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Charge-assisted hydrogen bond and nitrile  nitrile

interaction directed supramolecular associations
Cite this: New J. Chem., 2020,
44, 5473 in Cu(II) and Mn(II) coordination complexes:
anticancer, hematotoxicity and theoretical
studies†
Pranay Sharma,a Anshuman Gogoi,a Akalesh K. Verma,*b Antonio Frontera *c and
Manjit K. Bhattacharyya *a

Received 6th January 2020,
Accepted 5th March 2020
DOI: 10.1039/d0nj00075b
rsc.li/njc
Two new coordination complexes of Cu(II) and Mn(II), viz., [Cu(bpy)(H2O)4]SO42H2O (1) and [Mn(4-
CNpy)2(H2O)3SO4]H2O (2) (bpy = 2,2 0 -bipyridine, 4-CNpy = 4-cyanopyridine), have been synthesized
and characterized by using single crystal X-ray diffraction, elemental analysis, FT-IR spectroscopy,
electronic spectroscopic techniques and TGA. The crystal structure of 1 uncovers the formation of
sulfate–water assemblies involving lattice and coordinated water molecules, while complex 2 reveals the
presence of unconventional weak T-shaped CN  CN contacts in the layered architecture. We have
analysed the unconventional interesting interactions using DFT calculations, molecular electrostatic
potential (MEP), the NCI plot and QTAIM computational tools. The interaction energies of the two
H-bonded dimers in 1 are very large because of the coulombic attraction between the dicationic
H-bonded donor and the dianionic acceptor. It is interesting to observe that despite the energy of
the H-bonds being very small compared to the total dimerization energy, the final geometry of the assembly in
1 is due to the charge assisted directional H-bonds instead of the non-directional ion-pair interactions. The DFT
study reveals that the T-shaped CN  CN interaction in 2 is very weak, in good agreement with the small MEP
energy at the nitrile carbon atom. Anticancer studies of the compounds have been carried out using Dalton’s
lymphoma cell line using MTT and apoptosis assay. The results of compound 1 and 2 mediated cell cytotoxicity
on the DL cancer cell line showed a significant concentration-dependent reduction in cell viability, while
negligible cytotoxicity was observed in normal (PBMC) cells. The docking simulation results also confirm the
interaction of the complexes with the active sites of amino acids of the target proteins. Furthermore,
pharmacophore models (2D and 3D) for the compounds were mapped to the H-bond donor, positive ionisable
area and hydrophobic features that are important for establishing biological activities. No hematotoxicity was
recorded for the compounds after treatment in normal mice.

1. Introduction building blocks and fascinating topological architectures, but also

The design, construction and characterization of coordination
complexes involving interesting supramolecular association have
gained emphasis in the research field not only due to their versatile
a
Department of Chemistry, Cotton University, Guwahati-781001, Assam, India.
E-mail: manjit.bhattacharyya@cottonuniversity.ac.in
b
Department of Zoology, Cell & Biochemical Technology Laboratory, Cotton University,
Guwahati-781001, Assam, India. E-mail: akhilesh@cottonuniversity.ac.in
c
Departament de Quı́mica, Universitat de les Illes Balears, Crta de Valldemossa km 7.7,
07122 Palma de Mallorca (Baleares), Spain. E-mail: toni.frontera@uib.es
† Electronic supplementary information (ESI) available. CCDC 1827268 (1) and
1959920 (2). For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/d0nj00075b
due to their widespread potential applications.1,2 Generally, the
choice of the metal centers, organic moieties as ligands and
the reaction pathways and solvents influences the diversity in
the supramolecular assemblies of coordination complexes.3
Solvent-driven network topologies of crystalline materials
involving different self-assembly processes in the complexes com-
prising similar organic moieties have been reported recently.4
Stoichiometric ratios of the reactants also play key roles in the
synthesis and the construction of the desired metal–organic
assemblies in the crystal structures involving different topological
patterns.5 It is well established that the acidity/basicity of the
reaction media can also influence crystallization and growth of
metal–organic materials.6

This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2020 New J. Chem., 2020, 44, 5473--5488 | 5473

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Hydrogen bonding is a powerful organizing force in designing
molecular solids due to its directionality, selectivity and its rever-
sible formation at room temperature,7 and it plays a prominent
role in stabilizing supramolecular architectures.8 Besides, the
strong hydrogen bonds of types O–H  O and N–H  O, and weak
non-classical interactions such as C–H  X (X = O, Cl) play
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important roles in determining the stability of crystal structures.9
‘‘Charge-assisted’’ H-bonds are considered to be stronger and
shorter compared to neutral H-bonds,10 wherein the H-bond
donors and/or acceptors carry positive and negative charges,
respectively.11 There have been a few reports on the enhancement
of the strength of such hydrogen bonds in the presence of ionic
moieties.12
Anions play major roles in coordination compounds not only
as counter ions but also in directing self-assembly processes of
coordination networks in metal organic frameworks.13 Studies
on anion–water assemblies are of special importance in the
understanding of the hydration phenomena of inorganic anions
in nature and biochemistry.14 The interactions between the
anions and hydrogen bonded water lead to the formation of
self-assembled anion–water clusters.15
Nitrile  nitrile interactions in coordination compounds are
of particular interest from the stability and crystal engineering
viewpoint.16 C–N fragments present in organic cyanopyridines
are capable of exhibiting local dipole moments,17 and as a
consequence, such organic moieties engage in dipole–dipole
contacts and can serve as H-bond acceptors.18 C–N fragments
are involved in nitrile  nitrile interactions via different motifs
that involve (a) a sheared anti-parallel motif, (b) sheared
parallel motif and (c) T-shaped motif with antiparallel motif
as the most dominant one.19
Bipyridine and its analogue phenanthroline are very popular
ligands, which form complexes with a variety of transition
metals.20 Due to the chelating nature of these ligands in metal
complexes, they effectively control the aggregation behaviour by
chelation around the metal centers. Transition metal complexes
of 2,2 0 -bipyridine have potential applications in catalysis,21
as semiconducting materials,22 and as antimicrobial23 and
antitumor agents.24
Metal complexes involving zinc(II), copper(II), gold(III) and
ruthenium(III) have been developed with different degrees of
success as potential anticancer agents.25 It has already been
reported that the coordination of a Cu(II) ion with bioactive
ligands can improve drug pharmaceutical activity or reduce
toxicity effects.26–29 A large number of copper complexes involving
thiosemicarbazones (TSCs), imidazoles, phosphines, etc., have
been proposed as potential anticancer agents against different
cancer cell lines.27–30 Recently, it was reported that two copper
complexes have reached clinical assay, which paves the road to the
first copper-based anticancer therapeutics.28 M. Liu et al. also
reported the DNA binding and in vitro anticancer activities of a
Cu(II) complex of bipy and picrate.31 Manganese complexes of bipy
have also been reported to exhibit DNA cleavage and anticancer
activity against human hepatocarcinoma cell line via apoptosis.32
Similar biological activities are also reported for CNpy-based
coordination complexes.33
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Computer-aided drug design has become an indispensable tool
in the field of medicinal chemistry as well as in the pharmaceutical
industry and academia over the last decade,34 and it has been
employed during multiple stages of drug-design. Such com-
putational methods initially focus on reducing the overall
number of possible ligands/compounds; in the later stages,
the emphasis shifts to the reduction in experimental costs
and the duration required to make a discovery.35
Herein, we have reported two new coordination complexes
of Cu(II) and Mn(II), viz., [Cu(bpy)(H2O)4]SO42H2O (1) and
[Mn(4-CNpy)2(H2O)3SO4]H2O (2). The crystal structure of 1
reveals the formation of sulfate–water assemblies involving
coordinated and lattice water molecules leading to the self-
assembly of the cationic units into a 2D sheet structure; whereas
the crystal packing of 2 reveals the presence of T-shaped CN  CN
contacts in the layered architecture. Computational study has been
devoted to uncovering the energetic features of the sulfate–water
assembly that involves charge assisted hydrogen bonds and the
antiparallel p-stacked assembly of 1. The unusual T-shaped
CN  CN interactions in 2 are also studied theoretically using
DFT calculations and MEP analyses. Both compounds induced
cytotoxicity in DL cells through apoptosis. Furthermore, the
mechanism for cytotoxic activity of the compounds has been
explored with respect to their docking ability with some of the
cancer associated target proteins. Pharmacophore features
revealed the potential bioactivity of the compounds without
inducing toxicity in the host.
2. Experimental
2.1 Materials and methods
All reagents, viz., copper(II) sulfate pentahydrate, manganese(II)
sulfate monohydrate, 2,2 0 -bipyridine and 4-cyanopyridine, used
in this work were obtained from Sigma Aldrich and Merck
(India) Ltd and used as received. Deionised water was used as a
reaction medium throughout the experiments. Elemental analyses
(C, H and N) were carried out using a PerkinElmer 2400 Series II
CHN Analyzer. KBr phase FT-IR spectra were recorded on a Bruker
ALPHA (II) FTIR spectrophotometer in the mid-IR region (4000–
500 cm1). The electronic spectra were recorded using a Shimadzu
UV-2600 spectrophotometer. For UV-Vis-NIR spectral measure-
ment, BaSO4 powder was used as the reference (100% reflectance).
Thermogravimetric studies were carried out under the flow of N2
gas (25–700 1C) using a METLER TOLEDO Thermal Analyzer at a
heating rate of 10 1C min1. X-band EPR spectra were recorded
using a JEOL JES-FA 200 instrument. Room temperature magnetic
susceptibility was measured at 300 K on a Sherwood Mark 1
magnetic susceptibility balance by the Evans method.
2.2 Syntheses
2.2.1 Synthesis of [Cu(bpy)(H2O)4]SO42H2O (1). 2,20 -Bipyridine
(0.156 g, 1 mmol) was added to 20 mL of an aqueous solution of
copper(II) sulfate pentahydrate, CuSO45H2O (0.249 g, 1 mmol),
and stirred mechanically at room temperature for about 2 hours
[Scheme 1]. The light blue product obtained was filtered and
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2.3 X-ray crystallography

