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Keywords: The [Cu2(2,2′-bipy)2(L1)4] (1), [Cu2(1,10-phen)2(L1)4] (2), [Cu(2,2′-bipy)(L2)2]n (3) and [Cu2(1,10-phen)2(L2)4]
Mixed ligand Cu(II) complexes (4) complexes, where HL1 – 5-phenyltetrazole, and HL2 – 1H-tetrazole, have been synthesized. All complexes
1,10-Phenanthroline have been characterized by elemental analysis, IR, EPR spectroscopy and X-ray diffraction. The complexes
Tetrazole possess distorted tetragonal-pyramidal coordination geometry. Compounds 1, 2, 4 show μ-5-phenyl-tetrazole/
Cytotoxicity
tetrazole bridged dinuclear structures, while compound 3 reveals polymeric structure. The effect of compounds
MCF-7
on viability of the MCF-7 and Hep-2 cell lines was investigated in vitro. The study showed that tetrazole ligands
Hep-2
HL1 and HL2 are non-toxic at tested concentrations (1–50 μM), while 1,10-phen and 2,2′-bipy posses cytotoxicity.
All of the complexes exhibit significant dose-dependent cytotoxic effect and have the potential to act as efficient
cytotoxic drugs. The complexes [Cu(1,10-phen)Cl2] (5) and [Cu(2,2′-bipy)Cl2] (6) have also been obtained to
establish the influence of insertion of tetrazole ligands in compounds on their cytotoxic properties.
⁎
Corresponding author.
E-mail address: lisalider@ngs.ru (E.V. Lider).
https://doi.org/10.1016/j.ica.2018.12.011
Received 31 October 2018; Received in revised form 6 December 2018; Accepted 6 December 2018
Available online 07 December 2018
0020-1693/ © 2018 Published by Elsevier B.V.
J.A. Eremina et al. Inorganica Chimica Acta 487 (2019) 138–144
derivatives have already found their application in medicine as drugs All other complexes were synthesized by following a procedure si-
with antiviral, antifungal and antibacterial activity [15]. However, milar to that of [Cu2(2,2′-bipy)2(L1)4].
tetrazoles and copper complexes with tetrazole derivatives have been
poorly studied as antitumor agents. One of the possible reasons is the 2.3.2. Synthesis of [Cu2(1,10-phen)2(L1)4] (2)
tendency of tetrazoles to form practically insoluble metal-organic co- Complex [Cu2(1,10-phen)2(L1)4] have been previously synthesized
ordination polymers, which limits their use in medicine. by M. Saha and et al. using different method (metal mediated [2 + 3]
Many copper phen/bipy complexes with other co-ligands have been cycloaddition reaction between copper bound azide polymer and dif-
extensively studied, but there is still a gap to design and study new ferent organonitriles) [18].
ones. We were interested in the evaluation of the biological properties An aqueous solution (3 ml) of copper acetate (0.020 g, 0.1 mmol)
of complexes that combine pharmacologically active products (tetra- and an ethanol solution (2 ml) of 1,10-phenantroline (0.020 g,
zole derivatives) and endogenous metals, thereby insights were made 0.1 mmol) were mixed and the resulting deep blue solution was stirred
into the cytotoxicity of copper(II) complexes with tetrazole and diimine for 5 min. To the mixture was added an ethanol solution (3 ml) of HL1
ligands. In this work, we have synthesized a series of mixed-ligand (0.029 g, 0.2 mmol). During the stirring a solid precipitated from the
copper(II) complexes of the type [Cu2(diimine)2(tetrazole)4] and [Cu solution. Blue colored precipitate was filtered out, washed with ethanol
(diimine)(tetrazole)2]n, where tetrazole is 5-phenyltetrazole (HL1) or and water and dried in air. Deep blue crystals were obtained after a
1H-tetrazole (HL2) and diimine is 2,2′-bipyridine or 1,10-phenanthro- month from mother liquor.
line and studied their cytotoxic activity against MCF-7 (human breast Yield (0,02 g): 38%. Elemental analysis (%): Calc. for C52H36N20Cu2:
adenocarcinoma) and Hep-2 (human larynx carcinoma) cell lines. C, 58.5; H, 3.4; N, 26.2. Found: C, 57.4; H, 3.1; N, 25.9.
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J.A. Eremina et al. Inorganica Chimica Acta 487 (2019) 138–144
140
J.A. Eremina et al. Inorganica Chimica Acta 487 (2019) 138–144
Table 2
Assignment of the IR spectral bands of HL1, HL2 and complexes 1–4.
