Ternary copper(II) complexes with amino acid chains and heterocyclic bases: DNA binding, cytotoxic and cell apoptosis induction properties
Graphical abstract
Three new ternary copper(II) complexes which have potential chemotherapy characteristics with reduced Schiff base ligand and heterocyclic bases, and the ternary copper(II) complexes had significant cytotoxic activity against the human cancer cell lines. They also can induce the cancer cell apoptosis.
Introduction
Nowadays, the major focus of research in chemotherapy for cancer includes the identification, characterization and development of new cancer chemopreventive agents [1]. Cancer chemotherapy with platinum drugs has been used since the discovery of cisplatin's anti-proliferate properties by Rosenberg et al. [2]. As they possesses inherent limitations such as significant toxic side effects, general toxicity, and acquired drug resistance, attempts are being made to replace the platinum-based drugs with suitable alternatives, and numerous metal based complexes are synthesized and screened for their anticancer activities [3], [4], [5], [6], [7], [8].
Copper(II) ions are very important for many organisms. Like other trace metals, copper is essential to proteins that are involved in several biological processes, including respiration, metabolism, DNA synthesis, and oxidation–reduction reactions. In biological systems, copper exists as a variety of complexes which due to the coordinated forms of copper are more stable than the corresponding ionic species [9], [10], [11], [12]. 1,10-Phenanthroline (phen) and its substituted derivatives, both in the metal-free state and coordinated state, disturb the functioning of a wide variety of biological systems. The copper(II) complexes containing bpy or 1,10-phenanthroline have attracted much attention because they are much more active in the presence of the heterocyclic ligands [13], [14], [15]. Recently, several copper complexes containing heterocyclic bases, such as 1,10-phenanthraline, were screened for their anticancer activity [10], [13], [14], [15], [16], [17], [18], [19]. Tsang et al. reported that incubation of a human hepatic cell line (HepG2) with [Cu(phen)2]2 + can result in the internucleosomal DNA fragmentation [20].
It is well know that apoptosis is a crucial process related to a number of diseases. The apoptosis induced by copper and its complexes have been investigated extensively on the premise that endogenous metals may be less toxic [21], [22], [23], [24], [25]. Copper and its complexes can catalyze the formation of reactive oxygen species (ROS) [26]. As critical triggers in cell apoptotic pathways, the formation of ROS along with other intracellular cascade reactions (such as disruption of mitochondrial transmembrane potential, upregulation of Bax, down regulation of Bcl-2, and deficiency of p-53) can finally lead to cell apoptosis [27], [28], [29], [30]. Therefore, more accurate and indepth understanding about copper-induced apoptosis will be helpful in the development of copper-based antitumor drugs.
All of the above facts have stimulated our interest in the present work. Herein we report the synthesis, the calculated energy-minimized structure, DNA-binding, cytotoxic and apoptosis induction activities of three ternary copper(II) complexes [Cu(phen)(TBHP)]H2O (1), [Cu(dpz)(TBHP)]H2O (2) and [Cu(dppz)(TBHP)]H2O (3) (as shown in Scheme 1, phen = 1,10-phenanthroline, dpz = dipyrido [3,2-d:2′,3′-f]quinoxaline, dppz = dipyrido[3,2-a:2′,3′-c] phenazine). In order to investigate the biological activities of complexes 1–3, such as DNA binding, cytotoxicity and apoptosis induction activities, several methods were employed. Furthermore, the primary aim of the current study is to determine the cancer chemotherapeutic potential of metal-free phen and its substituted derivatives by using three human-derived cancer model cell lines of human lung cancer (A549), human esophageal cancer (Eca109) and human gastric cancer (SGC7901). Most importantly, our current results suggest the complexes 1–3 own the potential activities of conducting cell proliferation and apoptosis of three human cancer cells.
Section snippets
Materials and instrumentation
All starting materials were obtained commercially and used as received. Calf thymus DNA (CT-DNA) and ethidium bromide (EB) were obtained from Sigma Chemical Co. UV–visible (UV–vis) spectrometer was employed to check the solution of CT-DNA purity (A260: A280 > 1.80) and the concentration (ε = 6600 M− 1 cm− 1 at 260 nm) in the buffer. The ternary copper(II) complexes were dissolved in a mixture solvent of 5% CH3OH and 95% Tris–HCl buffer (5 mM Tris–HCl, 50 mM NaCl, pH 7.1) at concentration 1 × 10− 3 M. The A549
Syntheses
The mixed-ligand complexes of general formula [Cu(TBHP)(phen)]·(H2O), [Cu(TBHP)(dpz)]·(H2O) and [Cu(TBHP)(dppz)]·(H2O) were synthesized by a straightforward synthesis which yielded a blue or green microcrystalline powder. The reduced molar ratio of Schiff base ligand with corresponding polypyridyl ligands and copper(II) salt is 1:1:1. All the attempts to grow single crystals of diffractometric quality for these complexes failed. The new coordination complexes were soluble in water/ethanol in
Conclusion
Finally, we found that our copper complexes possess the potential for development as an agent for human cancer therapy. Further experiments are necessary to analyze the action of copper complexes in vivo.
Abbreviations
- CT-DNA
calf-thymus DNA
- ROS
reactive oxygen species
- EB
ethidium bromide
- MTT
3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide
- PVDF
polyvinylidene fluoride
- DMF
dimethylformamide
- DFT
density functional theory
- ECP
effective core potential
- HOMO and LUMO
highest occupied and the lowest unoccupied molecular orbitals, respectively
Acknowledgments
This work was supported in part by the fund of Science and Technology of Yixing (2013-21), the fund of the Natural Science Foundation of Jiangsu (BK20141122), the National Natural Science Foundation of China (21404033, 21401046, 21001040), Doctoral Scientific Fund Project of Henan Polytechnic University (72515/086, 61307/003), and the Foundation of State Key Laboratory of Solid Lubrication (LSL-1207).
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