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.

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.

Keywords: (59)Co NMR spectroscopy; Breast cancer; Calf thymus DNA; Cobalt(III) complex; Mitochondrial membrane potential; Thiosemicarbazone.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

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