Synthesis, crystal structure, electrochemical behavior and docking molecular of poly-nuclear metal complexes of Schiff base ligand derived from 2-amino benzyl alcohol

Article abstract of DOI:10.1016/j.ica.2019.119022

In the present work, we synthesized three novel Cu(II) and Mn(II) complexes (1–3) of a tridentate Schiff base ligand (H₂L¹) derived from 2-hydroxy-4methoxybenzaldehyde and 2-amino benzyl alcohol. The Schiff base ligand and its comple

Full text of DOI:10.1016/j.ica.2019.119022

Accepted Manuscript
Research paper
Synthesis, crystal structure, electrochemical behavior and docking molecular of
poly-nuclear metal complexes of Schiff base ligand derived from 2-amino ben-
zyl alcohol
Pardis Roozbahani, Mehdi Salehi, Rahime Eshaghi Malekshah, Maciej Kubicki
PII:
S0020-1693(19)30601-2
https://doi.org/10.1016/j.ica.2019.119022
119022
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ICA 119022
Inorganica Chimica Acta
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Please cite this article as: P. Roozbahani, M. Salehi, R. Eshaghi Malekshah, M. Kubicki, Synthesis, crystal structure,
electrochemical behavior and docking molecular of poly-nuclear metal complexes of Schiff base ligand derived
from 2-amino benzyl alcohol, Inorganica Chimica Acta (2019), doi: https://doi.org/10.1016/j.ica.2019.119022
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Synthesis, crystal structure, electrochemical behavior and
docking molecular of poly-nuclear metal complexes of Schiff
base ligand derived from 2-amino benzyl alcohol
Pardis Roozbahania, Mehdi Salehia,*, Rahime Eshaghi Malekshaha, Maciej Kubickib
aDepartment of Chemistry, Semnan University, Semnan, Iran
bFaculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznan, Poland
Correspondence
Mehdi Salehi, Department of Chemistry, Semnan University, P.O. Box 35195‐363, Semnan,
Iran.Email: msalehi@semnan.ac.ir
Abstract
In the present work, we synthesized three novel Cu(II) and Mn(II) complexes (1-3) of a tridentate
Schiff base ligand (H2L1) derived from 2-hydroxy-4methoxybenzaldehyde and 2-amino benzyl
alcohol. The Schiff base ligand and its complexes were characterized by FT-IR, UV-Vis and
elemental analysis. The molecular structures of products were determined by X‐ray diffraction,
which confirmed the formation of bi-nuclear (1), tetra-nuclear (2) and tri-nuclear (3) complexes.
In addition, the electrochemical properties of the complexes were examined by means of cyclic
voltammetry in tetrahydrofuran, which showed the irreversible processes. Molecular docking
studies of the free Schiff base ligand and its complexes were performed with BDNA and
Interleukin-6 (PDB ID: 1BNA and 1alu). The results of docked models showed that ligand and
complexes 1-3 preferentially bind to the minor groove of DNA receptor. In addition, complexes
1-3 exhibit higher binding affinity to Interleukin-6 as compared to ligand and drug of anticancer.
1

Keywords: Crystal structures, Di-, tetra and trinuclear complexes, Electrochemical behavior,
Molecular docking, Interleukin-6.
1. Introduction
Much energy has been spent on the synthesis of tridentate Schiff base ligands and their
complexes [1-3], owing to their high efficiency and stability. Therefore, these complexes have
been studied for different applications as anti-bacterial, anti-virus, anti-cancer agents, in medical,
and chemical industries, and so forth. Schiff bases derived from salicylaldehyde and their metal
complexes play major roles in a wide range of fields [4-8]. Pahonțu et al. studied the
antimicrobial activity of 2-hydroxy-4-methoxybenzaldehyde with ethyl-4-aminobenzoate and
their six new Cu(II) complexes, showing that the antimicrobial effects of copper complexes are
higher than those of ligands [9]. In another study, 4-substituted benzaldehyde derivatives were
proved capable of preventing the synthesis of melanin in various dermatological disorders [10].
Matusiak et al. have shown that mono- and poly-nuclear copper complexes show effective
phenoloxidase activity and cause apoptosis in vivo [11]. Jitaru and collaborators reported the
antiferromagnetic properties of poly-nuclear Mn-oxo complexes Fe(III) and Mn(II, III) [12].
Also, Hureau revealed the synthesis of Mn(II) complex by the formation of mixed-valent di-µ-
oxo-bridged dinuclear complexes [(L)MnIII(µ-O)2MnIV(L)](ClO4)3 [13]. Nowadays, millions of
people suffer from cancer, as it is one of the most fatal diseases. Many platinum-based drugs
such as cisplatin, carboplatin and oxaliplatin alone or in combination with other drugs are
important chemotherapeutic agents inhibiting tumor growth in cancer therapy. Their use is more
often than not accompanied by significant toxic side effects such as nephrotoxicity, drug
resistance, renal and cervical problems, and they are often sensitive to resistance mechanisms
[14, 15]. Therefore, there is an urgent need for more efficient anticancer drugs of non-platinum
2

