Theoretical Studies on DNA-Cleavage Mechanism of Copper(II

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Computational Biochemistry

Theoretical Studies on DNA-Cleavage Mechanism of Copper(II) Complexes: Probing Generation of Reactive Oxygen Species Tifang Miao, Qinghua Deng, Hui Gao, Xianliang Fu, and Shuang Li J. Chem. Inf. Model., Just Accepted Manuscript • DOI: 10.1021/acs.jcim.8b00055 • Publication Date (Web): 12 Mar 2018 Downloaded from http://pubs.acs.org on March 12, 2018

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Journal of Chemical Information and Modeling

Theoretical Studies on DNA-Cleavage Mechanism of Copper(II) Complexes: Probing Generation of Reactive Oxygen Species Tifang Miao*,†,‡, Qinghua Deng†, Hui Gao§, Xianliang Fu†, and Shuang Li† †

School of Chemistry and Materials Science, Huaibei Normal University, Huaibei 235000, P. R. China.

‡

Anhui Key Laboratory of Energetic Materials, Huaibei Normal University, Huaibei 235000, P. R.

China. §

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China.

ABSTRACT: Theoretical studies on DNA-cleavage properties of [Cu(bba)(diimine)] 1–4 have been carried out using density functional theory (DFT) and docking methods. The optimized structures of Cu(II) complexes were docked into DNA, glutathiones (GSH) and ascorbic acids (VC) so that the corresponding docking models were obtained. To explore DNA-cleavage properties of Cu(II) complexes, the docking models of complexes with GSH and VC were further optimized using DFT method, while the docking models of complexes with DNA were optimized using QM/MM method because DNA is a supramolecular system. The rate constants ket between complexes and DNA, GSH and VC, oxidation-reduction potentials of complexes, and binding energies of complexes with GSH and VC were computed. The DNA-cleavage abilities of Cu(II) complexes in the presence VC, GSH and H2O2 were explored and the experimental results could be reasonably explained. Finally, the DNA-cleavage mechanism of Cu(II) complexes was described in detail, which would contribute to future design of novel anticancer Cu(II) complexes.

INTRODUCTION Cancer, also known as malignant tumour, is a big threat to the human life. Exploring novel anticancer drugs with high efficacy and less toxicity has been a hot topic in the medical field1,2. Although metal-based anticancer drugs, e.g. cisplatin, have been applied to the clinical treatment of many types of cancer, yet their side effects, such as leukopenia,

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myelosuppression, neurotoxicity and nephrotoxicity, also cause inevitable harm to the health of patients. Hence, there is an urgent need to develop other metal complexes with high efficacy and less toxicity. Copper, as a fundamental micronutrient of cells, plays an important role in biological functions of human body. Since reduction of the Cu(II) to Cu(I) can induce DNA cleavage, copper complexes might be promising alternatives to platinum agents. 3,4 Many Cu(II) complexes can effectively cleave DNA by the generated reactive oxygen species (ROS), for example, singlet oxygen (1O2), superoxide anion radical (O2•−), hydroxyl radical (OH•), etc.5–9 It is widely believed that Cu(II) reduced to Cu(I) can lead to the generation of ROS.3,10,11 Some researchers believe that the generated OH• play an important role in DNA-cleavage, with the following reaction manner: (a) Cu(I) + H2O2→Cu(II) + OH− + OH•. Some regard O2•− crucial to DNA cleavage, with the following reaction manner: (b) Cu(I) + O2→[Cu(I)-O2⇌Cu(II)-O2•−]→Cu(II) + O2•−. Besides, other researchers believe that Cu(II) complexes cleave DNA by the generated 1O212 for some unknown reasons. In addition, there are conflicting views on Cu(II) complexes causing DNA cleavage, To be specific, some researchers believe that Cu(II) complexes bind to ascorbic acids (VC) first12,13 before the formed Cu(I) complexes cleave DNA by Eq. (a) or (b). Other have shown that Cu(II) complexes bind to glutathiones (GSH) first10, and similarly, the formed Cu(I) cleave DNA by Eq. (a) or (b). In brief, the DNA-cleavage mechanism of Cu(II) complexes is still unclear with some unsolved problems as follows. How does these ROS come about in vivo? What quantity of ROS is generated? How does the generated ROS cleave DNA? And what is the ROS-cleaving-DNA mechanism? Until recently, it is difficult to solve the above problems in experiment. Interestingly, 1O2, OH• and O2•−, etc, can be determined experimentally for Ru(II) complexes only under irradiation.14–16 As is known, the irradiation can accelerate the movement of electrons in complex. These moving electrons may contribute to ROS generated. Based on this idea, the reason of ROS generated by Cu(II) complexes will be explored in this work. Theoretical methods will also be used to explain the abilities of ROS in cleaving DNA in vivo. To explore the DNA-cleavage properties of Cu(II) complexes theoretically, we adopt 2


