Inorganic Chemistry Communications 103 (2019) 6–11

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Inorganic Chemistry Communications

journal homepage: www.elsevier.com/locate/inoche

Short communication

Synthesis, structure, and DNA-binding study of a novel Zn (II) complex with T

fleroxacin and 1,10-phenanthroline monohydrate
Yujie Zhu, Xinnuo Xiong, Zili Suo, Peixiao Tang , Qiaomei Sun, Xiaohui Ding, Hui Li
⁎ ⁎

School of Chemical Engineering, Sichuan University, Chengdu, Sichuan, China

GRAPHICAL ABSTRACT

ARTICLE INFO ABSTRACT

Keywords: A novel metal-based compound of zinc complexing with fleroxacin (flrx) was prepared in the presence of 1,10-
Zinc(II) complex phenanthroline (phen) monohydrate and characterized by various techniques. The crystal structure of the
Crystal structure complex ([Zn(flrx)(phen)(H2O)](NO3)·2H2O) was successfully disclosed through single-crystal X-ray diffraction,
Fleroxacin and Zn(II) connected with pyridone oxygen and the carboxylic oxygen atom of flrx by coordination bonds. The
DNA interaction
complex showed a square pyramid, and its structure was stabilized by intermolecular hydrogen bonding and π–π
Molecule docking
stacking. The interaction between the complex and calf thymus DNA (ctDNA) was studied. Results indicated that
[Zn(flrx)(phen)(H2O)](NO3)·2H2O bound to ctDNA through a static mechanism, and the hydrophobic force was
the main driving force in the binding process. Circular dichroism spectra, iodide quenching studies, and DNA
melting temperature experiments indicated that the complex bound to ctDNA in the groove. Molecular docking
further verified the groove binding mode and provided a visualized view for the interactions between the
complex and ctDNA.

1. Introduction
Metal organic complexes are considered to hold great therapeutic
and diagnostic potential [1]. A lot of research motivated the develop-
ment of new metal-based drugs to overcome the limitations of current
therapeutic products, particularly, in terms of toxicity, resistance, and
other pharmacological defects [2]. Various metal complexes have been
used in clinical practice in terms of anti-inflammatory [3], antibacterial
[4], anti-oxidative [5], and anti-tumor [6] activities. Among them, zinc
complexes have been testified to exert good gain effects in interacting
with biological macromolecules [7–9]. In addition, as a framework that
can be functionalized and designed, mixed ligands complexes provide
abundant opportunities for developing new drugs [10–12]. N-hetero-
cyclic carbons (NHCs) are a common class of auxiliary ligands to sta-
bilize metal ions and fulfill the structural qualification for organome-
tallic complexes [13,14].
It has been proven that the use of fluoroquinolones would result in
gene mutations and toxicities in the host cells [15]. Moreover, metal

⁎
Corresponding authors.
E-mail addresses: tangpeixiao@126.com (P. Tang), lihuilab@sina.com (H. Li).