Compound Assignment, cm−1
HL1 1 2 HL2 3 4
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J.A. Eremina et al. Inorganica Chimica Acta 487 (2019) 138–144
Table 3 Ligand HL1 showed negligible cytotoxic activity against Hep-2 cell
The g-tensor values of compounds 1 and 2 at 300 K obtained by the EPR line. As can be seen in Fig. 4A treatment of Hep-2 cells for 48 h with HL1
spectroscopy. initiated death no > 20% of cells after incubation with highest tested
Complex g⊥ g|| compound concentration (50 µM) (Fig. 4A). The 48-h incubation with
[Cu2(2,2′-bipy)2(L1)4] had stronger effect on Hep-2 cells: 19% and 29%
1 2.077(3) 2.27(1) of dead cells after incubation with 25 and 55 µM of the drug respec-
2 2.067(2) 2.25(1)
tively, while the percentage of apoptosis was 26–30%. Exposure of Hep-
2 cells to [Cu2(1,10-phen)2(L1)4] for 48 h was more potent than effect of
[Cu2(2,2′-bipy)2(L1)4] and initiated cell death at a level 96% already at
5 µM concentration of drug (Fig. 4E and F). The cytotoxic effect of the
3.4. EPR results complex [Cu2(1,10-phen)2(L2)4] with the nontoxic ligand HL2 on Hep-2
cells appears at concentration of 5 μM: the percentage of dead cells
Spectra are described by spin-Hamiltonian increases to 28%. At the same time, for the complex [Cu(2,2′-bipy)
H = g (Hx S x + Hy S y ) + g Hz Sz with S = 1/2 and the axial g-tensor (L2)2]n activity was observed only against the MCF-7 cell line. More-
(values presented in Table 3). The axial symmetry of g-tensors and over, our investigation revealed that MCF-7 cell line was significantly
unresolved hyperfine structure may point out to the presence of the more sensitive to 2,2′-bipyridine containing complexes 1, 3 than Hep-2
weak exchange interaction between paramagnetic centers. The mole- cell line. High level of apoptosis (30–40%) was observed while treating
cules of complexes are dimers according X-ray diffraction data, but MCF-7 cells with [Cu2(1,10-phen)2(L1)4] and Hep-2 cells with
there is no dipole-dipole interaction between paramagnetic centers [Cu2(2,2′-bipy)2(L1)4] (Fig. 4B and E).
despite the small distance between copper ions (R(Cu-Cu) = 3,99 (1), The half maximal inhibitory concentration (IC50) was calculated
3,97 (2)). from curves constructed by plotting cell survival (%) versus drug con-
centration (µM). Obtained IC50 values are summarized in Table 4. The
3.5. In vitro cytotoxicity study IC50 value of [Cu(2,2′-bipy)Cl2] was 34,7 μM, thus, replacement of
chloride-ion with nontoxic ligand HL1 in [Cu2(2,2′-bipy)2(L1)4] caused
The cytotoxic activity of HL1, HL2, 2,2′-bipyridine, 1,10-phenan- negligible reduction of cytotoxic activity (IC50 = 40,1 μM). Complex
troline, 1–6, CuCl2 and Cu(OAc)2 on the viability of Hep−2 cells was [Cu2(1,10-phen)2(L1)4] displayed the highest potency in killing Hep−2
examined in the presence of different concentrations of tested com- cells with an IC50 value of 2,7 μM. Compared to the cytotoxicity of [Cu
pounds dissolved in ethanol (copper(II) salts were dissolved in water). (1,10-phen)Cl2] (IC50 = 3,03 μM), presence of ligand HL1 in [Cu2(1,10-
MCF-7 cell line was also used to evaluate cytotoxicity of complexes 1–4. phen)2(L1)4] practically did not influence the IC50 value. The same
The cytotoxicity studies were carried out using dual staining with pattern was observed for mixed-ligand complexes with HL2.
Hoechst 33342/propidium iodide (PI) with differentiation of cells into Several trends were revealed from the cytotoxicity screening.
live and apoptotic. The half maximal inhibitory concentration (IC50) Firstly, cytotoxicity of the resulting compounds was apparently related
was defined as drug concentration that reduces the number of living to the presence of 1,10-phenanthroline and 2,2′-bipyridine in com-
cells by 50%. plexes. The IC50 values of complexes remained approximately at the
1,10-phenanthroline is a well-known divalent metal chelating same level as IC50 values of toxic ligands (1,10-phen, 2,2′-bipy). Thus,
agent, that forms strong complexes with most metal ions. Furthermore, insertion of HL1 and HL2 had a slight effect on cytotoxic activity of
1,10-phen possesses many biological activities, it is known as DNA in- complexes. However, it should be noted that complexation of copper
tercalating agent, cholinesterase and protease inhibitor [26–28]. acetate(II) with 1,10-phen and nontoxic ligands HL1 and HL2 led to the
Copper complexes with 1,10-phen also have DNA binding and cleaving formation of complexes with a bit higher cytotoxicity than 1,10-phen.
ability [29,30] while planar geometry of 1,10-phen facilitates the in- However, this pattern was not observed for 2,2′-bipy and its complexes.