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the density functional theory (DFT) method to compute the related properties. Here, we select the experimentally reported Cu(II) complexes17 [Cu(bba)(diimine)] 1–4, where bba is N,N′-bis(benzimidazol-2-ylmethyl)amine, and diimine = bpy(1), phen (2), 5,6-dmp (3) and dpq (4) (bpy = 2,2′-bipyridine, phen = 1,10-phenanthroline, 5,6-dmp = 5,6-dimethyl-1,10-phenanthroline, dpq = dipyrido[3,2-d: 2′,3′-f]quinoxaline), to perform a theoretical study18,19. The DNA-cleavage abilities of copper complexes under different conditions will be explored. The results will be of great significance for uncovering DNA-cleavage mechanism by Cu(II) complexes.

THEORY AND COMPUTATIONAL METHODS Geometric Optimizations of Complexes in Ground State. There are numerous glutathiones (GSH) and ascorbic acids (VC) residing in vivo. Hence, to study the interaction of Cu(II) complexes with GSH and VC, we show the structural diagrams of Cu(II) complexes 1–4, GSH and VC in Figure 1 and 2. A full geometry optimization was carried out on the complexes, GSH and VC in the ground state at the level of UB3LYP/6-31G(d). Based on the optimized results, the frequency computations were performed to verify whether the optimized geometries were an energy minimum.

Figure 1. Structural diagrams of complexes 1–4 and atomic label.

HO HS O HO

O

O

H

O

O

HO

H N N H O

OH NH2

OH HO

GSH

VC

Figure 2. Structural diagrams of GSH and VC.

Molecular Docking and Optimization. The optimized geometries of these Cu(II)

3



complexes 1–4 were further docked into DNA (data source: Protein Data Bank, pdb Id: 1BNA), glutathione (GSH) and ascorbic acid (VC) using Dock6.0 program20,21. The box size, grid space, energy cutoff distance, and maximum orientation were set as 30 Å, 0.3 Å, 9999 Å, and 200,000, respectively. The other docking parameters were set to default values. The mol files of docking structures for complexes with DNA were included in the Supporting Information. The obtained docking structures of complexes with DNA were further optimized by QM/MM method. The whole model was divided into two layers, i.e., high layer and lower layer. The high layer, the Cu(II) complex and its 6 surrounding base pairs, was optimized at the level of UB3LYP/6-31G(d). The other atoms resided in the lower layer, which was optimized using the UFF force. Hence, the stable structures of complexes with 6 base pairs of DNA were obtained. As GSH and VC were small molecules, their docking models with complexes were further optimized at the level of UB3LYP/6-31G(d), and the mol files of optimized results were included in the Supporting Information. Meanwhile, the frequency computations were also performed to verify whether the optimized structures were an energy minimum. Calculation of Oxidation-reduction Potentials of Complexes. On the basis of the optimized structures of complexes, we obtained the Gibbs free energies using single point computations in vacuo. Meanwhile we obtained the Gibbs free energies in aqueous solution by single point computations in aqueous solution with the CPCM model22,23. We used Scheme 1 to compute the standard redox potentials of these Cu(II) complexes. Take [Cu(bba)bpy]2+ complex for example, and the computational principle is described as follows: For comparison with experimental results, the standard redox potentials of ground-state Cu(II) complexes in contrast to the standard calomel electrode (SCE) are computed by Eq.1 using a thermodynamic-cycle method ( see Scheme 1). The Gibbs free energy change of the standard hydrogen electrode (SHE) (∆G◦SCE =−4.43 eV) is taken from the experimental result24, which equals to the Gibbs free energy change of Eq. 8. The Gibbs free energy change of SCE (∆G◦SCE = −4.1888 eV) was obtained by adding 0.2412 eV (the standard potential of SCE relative to SHE is −0.2412 V) to that of SHE (−4.43 4