Crystals of desired quality for single crystal X-ray diffraction
study of 1 and 2 were obtained from the mother liquor upon slow
evaporation. X-ray diffraction data collection was carried out on a
Bruker SMART CCD diffractometer with graphite monochromatized
Mo Ka radiation (l = 0.71073 Å). Semiempirical absorption
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Scheme 1 Syntheses of compounds 1 and 2.

washed with deionised water. The filtrate was kept undisturbed
from which blue needle shaped crystals were obtained by slow
evaporation after a few days. Yield: 1.45 g (85.2%); anal. calcd
for C10H20CuN2O10S: C, 28.33%; H, 4.76%; N, 6.61%; found: C,
28.29%; H, 4.70%; N, 6.59%; FT-IR spectral data (KBr cm1):
3440(s,br), 3109(w), 3057(w), 3028(w), 1608(s), 1572(m), 1492(w),
1476(m), 1440(s), 1315(m), 1249(w), 1153(sh), 1109(s), 1020(m),
904(w), 772(s), 727(m), 661(w), 615(s) [s, strong; m, medium; w,
weak; br, broad; sh, shoulder].
2.2.2 Synthesis of [Mn(4-CNpy)2(H2O)3SO4]H2O (2). An
aqueous solution of manganese(II) sulphate monohydrate,
MnSO4H2O (0.169 g, 1 mmol), and 4-cyanopyridine (0.208 g,
2 mmol) was added to a round bottom flask with 10 mL of
deionised water and stirred mechanically at room temperature
for about 2 hours [Scheme 1]. The light yellow product obtained
was filtered and washed with deionised water. The filtrate was
kept unperturbed from which yellow needle shaped crystals
were obtained by slow evaporation after a few days. Yield:
0.362 g (84%); anal. calcd for C12H16MnN4O8S: C, 33.42%; H,
3.74%; N, 12.99%; found: C, 33.38%; H, 3.72%; N, 12.97%;
FT-IR spectral data (KBr cm1): 3446(br), 3101(s), 3058(s),
2330(w), 2298(w), 2237(s), 2080(w), 1696(s), 1631(s), 1517(s),
1146(sh), 1099(s), 980(w), 752(s), 630(s) [s, strong; m, medium;
w, weak; br, broad; sh, shoulder].
correction, as well as scaling and merging the different datasets
for each wavelength, was performed with SADABS.36 Crystal
structure was solved by the direct method (SHELXT-2014/5)
and refined by the full matrix least squares techniques
(SHELXT-2014/5) with SHELXL-2018/33037 using the WinGX38
platform available for personal computers. All non-hydrogen
atoms were refined anisotropically. The hydrogen atoms were
found via difference Fourier synthesis and they were refined
isotropically. The hydrogen atoms, except those attached to
oxygen atoms of water molecules, were placed at their calculated
positions and refined in the isotropic approximation. The hydrogen
atoms of the lattice water molecules could not be located from the
difference Fourier maps and are fixed at their normalized distances
to obtain the hydrogen bonding patterns in the crystal structure. For
2, the thermal ellipsoid of the terminal nitrile nitrogen atom is
comparatively larger with a relatively higher degree of thermal
motion resulting from the dynamic disorder.39 The structural
diagrams were drawn with Diamond 3.2.40 Crystallographic results
for 1 and 2 are summarized in Table 1.
2.4 Computational methods
All DFT calculations were carried out using the Gaussian-16
program41 at the B3LYP-D3/def2-TZVP level of theory and using
the crystallographic coordinates (only the position of the H-atoms
has been optimized). The Grimme’s dispersion correction (GD3)
has been used in the calculations.42 To evaluate the interactions