tercalative interaction with DNA [10,31]. Biological properties of 2,2′- Secondly, treatment of cells with 1,10-phen and 2,2′-bipy led to fairly
bipy and its complexes have been little investigated. In this study, 1,10- high level of apoptosis (20–40%), while the percentage of apoptotic
phenanthroline and 2,2′-bipyridine were tested under the same condi- cells decreased after exposure to complexes. Cell death was primarily
tions as complexes. The IC50 values of 1,10-phen and 2,2′-bipy against due to the loss of membrane integrity without apoptosis. Thirdly,
Hep-2 cell line were 12,1 ± 0,2 and 6,9 ± 0,9 µM respectively. complexes containing 1,10-phenantroline were much more toxic than
Moreover, diimine ligands exhibit strong induction of apoptosis complexes containing 2,2′-bipyridine. This reduction of the cytotoxic
(30–40%) in Hep-2 cancer cells in comparison with complexes (Fig. 4C activity of 2,2′-bipy-complexes is possibly related to the fact that 1,10-
and D). phenanthroline provides more planarity for its complexes and enables
Cytotoxicity was not observed at tested concentrations (1–50 μM, their stronger intercalative interactions with DNA compared to com-
72 h) after exposing cells to water solutions of Cu(OAc)2 and CuCl2. plexes with 2,2′-bipy [38].
These results are in agreement with those reported in the literature
[32,33]. Li et al. studied the cell viabilities of different concentrations 4. Conclusions
of Cu(OAc)2 and CuCl2 against HaCaT (Human adult low Calcium high
Temperature) keratinocytes by MTT assay. The cytotoxic effects of A series of mixed-ligand copper(II) complexes with 1,10-phenan-
these copper compounds on HaCaT cells were observed at concentra- throline, 2,2′-bipyridine and tetrazole ligands have been synthesized
tion > 580 μM after 48 h of incubation. and fully characterized. All complexes possess cytotoxic activity against
[Cu(2,2′-bipy)Cl2] and [Cu(1,10-phen)Cl2] complexes were pre- Hep-2 and MCF-7 human cell lines. Cytotoxicity of the compounds was
pared according to the literature procedure [34] and used as a com- apparently related to the presence of cytotoxic 1,10-phenanthroline and
parison. The IC50 values of these two complexes were in the low mi- 2,2′-bipyridine in complexes. Complexes containing 1,10-phenanthro-
cromolar range and comparable to the results reported in the literature line were much more toxic than complexes containing 2,2′-bipyridine.
(IC50 < 8 µM for all tested cell lines) [35,36]. Nave et al. have reported Our results indicate that apoptosis wasn’t involved in mechanism of
that [Cu(1,10-phen)Cl2] showed potent cytotoxic effect toward dif- action of tested complexes. Cell death was primarily due to the loss of
ferent tumor cell lines studied by MTS assay. They also incorporated membrane integrity without apoptosis. But treatment of cells with 1,10-
complex in long circulating liposomes and showed that it kept the cy- phenanthroline and 2,2′-bipyridine led to fairly high level of apoptosis
totoxic properties [37]. (20–40%).
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J.A. Eremina et al. Inorganica Chimica Acta 487 (2019) 138–144
Fig. 4. Effect of some compounds on the viability of Hep-2 and MCF-7 cells determined by dual staining with Hoechst 33342/propidium iodide: A – HL1 (Hep-2 cell
line), B – [Cu2(1,10-phen)2(L1)4] (2) (MCF−7 cell line), C – 2,2′-bipyridine (Hep-2 cell line), D – 1,10-phenanthroline (Hep-2 cell line), E – [Cu2(2,2′-bipy)2(L1)4] (1)
(Hep−2 cell line), F – [Cu2(1,10-phen)2(L1)4] (2) (Hep-2 cell line).
Table 4 Acknowledgments
Cytotoxic activity (expressed by IC50) of the studied complexes and ligands
against Hep-2 and MCF-7 cell lines. This work was supported by the Russian Science Foundation
Compound IC50 (µM)–Hep-2 IC50 (µM)–MCF-7 (Project № 18-73-00294).
The authors thank Anna P. Zubareva and Valentina V. Ankudovich
Cu(OAc)2 > 50 – for the elemental analysis, Nina I. Alferova for the IR data, and Ilya V.
CuCl2 > 50 –
Korolkov for the X-ray phase analysis data. This work involved the use
HL1 > 50 –
[Cu2(2,2′-bipy)2(L1)4] (1) 40,1 ± 1,7 10,1 ± 5,1 of equipment from the Multi-Access Center “Proteomics” of Federal
[Cu2(1,10-phen)2(L1)4] (2) 2,7 ± 0,2 4,8 ± 0,5 Research Center of Fundamental and Translational Medicine
HL2 > 50 – (Novosibirsk, Russia).
[Cu(2,2′-bipy)(L2)2]n (3) > 50 31,9 ± 9,8
[Cu2(1,10-phen)2(L2)4] (4) 6,1 ± 0,5 3,8 ± 0,1
2,2′-Bipyridine 6,9 ± 0,9 –
1,10-Phenantroline 12,1 ± 0,2 – Appendix A. Supplementary data
[Cu(2,2′-bipy)Cl2] (5) 34,7 ± 0,4 –
[Cu(1,10-phen)Cl2] (6) 3,03 ± 0,39 – Supplementary data to this article can be found online at https://
doi.org/10.1016/j.ica.2018.12.011.
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