Synthesis and structure of a 1-D copper(II) coordination polymer bridged both by oxamido and carboxylate: In vitro anticancer activity and reactivity toward DNA and protein BSA

Article abstract of DOI:10.1080/00958972.2015.1009452

A 1-D copper(II) coordination polymer formulated as {[Cu₂(bdpox)(dabt)](NO₃)?H₂O}_n, where H₃bdpox and dabt denote N-benzoate-N'-[3-(diethylamino)propyl]oxamide and 2,2'-diamino-4,4'-bithiazole, respec

Full text of DOI:10.1080/00958972.2015.1009452

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Synthesis and structure of a 1-D
copper(II) coordination polymer
bridged both by oxamido and
carboxylate: in vitro anticancer
activity and reactivity toward DNA and
protein BSA
Xue-Jie Lia, Kang Zhenga, Yan-Tuan Lia, Cui-Wei Yanb, Zhi-Yong
Wua & Shi-Ying Xuanc
a Marine Drug & Food Institute, Ocean University of China,
Qingdao, PR China
b College of Marine Life Science, Ocean University of China,
Qingdao, PR China
Click for updates
c Qingdao Municipal Medical Group, Qingdao, PR China
Accepted author version posted online: 19 Jan 2015.Published
online: 11 Feb 2015.
To cite this article: Xue-Jie Li, Kang Zheng, Yan-Tuan Li, Cui-Wei Yan, Zhi-Yong Wu & Shi-Ying Xuan
(2015) Synthesis and structure of a 1-D copper(II) coordination polymer bridged both by oxamido
and carboxylate: in vitro anticancer activity and reactivity toward DNA and protein BSA, Journal of
Coordination Chemistry, 68:5, 928-948, DOI: 10.1080/00958972.2015.1009452
To link to this article: http://dx.doi.org/10.1080/00958972.2015.1009452
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Journal of Coordination Chemistry, 2015
Vol. 68, No. 5, 928–948, http://dx.doi.org/10.1080/00958972.2015.1009452
Synthesis and structure of a 1-D copper(II) coordination
polymer bridged both by oxamido and carboxylate: in vitro
anticancer activity and reactivity toward DNA and protein
BSA
XUE-JIE LI†, KANG ZHENG†, YAN-TUAN LI*†, CUI-WEI YAN‡, ZHI-YONG WU†
and SHI-YING XUAN*§
†Marine Drug & Food Institute, Ocean University of China, Qingdao, PR China
‡College of Marine Life Science, Ocean University of China, Qingdao, PR China
§Qingdao Municipal Medical Group, Qingdao, PR China
(Received 24 June 2014; accepted 21 November 2014)
A new 1-D copper(II) coordination polymer was synthesized and structurally characterized. In vitro
anticancer activity and reactivity toward DNA and protein of the copper(II) polymer was studied.
A 1-D copper(II) coordination polymer formulated as {[Cu2(bdpox)(dabt)](NO3)·H2O}n, where
H3bdpox and dabt denote N-benzoate-N′-[3-(diethylamino)propyl]oxamide and 2,2′-diamino-4,4′-bi-
thiazole, respectively, was synthesized and characterized by elemental analyses, molar conductance
*Corresponding authors. Email: yantuanli@ouc.edu.cn (Y.-T. Li); xuansy619@163.com (S.-Y. Xuan)
© 2015 Taylor & Francis

1-D copper(II) coordination polymer
929
measurement, IR and electronic spectra studies, and single-crystal X-ray diffraction. The crystal
structure analysis reveals that copper(II) ions are bridged by both cis-oxamido and carboxylato
groups to form a 1-D coordination polymer with corresponding Cu···Cu separations of 5.2420(10)
and 5.1551(8) Å. The endo- and exo-copper(II) ions of the cis-oxamido-bridge are located in dis-
torted square-planar and square-pyramidal geometries, respectively. There is a 2-D hydrogen bond-
ing network in the crystal. The in vitro anticancer activities suggest that the copper(II) complex is
active against selected tumor cell lines. The reactivities toward herring sperm DNA and bovine
serum albumin (BSA) reveal that the copper(II) complex can interact with DNA by intercalation and
effectively quench the intrinsic fluorescence of BSA via a static mechanism. The influence of hydro-
phobicity of the substituents in bridging ligands on DNA and protein binding properties and the
in vitro anticancer activities of such copper(II) polymers is discussed.
Keywords: 1-D Copper(II) coordination polymer; μ-Oxamidato-bridge; μ-Carboxylate-bridge crystal
structure; DNA-binding; Protein BSA interaction; In vitro anticancer activity
1. Introduction
The design and synthesis of transition metal complexes that can interact with DNA and pro-
tein by noncovalent modes have attracted interest in the field of metallo-pharmaceuticals.
Interest in this area stems from the facts that DNA and protein are commonly considered as
the main molecular targets in the action of drugs, and many metal complexes exert their
drug effects through binding to DNA or protein, which is the basis for designing and dis-
covering new and more efficient metal-based antitumor drugs [1–6]. Thus, the reactivity
toward DNA and protein of metal complexes are a fundamental requirement, not only for
the relevant theoretical interest to elucidate the mechanism involved in site-specific recogni-
tion of DNA, and the biochemical procedures governing protein sequencing, but also for
application of probes of DNA structure, and the exploitation of the rational design and
synthesis of new types of pharmaceutical molecules.
In the context of design and synthesis of metal complexes that are capable of binding
DNA and protein by noncovalent modes, most attention has centered upon selection of
metal ions and design of ligands. Metal complexes can accelerate drug action and increase
effectiveness of organic ligands [7], and medicinal properties of metal complexes depend
on the nature of metal ions and ligands. Thus, a combination of suitable metal as well as
ligand is important for construction of a highly efficient DNA and bovine serum albumin
(BSA) targeted drug. A number of copper(II) complexes with different ligands have been
widely studied [8–11], because copper, as a biologically active metal, has many correlations
with endogenous oxidative deoxyribonucleic acid damage associated with aging and cancer.
Furthermore, significant developments have occurred in recent years in the chemistry of
polymer–metal complexes, particularly in the study of interaction of polymer–metal com-
plexes with DNA [12, 13]. These polymer–metal complexes act as excellent models for
metalloenzymes, lead to the development of highly efficient catalysts [14, 15], and as poten-
tial candidates for selective delivery of anticancer agents to tumor tissue [16]. However,
examples of such polymer–metal complexes are still few, and comparatively little attention
has been given to the studies of interactions with DNA and proteins. This prompted us to
synthesize and study new polymer–metal complexes to gain some insight into their DNA/
protein binding property and antitumor activities.
In view of the bioactivities of copper(II) complexes with 2,2′-diamino-4,4′-bithiazole
(dabt) and its derivatives [17–19], and the effective bridging function of oxamide groups,
we reported the synthesis, structure, and DNA-binding of two 1-D copper(II) polymers with