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eV),25,26 which equals to the Gibbs free energy change of Eq. 9. ∆G(ogas )

∆Go (2)

∆Go (1)

∆Go =0

∆ G (oaq ) Scheme 1 Calculation of redox potentials of Cu(II) complexes using thermodynamic cycles.

o [ Cu(bba)bpy ] ( n+1) + /[ Cu(bba)bpy ] n +

E

=−

o ∆G[oCu(bba)bpy]( n+1)+ /[ Cu(bba)bpy ]n+ − ∆GSCE

nF

(1)

where ∆G[oCu(bba)bpy ] ( n+1)+ /[ Cu(bba)bpy ] n+ = − ∆Gaqo

(2)

o ∆Gaqo = ∆Ggas + ∆G o (2) − ∆G o (1)

(3)

o o o ∆Ggas = ∆H gas − T∆Sgas

(4)

o o ∆H gas = ∆ε SCF + ∆H corr + ∆ε ZPE

(5)

∆G o (2) = G o [Cu(bba)bpy]( n +1) + (aq ) − G o [Cu(bba)bpy]( n +1) + (gas)

(6)

∆G o (1) = G o [Cu(bba)bpy]n + (aq) − G o [Cu(bba)bpy]n + (gas)

(7)

1 H + (aq) + e- (gas) → H 2 (gas) 2 1 Hg 2 Cl2 (aq) + e(g) → Hg + Cl- (aq) 2

(8) (9)

All energies were computed under normal conditions, that is, at 298.15 K and 1 atmospheric pressure, with the concentration of Cu(II) complex in water at 1 mol/L and in the gas at 1 mol/L.

Calculation of Electron-transfer Rate Constants. The theory of Marcus semi-classical model27,28 can deal with the nonadiabatic electron-transfer (ET) process. Based on the theory, the rate constant can be computed by the following equation:

5



k et =

2π H h

2

DA

(

1 ) 1 / 2 exp[ − ( ∆ G 0 + λ ) 2 /( 4 λ RT )] 4 πλ RT

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(10)

Here, λ is the reorganization energy, h is the Planck’s constant, HDA is the ET matrix element, T is the temperature, and ∆G◦ is the normal Gibbs free energy change of the electron-transfer reaction, which was computed using Eq. 4.

Calculation of the Reorganization Energy λ. Research shows that Cu(II) complex is easily reduced Cu(I) complex when meeting reducing molecules, such as GSH, VC and DNA. This implies that Cu(II) complex can easily obtain an electron, Take [Cu(bba)bpy]2+ and GSH for example, and this process can be expressed as follows: [Cu(bba)bpy]2+ + GSH(VC, DNA)→[Cu(bba)bpy]+ +GSH+

(11)

According to reaction (11), electrons transfer from GSH to complex, at a moving speed of ket. After ET, the geometry of the system is relaxed, and now the reorganization energy (λ) is the average of λ1 (GSH) and λ2 (Cu complex), i.e.,

λ=

λ1 + λ2

(12)

2

To compute reorganization energy, the [Cu(bba)bpy]2+ and GSH in reaction (11) are replaced with the optimized complex and GSH in the ground state, respectively. Similarly, the [Cu(bba)bpy]1+ and GSH+ in reaction (11) are replaced with the complex and GSH of the optimized docking model, respectively. We first obtain the total energy of E(GSH) at its optimized geometry in the ground state, and the total energy of E(GSH+) at its geometry in the optimized docking models. Additionally, we also compute the energy E′(GSH) at the geometry of GSH+ and the energy E′(GSH+) at the geometry of GSH. Thus, we obtain λ1 by λ1= E′(GSH)+ E′(GSH+) – E(GSH) – E(GSH+)

(13)