complexes with significant anti-tumour activity and lower side effects compared to cisplatin. The
discovery and development of new anti-cancers drugs is a long-term, time consuming and
expensive process. Computer-aided drug discovery/design methods can act as a virtual shortcut
in the pharmaceutical industry and academia; they reduce the number of ligands and are
potentially less time consuming compared to the experimental procedures. Today, CADD has
become an effective and indispensable tool in the discovery and design of pharmaceutical
products [16]. In the current research, we introduced a simple procedure for the preparation of a
new Schiff base ligand H2L1 and its chelates with transition metal ions such as Cu(II) and Mn(II)
(Schema 1). The H2L1 ligand and its complexes were synthesized and studied by elemental
analysis, IR, UV-Vis, and electrochemical behavior. Complexes 1 - 3 were characterized by X-
ray crystallography, and molecular docking studies were discussed to elucidate the binding
modes associated with the anti-cancer properties of compounds with DNA and Interleukin-6.
Scheme 1.
2.1. Materials and physical measurements
The solvents for synthesis were purchased from Merck and used without further purification.
Elemental analysis was done on Elementar Vario EL III CHNOS Elemental Analyzer. FTIR
spectra were obtained using a FT-IR SHIMADZU spectrophotometer and electronic spectra were
carried out a Shimadzu UV-1650PC spectrophotometer. Electrochemical experiments were
accomplished on a Metrohm 757VA Computrace instrument at room temperature in THF
solution.
2.2. Synthesis
2.2.1. Synthesis of Schiff base ligand H2L1
3

The ligand was obtained from 2-hydroxy-4methoxybenzaldehyde (1mmol, 0.152 g) and 2-amino
benzyl alcohol (1mmol, 0.123 g). For preparation of this ligand, methanol was used as solvent.
The mixture was stirred at room temperature for 3h. The resulting yellow precipitate collected
through filtration and dried. Yield: 90%. Mol. Wt: 257.11 g/mol Anal. Calc. for C15H15NO3: C,
70.02; H, 5.88; N, 5.44%; Found: C, 70.08; H, 5.87; N, 5.53%. FT-IR: νmax cm-1 (KBr): 3326,
3133, 2835, 1624, 1584, 1564, 1538, 1507, 1482, 1457, 1406, 1356, 1315, 1290, 1250, 1214,
1184, 1128, 1047, 1016, 966, 885, 839, 799, 759, 743, 708, 673, 601, 586, 525, 505, 465, 414.
UV–Vis: λmax (nm) (CH3CN): 293, 417.
2.2.2. Synthesis of Cu2L1 and Cu4(L1 ) (1 and 2)
2
4
Solution of Cu(OAc)2.H2O (0.5mmol, 0.09 g) in methanol was added to ligand (0.5 mmol, 0.128
g and refluxed for 3 hours. The solution was filtered and two different kinds of crystals suitable
for x-ray diffraction were selected from the solution after a week.
In Complex 1:
Yield: 75%. Mol. Wt: 637.61 g/mol. Anal. Calc. for C30H26Cu2N2O6: C, 56.51; H, 4.11; N,
4.39%; Found: C, 56.28; H, 4.21; N, 4.35%. FT-IR: νmax cm-1 (KBr): 3167, 3128, 2930, 2852,
1736, 1686, 1653, 1608, 1576, 1565, 1516, 1488, 1455, 1400, 1323,1279, 1241, 1202, 1175,
1124, 1086, 1031, 982, 833, 756, 657, 619,553, 525, 481, 421. UV–Vis: λmax (nm) (THF): 277,
295, 335, 390, 602.
In Complex 2:
Yield 75%. Mol. Wt: 1421.40 g/mol. Anal. Calc. for C66H66Cu4N6O14: C, 58.06; H, 6.26; N,
3.98%; Found: C, 58.02; H, 6.19; N, 3.94%. FT-IR: νmax cm-1 (KBr): 2959, 2939, 2845, 1617,
1538, 1493, 1467, 1445, 1429, 1396, 1362, 1318, 1220, 1175, 1124, 1070, 1031, 976, 932, 910,
4