930
X.-J. Li et al.
asymmetric N,N′-bis(substituted)oxamide as bridging ligands and dabt as coligands
[20, 21]. In order to understand the influence of the various bridging ligands in polymeric
copper(II) complexes on structure, DNA- and BSA-binding properties as well as cytotoxic
activities, and to gain insight into the structure–activity relationship of this kind of poly-
meric copper(II) complex, in this article, we used N-benzoate-N′-[3-(diethylamino)propyl]
oxamide (H3bdpox) as bridging ligand and dabt as coligand to synthesize and structurally
characterize a new 1-D polymeric copper(II) complex, {[Cu2(bdpox)(dabt)](NO3)·H2O}n.
In vitro cytotoxic activity and the reactivity toward DNA and protein BSA of the polymeric
copper(II) complex were studied. The main results of the present investigation confirmed
that hydrophobicity of different substituent groups on bridging ligands in these polymeric
copper(II) complex systems can influence DNA-binding and the in vitro anticancer activity,
thus suggesting that the DNA-binding ability and the anticancer activity may be tuned
through differences of the bridge ligands in these polymer–copper(II) systems, which are
useful for the synthesis of new metal-based drugs targeting DNA.
2. Experimental
2.1. Materials and chemicals
All reagents were of AR grade and obtained commercially. N-benzoate-N′-[3(diethylamino)
propyl]oxamide (H3bdpox) was synthesized according to literature method [22]. Herring
sperm DNA (HS-DNA), Ethidium bromide (EB), and BSA were purchased from Sigma
Corp. and used as supplied.
2.2. Physical measurements
The C, H, and N elemental analyses were performed with a 240-Perkin-Elmer elemental
analyzer. Molar conductance was measured with a Shanghai DDS-11A conductometer. The
infrared spectrum was recorded with samples as KBr pellets in a Nicolet-470 spectropho-
tometer from 4000 to 400 cm−1. The UV–vis spectrum was recorded in a 1 cm path length
quartz cell on a Cary 300 spectrophotometer. Fluorescence was tested on an Fp-750w fluo-
rometer. A CHI 832 electrochemical analyzer (Shanghai CHI Instrument, Shanghai, China)
in connection with a glassy carbon working electrode (GCE), a saturated calomel reference
electrode, and a platinum wire counter electrode was used for electrochemical measure-
ments. The GCE surface was freshly polished to a mirror prior to each experiment with
0.05 μm α-Al2O3 paste and then cleaned in water for 5 min. Viscosity measurement was
carried out using an Ubbelohde viscometer immersed in a thermostatic water bath main-
tained at 298 K.
2.3. Synthesis of {[Cu2(bdpox)(dabt)](NO3)·H2O}n
To a stirred ethanol solution (10 mL) of H3bdpox (0.0151 g, 0.05 mM) and piperidine
(0.0128 g, 0.15 mM), an ethanol solution (5 mL) containing Cu(NO3)2·3H2O (0.0242 g,
0.1 mM) was added dropwise at room temperature. The mixture was stirred quickly for
30 min and an ethanol solution (5 mL) of dabt (0.0099 g, 0.05 mM) was added. The
reaction solution was heated at 333 K with stirring for 6 h and then cooled to room

1-D copper(II) coordination polymer
931
temperature. The resulting dark green solution was filtered and dark brown cube crystals of
the polymeric copper(II) complex suitable for X-ray analysis were obtained by slow evapo-
ration at room temperature after 15 days. Yield: 0.0296 g (82%). Anal. Calcd for
Cu2C22H28N8O8S2 (%): C, 36.51; H, 3.90; N, 15.48. Found (%): C, 36.62; H, 3.97; N,
15.32. ΛM (DMF solution): 78 S⋅cm2 M−1.
2.4. X-ray structure determination
The X-ray diffraction experiments were made on a Bruker APEX area-detector diffractome-
ter with graphite monochromated Mo Kα radiation (λ = 0.71073 Å) at 296 K. The crystal
structure was solved by the directed method followed by Fourier syntheses. Structure refine-
ments were performed by full matrix least-squares procedures using SHELXL-97 on F2
[23]. The hydrogens on dabt and water were found in a difference Fourier map. Then the
water hydrogens were treated as riding with restrained H–O distances (0.86 Å). The hydro-
gens on C and N of dabt were refined freely except restrained H–N bond lengths of N6
(0.86 Å). The remaining hydrogens were placed in calculated positions, with C–H = 0.96
(methyl), 0.97 (methylene), and 0.93 Å (aromatic), then refined in riding mode, with
Uiso(H) = 1.5 (methyl) or 1.2Ueq (carrier atoms). Crystal data and structural refinement
parameters are summarized in table 1 and selected bond distances and angles are listed in
table 2.
2.5. In vitro cytotoxic activity evaluation by SRB assays
In vitro cytotoxic activities of the polymeric copper(II) complex together with cis-platin
were evaluated against selected cell lines by using the sulforhodamine B (SRB) assays. All
Table 1. Crystal data for {[Cu2(bdpox)(dabt)]
NO3·H2O}n.
Formula
Formula weight
Crystal system
Space group
a (Å)
C22H28Cu2N8O8S2
723.76
Orthorhombic
Pbca
14.119(3)
b (Å)
15.077(3)
c (Å)
26.539(6)
α (°)
90
β (°)
90
γ (°)
90
5649(2)
V (Å3)
Z
8
D(Calcd) [g cm−3
]
)
1.702
1.715
2960
μ (Mo Kα) (mm−1
F(0 0 0)
Crystal size [mm]
Temperature (K)
Radiation [Å]
θ range
0.13 × 0.18 × 0.22
296
Mo Kα 0.71073
2.1–27.5
Tot., Uniq. Data, R(int)
Observed data [I > 2σ(I)]
R, ωR2, S
31,269, 6508, 0.052
4450
0.0364, 0.0900, 1.01
0.00, 0.00
Max. and Av. shift/error