Similarly, we obtain λ2 by λ2= E′[Cu(bba)bpy]2+ + E′[Cu(bba)bpy]1+ – E[Cu(bba)bpy]2+ – E[Cu(bba)bpy]1+ (14) The total reorganization energy λ was obtained via Eqs. 12, 13 and 14. Similarly, the λ of complex with VC was also obtained. As

a

hyper-molecular

system,

DNA cannot

be

optimized

fully

using

quantum-chemical method. The computational details of λ for complex with DNA can be described as follows. 6


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The DNA and [Cu(bba)bpy]2+ in reaction (11) are replaced with DNA of the docking model in the high layer and the optimized complex, respectively. Similarly, the [Cu(bba)bpy]1+ and DNA+ in reaction (11) are replaced with the complex and DNA of the optimized docking model in the high layer, respectively. Using the method above, the λ of complex with DNA was obtained.

Calculations of HAD. Koopmans’ theorem (KT)29,30 is applied to estimate HAD. Although KT method cannot estimate HAD accurately for a short range ET, it operates well for the long-distance ET31. For an anion system, the value of HAD can be approximated as one half of the energy gap between the lowest unoccupied molecular orbital (LUMO) and the second lowest unoccupied molecular orbital (LUMO+1) of the neutral compound in the transition state using KT method. Thus HAD is given as one half of the energy difference between LUMO and LUMO+1 at the transition state configuration. Similarly, for a cationic system, the value of HAD can be approximated as one half of the energy gap between the highest occupied molecular orbital (HOMO) and the second highest occupied molecular orbital (HOMO-1) of the neutral compound in the transition state using KT method. Thus HAD is given as one half of the energy difference between HOMO and HOMO-1 at the transition state configuration.

Binding Energies of Complexes with GSH and VC. To compute the binding energies accurately, the binding energies of Cu(II) complexes with GSH and VC were computed in vacuo at the M062X/DEF2TZVP level based on the optimized GSH-docking and VC-docking models using the UB3LYP/6-31G(d) method. Take GSH for example, the binding energies of complexes with GSH were computed as follows: ∆E = EGSH-Complex − EGSH − EComplex

(15)

Here, ∆E is the GSH-binding energy of complex; EGSH, EComplex and EGSH-Compex are the energies of GSH, the complex and the optimized GSH-complex docking model, respectively. Meanwhile, we consider the basis set superposition error (BSSE) by the counterpoise method32. The calculations above were performed with Gaussian09 program-package33.

7



RESULTS AND DISCUSSION Evaluation of Computational Accuracy for Optimization of the Ground-state Complexes. Since the crystal structure of complex 2 has been determined, we can directly compare the computed results and the corresponding experimental data. The geometry of complex 2 in the ground state was optimized fully using different methods, that is, UB3LYP/6-31G(d), UB3LYP/LanL2DZ and UB3LYP/genecp (LanL2DZ basis set for Cu atom and 6-31G(d) basis set for the other atoms). The computation results and the corresponding X-ray data are given in Table 1. By comparing the computation results of complex 2 with corresponding X-ray data, it is clear that the computation results of UB3LYP/6-31G(d) are better than those of UB3LYP/LanL2DZ and UB3LYP/genecp. Therefore, the UB3LYP/6-31G(d) method is adopted for the following calculations.

Table 1. Computed selective bond lengths (Å) and bond angles (°°) using UB3LYP methods and different basis sets and X-ray data for the complex 2. genecpa LanL2DZb 6-31G(d)c expt.17 Cu-N1 2.0296 2.0124 1.9911 1.979 Cu-N3 2.5417 2.5334 2.5056 2.477 Cu-N4 2.0296 2.0124 1.9912 1.999 Cu-N6 2.0642 2.0563 2.0314 2.034 Cu-N7 2.0642 2.0563 2.0313 2.001 N1-Cu-N3 76.1 77.0 76.9 77.5 N1-Cu-N4 90.4 90.5 90.4 89.1 a LanL2DZ basis set for Cu atom and 6-31G(d) basis set for the other atoms; b LanL2DZ basis set for all atoms; c6-31G(d) basis set for all atoms.