849, 799, 744, 650, 589, 567, 506, 463, 429, 407. UV–Vis: λmax (nm) (THF): 260, 263, 308, 388,
592.
2.2.2. Synthesis of Mn3L1 L2 (OAc)2. EtOH (3)
2
2
The novel complex 3 was synthesized according to the procedure similar to one mentioned above
for complex 1. The solution was dried and recrystallized in an acetonitrile:ethyl acetate 1:1
mixture. Crystals suitable for x-ray crystallography were obtained after two weeks. Yield: 73%.
Mol. Wt: 1141.77 g/mol Anal. Calc. for C50H46Mn3N2O16·C2H5OH: C, 57.10; H, 4.79; N, 2.66;
Found: C, 56.28; H, 4.69; N, 2.80%. FT-IR: νmax cm-1 (KBr): 1612, 1584,1557, 1528, 1497,
1406,1370, 1304, 1212, 1186,1124, 1018, 977, 850, 799, 764, 667, 621, 534, 412. UV–Vis: λmax
(nm) (THF): 206, 273, 390.
2.3. X-ray crystallography
Diffraction data was collected by the ω-scan technique at 130(1) K (1) and at 100(1) K (2, 3) on
Rigaku XCalibur four-circle diffractometer with EOS CCD detector and graphite-
monochromated MoKα radiation (λ=0.71073 Å). The data was corrected for Lorentz-polarization
as well as for absorption effects [17]. Precise unit-cell parameters were determined by a least-
squares fit of 3943 (1). 9173 (2) and 7908 (3) reflections of the highest intensity, chosen from the
whole experiment. The structures were solved with SHELXT-2013 [18] and refined with the
full-matrix least-squares procedure on F2 by SHELXL-2013 [18]. All non-hydrogen atoms were
refined anisotropically, hydrogen atoms were placed in idealized positions and refined as ‘riding
model’ with isotropic displacement parameters set at 1.2 (1.5 for methyl and hydroxyl groups)
times Ueq of appropriate carrier atoms. In the structure 3 the C-C distance in the solvent (ethanol)
molecule was restrained to typical value (DFIX).
5

Crystallographic data for the structural analysis was deposited with the Cambridge
Crystallographic Data Centre, Nos. CCDC-1855697 (1), CCDC-1885977 (2) and CCDC-
1855698 (3). The Copies of this information may be obtained free of charge from: The Director,
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK; e-mail: deposit@ccdc.cam.ac.uk, or www:
www.ccdc.cam.ac.uk.
2.4. Electrochemical studies
The electrochemical experiments of the synthesized complexes 1-3 were performed by means of
cyclic voltammetry with 0.1 mol/dm3 tetrabutylammonium hexafluorophosphate (TBAH) as
supporting electrolyte and complexes concentration of about 1×10-3 mol/dm3 in THF. All
electrode potentials were calibrated using the redox potential of the ferrocene/ferrocenium
couple as reference. The three-electrode cells were comprised of auxiliary platinum, a reference
Ag wire and glassy carbon as the working electrode. The solutions were deoxygenated by
purging dry Argon through the solution for 5 min prior to each experiment.
2.5. Molecular docking of the compounds with DNA duplex of sequence (PDB ID: 1BNA)
and Interleukins (PDB ID: 1alu)
To fathom the antitumor activity and the binding site of the target-specific region of compounds,
we used molecular docking simulation. The crystal structures of 1BNA (B-DNA Dodecamer:
right-handed double-stranded B helix (as rigid molecule) with the sequence (5'-
D(CpGpCpGpApApTpTpCpGpCpG)-3'), Interleukins (PDB ID: 1alu, (as rigid molecule)) and
anticancer drugs were downloaded from RCSB Protein Data Bank (ww.rcsb.org/pdb) and
Pubchem. The ligand H2L1 (as flexible ligand) was optimized via standard 6-31G** basis sets.
Complexes 1, 2 and 3 (as flexible ligand) were taken from the crystal structures as a CIF file and
converted to the PDB format using Mercury software. The molecular docking simulation and
6

