New DNA-Interactive Manganese(II) Complex of Amidooxime: Crystal Structure, DFT Calculation, Biophysical and Molecular Docking Studies

Article abstract of DOI:10.1021/acs.jced.0c00529

A manganese(II) complex [MnII(HL1)2(Cl)(CH3COO)](1) based on the amidooxime ligand was synthesized and characterized by single-crystal X-ray diffraction studies, elemental analysis, UV-vis, and IR spectroscopy. The structural and spectral parameters were further supported using DFT/B3LYP. The complex (1) is mononuclear, having an octahedral geometry. The interaction of 1 with calf thymus DNA was investigated by spectroscopic and calorimetric techniques. The complex was found to interact with DNA through the groove-binding mode. From the isothermal titration calorimetry experiment, the binding constant between 1 and DNA was estimated to be (4.39 ± 0.01) × 105 M-1. The negative standard molar Gibbs energy change (δG0) and positive entropy (TδS0) values obtained from the calorimetry study confirmed the spontaneity of 1-DNA complexation. Thermodynamic parameters also suggested that the process of interaction of 1 with DNA was entropy-driven. The molecular docking study revealed that 1 binds at G30, C29, T31, A14, and G13 base pairs of the DNA chain in the minor groove.

Full text of DOI:10.1021/acs.jced.0c00529

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Article
New DNA-Interactive Manganese(II) Complex of Amidooxime:
Crystal Structure, DFT Calculation, Biophysical and Molecular
Docking Studies
Urmila Saha, Malay Dolai,* Gopinatha Suresh Kumar, Ray J. Butcher, and Saugata Konar
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ABSTRACT: A manganese(II) complex [MnII(HL1)2(Cl)-
(CH3COO)](1) based on the amidooxime ligand was synthesized
and characterized by single-crystal X-ray diffraction studies,
elemental analysis, UV−vis, and IR spectroscopy. The structural
and spectral parameters were further supported using DFT/
B3LYP. The complex (1) is mononuclear, having an octahedral
geometry. The interaction of 1 with calf thymus DNA was
investigated by spectroscopic and calorimetric techniques. The
complex was found to interact with DNA through the groove-
binding mode. From the isothermal titration calorimetry experi-
ment, the binding constant between 1 and DNA was estimated to
be (4.39 0.01) × 105 M−1. The negative standard molar Gibbs
energy change (ΔG0) and positive entropy (TΔS0) values obtained
from the calorimetry study confirmed the spontaneity of 1-DNA complexation. Thermodynamic parameters also suggested that the
process of interaction of 1 with DNA was entropy-driven. The molecular docking study revealed that 1 binds at G30, C29, T31, A14,
and G13 base pairs of the DNA chain in the minor groove.
but a complex may also exhibit a mixed mode of binding. The
structural changes induced in the DNA helix for these
interactions may result in the disruption of the replication
process and transcription events, eventually leading to
apoptosis and cell death.23 Therefore, a quantitative study of
nucleic acid interaction with several proteins, enzymes, and
drugs is essential for drug development.24,25 Fluorescence and
chemiluminescence are widely used physicochemical tools for
monitoring the interaction of different small molecules with
DNA.26 For the nonfluorescent nature of DNA, the direct use
of the natural fluorescence emission properties of nucleic acids
is not applicable.27,28 Therefore, an extrinsic fluorescent probe
must be employed in the studies involving DNA.23,29
INTRODUCTION
■
Manganese is a crucial biologically relevant metal, especially for
its active participation in the formation of various enzymes and
proteins such as superoxide dismutase, glutamine synthetase,
and so forth.1,2 Manganese is implicated for assisting the
metabolism, neuro functions, balancing blood sugar, produc-
tion of sex hormones, and calcium absorption. However,
studies on the biological activity of manganese complexes are
scarce.3 Manganese is found in the active site of a plethora of
enzymes,4−6 anticancer agents (SC-52608), and MRI contrast
reagents such as [Mn(dpdp)]4− (dpdp = dipyridoxyldiphos-
phate) for detection of hepatocellular carcinomas.7 Further-
more, manganese complexes with diverse ligands are known to
exhibit bactericidal8−10 and antiproliferative effects11,12 on
several cancer cell lines and have antitumor activities.13
Consequently, the study of the bioactivity of novel manganese
complexes has gained prime interest in the recent times. These
observations have motivated the development of new
manganese-based drugs.
On the other hand, studies on the bioactivity of the oxime-
based manganese complexes are in their infant stage. Very few
studies have been reported in recent years,16−18,30 and work on
manganese complexes exhibiting bioactivity and DNA binding
has attracted special attention recently.
In the recent past, investigation on the association of small
molecules with nucleic acids has risen as functioning research
at the interface of chemistry and molecular biology.14 DNA
carries genetic information15 and is the prime cellular target of
many drugs and small molecules, interfering with its function.