932
X.-J. Li et al.
Table 2. Selected bond distances (Å) and angles (°) for 1.
Bond distances (Å)
Cu1–O1
Cu1–N2
Cu2–O3
Cu2–N4
Cu2–O2i
1.9174(19)
1.960(2)
1.9762(19)
1.977(2)
Cu1–N1
Cu1–N3
Cu2–O4
Cu2–N5
O1–C1
1.990(2)
2.058(2)
1.9552(19)
1.979(2)
1.278(3)
2.309(2)
Bond angles (°)
O1–Cu1–N1
O1–Cu1–N3
N1–Cu1–N3
O3–Cu2–O4
O3–Cu2–N5
O4–Cu2–N4
O4–Cu2–O2i
N4–Cu2–O2i
Cu1–O1–C1
Cu2–O4–C9
90.54(8)
93.60(8)
O1–Cu1–N2
N1–Cu1–N2
N2–Cu1–N3
O3–Cu2–N4
O3–Cu2–O2i
O4–Cu2–N5
N4–Cu2–N5
N5–Cu2–O2i
Cu1–N3–C15
154.26(10)
83.99(9)
96.50(9)
95.47(8)
91.99(7)
169.3(2)
95.42(9)
101.05(8)
112.66(18)
168.95(10)
83.87(8)
166.91(9)
169.05(10)
98.23(17)
97.80(8)
129.85(17)
112.22(17)
Note: Symmetry code: (i) −1/2 + x, 1/2 − y, 1 − z.
cells were cultured in RPMI 1640 supplemented with 10% (v/v) fetal bovine serum, 1%
(w/v) penicillin (104 U mL−1), and 10 mg mL−1 streptomycin. Cell lines are maintained at
310 K in a 5% (v/v) CO2 atmosphere with 95% (v/v) humidity. Cultures were passaged
weekly using trypsine-EDTA to detach the cells from their culture flasks. The polymeric
copper(II) complex was dissolved in DMSO and diluted to the required concentration with
culture medium when used. The content of DMSO in the final concentrations did not
exceed 0.1%. At this concentration, DMSO was non-toxic to the cells tested. Rapidly grow-
ing cells were harvested, counted, and incubated at the appropriate concentration in 96-well
microplates for 24 h. The polymeric copper(II) complex dissolved in culture medium was
then applied to the culture wells to achieve final concentrations from 10−4 to 10−1 μM. Con-
trol wells were prepared by addition of culture medium without cells. The plates were incu-
bated at 310 K in a 5% CO2 atmosphere for 48 h. Upon completion of the incubation, the
cells were fixed with ice-cold 10% trichloroacetic acid (100 mL) for 1 h at 277 K, washed
five times in distilled water, and allowed to dry in the air and stained with 0.4% SRB in 1%
acetic acid (100 mL) for 15 min. The cells were washed four times in 1% acetic acid and
air-dried. The stain was solubilized in 10 mM unbuffered Tris base (100 mL) and the OD
of each well was measured at 540 nm on a microplate spectrophotometer. The IC50 value
was calculated from the curve constructed by plotting cell survival (%) versus the polymeric
copper(II) complex concentration.
2.6. DNA-binding experiments
All experiments involving HS-DNA were performed in Tris–HCl buffer solution (pH 7.14),
which was prepared using deionized and sonicated triple distilled water. Solution of DNA
in Tris–HCl buffer gave the ratio of UV absorbance at 260 and 280 nm, A260/A280, of
ca.1.9, indicating that the DNA was sufficiently free of protein [24]. The concentration of
the DNA stock solution was determined according to its absorbance at 260 nm. The molar
absorption coefficient, ε260, was taken as 6600 M−1 cm−1 [25]. Stock solution of DNA was
stored at 277 K and used after no more than four days. Concentrated stock solution of the
polymeric copper(II) complex was prepared by dissolving the polymeric copper(II) complex

1-D copper(II) coordination polymer
933
in DMSO and diluting suitably with Tris–HCl buffer to required concentrations for all the
experiments. Absorption spectral titration experiments were performed by keeping the
concentration of the polymeric copper(II) complex constant while varying HS-DNA
concentration. Equal solution of HS-DNA was added to the polymeric copper(II) complex
solution and reference solution to eliminate the absorbance of HS-DNA itself. In the EB
fluorescence displacement experiment, 5 μL of the EB Tris–HCl solution (1 mM) was
added to 1 mL of HS-DNA solution (at saturated binding levels) [26] and stored in the dark
for 2 h. Then, the solution of the polymeric copper(II) complex was titrated into the
DNA/EB mixture and diluted in Tris–HCl buffer to 5 mL. Before measurements, the mix-
ture was shaken and incubated at room temperature for 30 min. The fluorescence spectra of
EB bound to HS-DNA were obtained at an emission wavelength of 584 nm in the fluorome-
ter. In viscosity measurement, HS-DNA sample approximately 200 base pairs in length was
prepared by sonication in order to minimize complexities arising from DNA flexibility [27].
Flow times were measured with a digital stopwatch, each sample was measured three times,
and an average flow time was calculated. Relative viscosities for HS-DNA in the presence
and absence of the polymeric copper(II) complex were calculated from the relation
ŋ = (t − t0)/t0, where t is the observed flow time of DNA-containing solution and t0 is that
of Tris–HCl buffer alone. Data were presented as (ŋ/ŋ0)1/3versus binding ratio [28], where
ŋ is the viscosity of DNA in the presence of the polymeric copper(II) complex and ŋ0 is the
viscosity of DNA alone.
2.7. BSA interaction experiments
All experiments involving BSA were performed in 50 mM NaCl/Tris–HCl buffer solution
(pH 7.14). Solutions of BSA protein and the polymeric copper(II) complex were prepared
by dissolving them in the NaCl/Tris–HCl buffer solution to required concentrations. For
UV absorption experiment, a 5 mL solution of BSA (10 μM) was titrated with various con-
centrations of the polymeric copper(II) complex. Equal solutions of the polymer were added
to the reference solutions to eliminate the absorbance of the polymeric copper(II) complex
itself. In the tryptophan fluorescence quenching experiment, quenching of the tryptophan
residues of BSA [29] was done by keeping the concentration of the BSA constant while
varying the polymeric copper(II) complex concentration, producing solutions with varied
mole ratio of the quenchers to BSA. Titrations were manually done using a micropipette for
addition of the polymeric copper(II) complex. The fluorescence spectra were recorded at an
excitation wavelength of 295 nm and an emission wavelength of 347 nm in the fluorometer
after each addition of quencher.
3. Results and discussion
3.1. Synthetic route and general properties of the polymeric copper(II) complex
In order to obtain polymeric copper(II) complex bridged by asymmetric N,N′-bis(substi-
tuted)-oxamide, N-benzoate-N′-[3-(diethylamino)propyl]oxamide (H3bdpox), which can
coordinate to metal ions through carbonyl oxygens and nitrogens of oxamido as well as
oxygens of carboxyl [22], was chosen as bridging ligand. Simultaneously, 2,2′-diamino-
4,4′-bithiazole (dabt) was used as coligand. In preparing the polymeric copper(II) complex,