calculations were performed by AutoDock 4.2 (The Scripps Research Institute, La Jolla, CA,
USA) with AutoGrid 4 and AutoDock 42, meaning all non-ring torsions were maintained.
Primarily, the heteroatoms including water molecules around the duplex were removed using
AutoDock tools; polar hydrogen atoms, Kollman united atom type charges and Gasteiger partial
charges were then added to the receptor molecule. All the docking simulations were defined by
use of a grid box with 74 × 64 × 117 Å points with a grid-point spacing of 0.375 Å for BNA, a
grid box with a size of 126 × 126× 126 Å with a grid-point spacing of 0.375 Å for IL-6. To study
this interaction, the molecular docking using a Lamarckian genetic algorithm method was
engaged. The number of genetic algorithm runs and the number of evaluations were set to 100.
The most optimized model with the lowest energy was selected from the one minimum energy
(root mean square deviation, RMSD = 0.0) and 100 runs to compare the structural similarity.
After that, the interactions of BNA and Interleukin and their binding modes with compounds
were analyzed using AutoDock program, UCSF Chimera 1.5.1 software, Discovery Studio 3.0
from Accelrys and DS Visualizer.
3. Results and discussion
3.1. Synthesis
The novel Schiff base ligand was synthesized by reacting 2-hydroxy-4-methoxybenzaldehyde
with 2-amino benzyl alcohol in methanol. Complexes 1-3 were synthesized by reacting
Cu(CH3CO2)2.H2O or Mn(CH3CO2)2.4H2O with Schiff base ligand in methanol. H2L1 ligand was
soluble in common organic solvents like methanol, ethanol, acetonitrile and dichloromethane,
but complexes 1-3 were readily soluble in THF. These compounds were characterized by
elemental analysis, FT-IR, UV-Vis and Cyclic Voltammetry (CV) methods. Furthermore,
complexes 1-3 were structurally characterized by X-ray crystallography.
7

3.2. Infrared spectra of ligand and its complexes
The structure can be easily verified through comparing the IR spectra of the free ligand with
those of their metal complexes (Figs. S1, S3, S5 and S7). The ʋ(C=N) absorption band of the
ligand at 1624 cm−1 was shifted towards lower energies 1608, 1617 and 1612 cm-1 in the spectra
of complexes 1, 2 and 3, respectively, suggesting the back bonding from the metals to the orbital
of azomethine nitrogen [19]. The phenolic ʋ(C–O) stretching vibration of the free Schiff base
ligand was observed at 1128 cm−1, and was shifted towards lower wave numbers after
complexation for complexes 1, 2 and 3 to 1086, 1070 and 1124 cm−1, respectively, suggesting
the participation of phenolic oxygen atoms linked to the Cu2+ and Mn2+ ions [20]. The signals
1565 and 1400 cm−1 in complex 1 can be assigned to the bonding of νasym(C-O-Cu) (bidentate)
and νsym(C-O-Cu) (bidentate), respectively. In addition, the intense bands at 1538 and 1396 cm-1
were assigned to νasym(C-O-Cu) (bidentate) and νsym(C-O-Cu) (bidentate vibrations), respectively
in complex 2. These results show that the acetate group acted as a bidentate bridging ligand.
Furthermore, the absorptions appearing at 1557 and 1406ꢀcm−1 for complex 3 indicated the
asymmetric and symmetric stretching frequencies of the acetate (µ-RCO2) groups, respectively
[12, 21]. The broad band exhibited at 3000–3500 cm–1 in the spectra of the free ligand is due to
the stretching vibration of νOH. The new bands appearing at 553–421, 567-429 and 621–412 cm−1
for complexes 1, 2 and 3, respectively, were assigned to ν(M–O) and ν(M←N) vibrations,
respectively [22].
3.3. UV spectra of compounds
UV-Vis spectra for ligand and its complexes were reported at a wavelength range of 200-800 nm
(Figs. S2, S4, S6 and S8). UV-Vis spectrum of ligand did not have any absorption peak of d-d
transition, but it exhibited maximum absorption bands around 293 and 417 nm associated with n-
8