DNA interacts with small molecules in three noncovalent
ways: intercalation, groove binding, and external binding,16−22
Received: June 8, 2020
Accepted: September 28, 2020
https://dx.doi.org/10.1021/acs.jced.0c00529
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© XXXX American Chemical Society
A

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Table 1. Sample Source, CAS Registry, and Initial Purity
material
2-pyrimidine carbonitrile
manganese(II) chloride tetrahydrate
hydroxylaminehydrochloride
sodium acetate
chemical formula
CAS
supplier
purity (mass fraction)
C5H3N3
14080-23-0
13446-34-9
5470-11-1
127-09-3
Merck, India
Merck, India
Merck, India
Merck, India
97%
≥98%
MnCl2·4H2O
NH2OH·HCl
CH3COONa
Calf thymus DNA
≥99.0%
≥99.0%
deoxyribonucleic acid sodium salt from calf
thymus
73049-39-5
Sigma-Aldrich 41.9 mol % G-C and 58.1 mol % A-T
bisbenzimide (Hoechst 33258)
citric acidmonohydrate
di-sodium hydrogen phosphate anhydrous
methanol
dimethyl Sulfoxide
manganese complex (1)
C25H24N6O·3HCl
HOC(COOH)(CH2COOH)2·H2O
Na2HPO4
CH3OH
(CH3)2SO
23491-45-4
5949-29-1
7558-79-4
67-56-1
Sigma-Aldrich ≥98%
Sigma-Aldrich ≥99.0%
Merck, India
Merck, India
Merck, India
Synthesis
chemically pure
≥99.8%
≥99.9%
99%
67-68-5
C12H15ClMnN8O4
Scheme 1. Synthetic Scheme of Complex 1
Herein, we have studied the in situ reaction of 2-
pyrimidinecarbonitrile with NH2OH·HCl in the presence of
MnII metal ions in methanolic medium at 60 °C to form the
Mn(II) complex based on 2-pyrimidine amidooxime. This
complex has also exhibited DNA binding activity, and this may
appear as a potential activity for biomedical applications.
mol): C, 33.86%; H, 3.55%; N, 26.32%. Found: C, 33.82%; H,
3.58%; N, 26.35%. IR (cm−1, KBr): ν(−OH), 3027; ν(CN),
1658; ν(CH3COO−), 1426.
Physical Measurements. Elemental analyses (carbon,
hydrogen, and nitrogen) of the metal complex were performed
with a PerkinElmer CHN analyzer 2400. IR spectra (400−
4000 cm−1) were recorded on a Nicolet Magna IR 750 series-II
FTIR spectrometer. UV−vis spectral titrations were carried out
on a JASCO V660 spectrophotometer (JASCO, Hachioji,
Japan). Fluorescence studies were performed on a Shimadzu
RF-5301PC spectrofluorimeter (Shimadzu, Kyoto, Japan). A
VP-ITC microcalorimeter (MicroCal, USA, now Malvern
Instruments, UK) was used to perform isothermal titration
calorimetry (ITC) experiments.
Crystallography. Single-crystal X-ray diffraction data of 1
were collected at 273(2) K on a quest diffractometer with
graphite monochromated Mo Kα radiation (λ = 0.71073 Å).
Data integration and reduction were done by using the Bruker
Smart Apex, data were integrated using the SAINT31 program,
and the absorption corrections were made with SADABS.32
The structure was solved by direct methods,33 and full-matrix
least-squares refinements were performed on F2 using
SHELXL-2014/17 with anisotropic displacement parameters
for all nonhydrogen atoms. All the nonhydrogen atoms were
refined with anisotropic thermal parameters. All the hydrogen
atoms belonging to carbon atoms were placed in their
geometrically idealized positions. Molecular view and packing
diagrams of complex 1 were produced with the Diamond Ver.
3.2 program.34 The crystal data and details of refinement are
given in Table 2.
EXPERIMENTAL SECTION
■
Materials. The starting materials (Table 1) such as 2-
pyrimidine carbonitrile, MnCl2·4H2O, NH2OH·HCl, and
NaOAc used for the preparation of complex were procured
from Merck, India. Calf thymus DNA (sodium salt, D1501)
and bisbenzimide (Hoechst 33258, ≥98% purity) were
purchased from Sigma-Aldrich Corp. (St. Louis, MO, USA).
All other solvents and chemicals were of reagent grade,
obtained from commercial sources, and used without further
purification.
Synthesis of the Complex [MnII(HL1)2(Cl)(CH3COO)]-
(1). [MnII(HL1)2(Cl)(CH3COO)](1) was prepared by the
following in situ preparation procedure (Scheme 1).30
A
mixture of 2-cyano pyrimidine (0.104 g, 1 mmol) and
hydroxylamine hydrochloride (0.069 g, 1 mmol) in methanol
(30 mL) was refluxed at 60 °C for 10 min to form pyrimidine
2-amidooxime (HL), and then, immediately MnCl2·4H2O
(0.199 g, 1 mmol) was added to the hazy white solution and
stirred for additional 25 min whereupon, the solution turned
bright yellow. The stirring was continued for further 1 h with
addition of NaOAC (0.082 g, 1 mmol) as a base, and the
resulting solution was filtered and kept undisturbed, allowing
slow evaporation for few days. The block-shaped yellowish
single crystals were collected by filtration and washed with cold
methanol. Anal. Calcd for C12H15ClMnN8O4 (MW 425.71 g/
Computational Details. The ground-state electronic
structure calculation in the gas phase of 1 has been carried
out using the density functional theory (DFT)35 method
B
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The steady-state fluorescence measurements were per-
formed keeping the excitation wavelength for 1 at 350 nm
with and excitation and emission band pass of 10 nm. Fixed
concentration of 1 (20 μM) was titrated over the incremental
concentration range of DNA (0−34 μM).