Computed Redox Potentials of Complexes. More recently, we have focused on the computation study on oxidation-reduction potentials. According to thermodynamic-cycle method, our results are in satisfying agreement with experimental results34–36. To obtain more accurate oxidation-reduction potentials, the computational method was changed in Eq. 5, in which enthalpy changes can be computed more accurately. Take [Ru(phen)3]2+ for example in reference 34, the computed Eox, Ered and E*red of the complex are 1.526 V, –1.065 V and 0.914 V, respectively, whereas those obtained by the computational method

8


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in this work are 1.520 V, –1.202 V and 0.871 V, respectively, closer to experimental results (1.27 V, –1.35 V and 0.70 V ). The computed redox potentials of Cu(II) complexes are given in Table 2 and the related data were computed under normal conditions (see Table S1). The calculated oxidation potentials (Eox) of complexes 1-4 are 2.681 V, 2.540 V, 2.608 V and 2.489 V, respectively. This shows that Cu(II) complexes have high oxidation potentials relative to Ru(II) polypyridyl complexes, e.g., [Ru(bpy)3]2+ (1.28 V) 37 and [Ru(bpy)2dppz]2+ (1.24 V) 14

. The different oxidation potentials may lead to different DNA-cleavage manners for

Cu(II) complexes and Ru(II) complexes. That means that Ru(II) complexes cleave DNA by the generated ROS under light irradiation whereas many Cu(II) complexes cause DNA cleavage by the generated ROS without light irradiation. Ru(II) complexes can be excited and undergo an intra-molecular electron transfer (ET) by the light irradiation, and rapid ET may lead to radical ions generated. Then these radical ions can react with O2, H2O or other compounds around, producing much ROS. By contrast, Cu(II) complexes have high oxidation potentials, whereas excellent reductants GSH and VC should have low reduction potential. Big differences between oxidation potentials of complexes and reduction potential of GSH and VC will accelerate the movement of electrons on complexes, resulting in radical ions on complexes. Then, these radical ions may react with O2/H2O or other molecules around to generate active particles (e.g., O2•−, 1O2 and OH•, etc.). This viewpoint has been proved by experimental research. It is shown that fast-moving electrons can easily form a radical ion on the complexes, which reacts with molecules around resulting in OH• generated38. Based on this idea, ET between Cu(II) complexes and GSH, VC and DNA will be explored in the following section.

Computed ET Rate Constants. Reference 17 shows that Cu(II) complexes prefer to bind to the DNA by the major groove, but its supporting information indicates that complexes bind to the DNA by the minor groove. This shows that the binding modes of complexes with DNA are difficult to be determined experimentally. For example, research shows that [Ru(phen)2(dppz)]2+ binds to DNA in an intercalative mode via the major groove39–42. However there are still debates on the binding detail of the complex with DNA.43–45 Our simulated computation demonstrates that complexes 1–4 bind to the DNA 9



by the minor groove. To explore the speed of ET between Cu(II) complexes and GSH, VC as well as DNA, the computed λ, HAD and ket are listed in Table 3. We can see that almost all ket of Cu(II) complexes with GSH and VC are much greater than those with DNA. This indicates that almost all speeds of ET between complexes and GSH, VC are much faster than those between complexes and DNA. This result means that many fast-moving electrons will appear when Cu(II) complexes meet excellent reductant GSH or VC. This supports my idea above: fast-moving electrons proceeds from excellent reductants GSH and VC. Hence the interaction of Cu(II) complexes with GSH and VC may play an important role in DNA cleavage. Actually, ET reactions are affected by fluctuations of polar environment (water, residues, etc.), but for some Cu(II) complexes, H2O molecules have slight influence on their reorganization energies46. In particular, Cu(II) complexes insert deeply into base pairs in DNA, leading to the good hydrophobicity of complexes, and thus H2O molecules have no effect on complexes almost. In addition, at present, we cannot perform the calculation considering the complex environment (residues, solvent, electronic polarizability, etc.) by quantum-chemical method, especially for a whole system. Therefore, the ET rate constants were computed only in vacuo. Usually, the diffusion controlled rate constant is about 109 s-1 for chemical reactions in water, but our computed rate constants are more than 109 s-1. The reason may be that: (1) ET reactions are influenced by many factors (residues, solvent, electronic polarizability, etc.), which was not considered in the calculations; (2) HAD is computed using an approximate method. Since the computed DNA-cleavage properties of Cu(II) complexes are in accordance with experimental data, this indicates that the computational limitations would not affect the main conclusions in this work.