π* and π-π* transitions, respectively [23, 24]. One band was observed in regions 277, 260 and
206 regarding complexes 1-3, respectively, which are assignable to LC transitions of the
aromatic groups [25]. The absorption bands of complex 1 and 2 at 335-390 and 388 nm were
specified to n-π* transition, and the absorption bands around 295 and 308 nm were due to π-π*
transition in complexes 1 and 2, respectively. Complexes 1 and 2 exhibited only one broad d–d
band, centered in the region of 602 and 592 nm [26, 27]. The band at 273 nm in 3 is related to π -
π* transition, while the peak around 390 nm belongs to ligand-metal charge transfer transitions
n→π*. It is to be noted that no d-d transition was expected for complex 3 [28-30].
3.4. Description of Crystal Structures
Figures 1-5 show the perspective view of the molecules. The collected data and refinement
parameters are summarized in Table 1. Table 2 lists the relevant geometrical parameters. Bi-
nuclear Cu2L1 complex 1 is Ci-symmetrical, as it lies across the inversion center (space group
2
P21/n), hence the fact that Cu2O2 ring is planar. Cu ions are 4-coordinated in a quite regular
square-planar environment – the four coordination centers make an, approximate plane
(maximum deviation from the least-squares plane is 0.052(1)Å), and the Cu ion lies well within
this plane (deviation 0.028(1)Å). Four-nuclear Cu4(L1 ) complex 2 is also Ci-symmetrical, as it
4
lies across the inversion center (space group P-1). Cu ions are 5-coordinated in a quite regular
square-pyramidal environment. In tri-nuclear Mn3L1 L2 (CH3COO)2 complex 3, all three Mn
2
2
centers are six-coordinated in an octahedral fashion. The neighboring cations are bridged by O
atoms from acetate fragments of both ligand molecules; terminal Mn ions are additionally
coordinated by NO centers from L1 molecules. Hence, terminal metal ions are NO5 coordinated,
while the central cation is O6-coordinated. Figure 4 shows the details of coordination scheme.
The conformation of ligand L1 molecules, as defined by dihedral angles between planar
9

fragments, depends on the complex (cf. Figure. 5, Table 2): this molecule is more planar in 1,
while it is significantly twisted in the more sterically demanding complex 2.
In crystal structures, electrostatic and dispersive interactions are mainly responsible for the
crystal architectures. In 2, the solvent-ethanol molecules are hydrogen-bonded with the complex
(one of the acetates: H···O 2.13Å, O···O 2.920(7)Å, O-H···O 157º).
Tables 1-2.
Fig.s 1-5.
3.5. Electrochemistry
The electrochemical properties of metal complexes were studied in order to explain minor
spectral and structural changes accompanying electron transfer. The compounds were
homogenized by magnetic stirring with THF and the voltamograms are shown in Figures 6-8.
The cyclic voltammograms of 1 and 2 showed one cathodic peak potential (Epc) Cu(II)/Cu(I) at -
0.91 and -1.07 V, respectively. In the anodic peaks of complex 1, the two direct oxidation of
Cu(I) → Cu(II) were observed at Epa = 0.826 and 1.17 V. Meanwhile, in complex 2, the two
direct oxidation of Cu(I) → Cu(II) were observed at Epa = 0.3, 0.47 V and one direct oxidation
of Cu(0) → Cu(I) was observed
at Epa= 1.33 V. Complexes 1 and 2 displayed
an irreversible oxidation wave [4, 31]. Complex 3 is electroactive with respect to the metal
center and exhibits two redox processes associated with a two-electron transfer at room
temperature. Under identical experimental conditions, the cathodic potentials (Epc) values for 3
were -0.76 (MnIII/MnII) and 1.64 V (MnII/MnI), and the corresponding Epa (MnII/MnIII) value
was 0.195. As shown in Figure 8, complex 3 exhibited irreversible characteristic [13, 32].
Fig.s 6-8.
10