Estimation of the Binding Parameters. The binding
affinity of 1 to DNA was estimated from absorbance and
fluorescence titration data using modified Benesi−Hildebrand
(BH) eq 142
Table 2. Crystal Data and Structure Refinement for 1
parameters
formula
1
C12H15ClMnN8O4
formula Weight
crystal System
space group
425.71
monoclinic
P21/c (no. 14)
a, b, c [Å]
13.1596(6), 15.2760(8), 8.7403(5)
α, β, γ [deg]
V [Å3]
90, 108.474(2), 90
1666.48(15)
1
ΔA
1
1
1
[M]
Z
4
=
+
×
D (calc) [g/cm3]
μ (Mo Kα) [mm]
F(000)
1.697
0.992
868
ΔAmax
(ΔAmax)KBH
(1)
Here, the difference in absorbance or fluorescence is denoted
by ΔA, and [M] is the concentration of DNA. By plotting the
reciprocal of the difference in absorbance/fluorescence
intensity against the reciprocal of DNA concentration, the
BH plot was constructed. The association constant (KBH) for
1−DNA complexation was calculated from the ratio of the
intercept to the slope.21,22,30
Continuous Variation Analysis (Job’s Plot). Stoichiom-
etry for the complexation of compound 1 with DNA was
determined by the continuous variation method (Job’s plot).43
The fluorescence signal was recorded for solutions where the
concentrations of both DNA and 1 were varied, while the sum
of their concentrations was kept fixed. The plot of difference in
fluorescence intensity (ΔF) of the compound at 430 nm was
plotted as a function of the input mole fraction of 1. Inflection
point in the resulting plot corresponds to the mole fraction of
the bound 1 in the DNA-1 complex. The stoichiometry was
obtained in terms of DNA-1[(1 − χcompound)/χcompound], where,
χ denotes the mole fraction of compound 1. The results
presented are average of three experiments.21
Determination of the Binding Mechanism by the
Hoechst 33258 Displacement Assay. The competitive
binding efficiency between Hoechst 33258 and 1 with DNA
was determined by fluorimetry in the range of 400−600 nm.44
Aliquots of stock solution of 1 (upto 0−32 μM) were added to
the equilibrated mixture of CT−DNA (20 μM) and Hoechst
33258 (1.91 μM) (termed as the Hoechst−DNA complex) at
room temperature. The excitation wavelength was set as 350
nm.
Circular Dichroism Spectral Study. Circular dichroism
(CD) spectra were performed on a JASCO J815 model unit
(JASCO International Co. Ltd. Japan) equipped with a JASCO
temperature controller (PFD 425L/15) at 298.15 0.5 K in
the region 200−400 nm by following the literature
methods.29,30 A rectangular stainless quartz cuvette of 1 cm
path length was used. Titrations were performed by the
addition of incremental concentrations of 1 to a fixed
concentration of DNA (60 μM). The molar ellipticity values
[θ] were calculated from the equation [θ] = 100 × θ/(C × l),
where C is the concentration in moles/lit, and l is the cell path
length of the cuvette in cm. The molar ellipticity [θ] (deg cm2/
dmol) values are expressed in terms of base pairs.43
crystal Size [mm]
temperature (K)
radiation [λ, Å]
θmin−max [deg]
data set
tot., uniq. data, R(int)
observed data [I > 2σ(I)]
Nref, Npar
0.18 × 0.29 × 0.35
100
0.71073
2.7, 33.2
−19: 19; −23: 23; −13: 13
27324, 6324, 0.045
5020
6324, 260
R, wR2, S
0.0417, 0.1011, 1.05
associated with the conductor-like polarizable continuum
model (CPCM).36 Becke’s hybrid function37 with the Lee−
Yang−Parr (LYP) correlation function38 was used throughout
the study. The absorbance spectral properties in dimethyl
sulfoxide (DMSO) medium was calculated by time-dependent
DFT (TDDFT)39 associated with the CPCM. We computed
the lowest 40 sextet−sextet transitions (as ligand environments
of Mn(II) is in weak field strength, so the metal center is in
high spin state with spin multiplicity 6 having the d5 system).
We employed 6-31+G** for C, H, N, O, Cl, and for Mn
atoms, and we used LanL2DZ as the basis set for all the
calculations. All the calculations were performed with the
Gaussian 09W software package.40 Gauss Sum 2.1 program41
was used to calculate the molecular orbital contributions from
groups or atoms.
DNA Binding Measurements. DNA binding measure-
ments were carried out following similar protocols elaborated
previously.21,22,29,30 The DNA sample exhibited a characteristic
ultraviolet absorption spectrum with an A260/A280 ratio
between 1.88 and 1.92 and an A260/A230 ratio between 2.12
and 2.22. The DNA concentration in base pairs was estimated
by recording absorbance at 260 nm employing a molar
absorption coefficient (ε) value of 13,200 M−1 cm−1. All
experiments were performed in filtered 10 mM citrate−
phosphate (CP) buffer, pH 7.0, prepared in triple-distilled
water. Biophysical experiments were carried out in 2% DMSO-
buffer (v/v) solution of the complex (1). The kinetic study of
the decomposition of the complex in the 2% DMSO buffer (v/
v) solution for 2.7 h was carried out to ascertain the stability of
the complex 1 in the testing media.