934
X.-J. Li et al.
O
Cl
O
O
H2N
N
OH
NH OH
O
O
O
OEt
NH
O
O
O
NH2 OH
THF/EtOH
THF
NH
N
OEt
H3bdpox (L)
+
NH2
S
O
nNO3
nH2O
N
N
O
O
N
O
N
Cu(NO3)2 3H2O
Cu
Cu
2,2'-diamino-4,4'-bithiazole
N
S
NH2
n
Scheme 1. The synthetic pathway for bridging H3bdpox (L) and its copper(II) polymer.
the use of piperidine as base makes the bridging ligand (H3bdpox) coordinate to copper(II)
through the deprotonated oxamido nitrogen and carboxyl oxygens. Elemental analyses
indicate that the reaction of H3bdpox with Cu(NO3)2·3H2O and dabt in 1 : 2 : 1 M ratio
yielded the new 1-D copper(II) coordination polymer, {[Cu2(bdpox)(dabt)](NO3)·H2O}n.
The synthetic pathway for the H3bdpox and its copper(II) polymer may be represented by
scheme 1.
The polymeric copper(II) complex is insoluble in non-polar solvents and common polar
solvents, and very soluble in DMF and DMSO to give stable solutions at room temperature.
In the solid state, the copper(II) coordination polymer is fairly stable in air so as to allow
physical measurements.
3.2. IR spectra
IR spectrum from 4000 to 400 cm−1 provides some information regarding the mode of
coordination in the polymeric copper(II) complex and is analyzed in a careful comparison
with that of free H3bdpox. The antisymmetric stretching vibration of the carboxylate vas
(COO), together with the carbonyl stretching vibration of oxamidate group v(C=O) at
1684 cm−1 of the bridging ligand H3bdpox are considerably shifted to lower frequency of
1644 cm−1 in the IR spectrum of the polymer–copper(II), implying that the carbonyl oxy-
gens of oxamido and oxygens of carboxylate bridge copper(II) ions form the coordination
polymer [30]. This shift has often been used as a diagnostic for oxamido-bridged structures
[22]. The v(C=N) stretch of the aromatic ring of dabt was found at 1577–1526 cm−1, indicat-
ing that the nitrogen of dabt are coordinated to copper(II) ions in the copper(II) polymer.
Furthermore, bands at 1384–1336 cm−1, typical for the ionic nitrate [30], were also
observed for the polymeric copper(II) complex.

1-D copper(II) coordination polymer
935
3.3. Electronic spectra
To obtain further structural information, the electronic spectrum of the polymeric copper(II)
complex was measured. For the polymeric copper(II) complex, two main absorptions with
varied intensities can be observed. The intense band at 233 nm is assignable to inter- or
intra-ligand (π–π*) transition, while the band at 274 nm in the polymeric copper(II) com-
plex can be assigned to the charge transfer transition between the ligand and metal [31].
These spectroscopic data of the polymeric copper(II) complex are further supported by
the determination of the crystal structure (vide infra).
3.4. Structure description of {[Cu2(bdpox)(dabt)](NO3)·H2O}n
As shown in figure 1, the asymmetric unit of the copper(II) coordination polymer {[Cu2(bd-
pox)(dabt)](NO3)·H2O}n is a bicopper(II) complex cation with a bridging cis-bdpox3−
ligand and a dabt coligand, with a nitrate ion and a solvent water molecule. These asymmet-
ric units bond end-to-end through the carboxyl bridges to form a 1-D coordination poly-
meric chain extending along the a-axis. The two copper(II) ions, Cu1 and Cu2, are in a
distorted {N3O} square-planar and {N2O3} square-pyramidal coordination geometries,
Figure 1. A view of 1 with the atomic numbering scheme. Displacement ellipsoids are drawn at the 30%
probability level and hydrogens are shown as small spheres of arbitrary radii. Dashed lines indicate hydrogen bonds
[symmetry codes: (i) −1/2 + x, 1/2 − y, 1 − z; (ii) 1/2 + x, 1/2 − y, 1 − z].

936
X.-J. Li et al.
Table 3. Hydrogen-bonding geometries (Å, °) for 1.
D–H···A
D–H
H···A
D···A
D–H···A
N6–H6A···O3
N6–H6B···O6
N6–H6B···O7
N7–H7A···O4
N7–H7B··· O5
C15–H15A···S1iii
0.85(2)
0.850(19)
0.850(19)
0.83(4)
0.83(4)
0.97
2.19(3)
2.31(2)
2.33(2)
2.15(4)
2.09(4)
2.85
2.889(3)
3.045(5)
3.135(6)
2.890(4)
2.898(6)
3.549(3)
140(2)
146(3)
158(3)′
148(3)
165(4)
129
Note: Symmetry code: (iii) 1 − x, −y, 1 − z.
respectively. The coordination distortion of Cu1 is very obvious, O1 deviates 0.1928(17) Å
off the plane of N1–N3. The tetrahedral volume of {N3O} is 1.528 Å3. Cu2 has a square-
pyramidal τ value of 0.04 [32] and is displaced from the basal plane 0.2064(12) Å with
axial Cu2–O2i distance of 2.308(2) Å [table 2, symmetry code: (i) x − 1/2, 1/2 − y, 1 − z].
The Cu···Cu distances through the cis-oxamido and the carboxyl bridges are 5.2420(10)
and 5.1551(8) Å, respectively. The bite angles of the oxamide-bridge at Cu1 and Cu2 are
83.98(9)° and 83.87(8)°, respectively. The torsion angles, Cu1–O1–C1–O2 [154.5(2)°] and
Cu2ii–O2–C1–O1 [−99.6(3)°, symmetry code: (ii) x + 1/2, 1/2 − y, 1 − z], indicate a
carboxylato-bridge in nonplanar skew–skew fashion [33, 34].
All seven N and O atoms of the bdpox3− ligand take part in coordination to copper(II)
ions forming four chelate rings. Two five-membered rings are planar, whereas the two six-
membered rings are puckered. Cu1–O1–C1–C2–C3–N1 ring is a compressed boat confor-
mation with puckering parameters [35] of Q [0.344(2) Å], θ [85.1(3)°] and φ [309.9(4)°].
N1 and C1 displace out of the boat bottom 0.332(3) and 0.253(4) Å, respectively. While
Figure 2. A 2-D hydrogen bonding network parallel to the plane (0 1 0). Symmetry codes: (i) x − 1/2, −y + 1/2,
−z + 1; (ii) x + 1/2, −y + 1/2, −z + 1; (iii) x, −y + 1/2, z + 1/2; (iv) x, −y + 1/2, z − 1/2.

