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Journal of Inorganic Biochemistry
Volume 197,
August 2019
, 110696
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Abstract
A water soluble trinuclear copper(II) complex and a binuclear cobalt(II) complex, namely Cu3(ppbm)2(SO4)3 (1) and Co2(ppbm)2(NO3)4 (2) (ppbm = 2-(pyridin-2-yl)-1-(pyridin-3-ylmethyl)- 1H-benzo[d]imidazole), have been successfully synthesized and characterized by elemental analysis, IR Spectroscopy, electrospray ionization mass spectra (ESI-MS). The interaction of the new complexes with DNA has been explored using spectroscopy methods, indicating that the complexes 1 and 2 bind to DNA via noncovalent interactions. DNA cleavage experiment suggested that the complex 1 exhibits efficient DNA cleavage activities in the presence of ascorbate (Asc), hydrogen peroxide may serve as the major cleavage active species. The cytotoxicity assay showed that complex 1 exhibited significant inhibitory activity toward the proliferation of several tumor cell lines, with a lower IC50 value than cisplatin and complex 2, indicating that it had the potential to act as effective anticancer agent. The morphological staining assays showed that 1 apparently induced the TFK-1 cells apoptosis. Besides, cellular uptake experiment on TFK-1 cells revealed that complex 1 accumulates primarily inside the nucleus. The apoptosis was attributable to the metal-assisted generation of reactive oxygen species (ROS).
Graphical abstract
A water soluble copper(II) complex 1 and cobalt(II) complex 2 bind to DNA via noncovalent interactions. Complex 1 exhibits efficient DNA cleavage and tumor cell inhibitory activity. Complex 1 accumulates primarily inside the nucleus and induced the TFK-1 cells apoptosis, which was attributable to generation of reactive oxygen species.
Introduction
The widespread success of cisplatin and related platinum-based drugs in the clinical treatment of various types of neoplasias has placed coordination chemistry of metal-based drugs in the frontline in the fight against cancer [1,2]. However, these platinum-based antitumor agents are associated with resistance, serious toxicity and other side effects during therapy processes, which severely limited its efficacy and applications in clinic [3,4]. To this end, alternative metal-based drug designs that are distinct from cisplatin and have different actions of mechanism at molecular level are being explored [5].
Currently, some inert metal complexes have been tested as anticancer agents [[6], [7], [8], [9], [10], [11]]. Copper as a biologically relevant element, is involved in enzymatic functions and could selectively permeate the cancer cell membranes [12]. Its complexes have exhibited potent anticancer activity with low general toxicity [13,14,15], whose biodistribution, accumulation, and proliferation inhibition process seem to be different from those of platinum complexes [16], which provide an opportunity to circumvent the tumor resistance to conventional platinum drugs. Also, cobalt, even being heavy metal, has been reported to be utilized in several tumor treatment [17]. Especially cobalt chloride, has been found to lead to apoptosis by inducing reactive oxygen species (ROS) generation [18,19,20,21], and CoCl2 comes to hypoxia mimicking mechanisms. Moreover, benzimidazole ligands complexed with diverse metals behave well in aspects of nuclease activities and cytotoxicity against tumor cells the planar, rigid and hydrophobic features [22]. In particular, benzimidazole derivative, such as (2-((quinolin-8-ylimino) methyl) pyridine), has been reported to possess a significant in vitro anticancer activities and markedly DNA cleavage, protein binding activities by coordinating with copper(II) [23].
With the exception of discovering new novel compounds structurally dissimilar to cisplatin, a recent strategy in the field of metal based anticancer drugs was proposed, which is designing some bimetallic or even multimetallic agents aiming to obtain biological and pharmacological features [12]. A trinuclear monofunctional platinum complex based on N,N,N′,N′,N″,N″-hexakis(2-pyridylmethyl)- 1,3,5-tris(aminomethyl) benzene performed higher cytotoxicity than cisplatin, which was also ascertained different from the scenario for cisplatin interaction with human serum albumin (HSA) [25]. Also, several multinuclear ntb-Cu(II) complexes exhibited a much stronger cytotoxicity than that of mononuclear Cu(II) complex (ntb = tris[(benzimidazol-2-yl)methyl]amine) [26].
Take these into account, two novel copper and cobalt-benzimidazole complexes were synthesized in this paper, hoping to obtain multinuclear complexes with improved potency and lowered side effects. Their structures have been characterized by several means. In vitro antiproliferative activity of Cu3(ppbm)2(SO4)3 (1) and Co2(ppbm)2(NO3)4 (2) (ppbm = 2-(pyridin-2-yl)-1-(pyridin-3-ylmethyl)- 1H-benzo[d]imidazole), was investigated against several cancer cell lines, the anticancer properties of the two complexes, which included cellular localization, cell death type determination, DNA interaction studies were explored using a variety of methods.
