New manganese(II), iron(II), cobalt(II), nickel(II) and copper(II) saccharinate complexes of 2,6-bis(2-benzimidazolyl)pyridine as potential anticancer agents

doi:10.1016/j.ejmech.2020.112535

European Journal of Medicinal Chemistry

Volume 202, 15 September 2020, 112535

https://doi.org/10.1016/j.ejmech.2020.112535 Get rights and content

Highlights

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Synthesis of metal(II) saccharinate complexes of 2,6-bis(2-benzimidazolyl)pyridine.
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High nuclease activity and major groove DNA binding of the metal complexes.
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High cytotoxicity of Mn and Cu against A549 and MCF-7 cells.
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Mn and Cu induce G0/G1 cell arrest and regulate expressions of Bcl-2 family proteins.
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Mn and Cu cause apoptosis via high ROS production, mitochondrial and DNA damage.

Abstract

New mononuclear complexes [Mn(NO₃)(sac)(H₂O)(bzimpy)]·2DMF (Mn), [Fe(sac)₂(H₂O)(bzimpy)]·2H₂O (Fe), [Co(bzimpy)₂](sac)₂·2H₂O (Co), [Ni(bzimpy)₂](sac)₂·H₂O·i-PrOH (Ni) and [Cu(sac)₂(bzimpy)]·3DMF (Cu) (sac = saccharinate and bzimpy = 2,6-bis(2-benzimidazolyl)pyridine) were synthesized and structurally characterized by elemental analysis, UV–Vis, IR, ESI-MS and X-ray diffraction. The anticancer activity of the metal complexes against A549 (lung), MCF-7 (breast), HT29 (colon) cancer cells and MCF10A (normal human breast epithelial) cells was tested and compared with those of cisplatin and bzimpy. The complexes displayed potent cytotoxic activity especially in MCF-7 and A549 cell lines, but they were practically inactive against the normal cells. Mechanistic studies with Mn and Cu complexes on A549 cells indicated that the complexes induced G0/G1 arrest. Both complexes increased intracellular ROS (reactive oxygen species) levels and successfully caused both mitochondrial dysfunction and double-strand DNA breaks. The up-regulated Bax and down-regulated Bcl-2 expression levels, caspase-3/7 activation and reduced Fas expression indicated that Mn and Cu induced ROS-dependent mitochondria-mediated intrinsic apoptosis in A549 cells.

Graphical abstract

Introduction

The complexes of saccharinate anion (sac) with different metal ions are an important class of coordination compounds [1]. Some of them display significant biological activity and the biological evaluation studies are mainly focused on bismuth(III), palladium(II), platinum(II), silver(I) and gold(I)/(III) complexes of sac. [Bi(sac)₃]_n and [Ph₂Bi(sac)]_n complexes exhibited in vitro antibacterial activity against Helicobacter pylori [2]. The silver(I) sac complexes with phosphines showed a promising growth inhibitory activity against Salmonella typhimurium and Staphylococcus aureus bacteria as well as towards A549 and MCF-7 cancer cells [3,4]. On the other hand, some palladium(II) and platinum(II) sac complexes were applied as potential anticancer agents [[5], [6], [7], [8], [9], [10], [11], [12], [13]]. Moreover, among a series of gold(I) and gold(III) sac complexes, [(PTA)Au(sac)] (PTA = 1,3,5-triaza-7-phosphaadamantane) was found to be highly cytotoxic against A2780 cancer cell line [14], while [(PEt₃)Au(sac)] displayed significant anti-inflammatory activities in vivo [15].

2,6-Bis(2-benzimidazolyl)pyridine (bzimpy) acts as a versatile ligand towards different metal ions and its metal complexes received considerable interest due to their biological properties [16]. Fe(II), Zn(II), Cd(II) and Hg(II) complexes of bzimpy showed broad-spectrum antimicrobial activity against both Gram positive and Gram negative bacteria [17]. [PtCl(bzimpy)]Cl exhibited higher cytotoxicity than cisplatin in HT29 and HepG2 cells [18], while Ru(II) complexes with bzimpy displayed a moderate anticancer activity towards a number of cancer cell lines [19]. Furthermore, [Rh(bzimpy)Cl₃] had significant cytotoxic activity in MCF-7 and HT29 cells compared to cisplatin [20].