Table 1 Crystallographic data and structure refinement for 1 and 2

Parameters 1 2
Formula C10H20CuN2O10S C12H16MnN4O8S
Formula weight 423.88 431.29
Temp., [K] 293(2) 293(2)
Crystal system Triclinic Monoclinic
Space group P1% P21/c
a, [Å] 7.782(5) 17.144(1)
b, [Å] 9.410(5) 8.399(8)
c, [Å] 11.461(5) 12.557(1)
a, [1] 87.598(5) 90
b, [1] 83.605(5) 94.50(4)
g, [1] 77.477(5) 90
V, [Å3] 814.1(8) 1802.8(3)
Z 2 4
F(000) 438 884
D (calcd), [mg m3] 1.729 1.589
Index ranges 8 r h r 9, 11 r k r 11, 13 r l r 14 20 r h r 20, 9 r k r 9, 14 r l r 14
Crystal size, [mm3] 0.17  0.25  0.32 0.30  0.20  0.10
y range, [1] 1.78–24.49 2.70–24.99
Independent reflections 2884 2473
Reflections collected 9079 3135
Refinement method Full-matrix least-squares on F2 Full-matrix least-squares on F2
Data/restraints/parameters 2884/0/217 3135/0/236
Goodness-of-fit on F2 1.075 1.099
Final R indices [I 4 2s(I)] R1 = 0.0293, wR2 = 0.0786 R1 = 0.0500, wR2 = 0.1483
R indices (all data) R1 = 0.0325, wR2 = 0.0803 R1 = 0.0515, wR2 = 0.1498
Largest hole and peak [e Å3] 0.312 and 0.391 1.191 and 0.718

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in the solid state, the crystallographic coordinates were used.
This procedure and level of theory have been successfully used to
evaluate similar interactions.43 The interaction energies were
computed by calculating the difference between the energies of
the isolated monomers and their assembly. Quantum theory of
atoms-in-molecules (QTAIM)44 analysis was performed at the
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same level of theory. The calculation of AIM properties was done
using the AIMAll program.45 The molecular electrostatic potential
(MEP) has been computed at the same level of theory and plotted
with 0.001 a.u. as a good estimate of the van der Waals surface.
The NCI plot46 has also been used to rationalize the non-covalent
interactions studied herein. It is based on the electron density
and its derivatives and the isosurfaces correspond to both favour-
able and unfavourable interactions. They are easily differentiated by
the sign of the second density Hessian eigenvalue and defined by
the isosurface color. The color scheme is a red-yellow-green-blue
scale with red for rcut+ (repulsive) and blue for rcut (attractive).
Yellow and green surfaces correspond to weak repulsive and weak
attractive interactions, respectively.
2.5 Cell line and treatment
The DL malignant cancer cell line was cultured in RPMI-1640
supplemented with 10% FBS, gentamycin (20 mg mL1), strep-
tomycin (100 mg mL1) and penicillin (100 IU) in a CO2
incubator at 37 1C with 5% CO2; 80% confluent exponentially
growing cells were sub-cultured and used in the present experi-
ment. The different dosages (0, 0.01, 0.1, 0.5, 1, 5 and 10 mM) of
compounds 1 and 2 were prepared freshly during the experi-
ment by dissolving in phosphate buffer saline (pH = 7.4). The
experimental protocol on a mice model was approved by the
Institutional Animals Ethics Committee (IAEC) of Cotton Uni-
versity (CU-P19/2019).
2.6 Cell proliferation and apoptosis assay
DL cell cytotoxicity after 24 hours of exposure with the synthesized
compounds was measured by MTT assay along with peripheral
blood mononuclear cells (PBMCs) as normal cells.47 After treat-
ment, 1 million DL cells from each treatment group were
incubated in a microtiter plate with 10 mL of the MTT reagent
(5 mg mL1 in phosphate-buffered saline) for 4 hours in a cool
dark room. Then, 100 mL of DMSO was added into each well and
gently shaken. The plates were checked for complete solubiliza-
tion of crystals followed by measurement of absorbance of all
the samples at 550 nm.48 Furthermore, for apoptosis study,
control and treated cells as mentioned above were stained with
acridine orange and ethidium bromide (AO/EB).49 The cells were
then thoroughly examined in six replicates under a fluorescence
microscope and photographed. About 1000 cells were counted,
and the percentage of apoptotic nuclei was determined for six
independent replicates based on the differential coloring pattern
of the nuclei.50
2.7 Molecular docking simulation
The observed significant increase in apoptotic cell death after
treatment with 1 and 2 prompted us to perform interaction
analysis of 1 and 2 with anti-apoptotic target proteins, BCL-2,
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BCL-XL and MCL-1, using Molegro Virtual Docker (MVD
2010.4.0) software for Windows.51 The 3D coordinates of all
target proteins were downloaded from the Protein Data Bank
(PDB) and hydrogen atoms were added wherever found missing.
The docking parameters were run using a grid of 15 Å radius and
0.30 resolution with number of runs: 10; algorithm: Moldock SE;
maximum interactions: 1500; maximum population size: 50;
maximum steps: 300; neighbour distance factor: 1.00; maximum
number of poses returned: 5 to cover the ligand-binding site of
the protein structures.52 The protein–ligand binding site was
further analyzed and visualized by Chimera software (https://
www.cgl.ucsf.edu/chimera/).53
2.8 Pharmacophore modelling
To determine the essential components of the synthesized
compounds responsible for biological activity, pharmacophore
features were determined using LigandScout software.54 The
optimised structures of the said compounds were loaded to
LigandScout software and key pharmacophore features for each
compound were identified including H-bond donor, H-bond
acceptor, hydrophobic, aromatic, positively and negatively
ionizable groups.
2.9 Hematotoxicity study
After four consecutive days of injection (i.p.) of 50 mg per kg body
weight dose of both the compounds, blood was collected from
mice (n = 10) and different blood parameters were compared with
normal (untreated) mice to determine hematotoxicity in the host.55
2.10 Statistical analysis
Data are expressed as mean  standard deviation (S.D.). To
determine the significance of the differences among the groups,
one-way ANOVA, n = 3 was performed considering P r 0.05 to be
statistically significant.
3. Results and discussion
3.1 Synthesis and general aspects
The complexes [Cu(bpy)(H2O)4]SO42H2O (1) and [Mn(4-CNpy)2-
(H2O)3SO4]H2O (2) have been isolated in high yield by reacting
one equivalent of the respective metal sulfate, MSO4nH2O,
with one equivalent of 2,2 0 -bipyridine and two equivalents of
4-cyanopyridine, respectively, in water. Interestingly, the products
obtained for compounds 1 and 2 during reaction resemble the
single crystals obtained from the slow evaporation of the respective
mother liquors, which has been confirmed by the FT-IR spectral
studies [Fig. S1, ESI†]. Complexes 1 and 2 are soluble in water;
however, their solubility in common organic solvents is low. The
complexes 1 and 2 show room temperature meff values of 1.73 BM
and 5.86 BM, respectively, confirming the presence of one and five
unpaired electrons, respectively, per metal ion.48,56
3.2 Crystal structure analyses
3.2.1 Crystal structure of [Cu(bpy)(H2O)4]SO42H2O (1).
The complex [Cu(bpy)(H2O)4]SO42H2O (1) crystallizes in the
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Table 2 Selected bond lengths (Å) and bond angles (deg.) of Cu(II) and
Mn(II) centers in 1 and 2, respectively

Bond d (Å) Angle Degree (1)

1
Cu1–O1 2.080(2) O1–Cu1–O3 88.0
Cu1–O2 2.045(2) O1–Cu1–O2 87.8
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Cu1–O3 2.066(2) O1–Cu1–N2 91.4