Section snippets
Materials and general methods
All reagents were commercially obtained and were used as received without further purification. Elemental analysis was carried out on a Flash EA 1112 elemental analyzer (Thermo Fisher Scientific, Waltham, MA, USA). Electrospray ionization mass spectra (ESI-MS) were measured on a Thermo Scientific LCQ fleet ESI-MS spectrometer. Infrared spectra with a KBr pellet were obtained using a Fourier transform infrared spectrometer (PerkinElmer, Waltham, MA, USA) in the region of 400–4000 cm−1. Circular
Crystal structure of Cu3(ppbm)2(SO4)3 (1)
As shown in Fig. 1, crystallographic analysis reveals that trinuclear copper complex 1 crystallizes in triclinic space group P-1.
The ORTEP diagram of complex 1 shows that there is a three copper centers in each structure. The asymmetric unit (ASU) consists of two ppbm ligands, three Cu (II) metal centers, three SO42− and five H2O molecules. Three copper metal centers have two different coordination modes, namely, the metal coordinate configuration of the two ends of the copper metal center Cu1,
Conclusions
In conclusion, this paper reported the synthesis and structural characterization of two complexes, Cu3(ppbm)2(SO4)3 (1) and Co2(ppbm)2(NO3)4 (2). The trinuclear complex 1 exhibited a moderate binding ability with DNA via intercalation mode. The new complexes were screened for cytotoxic activity against HCT116, Hela, TFK-1 cancer cell lines, and they were found to exhibit good cytotoxicity to cancer cells. The activity of complex 1 was significantly superior to that of cisplatin and 2. Complex 1
Acknowledgment
This study was supported by the National Natural Science Foundation of China (Nos. 21371046, 21401041).
References (44)
- L.M. Chen et al.
J. Inorg. Biochem.
(2016)
- A.Q. Ali et al.See AlsoSynthesis, characterization and properties of chromium(III) complex [Cr(SA)(en)2]Cl · 2H2OOptimal operation strategies to control the molecular weight distribution of polymer products
Polyhedron
(2014)
- J.A. Zhao et al.
Chinese. Chem. Lett.
(2017)
- X.B. Fu et al.
J. Inorg. Biochem.
(2015)
- G.K. Harris et al.
Mutat. Res.
(2003)
- C. Santini et al.
Inorg. Chim. Acta
(2004)
- F. Arnesano et al.
Coord. Chem. Rev.
(2009)
- T.W. Hambley
Dalton Trans.
(2007)
- M. Pellei et al.
Dalton Trans.
(2004)
- X.Y. Wang et al.
J. chem.soc.Rev.
(2013)
Curr. Opin. Chem. Biol.
(2014)
Angew. Chem. Int. Ed.
(2006)
Angew. Chem. Int. Ed.
(2011)
Bioactive luminescent transition-metal complexes for biomedical applications
Angew. Chem. Int. Ed.
(2013)
Med. Chem. Res.
(2013)
Anti Cancer Agents Med. Chem.
(2009)
J. Med. Chem.
(2013)
Med. 17Res. Rev.
(2010)
Biochem
(2009)
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Bioactive binuclear Cu(II) nanocomplex of 1,8-dihydro-6-13-di(2-hydroxybenzoyl)-dibenzo[b,i]-1,4,8,11-tetra-azacycloretradeca-4,6,11,13-tetraene) (H4L) derived from 3-formylchromone and o-phenylenediamine in molar ratio 2:2:2 has been designed via template methodology. The structure of macrocyclic ligand (H4L) has been determined by elemental analysis and FT-IR and 1HNMR spectroscopy. As well, the new complex with general formula: [Cu2(H2L)(NO3)2]; was characterized using elemental and thermal analyses, molar conductivity, magnetic susceptibility measurements, UV–Vis, FT-IR, EPR and mass spectroscopy. The crystallinity and morphology of the complex were analyzed by XRD and TEM measurements. On the basis of the spectroscopic data, the ligand behaves as a dianionic bis(tridentate) ligand through OON donor sites forming tetrahedral complex. Transmission electron microscope (TEM) analysis reveals that Cu(II) nanocomplex has high dispersed nanospherical morphology (2nm). In order to gain some insight into the structure–activity relationship; the binding of H4L and its Cu(II) nanocomplex with DNA was studied theoretically and by spectral titration. Absorption spectroscopic and docking investigation suggest that the H4L and Cu(II) complex bind to groove of DNA. The intrinsic binding constants (Kb) of H4L and Cu(II) complex with DNA are 0.69×104 and 0.90×104M−1, respectively. The antioxidant activities of prepared compounds were studied. Also, the cytotoxicity assay indicates that Cu(II) nanocomplex exhibited significant inhibitory activity toward HepG-2 cell line, with the lowest IC50 value with respect to H4L and standard drugs.