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Table 2. Calculated standard redox potentials (Eox and Ered) (V) in the ground state for complexes 1-4. Comp.

Eox

Ered

1 2 3 4

2.681 2.540 2.608 2.489

–0.295 –0.394 –0.422 –0.354

Table 3. Calculated λ1 (GSH, VC or DNA), λ2 (complex), λtot, HAD and ket for complexes 1-4. λ1/ kJ •mol–1 8.112 8.009 7.941 25.234 0.943 3.244 1.928 4.960 31.721 1.854 39.329 1.855

1a 2a 3a 4a 1b 2b 3b 4b 1c 2c 3c 4c

λ2/ kJ •mol–1 5.102 5.074 8.430 11.814 1.893 14.945 12.348 0.993 6.696 18.325 19.925 7.259

λtot/ kJ •mol–1 6.607 6.542 8.185 18.524 1.418 9.094 7.138 2.976 19.209 10.090 29.627 4.557

HAD/kJ •mol–1 4.731 4.062 3.804 5.596 1.017 2.051 2.249 1.999 1.378 1.447 2.942 3.231

ket/s-1 16.0 2.88×102 1.52×1011 5.09×1012 ≈0 9.76×1014 9.55×108 3.94×1015 ≈0 ≈0 ≈0 ≈0

“a” expresses complexes with GSH; “b” expresses complexes with VC; “c” expresses complexes with DNA.

DNA Cleavage of Complexes in the Presence of VC. Table 3 shows that the computed ket of complexes 1-4 with VC are 0, 9.76×1014, 9.55×108 and 3.94×1015 s-1. This result indicates that the speed of ET between complex 4 and VC is the fastest, followed by the speed between complex 2 and VC, and the speed between complex 1 and VC is the slowest. This means that complex 4 generates the most ROS, followed by the ROS generated by complex 2, and the ROS generated by complex 1 is the least. Therefore, complexes 1-4 exhibit DNA-cleavage abilities in the presence of ascorbic acid, which varies as 4 > 2 > 3 > 1, in accordance with experimental result17. Although DNA-cleavage abilities of complexes 1-4 in the presence of VC can be explained perfectly, fast-moving electrons seem unable to produce ROS for complex 1 in the presence of VC, for the reason 11



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that the computed ket of complex 1 close to 0. ROS generation may be explained as follows. Firstly, Cu(II) can be changed to Cu(I) for complex 1 in the presence of VC, then Cu(I) react to O2 around by Eq. (b), causing some ROS generated11. Fast-moving electrons should be the main reason for much ROS generated. Hence the quantity of generated O2•− by complex 1 should be far less than that by complexes 2-4. In the presence of VC, the DNA-cleavage abilities of complexes 1-4, i.e., 4 > 2 > 3 > 1, can be explained reasonably.

DNA Cleavage of Complexes in the Presence of GSH. Since a large quantity of GSH exists in vivo, complexes 1-4 can bind to GSH easily. The computed ket between complexes 1-4 and GSH are also listed in Table 3, which are 16.0, 2.88×102, 1.52×1011 and 5.09×1012 s-1, respectively. The ET speed for complex 4 is the fastest, that for complex

3 follows and that for complex 1 is the slowest. This means that much ROS is generated by complex 4 while little ROS is generated by complex 1. The DNA-cleavage abilities of complexes 1-4 in the presence of GSH can be predicted as 4 > 3 > 2 > 1.

DNA Cleavage of Complexes in the Presence of H2O2. Reduction of the Cu(II) complex to Cu(I) by binding to DNA has been reported for some Cu(II) complexes47–50, i.e., Cu(II) + DNA → Cu(I) + DNAOX. Then a large quantity of OH• can be produced by Eq. (a). The quantity of OH• depends on reduction potential of the Cu(II) complex, since the oxidation potential in Eq. (a) is a constant value. Table 2 indicates that the computed reduction potentials of complexes 1-4 are –0.295 V, –0.394 V, –0.422 V and –0.354 V, respectively. The DNA-cleavage trend of complexes 1-4 in the presence of H2O2 can be predicted to be 3 > 2 > 4 > 1, in accordance with experimental result17. The reason for Cu(II) complexes cleaving DNA in the presence of H2O2 can be explained reasonably.