1-D copper(II) coordination polymer
937
Cu1–N2–C10–C11–C12–N3 ring is close to a half-chair, the parameters are Q [0.584(3)
Å], θ [60.3(3)°], and φ [212.9(3)°]. The Cu1–N3 bond [2.058(2) Å] is longer than Cu1–N1
[1.990(2) Å] and Cu1–N2 [1.960(2) Å], consistent with stronger donor ability of the depro-
tonated amido nitrogen compared with the amino nitrogen [36].
Hydrogen bonding (table 3) and π–π stacking interactions play important roles in con-
struction of the supermolecule in the crystal. As shown in figure 2, there is a hydrogen
bonding chain formed by nitrate ions and solvent water molecules parallel to the a-axis, viz.
parallel to the complex chain. Furthermore, these two kinds of chains link to build up a 2-D
network parallel to a0c plane. As viewed from figure 3, an offset π–π stacking interaction is
observed between the benzene ring of a bdpox3− ligand and the S1-thiazole ring of another
bdpox3− ligand at 1 − x, −y, 1 − z (v), and vice versa. They have a dihedral angle of 13.27
(14)° and a center-to-center distance of 3.6895(19) Å. The angles of their center-to-center
vector with the normals to the benzene ring and thiazole ring are 21.33° and 21.23°,
respectively.
Comparing {[Cu2(bdpox)(dabt)](NO3)·H2O}n with our previously reported copper(II)
polymers
{[Cu2(dmaepox)(dabt)](pic)·H2O}n
[20]
and
{[Cu2(dmaepob)(dabt)]
(NO3)·0.6H2O}n [21], where H3dmaepox and H3dmapob stand for N-(2-carboxylatophe-
nyl)-N′-[3-(methylamino)-propyl]oxamidate and N-(2-carboxylatophenyl)-N′-[3-(dimethyl-
amino)propyl]oxamidate, respectively, the three copper(II) polymers have the same
coligand (dabt) and metal ions (Cu2+), with the bridging ligands skeleton also being similar.
Figure 3. A perspective view along the normal to the benzene ring (C2–C7) of an offset π–π stacking interaction
existing among the hydrogen bonding layers above. The separations of eclipsed atoms to the opposite aromatic
rings are 3.729(4) (C2v), 3.466(3) (C3v), 3.692(4) (C18v), and 3.425(3) Å (C19v). Symmetry code: (v) 1 − x, −y,
1 − z.

938
X.-J. Li et al.
The main difference is the substituents on nitrogen of the primary amino group, which
resulted in the present copper(II) polymer {[Cu2(bdpox)(dabt)](NO3)·H2O}n crystallizing in
orthorhombic with Pbca space group, while the previously reported copper(II) coordination
polymers {[Cu2(dmaepox)(dabt)](pic)·H2O}n and {[Cu2(dmaepob)(dabt)](NO3)·0.6H2O}n
were monoclinic with P21/c space group. These dissimilarities resulted in distinct structure
and further affect DNA/BSA binding properties and in vitro anticancer activities.
The present polymeric copper(II) complex in the solid state may be a discrete binuclear
species in solutions, although the molar conductance value of the polymeric copper(II) com-
plex (78 S cm2 (M−1) in DMF solution falls in the expected range for a 1 : 1 electrolyte
[37], and the electric spectra obtained for the polymeric copper(II) complex at different
concentrations (7.2 × 10−5 to 7.2 × 10−7 M) obeyed the Beer–Lambert law. Indeed, it is
difficult to determine whether the polymer–copper(II) stays intact in solutions as the 1-D
coordination polymer in the crystal structure, since the possibility of the polymeric copper
(II) complex falling apart in solutions cannot be excluded. Therefore, it would be more
reasonable to name the compound as 1 and replace the wording “coordination polymer”
with “complex 1” in the following biological activity studies.
3.5. DNA interaction studies
DNA is the primary target for many metal-based drugs, and many metal complexes exert
their drug effects through binding to DNA. Understanding the features that determine the
binding of metal complexes to DNA would be valuable in the rational design of sequence-
specific DNA binding molecules for application in chemotherapy and in the development of
tools for biotechnology. As a result, the elucidation of noncovalent interactions with DNA
by 1 was explored with the aid of different techniques and methods.
3.5.1. Electronic absorption titration. Electronic absorption spectroscopy is an effective
method to examine the binding mode and magnitude of DNA with metal complexes. In
general, hypochromism and red-shift are associated with the binding of the metal complexes
to the DNA helix, due to intercalative mode involving a strong stacking interaction between
the aromatic chromophore of metal complexes and the base pairs of DNA [38]. The absorp-
tion spectra of 1 in the absence and presence of HS-DNA are depicted in figure 4. In the
presence of incremental amounts of HS-DNA, a significant hypochromic effect accompa-
nied the moderate bathochromic shift (4 nm) of the absorbance maximum at 233 nm for the
copper(II) complex. Obviously, these spectral characteristics reveal that 1 can interact with
HS-DNA basically through the intercalation because intercalation would lead to hypochro-
mism and bathochromism in UV absorption spectra on account of the intercalative mode
involving a strong interaction between the aromatic chromophore and the base pairs of the
DNA [39]. These observations for 1 can be confirmed by the following. When 1 intercalates
the base pairs of HS-DNA, the π*-orbital of the intercalated ligand in 1 can couple with the
π-orbital of the base pairs, thus decreasing the π–π* transition energy and resulting in batho-
chromism. Furthermore, the coupling π*-orbital is partially filled by electrons, thereby
decreasing the transition probabilities and concomitantly resulting in hypochromism.
In order to quantitatively evaluate the strength of the binding affinity of 1 toward
HS-DNA, the intrinsic binding constant Kb of 1 with HS-DNA was determined by
monitoring the changes in absorbance at 233 nm with increasing concentration of HS-DNA
according to the following equation [40]:

1-D copper(II) coordination polymer
939
7
6
5
4
3
2
0.8
0.7
0.6
0.5
0.4
0.3
1
2
3
4
M
5
6
[DNA]×105
230
240
250
260
270
280
290
300
wavelength(nm)
Figure 4. Absorption spectra of 1 upon titration of HS-DNA. Arrow indicates the change upon increasing the
DNA concentration. Inset: plot of [DNA]/(εa − εf) vs. [DNA] for the absorption titration of HS-DNA with 1.
[DNA]=ðea ꢀ ef Þ ¼ [DNA]=ðeb ꢀ ef Þ þ 1=Kbðeb ꢀ ef Þ
(1)
where [DNA] is the concentration of DNA, εf, εa, and εb correspond to the extinction coeffi-
cient, respectively, for free 1, for each addition of DNA to their solutions and for 1 in the
fully bound form. From the [DNA]/(εa − εf) versus [DNA] plot (inset in figure 4), the Kb
value for 1 was estimated to be 6.16 × 104 M−1 (R = 0.9989 for six points), lower than that
of a classical intercalator, such as EB-DNA [41], but higher than those of some bi- [42–44]
and tetracopper(II) complexes [45], and has the same level as those of well-established
intercalation agents [46], indicating that 1 strongly binds to HS-DNA, and this may be
related to structural characteristics.
Comparing the Kb value of 1 (Kb, 6.16 × 104 M−1) with those of our previously reported
analogous polymeric copper(II) complexes {[Cu2(dmaepox)(dabt)](pic)·H2O}n (Kb,
1.25 × 104 M−1) and {[Cu2(dmapob)(dabt)](NO3)·0.6H2O}n (Kb, 1.04 × 104 M−1) [20], the
Kb value of 1 is higher than those of the previously reported polymeric copper(II) com-
plexes, indicating that 1 strongly binds to HS-DNA by intercalation. The main difference
among the three copper(II) compounds is that the substituents of nitrogen of the primary
amino group on the bridging ligands are one methyl group (H3dmaepox), two methyl
groups (H3dmapob), and two ethyl groups (H3bdpox), respectively, which would be
expected to hinder intercalation of 1, and hence lead to a lower DNA-binding affinity. How-
ever, the higher Kb value obtained suggests that the DNA-binding affinity of 1 may be due
to the fact that the two ethyl groups in 1 are involved in hydrophobic interaction with the
hydrophobic DNA surface leading to enhancement in DNA-binding affinity [47]. The
results suggest that modification of substituents on the bridging ligands may play a vital
role in DNA-binding of these copper(II) compounds. Therefore, the DNA-binding abilities
of copper(II) compounds bridged both by oxamido and carboxylate groups could be regu-
lated through varying the hydrophobicity of substituents on the bridging ligands. Indeed,
further investigations on this and similar systems are still required to confirm the effect and
gain deeper insights into DNA interactions.
We also compared the DNA-binding properties of 1 with those of previously reported
polycopper(II) complexes with various bridging ligands and polypyridines as terminal

940
X.-J. Li et al.
ligands [48–51], and we find that not only the interaction modes but also the DNA-binding
ability of these polycopper(II) complexes are different, suggesting that interactions of these
complexes toward DNA may be tuned by changing the bridging or terminal ligands. Such
strategy should be valuable in designing new polynuclear complex systems and understand-
ing the binding between these polynuclear complexes and DNA.
3.5.2. Fluorescence titration. To further verify the interaction mode between 1 and
HS-DNA, EB fluorescence displacement assay was also carried out. It has been found that
the intrinsic fluorescence intensity of DNA is very low and that EB in Tris–HCl buffer is
also not high due to the quenching by solvent. However, EB emits intense fluorescence in
the presence of DNA due to its strong intercalation between adjacent DNA base pairs. A
competitive binding of metal complexes to DNA can result in reduction of the emission
intensity due to decreasing of the binding sites of the DNA available for EB [45]. Thus, EB
can be used to probe the interaction of metal complexes with DNA, which will provide
indirect evidence for an intercalative binding mode. The extent of fluorescence quenching
may also be used to determine the extent of binding between the quencher and DNA. In
our experiment, as illustrated in figure 5, the fluorescence intensity of EB bound to
HS-DNA shows a remarkable decrease at 584 nm with increasing concentration of 1. The
observed decrease in fluorescence intensity clearly indicates that some EB molecules are
released from the EB-DNA system after exchange with 1, which results in fluorescence
quenching of EB. This is often considered as the characteristic of intercalation [52].
In order to understand quantitatively the magnitude of the binding strength of 1 with
HS-DNA, the classical linear Stern–Volmer equation was employed [53]:
I0=I ¼ 1 þ Ksv½Qꢁ
(2)
where I0 and I represent the fluorescence intensities in the absence and presence of
quencher, respectively. Ksv is a linear Stern–Volmer quenching constant and [Q] is the
concentration of quencher. The Ksv value is given by the quenching plot of I0/I versus
300
2.6
2.4
2.2
2
250
1.8
1.6
1.4
1.2
200
1
0
1
2
3
4
5
M
6
7
[complex]×10 6
150
100
50
0
550
560
570
580
590
600
610
620
630
wavelength(nm)
Figure 5. Emission spectra of HS-DNA-EB system upon titration of 1. Arrow shows the change upon increasing
concentration of 1. Inset: plot of I0/I vs. [complex] for titration of 1 to HS-DNA-EB system.

1-D copper(II) coordination polymer
941
[complex]. As shown in the inset to figure 5, the Ksv value for 1 is 8.46 × 106 (R = 0.9979
for eight points). Therefore, based on the EB fluorescence displacement experiments, we
conclude that 1 binds to HS-DNA through intercalation, which is in agreement with that
derived by electronic absorption spectra measurements.
3.5.3. Electrochemical titration. Optical photophysical probes are necessary, but not suf-
ficient clues to support a binding mode of metal complexes to DNA. Therefore, cyclic vol-
tammetry was also employed to explore the nature of DNA-binding of 1, as a complement
to the previously used spectral studies. As shown in figure 6, in the absence of HS-DNA
(red curve), 1 shows a quasi-reversible redox process corresponding to Cu(II)/Cu(I) with
the cathodic (Epc) and anodic peak potentials (Epa) being −0.554 and −0.150 V, respec-
tively. The separation of anodic and cathodic peaks (ΔEp) is 0.404 V, indicating that a
quasi-reversible, one-electron redox process occurred in 1. The formal potential of the Cu
(I)/Cu(II) couple (Ef00) taken as the average of Epc and Epa is −0.352 V. Upon addition of
HS-DNA (blue curve) with R = 4 (R = [DNA]/[polymer]), the voltammetric peak current
decreased, indicating that there exists interaction between 1 and HS-DNA [54]. The drop of
the voltammetric current in the presence of HS-DNA may be attributed to slow diffusion of
1 bound to HS-DNA. The cathodic and anodic peak potentials are −0.548 and −0.132 V,
respectively. The peak-to-peak separation becomes larger with ΔEp = 0.416 V, suggesting
that in the presence of HS-DNA, the electron-transfer process seems to become less revers-
ible for 1. The corresponding formal potential of the Cu(I)/Cu(II) couple in binding form
Eb00 (−0.340 V) is shifted positive by 0.012 V, validating that 1 could bind intercalatively to
HS-DNA [55]. This result is in agreement with the above spectral observations. The separa-
tion between Eb00 and Ef00 can be used to estimate the ratio of binding constants for the
reduced and oxidized forms to DNA using the equation as follows [55]:
Eb00 ꢀ Ef00 ¼ 0:059 log½KCuðIÞ=KCuðIIÞꢁ
(3)
where KCu(I) and KCu(II) are the binding constants of Cu(I) and Cu(II) forms to DNA,
respectively. The ratio of constants for the binding of the Cu(I) and Cu(II) ions to HS-DNA
Figure 6. Cyclic voltammograms of 1 in the absence (red line) and presence (blue line) of HS-DNA (see http://
dx.doi.org/10.1080/00958972.2015.1009452 for color version).