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Osmium(IV) pyrazole carbothioamide complexes with different substituted pyrazole carbothioamide heterocyclic ligands have been synthesized and characterized. The ligands have been characterized using 1H-NMR, 13C-APT, LC-MS, elemental analysis, and IR spectroscopy. Whereas, osmium(IV) compounds have been characterized using ESI-MS, ICP-OES, IR spectroscopy, magnetic, and conductance measurements. The compounds have been evaluated for various biological activities. The binding constant of ligands and complexes have been found in the range of 1.2–3.6 × 104 and 1.2–6.8 × 104 M−1, respectively. The docking energy values of complexes have been found in the range of −286.28 to −326.49 kJ/mol. The Ksv and Kf values of Os(IV) compounds evaluated using fluorescence quenching activity have been found in the range of 4.7–9.2 × 103 and 1.3–7.6 × 103 M−1, respectively. The minimum inhibitory concentration of osmium(IV) compounds and ligands have been found in the range of 50–75 µM and 120–135 µM, respectively. The LC50 values evaluated using brine shrimp lethality assay of osmium(IV) compounds and ligands have been found in a range of 7.52–16.12 µg/mL and 15.80–20.03 µg/mL, respectively.
First-row transition metal compounds containing benzimidazole ligands: An overview of their anticancer and antitumor activity
2021, Coordination Chemistry Reviews
Citation Excerpt :
This was one of the first examples of cobalt(II) compounds including mixed ligands, showing low cytotoxic compared to their copper(II) analogues. In addition, the biological activity of the binuclear cobalt(II) compounds Co-31, Co-32 and Co-33, was also tested in the same cell lines, under the same conditions as those of the copper(II) compounds Cu-76, Cu-80 and Cu-81 respectively (vide supra section 4.5) [102,104,105]. Here, the square-pyramidal compound Co-31 exhibited weak antiproliferative activity in SMMC-7721 with cell viability time- and dose-dependent; however, in the case of BGC-823 and HCT-116 the results were not significant.
Cancer can be defined as an irregular functioning of the cell cycle that results in a progressive loss of cell differentiation and uncontrolled cell growth. Moreover, despite countless research advances in prevention and therapy, cancer remains one of the leading causes of death worldwide. Besides surgery, radiotherapy and immunotherapy, chemotherapy is one of the most effective methods for cancer treatment. However, in many cases, commercial chemotherapeutic agents suffer of limited efficacy and serious side effects. In addition, major chemotherapy treatments often experience major hurdles, being multi-drug resistance (MDR) the biggest obstacle. Hence, major efforts have been devoted to the design of new anticancer drugs with enhanced efficacy against cancer cells with minimum side effects. Some of these commercial drugs include benzimidazole moieties on their structures, for instance abemaciclib, bendamustine, crenolanib, dovitinib, galeterone, glasdegib, liarozole, nocodazole, pracinostat, selumetinib, veliparib, among others. Thus, this manuscript reviews the in vitro anticancer and antitumor activity of the first-row transition metal compounds containing benzimidazole-based ligands on their structures. Factors such as the effect of ligand type, metal centre, molecular structure and geometry on biological activity were analysed; and the relevance of the first-row transition metals in the health area was discussed, including the different assays used in the determination of their cytotoxic activity. We hope that this review may serve to further stimulate and advance the design of novel metal coordination compounds including first-row transition metals and the use of benzimidazole ligands as an ideal combination to produce very active, yet selective potent metallodrugs.
Synthesis, DNA binding, antibacterial and anticancer properties of two novel water-soluble copper(II) complexes containing gluconate
2021, European Journal of Medicinal Chemistry
Citation Excerpt :
The results of the viscosity experiments were rendered as (η/η0)1/3 vs. R/[DNA] (R = [EB] or [Complex]) [58], where η was the relative viscosity of the CT-DNA solution with different concentrations of the complexes, and η0 was the relative viscosity of DNA alone. The binding modes and binding sites of the Cu(II) complexes with DNA were studied by using AutoDock 4.2 to carry out molecular docking [59,60]. The original structures of the complexes were sketched using YASARA1 software, and then geometry optimizations were performed with GAMESS (US) software via the hybrid density functional theory (B3LYP) method.