Hydrodynamic Studies. Hydrodynamic studies were
carried out to characterize the binding mode of the complex
with DNA. The details of hydrodynamic studies are described
in Supporting Information.
Absorbance and Fluorescence Spectral Titrations.
The absorption and fluorescence spectral titrations were
performed at 298.15
0.5 K using quartz cuvettes of path
length 1 cm, following the methods standardized in our
laboratory and reported earlier.21,22,29,30 The electronic spectra
of 1 were monitored as a function of the concentration of
DNA. In each case, a fixed concentration of 1 (20 μM) was
titrated with increasing concentration of DNA (0−30 μM).
ITC Study. ITC studies were executed on a VP-ITC
microcalorimeter to derive the binding and thermodynamic
parameters of 1-DNA association. During the titration, aliquots
of 1 (128 μM) were injected from the rotating syringe into the
isothermal chamber containing 60 μM, 1.4235 mL of DNA
C
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Figure 1. (a) ORTEP view (30% ellipsoid probability), (b) polyhedral representation of metal center, (c) supramolecular dimer formed by type-A
intermolecular hydrogen-bonding interactions, (d) supramolecular dimer formed by type-B hydrogen-bonding interactions and by CH···π
interaction of 1.
solutions maintained at 298.15 K. The titration was
accomplished in 28 sequential injections, and each injection
released 10 μL aliquots from the syringe into the calorimeter
cell. To avoid any bubble formation during the titration, the
buffer solutions were degassed thoroughly. The heat
accompanying each injection was noticed as a heat spike,
which is eventually the quantity of the power needed to
preserve the sample and reference cells at equal temperatures.
The area under each peak was integrated to get the heat
accompanying the injections. The corresponding dilution
study was performed injecting same volumes of the identical
concentration of 1 into the buffer alone in a separate
experiment. The heats of dilution (control heats) were
subtracted and the data fitted using the Origin software to a
“one set of binding sites” model.29,30,43 The corrected injection
heats were thereafter plotted as a function of the molar ratio to
calculate the equilibrium constant (K), the binding stoichiom-
etry (N), the standard molar enthalpy change (ΔH0) of
association, and standard molar entropy changes (ΔS0). The
standard molar Gibbs energy change (ΔG0) was calculated
using the standard relationship
(PDB) identifier 258D (GC content 33.33%) format of three-
dimensional (3D) X-ray crystal structure of CT−DNA. The
3D structure of 1 was saved in a PDB format with the aid of
the program Mercury 3.2. The graphical user interface Auto-
Dock tools was devoted to set up the protein: the water
molecule was deleted from the crystal of the protein, only polar
hydrogen was added, computed Gasteiger charge was
calculated as −25.9962, and nonpolar hydrogen was merged
to the carbon atom. Rotatable bonds of the complex molecules
were identified with AutoDock tools. The AutoDock program
was used to make the docking input file. Grid maps for 1 of 40
× 44 × 60 Å with grid spacing of 1 Å were generated using the
AutoGrid program. Both receptor and 1 were saved in the
pdbqt format. A distance-dependent function of the dielectric
constant was used for the calculation of the energetic map.
Lamarckian genetic algorithm was used to carry out the
docking calculations. Each run of the docking simulation was
set to conclude after a maximum of 250,000 GA energy
evaluations.44 The optimized docked model with lowest
docking energy was chosen for further analysis of docking
simulations. The docked poses were analyzed and viewed in
PyMOL software.
ΔG0 = −RT ln K
RESULTS AND DISCUSSION
where R (1.9872036 cal K−1 mol−1) is the gas constant, and T
is the temperature in Kelvins (K).
■
Structural Description. The reaction of MnCl2·6H2O (1
equiv) with the in situ formed amidooxime ligand (pyrimidine
2-carbonitrile and hydroxylamine hydrochloride in 1:1 ratio in
methanol) and NaOAc (1 equiv) as the base in MeOH yielded
the corresponding mononuclear MnII complex 1, the yellow
single crystals of which were obtained by slow evaporation of
the solvent.
Molecular Docking Studies. To get explicit perception of
the interaction and the mode of binding of 1 with CT−DNA,
molecular docking simulations were carried out using the
AutoDock 4.0 software package as accomplished by the
graphical user interface AutoDock 4.0 (AD4.0-bound.dat). The
macrocyclic receptor was chosen as the Protein Data Bank
D
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The structural analyses from single-crystal X-ray diffraction
studies show that complex 1 is a MnII mononuclear species
that comprises one MnII ion, two dicoordinating N2 donor-
based 2-pyrimidine amidooxime ligands, and two one-terminal
acetate (OAc−) ions and one-terminal Cl− ions. It is
crystallized in a monoclinic system with space group P21/c.