https://doi.org/10.1016/j.inoche.2019.02.039
Received 23 January 2019; Received in revised form 22 February 2019; Accepted 24 February 2019
Available online 26 February 2019
1387-7003/ © 2019 Elsevier B.V. All rights reserved.
Y. Zhu, et al.
ions, given their positive electricity, are likely to bind negatively
charged nucleic acids [16]. Higher affinities towards DNA caused high
cytotoxicities [17]. As a result, the metal-fluoroquinolone complexes
might potentially lead to DNA damage, even mammalian cell cyto-
toxicity. Hence, studies on the interaction between metal-based com-
plexes and mammal DNA can indicate their affinities, and provide the
basis for determining the impact of complexes on the structure and
function of DNA [18].
Fleroxacin (flrx) is a widely used fluoroquinolones with the target of
topoisomerase II and IV [19]. However, it has been studied rarely in
metal complexes [20]. In our previous research, several Cu (II) com-
plexes with flrx and 1, 10-phenanthroline (phen) were synthesized and
characterized [21]. As an extension of our previous work, we synthe-
sized a Zn-based drug with flrx and phen as ligands and acquired a
single crystal. The structure was analyzed by X-ray crystallography and
characterized cooperating with other techniques. To explore the con-
formation damage in DNA induced by the binding of the Zn-fleroxacin
complex, the interaction between the complex and ctDNA was in-
vestigated. Molecular docking was performed to show the details of
binding visually, which has been seldom applied in previous reports on
metal–quinolone compounds.
2. Results and discussion
A clear crystal structure is necessary for new drug research and
development. Single-crystal X-ray diffraction (SXRD) was used to
characterize the structure of the complex. Crystal data and structure
refinement are listed in Table A1, which suggests that the synthesized
compound is in triclinic form with its space group behaving as p-1.
Fig. 1 exhibits a molecular model of the complex. We observed that the
complex is a penta-coordinate compound. The ligating atoms consist of
central Zn(II), two nitrogen atoms from phen, a pyridone oxygen, a
carboxylate oxygen atom from the deprotonated flrx, and an oxygen
atom from water. The coordination of N1 and N2 of phen and Zn(II)
formed a stable five-membered ring, and then the coordination of O1
and O3 of flrx and Zn(II) constituted a stable six-membered ring. The
existence of this structure is beneficial to the stability of complex mo-
lecules. Similar structures and space group have been reported in pre-
vious Zn(NO3)2-phen complexes [22,23]. But in this work, the aromatic
ring of the flrx ligand is nearly in the same plane of the phen (Fig. A1),
which prefers to form aromatic ring accumulation force so as to make
the complex crystal more stable.
This research demonstrates a penta-coordinate environment around
Zn(II) with square pyramid geometry which is deduced by pivotal bond
distances and angles listed in Table 1. The angles of the Zn(II) with
oxygen atoms and nitrogen atoms [O(1)-Zn(1)-N(1) = 153.56(14)°, O
(3)-Zn(1)-N(2) = 159.95(13)°] show that the central Zn(II) almost lo-
cates in the same plane with its coordination atoms from flrx and phen.
Fig. 1. Molecular structure of [Zn(flrx)(phen)(H2O)]·NO3·2H2O.
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Inorganic Chemistry Communications 103 (2019) 6–11
Table 1
Selected bond distance and angles for complex.
Bond distance (Å)
Zn(1)-O(1) 1.956(3) Zn(1)-O(3) 2.045(3)
Zn(1)-N(1) 2.082(3) Zn(1)-N(2) 2.113(3)
Zn(1)-O(4) 2.010(3)
Bond angle (°)
O(1)-Zn(1)-O(3) 90.24(12) O(1)-Zn(1)-O(4) 103.37(15)
O(1)-Zn(1)-N(1) 153.56(14) O(1)-Zn(1)-N(2) 90.31(13)
O(3)-Zn(1)-N(1) 91.76(12) O(3)-Zn(1)-N(2) 159.95(13)
O(4)-Zn(1)-O(3) 92.98(13) O(4)-Zn(1)-N(1) 102.85(13)
O(4)-Zn(1)-N(2) 106.38(14) N(1)-Zn(1)-N(2) 79.09(13)
The angles of Zn(II) and H2O and oxygen atoms [O(4)-Zn(1)-O
(1) = 103.37(15)°, O(4)-Zn(1)-O(3) = 92.98(13)°, O(4)-Zn(1)-N
(1) = 102.85(13)°, and O(4)-Zn(1)-N(2) = 106.38(14)°] explain the O
(4) in the coordinative water is nearly perpendicular to the bottom
plane. The entire complex molecule involves a square pyramid.
Therefore, the distances between the central Zn(II) and its coordinative
atoms are approximate [Zn(1)-O(1) = 1.956(3) Å，Zn(1)-O
(3) = 2.045(3) Å，Zn(1)-N(1) = 2.082(3) Å，Zn(1)-N
(2) = 2.113(3) Å，Zn(1)-O(4) = 2.010(3) Å].
Fig. A1 exhibits the hydrogen bonds among adjacent complex mo-
lecules, and the specific data are recorded in Table A2. The main types
of hydrogen bonds present in this system are OeH⋯O and OeH⋯N.
The oxygen atoms belong to coordinative water molecules, crystal
water molecules, flrx and nitrate ions, whereas nitrogen atoms were
derived from phen. According to the stacked plot, complex molecules
showed anti-parallel structure. The distance between flrx and phen was
shorter than 3.4 Å, and the degree of the angle was less than 20°. Thus,
π–π stacking exists between neighboring asymmetric molecules [24].
The existence of hydrogen bond forces and aromatic ring accumulation
force together maintain the stability of the crystal structure.
Crystallographic data of the complex was submitted to the
Cambridge Crystallographic Data Centre (CCDC), and it was given the
deposition numbers CCDC–1848167.
FT-IR spectroscopy illustrates the mechanism by showing changes in
the functional groups before and after synthesis. Information obtained
from the spectra (Fig. 2 (a)) shows that stretching vibrations caused by
v(C]O)carboxylate and v(CeO)carboxylate of the carboxylate (eCOOH) in
free flrx produce peaks in 1720 and 1286 cm−1. After synthesis, the
peak in 1720 cm−1 disappears, whereas two new peaks appear in 1582
and 1326 cm−1 as the asymmetric [νasym(CO2)] and symmetrical
[νsym(CO2)] stretching vibrations of carbonxylate. This result means
that the carboxylate oxygen atom of the flrx ligand chelates to Zn(II).
The coordination mode of carboxylate ligand can be predicated as
monodentate mode due to Δ[ν(CO2)asym-ν(CO2)sym] = 256 cm−1. The
vibration absorption peak of keto groups of free flrx in 1625 cm−1
hypochromatic shifted to 1622 cm−1 after synthesis. Thus, we con-
sidered that the flrx ligands coordinate with Zn(II) by oxygen atoms of
3-carboxylate and 4-keto [25]. The conclusion was consistent with the
analytical results of the single crystal structure.
Thermogravimetric (TG) analysis was used to determine the com-
positions of complex single crystal. The results shown in Fig. 2(b)
suggest that the complex dehydrates in two steps. The initial mass loss
stage was from 40 °C to 60 °C with a weight loss of 4.84%. Then, the
complex lost 2.48% weight at 108 °C to 150 °C. The two crystal water
molecules (Clacd = 4.93%) were lost in the first step, whereas a co-
ordinated water molecule (Clacd = 2.47%) was lost in the second step.
That mean the complex molecule can remain stable below 108 °C. The
following thermal decomposition consists of two processes. The first
course began in 217 °C and finished in 405 °C with the loss of phen at
25.09% (Calcd = 24.70%) in weight. In the next course, in the range of
420 °C–630 °C, a weight loss of 57.24% (Calcd = 56.72%) was achieved
because of the releases of flrx and NO2. The remaining product weight
of 10.71% (Calcd = 11.11%) corresponded to ZnO.
Y. Zhu, et al. Inorganic Chemistry Communications 103 (2019) 6–11