In this paper, two new Cu(II) complexes, [Cu(Gluc)(HPB)(H2O)]Gluc (CuG1) and [Cu(Gluc)(HPBC)(H2O)]Gluc (CuG2) (where HPB=2-(2′-pyridyl)benzimidazole, HPBC=5-chloro-2-(2′-pyridyl)benzimidazole, Gluc=d-Gluconic acid), with good water solubility were synthesized and characterized. These complexes exhibited a five-coordinated tetragonal pyramidal geometry. The DNA binding and cleavage properties of the complexes were investigated using multi-spectroscopy, viscosity measurement, molecular docking and gel electrophoresis analysis methods. The results showed that the complexes could interact with DNA by insertion and groove binding, and cleave CT-DNA through a singlet oxygen-dependent pathway in the presence of ascorbic acid. The studies on antibacterial and anticancer activities invitro demonstrated that both complexes had good inhibitory activity against three Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis, Listeria monocytogenes) and one Gram-negative bacterium (Escherichia coli) and good cytotoxic activity toward the tested cancer cells (A549, HeLa and SGC-7901). CuG2 showed higher antimicrobial and cytotoxic activities than CuG1, which was consistent with their binding strength and cleavage ability to DNA, indicating that their antimicrobial and cytotoxic activities may be related to the DNA interaction. Moreover, the cell-based mechanism studies have indicated that CuG1 and CuG2 could arrest the cell cycle at G2/M phase, elevate the levels of intracellular reactive oxygen species (ROS) and decrease the mitochondrial membrane potential (MMP). The results showed that the complexes could induce apoptosis through DNA-damaged and ROS-mediated mitochondrial dysfunction pathways. Finally, the invivo antitumor study revealed that CuG2 inhibited tumor growth by 50.44%, which is better than that of cisplatin (40.94%).
Synthesis, structure elucidation and dft study of a new thiazole–pyridine anchored nnn donor and it's cobalt(II) complex: In-vitro antitumor activity against U937 cancer cells, dna binding property and molecular docking study
2021, Journal of Molecular Structure
The reaction between 4-(2-bromoacetyl)benzonitrile and 2-benzoylpyridine thiosemicarbazone produces a tridentate NNN ligand, 4-(2-(2-(phenyl(pyridine-2-yl)methylene)hydrazinyl)thiazole-4-yl)benzonitrile (ppytbH). The ligand constructs an octahedral complex with composition [Co(ppytbH)2](ClO4)2.3(H2O) (1) when reacted with cobalt(II) perchlorate salt in acetonitrile methanol (1:1) solution. The structures of ppytbH and 1 have been established by single X-ray crystallography, spectroscopic (1H NMR, IR, UV-Visibleand fluorescence), thermal and electrochemical methods. The chemical reactivity and HOMO–LUMO energy of the compounds have been calculated using Density Functional Theory (DFT). The compounds ppytbH and 1 exhibit potential anticancer activity against U937 human monocytic cells and IC50 values are found 12.76±0.75 and 12.83±1.37µM, respectively. The fluorescence and molecular docking study interpret the intercalative DNA binding mode with the titled molecules.
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2020, Journal of Inorganic Biochemistry
Citation Excerpt :
In 1952, the first reported studies regarding the biological activity of cobalt complexes examined the toxicity of the optical isomers of [Co(en)3](NO3)3 (en = ethylenediamine) [3]. Since then, many cobalt complexes of biological interest have been reported with the majority of them showing antiproliferative [4–7], antimicrobial [8–10], antifungal [11,12], antiviral [13,14], and antioxidant [15–17] activity. Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed classes of medication for pain and inflammation [18].
The interaction of cobalt chloride with the non-steroidal anti-inflammatory drug indomethacin (Hindo) led to the formation of the polymeric complex [Co(indo-O)2(H2O)2(μ-Cl)]n·n(MeOH·H2O) bearing one chlorido bridge between the cobalt atoms. The presence of the nitrogen-donor co-ligands 2,2′-bipyridine (bipy), 2,2′-bipyridylamine (bipyam), 1,10-phenanthroline (phen) or 1H-imidazole (Himi) resulted in the isolation of complexes [Co2(μ-indo-O,O′)2(indo-O)2(bipy)2(μ-H2O)]·3.3MeOH, [Co(indo-O,O′)2(bipyam)]·0.9MeOH·0.2H2O, [Co(indo-O,O′)2(phen)] (4) and [Co(indo-O)2(Himi)2] (5), respectively, where the indomethacin ligands were coordinated in diverse manners. The study of the affinity of the complexes for calf-thymus DNA revealed their intercalation between the DNA-bases. The binding of the complexes to albumins was also examined and the corresponding binding constants and binding subdomain were determined. The free radical scavenging activity of the compounds was evaluated towards 1,1-diphenyl-picrylhydrazyl and 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid). Molecular modeling calculations may usually provide a molecular basis for the understanding of both the impairment of DNA by its binding with the studied complexes and the ability of these compounds to transportation through serum albumin proteins. This study can provide information for the elucidation of the mechanism of action of the compounds in a molecular level.
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