida International University
William L. Jarrett, University of Southern MississippiFollow
Alvin A. Holder, Old Dominion UniversityFollow

Document Type

Article

Publication Date

2-1-2020

School

Polymer Science and Engineering

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)₃ 3. Subsequently, anhydrous [Co(phen)₂(H₂O)₂](NO₃)₃ 3 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 (K_b = 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 (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.

Comments

© 2020. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/.

Publisher's Version

Publication Title

Journal of Inorganic Biochemistry

Volume

203

Recommended Citation

Beebe, S., Celestine, M., Bullock, J., Sandhaus, S., Arca, J., Cropek, D., Ludvig, T., Foster, S., Clark, J., Beckford, F., Tano, C., Tonsel-White, E., Gurung, R., Stankavich, C., Tse-Dinh, Y., Jarrett, W., Holder, A. (2020). Synthesis, Characterization, DNA Binding, Topoisomerase Inhibition, and Apoptosis Induction Studies of a Novel Cobalt(III) Complex With a Thiosemicarbazone Ligand. Journal of Inorganic Biochemistry, 203.
Available at: https://aquila.usm.edu/fac_pubs/17877