Fig. 2. (a) FT-IR spectra of flrx and [Zn(flrx)(phen)(H2O)]·NO3·2H2O. (b) TG-DTG curves of [Zn(flrx)(phen)(H2O)]·NO3·2H2O. (c) PXRD pattern of [Zn(flrx)(phen)
(H2O)]·NO3·2H2O.

Fig. 2(c) shows the PXRD result. The simulated PXRD pattern based
on the single-crystal X-ray result and the measured PXRD contrasts to
the seam coordinate system. The diagnostic peaks were at 6.05°, 9.15°,
17.81°, 21.82°, 22.74°, 25.47°, and 29.58°. The two patterns obviously
matched well, which indicates that the single-crystal X-ray information
was authentic.
The DAD signal shown in Fig. A2 was detected at 286 nm based on
the absorption spectra (Fig. A3). Evidently, the complex peak
(tr = 16.775 min) appears at different time from flrx (tr = 2.244 min)
and phen (tr = 12.101 min). It is reasonable to believe that the complex
still maintains a stable complexing form in aqueous solution. Certainly,
the above conclusion can be reflected through that the synthesis of the
complex also happened in solution. The stability of the complex in
solution provides premise for following research. The solubility of the
complex in water is 2.6275 ± 0.0102 mM at 310 K.
Fluorescence spectra are used to provide information on the binding
methods of complexes to ctDNA. Fig. 3 (a) reveals a decrease in fluor-
escence intensity of the complex when the ctDNA was titrated into a
fixed concentration of the complex. The quenching mechanisms can be
determined by the distinctions in behavior depending on temperature
and calculated by the Stern–Volmer equation [26]:
F0 / F = 1 + K SV [Q] (1)
The binding constants were also computed with the following fitting
formula [21]:
lg [(F0 F )/ F ] = lg K a + n lg [Q] (2)
where F0 and F represent the fluorescence intensities when the ctDNA is
absent and present, respectively; [Q] represents the concentration of
the complex; KSV is the Stern–Volmer quenching constant, obtained
through the linear regression plot of F0/F against [Q]; Ka is the binding

Fig. 3. (a) Fluorescence spectra of [Zn(flrx)(phen)(H2O)]·NO3·2H2O (25 μM) in the absence and presence of ctDNA at 298 K. DNA concentrations from a to h: 0, 12.5,
25.0, 37.5, 50.0, 62.5, 75.0, and 87.5 μM. (b) Stern–Volmer plots for complexes interacting with ctDNA at three different temperatures. (c) Plot of log[(F0–F)/F]
versus log[Q] for the complex–ctDNA system at three different temperatures. (d) Van't Hoff plot of the complex–ctDNA system.