Cu1–O4 2.095(3) O1–Cu1–N1 90.8
Cu1–N1 2.062(2) O1–Cu1–O4 176.9
Cu1–N2 2.071(2) O3–Cu1–O2 89.6
O3–Cu1–N2 175.4
O3–Cu1–N1 95.7
O3–Cu1–O4 90.4
O2–Cu1–N2 94.9
O2–Cu1–N1 174.4
Fig. 1 Molecular structure of 1; ellipsoids are represented at 50% prob- O2–Cu1–O4 89.4
ability level. N2–Cu1–N1 79.8
N2–Cu1–O4 90.3
N1–Cu1–O4 92.0
triclinic system, space group P1% with the entire formula unit 2
comprising the asymmetric unit. The asymmetric unit contains Mn1–O1 2.104(3) O1–Mn1–O2 91.3
a complex cation [Cu(bpy)(H2O)4]2+, one SO42 anion and two Mn1–O2 2.065(3) O1–Mn1–O3 92.2
Mn1–O3 2.111(3) O1–Mn1–O4 173.4
water molecules. The Cu–N bond distances are 2.06(2) and Mn1–O4 2.118(3) O1–Mn1–N1 88.1
2.07(2) Å and Cu–Ob(H2O) bond distances range from 2.05(2) to Mn1–N1 2.138(3) O1–Mn1–N3 88.5
2.09(2) Å, which are similar to that reported for Cu(II) complexes Mn1–N3 2.250(3) O2–Mn1–O3 91.1
O2–Mn1–O4 88.6
involving bpy.57 The N–Cu–N angle is 79.81. The two nitrogen O2–Mn1–N1 178.8
atoms (N1 and N2) from bpy occupy equatorial sites in a cis- O2–Mn1–N3 88.3
position. The oxygen atoms O1 and O4 of the coordinated water O3–Mn1–O4 94.4
O3–Mn1–N1 87.8
molecules occupy the axial positions at a distance longer than O3–Mn1–N3 179.1
the equatorial ones (O2 and O3), which is a consequence of O4–Mn1–N1 92.1
Jahn–Teller distortion (two electrons in dz2 orbital). The basal O4–Mn1–N3 85.0
N1–Mn1–N3 92.9
plane comprising atoms Cu1, O2, O3, N1 and N2 is nearly
planar (rms deviation = 0.0104 Å). However, the coordinated
bpy ring shows significant deviation from planarity (rms deviation = 3.2.2 Crystal structure analysis of [Mn(4-CNpy)2(H2O)3-
0.1001 Å). Fig. 1 depicts the dicationic complex [Cu(bpy)(H2O)4]2+ in SO4]H2O (2). The molecular structure of compound 2 is shown
association with free water and the SO42 anion, forming complex 1. in Fig. 3. Selected bond distances and bond angles of the Mn(II)
Table 2 lists the selected bond lengths and bond angles. centre are given in Table 2. Single crystal X-ray diffraction
Crystal structure analysis of 1 reveals intermolecular C–H  O analysis reveals that compound 2 crystallises in the monoclinic
and O–H  O hydrogen bonding interactions. It is also observed crystal system having space group P21/c. The coordination
that one of the coordinated water molecules (O1), lattice water sphere of Mn(II) in 2 is six coordinated, consisting of two
molecules and sulfate anions form a small sulfate–water assembly 4-CNpy molecules, three aqua molecules and one monodentate
via O–H  O hydrogen bonds with a discrete [(H2O)6(SO4)2]4 core SO42 ion. In addition, one lattice water molecule is also
[Fig. 2(a)]. Detailed structural analysis further reveals that the present in the asymmetric unit of 2. In compound 2, the two
[Cu(bpy)(H2O)4]2+ complex cations and sulfate anions form a 4-CNpy ligands are coordinated to the metal centre in a mono-
supramolecular 2D sheet structure stabilized by highly directional dentate fashion via the pyridyl-N atoms in a cis (adjacent) position.
C–H  O and O–H  O hydrogen bonds and p–p stacking inter- The axial positions are occupied by one 4-CNpy molecule (N3) and
actions [Fig. 2(b)]. The 2D sheet structure of 1 is formed by extensive one coordinated water molecule (O3); whereas, the equatorial
O–H  O and C–H  O hydrogen bonding interactions involving plane is formed by two aqua ligands (O2 and O4), one 4-CNpy
the coordinated water molecules (O1, O2, O3 and O4), carbon atoms ligand (N1) and the monodentate SO42 anion (O1). The sum of
(C4 and C7) of bpy and sulfate anion, and it runs along the the bond angles of N1–Mn1–O4 [92.06(1)1], O2–Mn1–O4
crystallographic bc plane, [Fig. 2(c)]. The donor–acceptor [88.56(1)1], O1–Mn1–O2 [91.39(1)1] and O1–Ni1–N1 [88.12(1)1]
C–H  Osulfate distances are in the range of 3.22 to 3.25 Å, while is 360.131, which shows that O1, N1, O4 and O2 atoms are
O–H  Osulfate distances are in the range of 2.65 to 2.74 Å almost co-planar (mean rms deviation of 0.0664 Å). The average
(Table 3). In addition, the 2D sheet structure is also stabilized Mn–N and Mn–O bond distances are found to be 2.1945 Å and
by aromatic p–p stacking interactions between the bpy rings of 2.0992 Å, respectively, which are quite similar to those of the
adjacent [Cu(bpy)(H2O)4]2+ complex cations [Fig. 2(c)]. The ring reported structures.59
centroid (N2, C6–C10)–centroid (N2, C6–C10) separation was Along the crystallographic b axis, the neighboring molecules
found to be 3.670 Å with a closest distance of 3.536 Å between of 2 are interconnected via strong non-covalent O–H  O hydrogen
two carbon atoms (C9–C7).58 bonding interactions [Fig. 4]. The non-coordinate O atom (O5) of

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Table 3 Selected hydrogen bond distances (Å) and angles (deg.) for 1 and 2

D–H  A d(D–H) d(D  A) d(H  A) +(DHA)

1
O1–H1A  O6#3 0.878(2) 2.691(3) 1.814(2) 177.5
O1–H1B  O10 0.887(2) 2.656(3) 1.774(2) 172.3
O2–H2A  O7 0.890(2) 2.731(3) 1.844(2) 173.8
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O3–H3A  O8#1 0.877(2) 2.670(3) 1.800(2) 171.7

O3–H3B  O7#2 0.892(2) 2.790(3) 1.906(2) 170.9
O4–H4A  O9#1 0.861(2) 2.708(3) 1.848(2) 176.2
O5–H5A  O8 0.805(2) 2.741(3) 1.937(2) 176.4
O5–H5B  O1#3 0.865(2) 2.850(3) 1.985(2) 178.7
O6–H6A  O10 0.869(2) 2.745(4) 1.905(7) 162.1
C7–H7  O10#4 0.931(3) 3.222(4) 2.438(2) 144.9
C4–H4  O9#4 0.931(3) 3.255(4) 2.372(2) 158.5
C9–H9  O4#5 0.931(3) 3.573(4) 2.755(2) 147.3

2
O4–H4B  O5 1.034(2) 2.670(3) 1.641(3) 172.4
O8–H8A  O5 1.058(3) 3.065(4) 2.056(3) 158.4
O8–H8A  O7 1.058(3) 3.077(4) 2.255(4) 133.1
C1–H1  N2 0.929(4) 3.384(8) 2.666(6) 134.5
C8–H8  N4 0.929(5) 3.648(7) 2.988(5) 129.3
O2–H2A  O6 1.009(3) 2.716(3) 1.805(2) 148.2
Symmetry transformations used to generate equivalent atoms for 1: #1
x, +y  1, +z; #2 x, y + 1, z + 1; #3 x + 1, y + 1, z + 1; #4 x + 1,
y + 1, z; #5 x, y + 1, z.