The structure consists of discrete [MnII(HL)2(Cl)-
(CH3COO)] as a neutral species in which the 2-pyrimidine
amidooxime ligand is neutral, as shown in Figure 1a. It shows
that the structure of [MnII(HL)2(Cl)(CH3COO)](1) is
mononuclear in octahedral geometry surrounded by two
neutral N2 donor amidooxime ligands, occupying cis positions,
while the two mono-negatively charged coligands (one
chloride and one acetate) coordinated at the cis position to
each other and satisfied the hexacoordination of the metal
center. The Mn atom thus adopts distorted octahedral
geometry being hexacoordinated with cisoid polyhedral shapes
(Figure 1b). The bond lengths around the central MnII ion are
Mn−N1A(pyrimidine-N) = 2.289(1) Å, Mn−N1B-
(pyrimidine-N) = 2.323(1) Å, Mn−N2A(oximato) =
2.328(2) Å, Mn−N2B(oximato) = 2.224(1) Å, Mn−O11-
(acetato) = 2.116(1) Å, and Mn−Cl1(chloro) = 2.461(5) Å.
The selected bond lengths and bond angles are given in Table
3; these agreed well with the normal reported values in
(Figure 2a) through intermolecular hydrogen-bonding inter-
actions (Table S2) (between amido H atom (H4B2 and
H4A2) with oximate-O(O1B) and acetate-O(O11): N4B−
H4B2···O1B = 2.921 Å and N4A−H4A2···O11 = 2.162 Å
interactions) along the crystallographic b axis. This 1D
supramolecular assembly is further extended to the two-
dimensional (2D) framework in the crystallographic bc plane
(Figure 2b).
The dimer type B is also extended in a 1D framework
(Figure S1) through intermolecular hydrogen-bonding inter-
actions [between the pyrimidine ring C−H atom (H2BA) and
chlorine atom (Cl1); C2B−H2BA···Cl1 = 2.905 Å] along the
crystallographic c axis. The close packing interaction exhibits
that the supramolecular 2D structure is expanded to form a 3D
network along the crystallographic a axis (Figure 2c).
Geometry Optimization and Electronic Structure. The
geometry of complex 1 was optimized in the ground state. The
optimized geometry of 1 is comparable with the molecular
structure from single-crystal X-ray diffraction (SCXRD) in
Figure 3. The energy difference between highest occupied
molecular orbital (HOMO) and lowest unoccupied molecular
orbital (LUMO) is 3.61 eV (Figure 3a). The Frontier
molecular orbital (FMO) diagram with the respective positive
and negative regions of the optimization of 1 is shown in
Figure 3. The positive and negative phases are represented in
green and blue, respectively.
Table 3. Selected Bond Distances and Bond Angles of 1
The electronic spectrum of 1 in DMSO (2 × 10−5 (M))
solution shows a band at 283 nm (ε = 1.75 × 104 M−1 cm−1).
This is attributed to ligand-to-metal charge transfer transition
(LMCT). The experimentally observed absorption bands of
the complex have been explained with the help of TD-DFT
calculations in application of the CPCM model assuming
Mn(II) is in high spin state having a spin multiplicity of 6. The
theoretical bond lengths in the gas phase are compared with
crystallographic bond distances (Table S3).
The absorption spectra of 1 were studied at room
temperature in DMSO. The complex (1) shows a well-
resolved absorption band located at 298.36 nm, having LMCT,
which is in good agreement with the experimental result of 283
nm. This absorption band can be assigned to the S0→ S40
electronic transition (Table 4) with an oscillator strength f =
0.0066 (Figure 3b).
DNA Binding Studies. Absorbance Spectral Studies.
UV−visible absorption spectroscopy is one of the most used
methods for studying the binding interaction of small
molecules with DNA. Usually, when a molecule or compound
binds with the DNA helix, variations in the absorbance maxima
and/or the shift in the peak position are observed.45−48 The
efficacy of interaction is associated with the extent of changes
or shifting of the peak position in the absorbance spectra. The
electronic absorption of 1 at 283 nm was monitored in the
presence and absence of DNA which showed 54% hyper-
chromism and 4 nm red shift upon incremental addition of
DNA (Figure 4). Such spectral observation may be ascribed to
an effective interaction among the DNA base pairs with the π
electron clouds of the interacting moiety.49 Binding data
collected from the absorbance titration were used to construct
the BH plot to evaluate the apparent equilibrium constant
(KBH). From spectrophotometry, the magnitude of apparent
equilibrium constant (KBH) for 1-DNA complexation was
deduced to be (3.67 0.04) × 105 M−1 (Table 5). Again, the
kinetic studies of the decomposition of the complex exhibited
bond length
(Å)
bond angles
(deg)
bond type
Mn−Cl1
Mn−O11
Mn−N1A
Mn−N1B
bond type
2.4613(5)
O11−Mn−N2A
O11−Mn−N2B
N1A−Mn−N1B
N1A−Mn−N2A
N1A−Mn−N2B
N1B−Mn−N2A
N1B−Mn−N2B
N2A−Mn−N2B
O11−Mn−N1A
O11−Mn−N1B
Cl1−Mn−N2B
89.43(5)
100.55(5)
94.28(5)
70.15(5)
164.22(5)
83.29(5)
71.13(5)
101.34(5)
92.79(5)
167.49(5)
94.66(4)
2.1158(11)
2.2892(14)
2.3226(13)
2.3280(15)
2.2243(14)
Mn−N2A
Mn−N2B
bond angles (deg)
Cl1−Mn−O11
Cl1−Mn−N1A
Cl1−Mn−N1B
Cl1−Mn−N2A
97.45(4)
91.91(4)
92.62(4)
161.15(4)
analogous MnII complexes.30 The Mn···Mn intermolecular
distance is 6.729 Å. The dihedral angle between two well-
defined planes around Mn (Mn N1B N2B O11N1A) and (Mn
N1A N2A N2BCl1) is 89.76°. The mean deviation of these
two intersecting perpendicular planes is 0.000 Å. The
intramolecular H-bonds are between oxime-OH (O1B) and
acetate-O(O12); O1B−H1B···O12 = 1.815 Å. The bond
valence sum calculation results are shown in Table S1, where it
can be seen that the oxidation state of manganese is 2.020
(∼2). Thus, the central metal atom Mn is in a +2 oxidation
state.