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Y. Zhu, et al. Inorganic Chemistry Communications 103 (2019) 6–11

Table 2
Binding constants, quenching constants, and thermodynamic parameters of three temperatures.
T(K) KSV × 103 (M−1) Ka × 103 (M−1) n ΔG (KJ·mol−1) ΔH (KJ·mol−1) ΔS (J·mol−1·K−1)

298 2.151 ± 0.165 0.681 ± 0.155 0.872 −16.372 96.767 379.659

304 1.829 ± 0.056 1.907 ± 0.419 1.010 −18.650
310 1.586 ± 0.127 2.898 ± 0.227 1.073 −20.928

constant; and n is the number of binding sites [27]. The linear regres-
sion diagrams of three temperatures (298 K, 304 K, and 310 K) are
displayed in Table 2.
KSV obviously decreased with increased temperature for the
complex–DNA system; therefore, the quenching mechanism can be
considered as static quenching because of their dependence on the
generation of a ground-state complex. Every value of n is approximately
1, which suggests that the complex tends to bind to a single site in
ctDNA. To estimate the binding force of the complex–ctDNA system
preliminarily, the Van't Hoff equation is run to obtain these thermo-
dynamic parameters, including ΔH (enthalpy change), ΔS (entropy
change), and ΔG (Gibbs' free energy change):
ln K a = ( H / T + S )/R
G= H T S
where Ka is the binding constant and R is the gas constant. The calcu-
lations are exhibited in Table 2. The values of Ka are in the range of
102–103 M−1, which are lower than that of many other reported Zn(II)
complexes-DNA systems ranging from 104 to 106 M−1 (Table A3)
[28–30]. Intercalative binding generally produce a larger binding
constant than groove binding. The low binding affinity illustrates that
the complex shows weak binding with DNA and the binding mode
should be non-intercalative. So the binding of the complex resulted in
very limited conformation changes in DNA, and did not lead to sus-
taining bioaccumulative toxicity in mammalian cells. All the values of
ΔG were less than 0; thus, the binding of this system is spontaneous.
Moreover, the magnitude of ΔH of all intercalators was negative be-
cause they altered the DNA conformations [30]. On the contrary, the
positive enthalpy indicated that the complex hardly altered the DNA
conformation. And ΔH and ΔS are both positive, which can be used to
demonstrate that hydrophobic force plays a key role in the binding of
complexes to ctDNA [31,32]. As shown in Table A3, in other zinc
complex and DNA interaction systems, the dominant role is mainly
hydrogen bond, a stronger intermolecular force, which should be one of
the primary reasons why the binding of this complex and DNA is
weaker than that of other systems.
To further verify the quenching mechanism, the time-resolved
fluorescence lifetime was measured, which is the most reliable method
to distinguish the mechanism between static and dynamic quenching at
present. The following equation is used to obtain the average fluores-
cence lifetime ({τ}).
= 1 1 + 2 2
Fig. A4 shows the fluorescence lifetime curve of the complex. As
shown in Table 3, the average lifetime of the free complex was
0.5152 ns. After DNA addition, the average lifetime of the system was
almost unchanged with values of 0.5211 and 0.5289 ns. The mechanism
of static quenching involves the formation of a static ground-state
complex, which must maintain the complex's decay time constant. This
observation is consistent with the previous conclusion.
CD is considered as a credible tool for studying the structural
changes. The characteristic peaks of DNA located in 245 and 275 nm
were attributed to the helicity and base stacking effect. No change in
position and strength was noted regardless of the presence and absence
of the complex (Fig. A5 (a)). This result suggested that the structure of
DNA was almost unchanged by the binding of the ligand. Hence, small
molecules may well bind to DNA in the groove [33]. While comparing
with intercalative binding, groove binding has slighter impact on the
structure of DNA.
The above inference was also proven by iodide quenching studies.
(3)
The iodide and DNA phosphate backbone both carry the negative
(4) charge, which brought repulsion when iodide was in contact with the
DNA phosphate backbone. When small molecules intercalated into the
DNA base pairs, they were protected away from an ionic quencher. In
the groove mode, DNA only provided limited protection to small mo-
lecule fluorescence, which led to an easier quenching by KI than in the
intercalation mode [34]. Fig. A5(b) shows clearly that the KSV of the
complex–KI system (15.57 M−1) with DNA was slightly greater than
that (14.95 M−1) in the absence of DNA. The value of KSV was obtained
through the slope of the linear fit. This test also demonstrated that the
binding mode of the complex was groove binding.
Afterward, the DNA melting temperature Tm was also measured to
serve as evidence of groove binding. Tm represents the temperature at
which the H bonds between DNA base pairs break and allow half of the
double-stranded DNA to transform to single-stranded DNA. In Fig.
A5(c), the Tm performs as the temperature corresponding to the UV
absorption reached half of the maximum. The calculated Tm are given in
Table 4. We observed that Tm remained almost the same in the absence
and presence of complex. As reported, the intercalation into the double
helix would make the DNA helix become compact so as to increase Tm,
while groove binding did minimal effect on transitions in the DNA
double helix conformation [35]. Therefore, the DNA melting tempera-
ture test provides strong evidence for the groove binding mode of this
system.
The docking exploration was carried by the YASARA software to
provide information about binding mode, binding site and binding
force type between complex and ctDNA. We further identified the
preponderant binding mode as groove binding as suggested in Fig. 4.
The binding model shown in Fig. 4 is derived by the Chimera pro-
(5) gram from the top-rated result in accordance with the YASARA scores.
Then, we obtained a 2D map by LigPlot. As revealed, the complex links
to the DG10, DG12, DA17, DA18, and DT19 bases of DNA by hydro-
phobic interaction. Meanwhile, hydrophobic force also existed between
the small molecule and adjacent backbone phosphodiester groups. In