Fig. 3 Molecular structure of 2; ellipsoids are represented at 50% prob-

ability level.

Fig. 2 (a) Perspective representation of a discrete [(H2O)6(SO4)2]4 core.

(b) Supramolecular tetrameric assembly generated by antiparallel p–p,
O–H  O and C–H  O interactions of 1. Lattice water molecules are
not shown for clarity. (c) A view of the 2D sheet structure formed via
p–p, C–H  O and O–H  O along with the sulfate–water assembly along
the crystallographic bc plane.
the SO42 ion is involved in O–H  O hydrogen bonding inter-
actions with the coordinated aqua molecules (O4) having
O4–H4B  O5 = 1.641 Å.
The adjacent 1D chains of 2 are self-assembled in the crystallo-
graphic bc plane via non-covalent O–H  O, C–H  N and C–H  O
Fig. 4 View of 1D chain of 2 formed via O–H  O hydrogen bonding.
hydrogen bonding interactions into a 2D layered architecture
[Fig. 5]. The lattice water molecule of 2 plays a vital role in the
stabilization of the layered architecture in the bc plane. The
uncoordinated O atoms (O5, O6 and O7) of SO42 ions are
involved in O–H  O hydrogen bonding interaction with the
lattice water molecule (O8) and coordinate aqua ligand (O2)
having O8–H8A  O5 = 2.056 Å; O8–H8A  O7 = 2.255 Å;

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Fig. 5 Layered assembly of 2 via O–H  O, C–H  N and C–H  O

hydrogen bonding interactions.

O2–H2A  O6 = 1.806 Å. The lattice water molecule further

interconnects two adjacent 1D chains of 2 via O–H  O hydrogen
bonding interactions involving the coordinated aqua molecules
(O3 and O4) having O3–H3B  O8 = 1.798 Å; O4–H4A  O8 =
1.945 Å. Moreover, the non-coordinated N (N2 and N4) atoms of
4-CNpy moieties are involved in C–H  N hydrogen bonding
interactions with the –CH groups of neighboring 4-CNpy molecules
[C1–H1  N2 = 2.666 Å; C8–H8  N4 = 2.988 Å]. In addition, the non-
coordinated O atom (O6) of SO42 is also involved in C–H  O
interactions with the –CH moiety of 4-CNpy [C4–H4  O6 = 2.754 Å].
The most striking aspect of the crystal packing of 2 is the
formation of a closed supramolecular box-like60 layered archi-
tecture along the ab plane via weak T-shaped nitrile  nitrile
contacts. As shown in Fig. 6(a), the non-coordinated –CRN
moieties of neighboring monomeric units are involved in
T-shaped nitrile  nitrile interactions to form a supramolecular
box-like pattern having –C6RN2  Cg = 3.642 Å (Cg is the
centroid of the p system of C12RN4 fragment); –C12RN4  Cg =
3.572 Å (Cg is the centroid of the p system of C6RN2 fragment)
[Fig. 6(a)]. The dynamic disorder of the terminal nitrogen atom
(observed in the molecular structure of 2 in Fig. 3 at 50% probability
level) of the free nitrile group of coordinated 4-CNpy suggests the
relatively weak nature of the nitrile  nitrile contacts (vide infra).
Weak p-stacked interaction in the crystal structure involving guest
benzonitrile has been explained on the basis of the significant
thermal motion resulting from dynamic disorder of the nitrogen
atom of the nitrile moieties.39 The interesting nitrile  nitrile
interactions involving 4-CNpy result in the formation of a
layered architecture running along the ab plane [Fig. 6(d)].
Moreover, the N atom (N2) of the 4-CNpy moiety is involved in
C–H  N interactions with the –CH moiety (–C8H8) of neighboring
4-CNpy moieties [C8–H8  N2 = 2.744 Å]. With all these supra-
molecular interactions involving the 4-CNpy ligands in the two
Fig. 6 (a) Perspective representation of the closed supramolecular box via
planes of the crystal structure of 2 being in perpendicular direc-
T-shaped nitrile  nitrile contacts. (b) Two different T-shaped nitrile  nitrile
tions, the crystal packing results in a 3D architecture. A twenty-six contacts observed between three Mn(II) monomeric units. (c) Propagation of
member supramolecular ring motif having the graph-set notation the closed supramolecular box via O–H  O hydrogen bonding interactions.
of Etter61 of R22(26) is formed between two monomeric units of 2 (d) Layered assembly of 2 along ab plane assisted by T-shaped nitrile  nitrile
via perpendicular nitrile  nitrile interactions. contacts and O–H  O hydrogen bonding interactions.