942
X.-J. Li et al.
was estimated to be 1.60 for 1, intimating that the reduced form of 1 interacts more strongly
than the oxidized one. Thus, the electrochemical results are in agreement with the above
spectral studies, further reinforcing the conclusion that 1 can bind to HS-DNA by
intercalation.
3.5.4. Viscosity measurements. Further clarification of the interaction between 1 and
HS-DNA is carried out by viscosity measurements. Sensitive to changes in the length of
DNA molecule, viscosity measurement is regarded as the least ambiguous and most critical
means of studying the binding of metal complexes with DNA in solution in the absence of
crystallographic structural data, and provides reliable arguments for intercalative binding
mode [27]. Generally, viscosity depends on both size and shape, and viscosity increases
suggest that the DNA adopts a more open structure, due to classical intercalation. On the
contrary, a partial or non-classical intercalation causes a compaction in DNA helix reducing
its effective length and thereby its viscosity. The effects of 1 on the viscosity of HS-DNA
are shown in figure 7. As illustrated in this figure, with increasing concentration of 1, the
relative viscosity of HS-DNA increases steadily, proving that 1 can bind to HS-DNA by
intercalation [56]. The viscosity studies further validate those obtained from electronic
absorption titration, fluorescence titration, and electrochemical titration.
These DNA studies for 1 prompt us to explore its protein binding activity.
3.6. Protein BSA-binding activity studies
Proteins are major targets for many types of medicines, which may influence the pharma-
ceutical pharmacokinetics and structure–activity relationships. Thus, it is important to
understand the mechanism of interaction of a bioactive compound with proteins. The nature
and magnitude of drug–protein interaction influence the biological activity of the drug [56].
It is important to study the binding parameters to control the pharmacological response of
2
1.9
1.8
1.7
1.6
1.5
1.4
1.3
1.2
1.1
1
0.00 0.02 0.04 0.06 0.08 0.10 0.12 0.14
[Complex]/[DNA]
Figure 7. Effect of the increasing amount of 1 on the relative viscosity of HS-DNA at 289( 0.1) K, [DNA]
= 0.1 mM.

1-D copper(II) coordination polymer
943
drugs and design of dosage forms. Studies on binding of metal complexes with protein may
provide salient information on the structural features that determine the therapeutic effec-
tiveness of drugs and are becoming increasingly important for interpreting metabolism and
transporting processes. Serum albumins, the most abundant protein in the blood circulatory
system, play important roles in transport and deposition of a variety of exogenous com-
pounds. In the present work, BSA was chosen as the model protein due to its structural
homology with human serum albumin, its availability, and unusual ligand binding proper-
ties. Therefore, the BSA-binding activities of 1 were studied through tryptophan quenching
and UV absorption spectral experiments.
3.6.1. Tryptophan quenching experiment. Studies related to the binding of metal
complexes with BSA are usually examined by fluorescence spectroscopic techniques. BSA
contains three fluorophores including tryptophan, tyrosine, and phenylalanine, while the
intrinsic fluorescence of BSA is mainly attributed to tryptophan [57]. Therefore, the trypto-
phan fluorescence of BSA can provide structural information of the protein and it can be
employed in understanding the protein folding mechanism and association reactions. There
are two tryptophan residues (Trp-134 and Trp-212) in a BSA molecule. Trp-134 is located
in a hydrophilic environment close to the protein surface, while Trp-212 is surrounded by a
hydrophobic environment within a protein pocket. The emission intensity depends on the
degree of exposure of the two tryptophan side chains, Trp-134 and Trp-212, to polar solvent
[58]. Quenching can occur by different mechanisms, which are usually classified as
dynamic quenching and static quenching [59]. Static quenching refers to fluorophore–
quencher complex formation, while dynamic quenching refers to a process where the fluo-
rophore and the quencher come into contact during the transient existence of the excited
state [60].
To further investigate the binding activity of 1 with protein, tryptophan emission-
quenching experiments were carried out using BSA in the presence of 1. As illustrated in
figure 8, the fluorescence emission intensity of BSA at 347 nm decreases with increasing
1.9
1.8
500
1.7
1.6
1.5
1.4
400
1.3
1.2
1.1
1
300
0
1
2
3
4
5
6
7
8
6
[complex]×10
M
200
100
0
300
320
340
360
380
400
420
wavelength(nm)
Figure 8. Emission spectra of BSA upon titration of 1. Arrow shows the change upon increasing concentration of
1. Inset: plot of I0/I vs. [complex] for titration of 1 to BSA.

944
X.-J. Li et al.
concentration of 1, indicating that the interaction of 1 with BSA results in changes in
protein secondary structure, therefore leading to changes in tryptophan environment of BSA
[61]. The linear Stern–Volmer equation is also employed to understand quantitatively the
ability of 1 to quench the emission intensity of BSA:
I0=I ¼ 1 þ Ksv½Qꢁ ¼ 1 þ Kqs0½Qꢁ
(4)
where I0 and I represent the fluorescence intensities in the absence and presence of
quencher, respectively. Q is the concentration of quencher. Ksv is a linear Stern–Volmer
quenching constant. Kq is the biomolecular quenching rate constant and τ0 is the average
lifetime of the fluorophore in the absence of the quencher (10−8 s). From the quenching plot
of I0/I versus [complex] (inset in figure 8), Ksv and Kq for 1 are 1.17 × 105 M−1 and
1.2 × 1013 M−1 s−1 (R = 0.9951 for nine points), respectively. Obviously, Kq of BSA
quenching initiated by 1 is higher than 2.0 × 1010 M−1 s−1, which is the maximum collision
quenching constant of various kinds of quenchers to biomacromolecule [62], indicating that
the above quenching is not initiated by dynamic collision but via the static quenching
mechanism, and this viewpoint was also validated by the following UV absorption spectral
studies.
3.6.2. UV spectral titration. UV absorption spectra help study interactions between metal
complexes and plasma proteins. In general, serum albumin has been used because of its
high sensitivity, rapidity, and ease of implementation [63]. To confirm the probable quench-
ing mechanism of 1, UV absorption spectral experiments were employed. The UV absorp-
tion spectral titrations of BSA in the presence of different concentrations of 1 are shown in
figure 9. Free BSA has two absorptions, one strong absorption at 226 nm from the π–π*
transition of the characteristic polypeptide backbone structure C=O groups and the other
weak absorption at 278 nm due to polarity of the microenvironment around tyrosine and
tryptophan residues of BSA. From figure 9, the intensity of the absorption at 226 decreased
3.0
0.45
2.5
0.40
2.0
0.35
1.5
0.30
265
1.0
0.5
0.0
270
275
280
285
290
wavelength(nm)
230
240
250
260
270
280
290
300
wavelength(nm)
Figure 9. Absorption spectra of BSA upon titration of 1. Arrow indicates the change upon increasing
concentration of 1.

