1. Synthesis, characterization, DNA binding, topoisomerase inhibition, and apoptosis induction studies of a novel cobalt(III) complex with a thiosemicarbazone ligand
- Author
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Yuk-Ching Tse-Dinh, Courtney E. Stankavich, Sydney R. Foster, Jimmie L. Bullock, Jasmine S. Clark, Donald M. Cropek, Jessa Faye Arca, Shayna Sandhaus, Stephen J. Beebe, Raj K. Gurung, William L. Jarrett, Criszcele M. Tano, Michael J. Celestine, Alvin A. Holder, Floyd A. Beckford, Elizabeth A. Tonsel-White, and Tekettay A. Ludvig
- Subjects
Thiosemicarbazones ,Programmed cell death ,Stereochemistry ,Topoisomerase Inhibitors ,Caspase 3 ,Antineoplastic Agents ,Apoptosis ,010402 general chemistry ,Cleavage (embryo) ,01 natural sciences ,Biochemistry ,Article ,Inorganic Chemistry ,chemistry.chemical_compound ,Mice ,Coordination Complexes ,Cell Line, Tumor ,medicine ,Organometallic Compounds ,Animals ,Humans ,Semicarbazone ,Cisplatin ,biology ,010405 organic chemistry ,Topoisomerase ,Cobalt ,DNA ,0104 chemical sciences ,DNA Topoisomerases, Type II ,chemistry ,DNA Topoisomerases, Type I ,biology.protein ,medicine.drug - Abstract
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.
- Published
- 2019