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3.3 Computational study
Fig. 7 shows a partial view of the X-ray solid state structure of 1,
focusing on the 1D infinite supramolecular assembly that is
governed by the formation of O–H  O H-bonds between the
sulfate dianion and the coordinated water molecules. Each 1D
chain interacts with the adjacent one by a combination of
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p-stacking interactions and C–H  O H-bonds, thus generating
a 2D sheet. We have evaluated the interaction energies of two
H-bonded dimers extracted from the X-ray structures, which are
shown in Fig. 7(a and b). The interaction energies are very large
(DE1 = 319.9 kcal mol1 and DE2 = 249.1 kcal mol1)
because of the dicationic nature of the H-bond donor and the
dianionic nature of the acceptor. Therefore, most of the inter-
action energy is simply due to the coulombic attraction between
the two charges of opposite sign. The dimer shown in Fig. 7(b)
(O–H  O H-bonds) presents stronger energy than that in
Fig. 7(c) simply because the positive and negative charges are
closer. In order to measure the strength of the H-bonding
contacts described above, we carried out a topological analysis
of the electron density distribution within the framework of the
quantum theory of ‘‘atoms-in-molecules’’ (QTAIM method). We
have defined energies for the studied contacts according to the
conventional approach suggested by Vener et al., which was
developed specifically for HBs. The binding energy (in kcal mol1)
for each H-bond was derived from the Lagrangian kinetic energy
G(r) by using the expression 0.429  G(r) at the bond CP that
connects the H-atom to the oxygen atom. In Fig. 7, the values (in
a.u.) of G(r) at the bond CPs are given in black and the dissociation
energy is given in red (kcal mol1). It can be observed that the
O–H  O H-bonds are stronger (6.62 and 5.27 kcal mol1) than the
C–H  O bonds (2.12 and 1.96 kcal mol1). It is worth highlighting
Fig. 7 (a) Partial view of the X-ray structure of 1. Distances in Å. (b and c)
AIM distribution of bond and ring critical points (green and yellow spheres,
respectively), and bond paths obtained for the H-bonded dimers of
compound 1. The dissociation energies of the H-bonds obtained using
the G(r) values at the bond CP are indicated in red (kcal mol1).
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that despite the energy of the H-bonds being very small compared
to the total dimerization energy, the final geometry of the assembly
is adjusted by the directional H-bonds instead of the non-
directional ion-pair interaction.
Fig. 8(a) shows the MEP surface of compound 2. The most
negative part of the molecule corresponds to the sulfate anion
(88 kcal mol1) and the most positive part corresponds to the
H-atoms of the coordinated water molecules (90 kcal mol1). In
order to examine the charge density around the CN group more
precisely, we have represented the MEP using a smaller energy
range, which is highlighted in Fig. 8(a). The MEP value at the
location of the lp of N is negative (24 kcal mol1) and it is
positive over the C atom (+10 kcal mol1); thus, a T-shaped
supramolecular dimer between two cyano derivatives is expected
to be electrostatically favoured. In Fig. 8(b), we show the QTAIM
distribution of bond CPs and bond paths of the dimer and,
indeed, it reveals the presence of two bond CPs and bond paths
connecting the N-atom of the nitrile group of one monomer to
the C-atom of the nitrile group and also an aromatic H-atom of
the adjacent monomer. For this study, we have selected the dimer
with the shortest distance [3.572 Å, see Fig. 6(b)]. The formation
energy of this dimer is very modest (DE3 = 2.2 kcal mol1) and,
moreover, the contribution of the C–H  N hydrogen bond is
1.67 kcal mol1 using the G(r) value that is indicated in Fig. 8(b).
This analysis suggest that the T-shaped interaction is very weak
(only 0.5 kcal mol1), in good agreement with the small MEP
energy at the C-atom of the nitrile. It should be mentioned that
the N  C distance in the dimer is longer than the sum of van der
Waals radii (3.25 Å), thus explaining the small contribution of the
T-shaped CN  CN interaction. Finally, it should be kept in mind
that the interaction energy obtained for this contact is within the
accuracy of the DFT method used in this work. However, both the
NCI plot and QTAIM computational tools reveal the existence of
contact and its attractive nature, as further discussed below.
We have also obtained, using the B3LYP-D3/def2-TZVP wave
function, the ‘‘non-covalent interaction plot’’ (NCI plot) of a
tetrameric fragment of compound 1 (two anions and two cations)
Fig. 8 (a) MEP surface of compound 2 at the B3LYP-D3/def2-TZVP level
of theory and using the 0.001 a.u. isosurface. The energies are given
in kcal mol1. (b) AIM distribution of bond and ring critical points
(red and yellow spheres, respectively), and bond paths obtained for the
T-shaped dimer of compound 2. The dissociation energies of the
H-bonds obtained using the G(r) values (in black, a.u.) at the bond CP
are indicated in red (kcal mol1).

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Fig. 9 (a) NCI surface of the tetrameric assembly of compound 1 and (b)
dimeric fragment of 2. The gradient cut-off is s = 0.35 a.u., and the color
scale is 0.04 o r o 0.04 a.u.
in order to characterize the antiparallel p–p interactions high-
lighted in Fig. 2(b) and in a dimeric fragment of 2 to analyse the
T-shaped CN  CN interaction [see Fig. 6(b)]. The NCI plot is an
intuitive visualization index that allows the characterization of
non-covalent interactions efficiently and, consequently, it is
convenient to analyse supramolecular interactions since it clearly
shows which molecular regions interact. The colour scheme is a
red-yellow-green-blue scale with red (repulsive) and blue (attrac-
tive). Yellow and green surfaces correspond to weak repulsive and
weak attractive interactions, respectively. The representation of the
NCI plot is shown in Fig. 9(a) and it clearly shows that the p–p
interaction is characterized by the presence of a large green
isosurface located between the aromatic rings, thus confirming
the interaction. The NCI plot also reveals the existence of small
isosurfaces located between the sulfate O-atoms and two CH
bonds of the aromatic ring. Such small and green isosurfaces
agree well with the energetic analysis summarized in Fig. 7, which
evidences that the dissociation energies of the C–H  O H-bonds
are small. In contrast, the O–H  O H-bonds are characterized by
blue isosurfaces, thus suggesting stronger interaction in agree-
ment with the dissociation energies of these H-bonds [6.62 and
5.27 kcal mol1, see Fig. 7(b)]. In compound 2 [see Fig. 9(b)], the
presence of two small and green isosurfaces confirms the existence
of both C–H  N and T-shaped CN  CN interactions and agrees
well with the modest interaction energy computed for this assem-
bly and also in line with the long CN  CN distance.
3.4 Infrared spectroscopy
The FT-IR spectra of compounds 1 and 2 have been recorded in
the region 500–4000 cm1 [Fig. 10]. The IR spectra of 1 and 2
exhibit bands at around 3440 cm1, which can be assigned to the
n(O–H) vibration of the coordinated and lattice water molecules.62
The bands near 1109 and 615 cm1 in 1 are assigned to the n3(F2)
stretching [nd(SO)] and n4(F2) bending [dd(OSO)] modes of the free
sulfate (Td point group) anion, respectively.63 The in-plane ring
vibration and C–H deformation bands of bpy are observed at 1608
and 1440 cm1. The peaks at 1020, 772 and 661 cm1 for 1 are
attributed respectively to in-plane ring breathing, out-of-plane C–H
vibration, and out-of-plane ring stretching vibrations of bpy
ligand.64 These vibrations are somewhat shifted, suggesting
coordination of bpy to the copper(II) centre. The appearance of
the absorptions at 983, 1093, and 1146 cm1 in the FT-IR
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Fig. 10 KBr phase FT-IR spectra of 1 and 2.
spectrum of 2 for the n1, n3a, and n3b vibrations of the sulfato
ligand suggests that the anion may be coordinated to the Mn2+
ion in the monodentate coordination mode.65 The strong
vibrations at 2237 cm1 for 2 can be assigned to the nitrile
stretching frequency n(C–N) of the 4-CNpy ligand.66 The absorption
position of the n(C–N) band in 2 remains almost the same com-
pared to that of the free ligand, indicating that 4-CNpy is not
coordinated to the metal through the nitrile group and coordinates
only via the N atom of the pyridine ring.67
3.5 Electronic absorption spectroscopy
The solid-state UV-Vis-NIR spectrum of complex 1 exhibits two
intense peaks at 296 and 310 nm assigned to p - p* transitions
of the coordinated bpy ligand68 whereas the band at around
396 nm is assigned to the charge transfer transition.69 The
spectrum [Fig. 11(a)] shows broad absorptions at 674 nm with
shoulders at 831 and 1141 nm, both of which may be thought to
result from the splitting of the usual 2Eg - 2T2g transition for
octahedral complexes. Studies on solid samples of Cu(II) complexes
showed that up to three absorption bands may be observable due
primarily to Jahn–Teller distortion.70 In the UV-Vis spectrum
[Fig. 11(b)], the absorption peaks for p - p* and charge transfer
transitions are obtained at 297, 306 and 351 nm, respectively. The
broad band at 665 nm may be attributed to the 2Eg - 2T2g
transition for the octahedral Cu(II) metal centre in 1.70
The solid state UV-Vis-NIR spectrum and aqueous phase
UV-Vis spectrum of 2 are shown in Fig. 12(a and b), respectively.
The spectra show no d–d bands, because the Mn2+ ion, which is
a d5 system, has all electronic transitions from the 6A1g ground
state doubly forbidden.59,71 In the aqueous state UV-Vis spec-
trum [Fig. 12(b)], the absorption peak at 228 nm can be
assigned to the p - p* absorption of 4-CNpy, whereas the
peak at around 273 nm is attributed to a LMCT (ligand to metal
charge transfer) transition.72 In the solid state UV-Vis-NIR
spectrum [Fig. 12(a)], these absorption peaks were obtained at
225 and 278 nm, respectively.
The electronic spectral studies reveal that complexes 1 and 2
do not show marked differences in the position of the absorption
peaks in the solid and aqueous phases, and therefore, it may
be assumed that bonding modes and the geometries of the
synthesized complexes do not change in the solution phase.73
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Fig. 11 (a) UV-Vis-NIR spectrum of 1. (b) UV-Vis spectrum of 1 in water.
Fig. 12 (a) UV-Vis-NIR spectrum of 2. (b) UV-Vis spectrum of 2.
The UV-Vis spectra of compounds 1 and 2 in DMSO also suggest the
structural similarity with the aqueous phase [Fig. S2 and S3, ESI†].
3.6 EPR spectral analyses of 1 and 2
The X-band EPR spectrum of a crystalline sample of 1 was
recorded at room temperature and is shown in Fig. 13. An axial
spectrum with g8 = 2.29 and g> = 2.08 was observed. The spectral
lines are broad and no hyperfine splitting was observed, which may
be attributed to the existence of spin exchange between the copper(II)
centers in the crystal structure. The observed g values from the solid
Fig. 13 Room temperature EPR spectrum of a crystalline sample of 1.
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state spectrum with g8 4 g> 4 2.0023 are characteristic of a
copper(II) ion in axial symmetry with unpaired electron residing in
the dx2–y2 orbital.74 The g value of the complex is consistent with a
distorted octahedral geometry around the copper(II) ion.75
Fig. 14 represents the X band EPR spectrum of a crystalline
sample of compound 2 at room temperature and is characterized
by several resonances. The spectrum shows an intense signal
centered on g = 2.69. The spectrum is very similar to those of six
coordinated Mn(II) complexes with the 6S5/2 ground state.76 The
g = 4.6 signal may be ascribed to distorted octahedral mononuclear
Fig. 14 Room temperature EPR spectrum of a crystalline sample of 2.