Binding Energies of Complexes with GSH and VC. The computed binding energies

of

complexes

1-4

with

GSH

and

VC

at

the

level

of

M062X/DEF2TZVP//B3LYP/6-31G(d) are listed in Table 4. We can see that the binding energies of complexes 1-4 with GSH are –206.84 kJ•mol–1, –206.00 kJ•mol–1, –203.33 kJ•mol–1, and –205.48 kJ•mol–1, respectively. After correction of the basis set superposition error by the counterpoise method, the GSH-binding energies of complexes

1-4 are slightly reduced to –202.28 kJ•mol–1, –201.45 kJ•mol–1, –198.78 kJ•mol–1, and –202.33 kJ•mol–1, respectively. Similarly, after correction, the VC-binding energies of 12


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complexes 1-4 are slightly reduced to –166.54 kJ•mol–1, –129.34 kJ•mol–1, –129.45 kJ•mol–1, and –104.58 kJ•mol–1, respectively. Obviously the binding energies of complexes 1-4 with GSH are much stronger than those with VC. This shows that complexes 1-4 will prefer to bind to GSH. Therefore, the interaction of Cu(II) complexes with GSH may be the main reason leading to much ROS generated.

Table 4. Computed binding energies, ∆E (BSSE uncorrected) and ∆Ecp (BSSE corrected) of complexes 1-4 with GSH and VC (all energies in kJ •mol–1). Comp.

EGSH(VC)-Complex

EGSH(VC)

EComplex

∆E

∆Ecp

1a

–11639261.21

–3689199.67

–7949854.70

–206.84

–202.28

2a

–11839410.67

–3689199.87

–8150004.79

–206.00

–201.45

3a

–12045831.96

–3689200.12

–8356428.51

–203.33

–198.78

4a

–12327022.53

–3689188.45

–8637628.60

–205.48

–202.33

1b

–9747953.09

–1797928.81

–7949854.27

–170.01

–166.54

2b

–9748074.87

–1797933.40

–8150009.71

–131.77

–129.34

3b

–10154497.38

–1797931.51

–8356433.65

–132.22

–129.45

4b

–10435660.50

–1797930.98

–8637622.14

–107.38

–104.58

“a” expresses complexes with GSH; “b” expresses complexes with VC.

Moreover, considering dispersion interactions, the docking structures of complexes with DNA, GSH, and VC were further optimized using M062X/6-31g(d) method. The binding energies of complexes 1-4 with GSH and VC and the rate constants ket of complexes with DNA were recomputed and the computed results are given in Tables S2 and S3. We can clearly see that the computed the binding energies of complexes with GSH and VC at the level of M062X/DEF2TZVP//M062X/6-31G(d) are close to those at the level of M062X/DEF2TZVP//UB3LYP/6-31G(d). Meanwhile, the computed rate constants ket of complexes with DNA at the level of M062X/6-31G(d) are almost to 0, and close to those at the level of UB3LYP/6-31G(d). This shows that the computed results of B3LYP method are reliable, and close to those of M062X method.

13



DNA-cleavage Mechanism of Cu(II) Complexes. Cu(II) complexes 1-4 can cleave DNA by the generated ROS, but the reason is unclear. The computed ket of complexes 1-4 shows that the interaction of complexes 1-4 with GSH, VC may cause much ROS generated, whereas that with DNA leads to little ROS generated. The ROS generated may be caused by the interaction of complexes with GSH and VC. The computed binding energies show that Cu(II) complexes 1-4 give preference to binding to GSH relative to VC. This means that the interaction of complexes with GSH cause much ROS generated. Therefore, the DNA-cleavage mechanisms of complexes 1-4 are shown in Figure 3 and described as follows: When Cu(II) complexes approach DNA, Cu(II) complexes give preference to reacting with GSH in the vicinity of DNA relative to VC. Complexes 1-4 have high oxidation potentials (see Table 2), while GSH has low reduction potential. When complexes 1-4 meet GSH, electrons transfer from GSH to complexes easily, forming Cu(I) complexes. Meanwhile big differences between oxidation potentials of complexes and reduction potential of GSH will accelerate the movement of electrons on complexes, resulting in radical ions on complexes. These radical ions may react with O2/H2O or other molecules around to generate active particles (e.g., O2•−, 1O2 and OH•, etc.). Then, the formed Cu(I) complexes approach DNA rapidly through cell membrane and bind to DNA. Meanwhile, the generated ROS, adhering to complexes, goes near DNA. Since guanine has the least oxidation potential, the ROS attacks guanine of DNA first (especially at the position N7),51,52 and thus DNA was cleaved. Therefore, in vivo the DNA-cleavage abilities of complexes 1-4 by the computed ket of complexes with GSH should be 4 > 3 >