Inspection of molecular assemblies through supramolecular
interactions shows that 1 forms two types (A and B) of
supramolecular dimers. Type A: the intermolecular H-bonding
is between oxime-OH(O1A) and acetate-O(O12); O1A−
H1A···O12 = 1.821 Å (Figure 1c) and type B: the
intermolecular H-bonding is between the pyrimidine ring
C−H atom (H1BA) and chlorine atom (Cl1); C1B−H1BA···
Cl1 = 2.878 Å and noncovalent CH···π interaction (3.128 Å)
(Figure 1d) between H atom (H1AA) of one pyrimidine ring
and the centroid of the neighboring pyrimidine ring. The
dimer type A is extended in an one-dimensional (1D) network
E
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Figure 2. (a) Supramolecular 1D network through the type A intermolecular hydrogen-bonding interactions; (b) extended 2D supramolecular
framework in the crystallographic bc plane; (c) close packing diagram of the 3D framework along the crystallographic a axis of 1.
Figure 3. (a) FMOs (left) and optimized geometry (right) of 1, (b) FMOs involved in the UV−vis absorption of 1 in DMSO solution.
Table 4. Comparable Calculated Absorbance λmax with Experimental Values for 1
theoretical (nm)
298.36
experimental (nm)
283
composition
CI
transition
energy (eV)
4.1556
f
HOMO − 2(α) → LUMO + 3(α)
HOMO − 2(α) → LUMO + 2(α)
HOMO − 3(α) → LUMO + 3(α)
HOMO − 2(β) → LUMO + 2(β)
HOMO − 4(β) → LUMO + 1(β)
0.13323
0.17607
0.14466
0.31646
0.19340
S0 → S40
0.0066
F
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Figure 5. Steady-state fluorescence titration of 1 (20 μM) with DNA
[0−34μM]; λexcitation = 350 nm; inset: modified B−H plot.
Figure 4. Absorbance titration profile of 1 (20 μM) in the presence of
increasing concentration of DNA [0−30μM]; inset: modified BH
plot.
that complex 1 shows sufficient stability in the testing media
(t1/2 ∼ 15 h) (Figure S2).
Steady-State Fluorescence Titration. The complex (1)
exhibited an emission maximum at 430 nm when excited at
350 nm. The steady-state fluorescence titration was carried out
by a fixed concentration of 1 (20 μM) with incremental
addition of DNA. About 10-fold enhancement in the emission
intensity of 1 was observed without any appreciable shift in the
emission maximum (Figure 5). This increase in the emission
intensity upon binding to DNA indicates a significant
interaction of compound 1 with DNA. From BH plot, the
binding affinity (KBH) was estimated as (4.10 0.04) × 105
M−1 (Table 5).
CD Spectral Study. The effect of 1 on the conformation of
DNA was further investigated by CD spectroscopy. CD
spectrum of CT DNA displayed a classical B-form con-
formation with a large positive band around 270−280 nm, a
negative band at 248 nm, and a small positive band in the
210−220 nm regions (Figure 6). In the presence of the
manganese compound 1, only a lessening of the molar
ellipticity of the DNA bands was observed, indicating that 1
binds to DNA with retention of the actual B-conformation of
free DNA.29,30
Figure 6. CD spectral profile of DNA (60 μM) on addition of 1 (40
μM) in 10 mM CP buffer.
Continuous Variation Analysis (Job’s Plot). The
continuous variation protocol (Job plot) was used to estimate
the binding stoichiometry of 1 in the 1-DNA complexation.21
The plot of fluorescence intensity difference (ΔF) at λmax
versus the mole fraction of 1 revealed a single binding mode.
From the inflection point, χ value was found to be 0.512, from
which the stoichiometry was estimated to be around 0.95
(Figure 7).
Figure 7. Job’s plot for depicting the change in fluorescence intensity
vs mole fraction of 1.