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Mn(II) complexes.77 The broad signals of compound 2 are due to
dipolar interactions and random orientations of the Mn2+ ions.78
Manganese hyperfine splitting is not observed in the solid state
room temperature spectrum of 2.78
3.7 Thermogravimetric analysis (TGA)
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Thermogravimetric analysis of 1 and 2 was carried out in the
range of 20–700 1C under a N2 atmosphere at a heating rate of
10 1C min1 [Fig. S4, ESI†]. For 1, the weight loss of 6.8% (calc.
8.4%) in the temperature range of 85–104 1C is attributed to the
loss of two lattice water molecules.79 The second step involves
continuous weight loss indicating the removal of coordinated
water molecules, bpy and sulfate in the temperature range of
180–272 1C with an observed weight loss of 75.9% (calc. =
76.4%).80 For 2, the weight loss of 14.98% (calc. 16.69%) in the
temperature range of 25–164 1C is attributed to the loss of three
coordinated and one lattice water molecules. The second step
indicates the loss of sulfate anion in the temperature range of
166–326 1C with an observed weight loss of 20.83% (calc.
22.27%).81 In the temperature range of 330–690 1C, the weight
loss of 46.44% (calc. 48.27%) indicates the loss of two 4-CNpy
moieties.82
3.8 Cell proliferation and apoptosis assay
MTT assay is considered to be one of the most common pre-
liminary methods for studying cell cytotoxicity of any chemical.83
The principle of this assay depends on enzymatic reduction
of 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide
(MTT) to MTT-formazan catalyzed by mitochondrial dehydrogenase.
Hence, the MTT assay is dependent on mitochondrial activity,
polarisation state (high or low), and cell viability and also serves
to differentiate the metabolically active and inactive cells.84 The
results of compound 1 and 2 mediated cell cytotoxicity in the DL cell
line showed significant (P r 0.05) concentration dependent
reduction in cell viability [Fig. 15 and 16]. Approximately, 10–45%
cell cytotoxicity was obtained for both the compounds in the dose
range of 1–10 mM. At the same time, negligible cytotoxicity (B10%)
was observed in normal (PBMC) cells as compared to that in DL
(cancer) cells. Since the DNA repair mechanism is very poor in
cancer cells85 in comparision to healthy cells, this may have
Fig. 15 Morphological features of apoptotic and viable cells observed under a fluorescence microscope. Cisplatin treatment (a) showed apoptotic cells
(red/orange color nucleus), control DL cells (b) showed viable cells (green nucleus) and complex 1 and 2 treated groups (c and d) at different doses (0.01,
0.1, 0.5, 1, 5 and 10 mM) showed apoptotic nuclei with membrane damage and chromatin condensation. Scale bar 10 mm.
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caused the compound 1 and 2 mediated selective and signifi-
cant cytotoxicity in DL cells as compared to normal cells.
Treatment of DL cells with the synthesized compounds led to
the development of apoptotic features as observed morphologi-
cally by the acridine orange (AO)/ethidium bromide (EB) dual
staining method. AO is a membrane-permeable dye that inter-
calates with DNA of all cells in the sample and makes a cell
green, whereas EB can only stain cells that had lost their membrane
integrity due to apoptosis and appears red or orange.86 Treated cells
demonstrated the morphological characteristics of typical apoptotic
cells including membrane blebbing, chromatin condensation and
formation of apoptotic bodies [Fig. 15 and 16]. Moreover, cancer
cells have a higher oxidative status than normal cells and therefore
suffer more oxidative DNA damage. Compound 2 has higher
cytotoxicity and apoptosis-inducing ability than compound 1 after
24 hours of exposure. There are some reports of antiproliferative
activity of transition metal compounds involving 2,20 -bipyridine and
4-cyanopyridine. Mixed-ligand copper(II) complexes, viz., [Cu2(2,2 0 -
bipy)2(L1)4] and [Cu(2,2 0 -bipy)(L2)2]n [where L1 = 5-phenyltetrazole,
and L2 = 1H-tetrazole], exhibit in vitro cytotoxicity against human
cancer cell lines.87 M. Altaf et al. have also recently reported
anticancer activity of bipyridine and bipyrimidine gold(III) dithio-
carbamate compounds against different human cancers including
lung cancer (A549), androgen-sensitive prostate cancer (DU145),
androgen-resistant prostate cancer (PC3), breast cancer (MCF-7),
and osteosarcoma (MG-63).88 Similar in vitro cytotoxicity was also
observed in coordination compounds involving 4-cyanopyridine.89
3.9 Molecular docking simulation
The present study utilizes a molecular docking algorithm to
predict possible interactions between anti-apoptotic proteins
(BCL-2, BCL-XL and MCL-1) with the compounds 1 and 2 to
further understand the possible apoptotic inducing mechanisms.
The molecular docking method can be used to design novel
inhibitors against important biological targets and by utilizing
this algorithm, it is possible to elucidate fundamental biochemical
processes by studying behaviour of small molecules in the binding
site of target proteins.90 Several anti-apoptotic proteins are reported
to interact with pro-apoptotic proteins to execute the process of
apoptosis.91 High expression of these anti-apoptotic proteins is
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Fig. 18 Docking structure of compound 2 with BCL-2 receptor. Chemical

interactions are shown along with ligand atoms and interacting amino
acids in the inhibitor-binding sites of BCL-2 receptor.