3.6. Molecular docking compounds with BNA
Cancer is one of the most fatal diseases, originating from different cancer-causing agents
(carcinogens) ranging from environmental pollutants to genetic mutations [33]. DNA is the
primary intracellular target of anticancer drugs that intercalate into DNA and interfere with the
activity of topoisomerases when they bind to nuclear DNA. Over the recent decades, DNA-
binding molecules have become critically important in clinical cancer therapy [34]. Generally,
many antitumor drugs have shown their cytotoxic effect on replication, transcription and
consequent induction of programmed cell death (PCD [35-37]. In areas of pharmaceutical
research, it is necessary to discover and synthesize possible effective DNA–metal complexes as
chemotherapeutic agents and the interaction modes and mechanism of such compounds. Binding
affinity of the compounds and the hydrogen bonding interactions with DNA estimated at the
molecular level is based on physical interactions (electrostatic, van der Waals, hydrophobic,
specific hydrogen bonding, etc.). One of the extensively developing trends in computer
simulations is the prediction of pharmacological action of drugs at the molecular level and a
strong base for the experimental synthesis of novel bioactive molecules. Molecular docking
simulation is one of the most valuable approaches to predicting the interaction of all possible
configurations and determining the optimal orientation of compounds between biological
macromolecule-compounds [37, 38]. The lowest energy conformations were rated based on
docking calculations of the lowest free binding energy. The docking results are shown as binding
free energy in Figure. 9 and listed in Table 3. The minimum energy of each compound was
applied to the best possible geometry of compounds inside the DNA double helix. Moreover,
anti-cancer chemotherapeutic drugs, Mitoxantrone and Trifluridine (FTD) as DNA-drug
interaction, were used to compare their results with the compounds. The calculated binding free
11

energies (ΔGbinding) for the free ligand, complexes 1, 2, 3 and anti-cancer drugs to DNA
(Trifluridine and Mitoxantrone) were -7.56, -7.74, -6.45, -9.87, -9.09 and -5.88 kcal/mol,
respectively; the binding of the compounds to the DNA is spontaneous. The more negative
relative binding energy of complex 3 suggests more ability to bind to the DNA compared with
the free ligand and complexes 1, 2 and anti-cancer drugs to DNA (Trifluridine and
Mitoxantrone) [39, 40]. Results suggest that complex 3 can act as the DNA-damaging anticancer
agent. Moreover, the binding free energy values were dominated by the vdW + Hbond + desolv
energy (kcal/mol) energy in the final energy, which is principally related to the formation of
hydrogen bonds between the compounds and receptor. The lowest-energy conformations show
that all the compounds bind to the minor groove. In order to determine the binding site and to
obtain information about the hydrogen bonding interactions of the compounds, hydrogen
bonding interactions are illustrated in Figure. 10. As shown in Figure. 10, there are two hydrogen
bonding interactions between OH of the ligand and the phosphate oxygen atoms of DNA helix
2.06 and 2.28 (Å), respectively. On the other hand, complexes 1 and 3 interacted with DNA
through hydrogen bonding with DC116 (2.96 Å) and DA55 (1.71 Å), respectively. However,
complex 2 interacted with phosphates and ribose group through hydrogen bonding 2.85 and 2.98
Å, respectively [40]. Moreover, Trifluridine interacted with groups of guanine DG110 (2.54 Å)
and DG116 (1.69 Å) by forming hydrogen bonds, meanwhile, Mitoxantrone displayed hydrogen
bond interaction with DA118 (1.89 Å).
Fig.s 9-10.
Table 3.
3.7. Molecular docking of compounds with Interleukin 6
The increase in the levels of IL-6 augments the tumor growth risk, and weakens the immune
systems of HIV-positive people. Human interleukin-6 (IL6) is one such inflammatory molecule,
12

produced and secreted by tumor cells into IL-6 receptor α(IL-6Rα) subunit of microenvironment
[41]. It is involved in the proliferation, survival, and metastatic dissemination of malignant cells,
and it is abundantly found in the serum and tumor tissues of a majority of cancers, namely
gastric, multiple myeloma, melanoma, pancreatic, breast, colorectal, myeloma, cervical and lung
cancer. A lower level of IL-6 is associated with a better response to therapy. Anticancer drugs
and ionizing radiation used during cancer therapy induce the expression of different pro-
inflammatory cytokines (IL-6), chemokines and anti-apoptotic genes in tumor by activating
STAT-3 and NF-kB signaling, which leads to the resistance of cells to chemotherapy. Moreover,
IL-6, a potent immunosuppressive cytokine, plays an important role in protecting cancer cells
from therapy-induced DNA damage, oxidative stress, endogenous and exogenous (chemotherapy
drugs, ionizing radiation) damage and apoptosis [42, 43]. These observations suggest that IL-6 is
blocked for therapy in cancers. The present study was conducted to design and develop the
exploration of IL-6 inhibitors with high efficiency and high selectivity based on molecular
docking calculations. The docking calculations of copmounds were further performed to describe
the mode of binding to Interleukin-6. The values of docking energy were -5.71, -7.66, -7.72, -
7.70 and -6.34 kcal/mol for ligand, 1, 2, 3 and Lenalidomide, respectively, Fig. 11, Table 4.
Comparing the relative binding energy (ΔGbinding) of compounds with Interleukin-6 proved that
complex 2 was more effective than other compounds and the anti-cancer drug (Lenalidomide).
The active sites of compounds and drug are shown in Fig 11. The interaction between the ligand
and Interleukin-6 were dominated by hydrogen bonds Ser A175 and Glu A172 in site Helix D.
No H-bonds were observed for complex 1, but complex 1 was docked into the active site II. In
addition, a hydrogen interaction is suggested between Lys A128 residue in the active site II and
O-CH3 of aromatic ring for complex 2. Finally, complex 3 was able to interact with the Helix S
13