Determination of the Binding Mechanism by the
Hoechst 33258 Displacement Assay. A synthetic N-
methylpiperazine analogue Hoechst 33258 displays a precise
binding affinity for the A-T rich sequences at the minor
grooves of DNA. For investigation the binding site of 1 in the
DNA helix, the Hoechst displacement assay was carried out. In
the presence of DNA, a sharp increase in the emission intensity
a
Table 5. Binding Parameters for the Association of DNA with Oxime-Based Mn Complexes
complexes
[Mn(HL1)2](Cl)2]
[Mn(HL1)2](Cl)(N3)]
[Mn(HL2)2](Cl)2]
[Mn(HL2)2](Cl)(N3)]
spectrophotometry Ki (M−1
)
spectrofluorimetry Ki (M−1
)
binding Mode
refs
2.18 × 105
1.79 × 105
2.05 × 104
1.52 × 104
1.63 × 106
3.67 × 105
2.22 × 105
1.56 × 105
2.97 × 104
1.61 × 104
1.59 × 106
4.10 × 105
partial intercalation
30
30
30
30
29
”
”
”
[Mn3O(5-Br-salox)3(NO3)(H2O)4]
[MnII(HL1)2(Cl)(CH3COO)]
minor groove
minor groove
this work
a
HL1 = pyrimidine amidooxime, HL2 = pyridine amidooxime.
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of Hoechst is observed, which is due to the greater planarity of
the N-methylpiperazine moiety of Hoechst when bound to
double-stranded DNA and its protection from collisional
quenching.50 If 1 competes for the similar DNA binding sites
of Hoechst, a reduction of the fluorescence intensity of the
latter must be detected. As depicted in Figure 8, the
ITC Studies. ITC is an extremely sensitive and reliable
technique for investigation of the binding parameters when a
molecule forms complex with DNA. A single ITC experiment
can yield all values of thermodynamic parameters such as
equilibrium constant (K), stoichiometry (N), standard molar
Gibbs energy change (ΔG0), standard molar enthalpy change
(ΔH0), and entropic contribution (TΔS0) to the bind-
ing.21,29,43 In order to get an in-depth knowledge on the
binding of 1 to DNA, ITC study was performed.29 Figure 10
Figure 8. Fluorescence emission spectra of the competition between
the Hoechst−DNA complex (λexc: 350 nm) and 1. CHoechst = 1.91 μM
and CDNA: 20 μM, C1: 0.0−32 μM. Inset: plot of relative quenching of
Hoechst−DNA complex by 1.
fluorescence of the Hoechst−DNA complex was reduced
(∼70%) by the addition of 1. Figure 9 represents the Stern−
Figure 10. ITC profile 1-DNA interaction at T = 298.15 K. The top
panel represents the raw data resulting from the sequential injection
of 1 (128 μM) into 60 μM DNA solution. The first series of peaks in
the top panel are the control heats, that is, dilution heats for injecting
identical volumes of the same concentration of the 1 into the buffer.
The lower panel represents the corresponding normalized heat signals
●
vs molar ratio. The data points ( ) are the experimental injection
heats, while the continuous line is the best fit curve using a single-
binding site model.
depicts the calorimetric profile for the titration of 1 into the
DNA solution at 298.15 K. The thermogram reveals
exothermic interaction with one binding event. The binding
constant was deduced to be (4.39 0.01) × 105 M−1, which is
in close agreement with the binding constant values obtained
from spectroscopic analysis. The stoichiometry value (N) was
found to be 0.193. The site size value (n) is defined as the
reciprocal of the stoichiometry value (N). Here, the value of n
comes out to be 5.18. The standard enthalpy value as
determined from ITC is −2.45 kcal mol−1. The thermody-
namic parameters clearly indicate that the interaction of 1 with
DNA was favored by small negative enthalpy (ΔH0 = −2.45
kcal mol−1) and large positive entropy (TΔSo = 5.25 kcal
mol−1) changes. Therefore, it can be concluded that the
binding process is entropy-driven.21 The thermodynamic
parameters are enlisted in Table 6.
Figure 9. Stern−Volmer plot for the fluorescence quenching of the
Hoechst−DNA complex system by 1.
Volmer plot for the fluorescence quenching of the Hoechst−
DNA system by 1. This observation suggests that 1 can
dislocate Hoechst essentially from the adenine- and thymine-
binding sites in the minor groove of DNA.29,30,44
Hydrodynamic Studies. Hydrodynamic study is an
important method for ascertaining the mode of binding of
small molecules with DNA. During intercalation, the axial
length and rigidity of the helical duplex increases. Both factors
enhance the frictional coefficient and the viscosity of DNA in
solution.21 On the other hand, the effective length of DNA
decreases in case of surface or groove binding, leading to a
minor decrease in the relative viscosity of the DNA solution.