The biological properties of the first-row transition metal complexes of sac received little attention and only a few papers appeared in this field. Several mono and binuclear Cu(II) sac complexes with the Schiff bases exhibited significant anticancer and antimicrobial activity [[21], [22], [23]], while Co(II), Ni(II) and Cu(II) sac complexes bearing dipyridophenazine displayed promising antimicrobial activity [24]. In the present study, new manganese(II), iron(II), cobalt(II), nickel(II) and copper(II) sac complexes with bzimpy were synthesized and structurally characterized. These complexes were tested against A549, MCF-7, HT29 cancer cells and nontumorgenic MCF-10A cells. The cytotoxicity results were compared with those obtained with the bzimpy ligand and cisplatin. The potent complexes were further subjected to clarify their mechanism of action in A549 cells using Hoechst/Propidium iodide double staining and flow cytometry assays including annexin V positivity and caspase 3/7 activity, detection of cell arrest, oxidative stress, mitochondrial membrane depolarization and double-strand DNA breaks (DSBs). In addition, Western blot analysis of apoptosis-associated proteins (Bax, Bcl-2 and Fas) was performed.

Section snippets

Synthesis, characterization and stability

Five novel metal(II) sac complexes of bzimpy were synthesized by the corresponding metal salts with bzimpy in the presence of Na(sac)·2H₂O in aqueous solution, and obtained in high yields over 85%. Although the same method was used to synthesize all the complexes, Mn, Fe and Cu were obtained as neutral complexes, whereas Co and Ni were ionic. The complexes were crystallized from aqueous solutions of DMF or isopropanol (i-PrOH) and the crystals of the complexes were used in the characterization

Conclusions

In conclusion, a series of new manganese(II), iron(II), cobalt(II), nickel(II) and copper(II) sac complexes of bzimpy were synthesized and structurally characterized by spectroscopic methods. The single crystal X-ray diffraction analysis indicates that Co and Ni are both cationic, while the other complexes are neutral. The complexes show considerable anticancer effects against A549 and MCF-7 cancer cells. All the complexes exhibit significant nuclease activity in the absence of external agents,

Measurements

C, H and N contents of the complexes were determined using a Costech elemental analyzer. UV–Vis and FTIR spectra were measured on a PerkinElmer Lambda 35 and PerkinElmer Spectrum Two FT-IR spectrophotometers, respectively. The ESI mass spectra were recorded using a Bruker Daltonics Microtof II-ESI-TOF mass spectrometer. Magnetic susceptibility was measured using a Sherwood Scientific MXI model Evans magnetic balance at rt. The electrical conductivity of the complexes in DMSO was estimated using

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

We thank Bursa Uludag University for financial support.

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New manganese(II), iron(II), cobalt(II), nickel(II) and copper(II) saccharinate complexes of 2,6-bis(2-benzimidazolyl)pyridine as potential anticancer agents

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Synthesis, characterization and stability

Conclusions

Measurements

Declaration of competing interest

Acknowledgements

Coord. Chem. Rev.

J. Photochem. Photobiol. B Biol.

Inorg. Chim. Acta.

Polyhedron

Bioorg. Med. Chem.

J. Inorg. Biochem.

Eur. J. Med. Chem.

Eur. J. Med. Chem.

J. Inorg. Biochem.

J. Inorg. Biochem.

Coord. Chem. Rev.

Eur. J. Med. Chem.

Inorg. Chim. Acta.

Eur. J. Med. Chem.

Polyhedron

Polyhedron

J. Mol. Struct.

Inorg. Chim. Acta.

Coord. Chem. Rev.

Inorg. Chim. Acta.

Neoplasia

Blood

Biochim. Biophys. Acta Bioenerg.