of Interleukin-6 by the hydrogen bond between O-CH3 of aromatic ring and Lys A150.
Complexes 1-3 proved to be potent anti-cancer agents compared with ligand with DNA and
Interleukin-6 in computer–aided molecular docking studies. In addition, the results of molecular
docking showed that complex 2 is a potential therapeutic strategy for the development of new
chemotherapeutic drugs regarding the treatment of cancers as IL-6 inhibitors.
Table 4.
Fig 11.
4. Conclusion
Metal complexes of the Schiff base were synthesized and characterized by use of elemental
analyses, cyclic voltammetry (CV), electronic absorption and IR- spectroscopy. The crystal
structures of all complexes were determined by X-ray crystallography. The X-ray structure
determination showed that the structures around Cu(II) (1 and 2) and Mn(II) (3) were square-
planar, square-pyramidal and octahedral geometry, respectively. The electrochemical reduction
of these complexes in THF solution is electrochemically irreversible. The compounds were
computationally investigated by use of molecular docking simulation. Our data points to the
higher probability of the interaction in the minor groove of DNA helix. Based on the docking
simulation, complexes were found to have stronger binding propensity as compared to ligand.
Acknowledgements
We thank Semnan University for supporting this study.
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19

Fig.1. Perspective view of the complex 1; ellipsoids are drawn at the 70% probability level,
hydrogen atoms are shown as spheres of arbitrary radii. Non-labelled atoms are related to the
labelled ones by symmetry operation 1-x,2-y,1-z.
20

Fig.2. Perspective view of the complex 2; ellipsoids are drawn at the 30% probability level;
hydrogen atoms are shown as spheres of arbitrary radii.
Fig.3. Perspective view of the complex 3; ellipsoids are drawn at the 30% probability level;
hydrogen atoms are shown as spheres of arbitrary radii.
21

Fig. 4. Coordination of Mn cations; L1 molecules are green, L2 – orange and purple, acetates –
blue and red.
Fig. 5. Comparison of the L1 conformations (red: 1, green: two molecules in 3); the phenyl A
rings are fitted one onto another.
22

Fig. 6. Cyclic voltammogram of complex 1 (1 × 10-3 mol/L / THF, 0.1 M tetrabutylammonium
hexafluorophosphate (TBAH) at 100 mV/s).
23

1.33
Cu0 CuI
CuI CuII
0.47
CuI CuII
0.3
- 1.07
-2
-1
0
1
2
3
E (V), (vs, Ag)
Fig. 7. Cyclic voltammogram of complex 2(1 × 10-3 mol/L / THF, 0.1 M tetrabutylammonium
hexafluorophosphate (TBAH) at 100 mV/s).
24

Fig. 8. Cyclic voltammogram of complex 3 (1 × 10-3 mol/L / THF, 0.1 M tetrabutylammonium
hexafluorophosphate (TBAH) at 100 mV/s).
25

26

27

Fig. 9. Docking conformation of the ligand, complexes 1, 2, 3 and anti-cancer drugs to DNA
(Trifluridine and Mitoxantrone).
Ligand H2L1
Complex 1
28

Complex 2
Complex 3
Trifluridine
Mitoxantrone
Fig. 10. Hydrogen bonding interactions of ligand, complexes 1, 2, 3 and anti-cancer drugs to
DNA (Trifluridine and Mitoxantrone).
29