Table 3 Table 4
Fluorescence decay fitting parameters for the complex–ctDNA system with DNA melting temperatures in the presence and absence of
different concentrations of ctDNA. complex.
Sample τ1 (ns) α1 τ2 (ns) α2 τ (ns) χ2 System Tm

Free complex (0.5 μM) 0856 0.507 1.697 0.048 0.515 1.061 Free DNA 64.869
Complex:ctDNA (1:2) 0.849 0.498 1.640 0.060 0.521 1.095 ctDNA:Complex = 1: 0.5 64.874
Complex:ctDNA (1:3.5) 0.874 0.513 1.785 0.045 0.529 1.065 ctDNA:Complex = 1: 1 65.288

9
Y. Zhu, et al.
Fig. 4. Molecular modeling results of the energy-minimized structure of the complex–DNA system (left) and the 2D map of interaction calculated using LigPlot
(right).
conclusion, the hydrophobic force plays the leading role in the com-
plex–DNA system, which was identified with the result from fluores-
cence research.
3. Conclusion
In this study, a new metal-based compound of Zn(II) was synthe-
sized with the quinolone antibacterial drug flrx as main ligand and
phen as auxiliary ligand. The crystal structure was revealed as space
group p-1 of triclinic. The structure chart showed that the central Zn(II)
coordinated with two nitrogen atoms from phen, one pyridone oxygen,
and one carboxylate oxygen atom from the deprotonated flrx. This
structure stabilizes the compound. In the binding of the complex to
ctDNA, the quenching mechanism was considered in a static manner,
and the complex combined with the groove region of DNA through
hydrophobic force primarily. This research indicated that the
Zn–flrx–phen complex would cause incredibly tiny damage to mam-
malian cell DNA. Given its stability and low genetic toxicity, the
Zn–flrx–phen complex may be used as a metallodrug.
Conflict of interest
The authors declare no conflicts of interest.
Acknowledgements
This work was supported by Sichuan Science and Technology
Program (Grant No. 2018JY0188), the Fundamental Research Funds for
the Central Universities (Grant No. 2018SCU12043), and the Large-
10
Inorganic Chemistry Communications 103 (2019) 6–11
scientific Instruments Sharing Platform Ability Construction of Sichuan
Province (Grant No. 2016KJTS0037).
Appendix A. Supplementary material
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.inoche.2019.02.039.
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