The viscosity of the DNA solution was estimated in the
presence of increasing concentrations of 1 (Figure S3). Only
marginal change was found in the relative viscosity of DNA in
the presence of 1. Such minor changes in relative viscosity may
be associated to a groove binding model.29
Molecular Docking Studies. Molecular docking simu-
lations have now appeared as an emerging tool in drug
discovery for showing the binding mode and interaction
between small molecules as the complex and DNA.23 The
docked conformations of 1 with CT−DNA are displayed in
H
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Table 6. Thermodynamic Parameters for the Association of 1 with CT−DNA at 298.15 K
compound
10−5 K/M−1
4.39 0.01
ΔH0/kcal mol−1
−2.45 0.01
TΔS0/kcal mol−1
ΔG0/kcal mol−1
−7.70 0.05
1
5.25 0.01
Figure 11. (a) Capped-ball and stick model viewed into the minor groove of DNA with 1. The important interactions between different sections of
the 1-DNA complex are illustrated with a red solid line and by gray dashed lines. The noncoordinated oxime-OH group forms strong hydrogen
bonds with the phosphate−O; they are colored sky blue, white, red, blue, yellow, magenta, and green (C, H, O, N, P, Mn, and Cl, respectively); (b)
space-filled model of the binding mode and hydrophobic interaction of 1 with DNA; (c) DNA is shown in surface; the interactions are shown in
the solid surface with 50% transparency.
Table 7. Parameters from Molecular Docking Studies for DNA−1 Interaction
simulation energies
kcal mol−1
mode of
interaction
complex
complex-PDB
DNA-PDB source
atoms involvement (DNA)
1
CIF file from SCXRD
(CCDC no-2000190)
258D (GC content 33.33%) free binding
format energy = −6.66
G30, C29, T31, A14, G13 and
phosphate linkage
minor Groove
intermolecular
energy = −13.65
electrostatic
energy = −2.25
free torsional
energy = +4.79
Figure 11. It can be observed that the complex is well fitted in
the active side of the DNA, which corroborates well with the
experimental binding parameters obtained from ITC measure-
ments and with docking studies. The favorable calculated free
binding energy of 1 with DNA is −6.66 kcal/mol, and the final
intermolecular energy is −13.65 kcal/mol (vdW + H-bond +
desolvation energy = −13.01 kcal/mol). Other energies which
are related for calculating the binding modes (Table 7), that is,
electrostatic energy = −2.25 kcal/mol; free torsional energy =
+4.79 kcal/mol. The complex shows supramolecular inter-
action with G30, C29, T31, A14, and G13 base pairs of the
DNA chain and hydrogen bonding interactions between
oxime-OH and oxygen of phosphate linkages (Figure 11a).
The complex also exhibits hydrophobic interactions with base
pairs of the DNA chain (Figure 11b). Docking study reveals
that interaction of the said compound with DNA is
energetically the most favorable binding mode, and the surface
model is shown in Figure 11c. This induces some additional
steric hindrance to the moiety of 1 affecting the minor groove
binding and the binding energy. Thus, the molecular docking
study explained the different binding modes and binding
affinities theoretically, which are consistent with the exper-
imental observations.
I
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National Post-Doctoral Fellowship to the US (ref. no. PDF/
2016/000080) and M.D. (ref. no. PDF/2016/000334). M.D.
thanks Pradip Bera, Department of Chemistry, Kandi Raj
College, Murshidabad, West Bengal, India, for his help in
molecular docking studies. G.S.K. acknowledges financial
support by the Council of Scientific and Industrial Research
(CSIR), Govt. of India, to his laboratory through the Net
Work Project “BIOCERAM” (ESC 0103).
CONCLUSIONS
■
The octahedral mononuclear Mn(II) complex based on the
amidooxime ligand was synthesized by the reaction between
cyanopyrimidine and hydroxylamine hydrochloride in the
presence of Mn(II) ions and NaOAc. The structural
characterization is done by single-crystal X-ray crystallography
and compared with theoretical optimization using DFT/
B3LYP. The interaction of the compound with CT−DNA was
studied and confirmed by spectroscopic (viz: UV−vis,
fluorometry, and CD), hydrodynamic, and calorimetric
techniques which showed that 1 binds with CT−DNA
through the groove binding mode. Hoechst displacement
studies further confirmed that 1 interacts with double stranded
DNA at the adenine and thymine (A-T)-binding sites located
in the minor groove. From the thermodynamics study, the
binding constant was estimated to be (4.39 0.01) × 105 M−1.
The calorimetric technique further confirms the spontaneity of
the binding of 1 with DNA through an entropically driven
interaction. Thus, this complex may be employed as a DNA
targeted probe in the near future after physiological study and
toxicity measurements. Molecular docking study also revealed
that 1 is a minor groove binder toward DNA.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.jced.0c00529.
■
sı
CCDC 2000190 containing the supplementary crystallo-
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AUTHOR INFORMATION
Corresponding Author
Malay Dolai − Department of Chemistry, Prabhat Kumar
College, Purba Medinipur 721404, West Bengal, India;
orcid.org/0000-0001-7697-3376; Email: dolaimalay@
yahoo.in
■
Authors
Urmila Saha − Organic and Medicinal Chemistry Division,
CSIR-Indian Institute of Chemical Biology, Kolkata 700 032,
India
Gopinatha Suresh Kumar − Organic and Medicinal Chemistry
Division, CSIR-Indian Institute of Chemical Biology, Kolkata
700 032, India; orcid.org/0000-0002-3596-979X
Ray J. Butcher − Department of Chemistry, Howard University,
Washington, D.C. 20059, United States
Saugata Konar − Department of Chemistry, The Bhawanipur
Education Society College, Kolkata 700020, India;
orcid.org/0000-0001-5404-9107
Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge the Science & Engineering
Research Board (SERB), Govt. of India, for the award of the
■
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