2 > 1. If Cu(II) complexes go near DNA of cancerous cell (CDNA), similarly, the interaction of Cu(II) complexes with GSH causes much ROS generated, leading to the cleavage of CDNA. In vivo, the abilities of complexes 1-4 cleaving CDNA should be 4 >

3 > 2 > 1, too. Experimental results show the presence of great amounts of H2O2 in cancer cells53, in which Cu(I) complexes will be oxidized by Eqs. (a) and (b). The quantity of O2•− and OH• will increase as a result. From Table 2, we can see that the computed Ered (3) 14


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and Ered (4) are –0.422 V and –0.354 V, showing that the reactions of complex 3 by the Eqs. (a) and (b) are much stronger than those of complex 4. The reaction results lead to the generation of much active O2•− and OH• for complex 3 relative to complex 4. The quantity of O2•− and OH• may affect DNA-cleavage abilities of 3 and 4. Therefore, the abilities of complexes 1-4 cleaving CDNA should be 3 > 4 > 2 > 1 in vivo. Coincidentally, this result is consistent with the cancer-killing abilities of complexes: 3 > 4 > 2 > 117. The ROS generated by Cu(II) complexes may have a great influence on cancer cells in vivo. Hopefully, the research results are helpful for exploring anticancer properties of Cu(II) complexes.

Figure 3. Possible DNA-cleavage mechanism of Cu(II) complexes.

CONCLUSIONS In this paper, the DNA-cleavage mechanism of Cu(II) complexes 1–4 has been explored by theoretical methods. We draw the following conclusions: (1) The DNA-cleavage abilities of complexes 1–4 in the presence of GSH, VC and H2O2 were explored and predicted by the computed ket and redox potentials of complexes, in accordance with experimental result. (2) The computed binding energies show that Cu(II) complexes give preference to binding to GSH relative to VC and the interaction of Cu(II) complexes with GSH may be the main reason leading to much ROS generated, which plays an important role in DNA cleavage. (3) The DNA-cleavage mechanism of Cu(II) complexes was described.

ASSOCIATED CONTENT Supporting Information Redox-potential data (Table S1), binding energies (Table S2), rate constants ket (Table S3), mol

15



files of docking models for complexes with DNA and mol files of optimized docking-models for complexes with GSH and VC. This information is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] (Miao T.).

ORCID Tifang Miao: 0000-0001-5755-482X Hui Gao: 0000-0002-8736-4485 Xianliang Fu: 0000-0001-9295-6314

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We are pleased to thank the financial support of the National Natural Science Foundation of China (No.21473066), the Major Program of the National Natural Science of Anhui university (No.KJ2016SD52), the Key Program of the National Natural Science of Anhui university for Young and middle-aged key talent to study in the domestic (No.gxfxZD2016097) and Anhui Provincial Innovation Team of Design and Application of Advanced of Energetic Materials (No.KJ2015TD003).

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Graphical abstract

Theoretical studies on DNA-cleavage properties of Cu(II) complexes 1–4 have been carried out using the density functional theory and docking methods. The DNA-cleavage abilities of Cu(II) complexes in the presence glutathiones, ascorbic acids and H2O2 were explored and the DNA-cleavage mechanism of Cu(II) complexes were described in detail.

Cell glutathione ROS ascorbic acid

ROS

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Theoretical Studies on DNA-Cleavage Mechanism of Copper(II

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