Fig. 16 Compound 1 and 2 mediated percentage cell viability and apop-

totic cells after treatment with different dosages in normal and DL cells.
Cisplatin (CP) was used as a positive (reference drug) control.

associated with malignant behaviour in several types of cancers by

escaping the apoptosis pathway. Several recent literature reports
described the involvement of pro- and anti-apoptotic BCL-2 family
members in tumour-pathogenesis and hence used them as a target
for development of more efficient and more precisely targeted
treatment regimens.92,93 Both compounds 1 and 2 showed strong
interactions with BCL-2, BCL-XL and MCL-1 [Fig. 17–19], whereas
compound 2 showed strong hydrogen bond interactions as com-
pared to compound 1. Compound 1 showed four hydrogen bond
interactions with BCL-2 involving active site amino acids such as
Gln96, Phe101, Tyr199 and Arg104, whereas, in the case of 1, Phe101
and Ala97 play important roles during chemical interactions. More
interestingly, Phe101 is found to be a common interacting amino
acid in the case of 1 and 2. Interestingly, compounds 1 (docking

Fig. 19 Heatmap of compounds 1 and 2 showing different binding scores

for target protein–compound interactions. Five different pose values
(docking scores) are shown for each target protein. Comparison is done
column-wise where red: high interactions, black: moderate interactions
and green: low interactions.

score: 132) and 2 (docking score: 147) showed comparable

Fig. 17 Docking structure of compound 1 with BCL-2 receptor. Chemical
interactions are shown along with ligand atoms and interacting amino
acids in the inhibitor-binding sites of BCL-2 receptor.
docking scores with the reference ligand (docking score: 152),
which was already integrated in the active site of the receptor in the
crystallographic PDB file (PDB ID: 2O22). The docking result in
MVD software produces five poses against each protein–compound
interaction. Heatmaps of compounds 1 and 2 are shown on the
basis of five pose scores (docking scores) showing different binding
scores for target protein–compound interactions [Fig. 19]. Thus,
based on the docking simulation result, it can be suggested that the
compounds possess apoptotic-inducing ability due to well-
organized interaction with anti-apoptotic target proteins.

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3.10 Pharmacophore modelling
Pharmacophore modelling produces functional sites in chemical
structures.94 Pharmacophore models (3D) for the compounds 1
and 2 mapped to the H-bond donor (green), positive ionizable
area (blue star) and hydrophobic (yellow)features. The 2D view
displays the structural formula of complexes and their associated
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pharmacophore [Fig. 20] features. These features are most com-
monly used in the field of medicinal chemistry, recognized by the
active site amino acid residues in receptors that are responsible
for the molecular biological activities.95 It has been established
that a set of structural features may be common in multiple
compounds that bind to the same protein target and hence
similar compounds may produce similar biological activities.96
The results of such a study rely on the individual features such as
hydrogen-bond donors or acceptors, positively or negatively
charged groups, hydrophobic regions, aromatic rings, etc. that
are usually arranged in specific 3D conformations.97 The phar-
macophore features obtained from the in silico study for 1 and 2
can be used to screen chemical libraries to search similar
compounds with high efficacy. Additionally, this technique can
also be applied for the prediction of ligand binding modes or
ligand 3D alignments for studying biological activities.98
3.11 Hematotoxicity study
Several clinical units are studying the effect of new chemical
agents on different blood parameters in phase I evaluation.99
Hematotoxicity results could be coordinated so that high-
performance, optimized technical protocols are used for prospective
and retrospective clinical evaluations to produce clinically viable
drug(s). After four consecutive days of injection (i.p.) of 50 mg per kg
body weight dose of compounds 1 and 2, there was no statistically
significant difference in treated and control (normal) groups
Fig. 20 Pharmacophore features (3D and 2D) of compounds 1 (a and a 0 )
and 2 (b and b 0 ) predicted using LigandScout software. Pharmacophore
features in both the compounds include hydrophobic (H), positive ionizable
(PI), negative ionizable (NI), hydrogen bond donor (HBD) and hydrogen
bond acceptor (HBA) moieties.
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Fig. 21 Effect of compounds 1 and 2 on different blood parameters after
four consecutive days of injection (i.p.) in mice.
[Fig. 21] with regard to total red blood cell (RBC), white blood count
(WBC), haemoglobin, platelet count and erythrocyte sedimentation
rate (ESR).99
4. Conclusion
Two new coordination compounds of Cu(II) and Mn(II) have been
synthesized and characterized by using single crystal X-ray diffrac-
tion, electronic, FT-IR and EPR spectroscopy and TGA. Crystal
structure analysis of 1 reveals the presence of anion–water assem-
blies via intermolecular O–H  O hydrogen bonding interactions.
Perpendicular unconventional T-shaped nitrile  nitrile interactions
play a crucial role in the stabilisation of a layered assembly of 2. The
individual contributions of the charge assisted H-bonds in 1 have
been evaluated using the Lagrangian kinetic energy, which are
modest in comparison to the coulombic attraction between the
complex cations and counter anions, but important to determine
the final geometry of the assemblies. In 2, the DFT study reveals that
the unconventional T-shaped CN  CN interaction is very modest.
Compounds 1 and 2 significantly inhibit cell viability by inducing
apoptotic cell death in the DL cell line with negligible cytotoxicity in
healthy cells (PBMC). Moreover, the compounds have been found to
be safe against different blood parameters. The docking simulation
results showed that the compounds interact well in the active sites of
amino acids of all the target proteins under study and comparable
interactions were also noted for reference inhibitors. Furthermore,
the pharmacophore features embedded with apoptotis studies of the
synthesized complexes may play important role in medical fields.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Financial support from the University Grants Commission
(UGC), New Delhi [Grant number: F. No. 42-377/2013]; and
New J. Chem., 2020, 44, 5473--5488 | 5485

Paper
the MINECO of Spain (project CTQ2017-85821-R FEDER funds)
is gratefully acknowledged. The authors thank IIT, Guwahati
for providing the single crystal X-ray diffraction data and EPR
data and the Department of Chemistry, Gauhati University,
Guwahati for providing TG data.
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