1-D copper(II) coordination polymer
945
-0.1
-0.3
-0.5
-0.7
-0.9
-1.1
-6
-5.8
-5.6
-5.4
-5.2
Log[Q]
Figure 10. Plot of log[(F0 − F)/F] vs. log[Q] for titration of 1 to BSA.
with addition of 1, accompanied by red-shift of 7 nm, whereas the intensity of the peak at
278 nm increased with slight blue-shift. These results indicate that the interaction of 1 with
BSA may cause conformational changes in BSA and change the polarity of the microenvi-
ronment around tyrosine and tryptophan residues of BSA [60]. Moreover, it confirms that 1
interacted with BSA to form a ground-state system, validating that the fluorescence quench-
ing was mainly through a static quenching process [64], in agreement with the observation
derived by the tryptophan emission-quenching studies.
3.6.3. Binding constant and number of binding sites. It is well documented [65, 66] that
when small molecules bind independently to a set of equivalent sites on a macromolecule,
the equilibrium between the free and bound molecules is given by:
log ½ðF0 ꢀ FÞ=Fꢁ ¼ log K þ n log½Qꢁ
(5)
where F0 and F represent the fluorescence intensities in the absence and presence of
quencher, respectively. K is the binding constant of 1 with BSA and n is the number of
binding sites. From the quenching plot of log[(F0 − F)/F] versus log[Q], as illustrated in
figure 10, the K and n of 1 can be obtained. The K and n values are 4.49 × 105 (R = 0.9948
for eight points) and 1.12, respectively. The number of binding sites n is about 1, indicating
that there is just a single binding site in BSA for 1. Considering the large size and steric
effect of 1, we believe that 1 does not rapidly penetrate the hydrophobic interior of BSA
and only those tryptophan residues on the surface of the protein are quenched. Therefore, 1
most likely binds to BSA through the surface site Trp-134 [67].
In view of the premise that 1 displayed an appreciable interaction with biological macro-
molecules, such as DNA and protein BSA, it was pertinent to investigate the in vitro anti-
cancer activity of 1.
3.7. In vitro antitumor activity studies
To explore the potential antitumor activities of 1, cytotoxicity assays of 1 and cisplatin
against human hepatocellular carcinoma SMMC-7721 and human lung adenocarcinoma

946
X.-J. Li et al.
A549 were conducted. The IC50 values 9.2 0.4 and 10.5 0.9 μM for SMMC-7721 and
A549, respectively, indicate that 1 demonstrated anticancer activities. This may be partially
attributed to its strong intercalation. Furthermore, the IC50 values of 1 are higher than those
of cisplatin (IC50 values are 5.4 0.2 and 7.6 0.4 μM to these two kinds of cancer cell
lines, respectively), suggesting that the cytotoxic activities of 1 are less than that of cis-
platin. However, the inhibition of cell proliferation produced by 1 on the same batch of cell
lines is significant. The hydroxo-bridged oligomeric and polymeric species (the hydrolyzed
product in vivo) of platinum complexes are toxic to the body and such polymeric species
may have lower water solubility. These two factors may be incorporated in the list of drugs,
which should be further studied in order to obtain some insights into the anticancer mecha-
nism of this kind of polymer–metal systems.
Comparing the IC50 values of 1 with those of our previously reported analogous copper
(II)
compounds
{[Cu2(dmaepox)(dabt)](pic)·H2O}n
and
{[Cu2(dmapob)(dabt)]
(NO3)·0.6H2O}n, we found that 1 possessed the lowest IC50 values for the same cancer cell
lines among the three copper(II) compounds [20], indicating that 1 has the most potent
inhibitory effect against the two selected cancer cell lines under identical experimental con-
ditions. This may be due to the enhanced hydrophobicity of the two methyl groups on the
bridging ligand in 1, which may favor the permeation through the lipid layers of the cell
membrane. Thus, according to these results, we conclude that the hydrophobic interaction
of the ethyl groups on the bridging ligand in 1 may be the major cause of the enhanced
activity. The order of the in vitro anticancer activities of the three copper(II) compounds
against the selected cancer cell lines is in accord with their DNA-binding abilities, implying
that the in vitro anticancer activities of these copper(II) compounds may be closely related
to or originate from their ability to intercalate the base pairs of DNA. Thus, these copper(II)
compounds might target DNA, leading to cell death. This fact indicates that the DNA-bind-
ing and the in vitro anticancer activities could possibly be tuned through varying the hydro-
phobicity of the substituents on bridging ligands in these polymeric copper(II) compounds.
This strategy offers perspectives in understanding the anticancer activities and DNA-binding
behaviors of this kind of copper(II) compounds, providing information on the mechanism
of anticancer drugs binding to DNA and thus will be beneficial to new drug design.
4. Conclusion
To investigate the influence of hydrophobic interaction of different substituents on bridging
ligands in polymeric copper(II) complexes on DNA/BSA binding properties and in vitro
anticancer activities, and also gain insight into structure–activity relationships of polymeric
copper(II) systems, our article describes the synthesis and structural characterization of a
copper(II) polymer bridged by oxamide and carboxylate groups, {[Cu2(bdpox)(dabt)]
(NO3)·H2O}n. The DNA and protein BSA binding properties as well as in vitro anticancer
activities of the polymeric copper(II) complex are investigated and compared with other
polycopper(II) complexes. Reactivity toward HS-DNA and BSA reveals that 1 interacts
with HS-DNA by intercalation and to BSA through quenching of tryptophan fluorescence
by static quenching mechanism. The in vitro cytotoxic activities suggest that 1 is active
against selected tumor cell lines. Comparing the DNA-binding properties and in vitro anti-
cancer activities with our previously reported polymeric copper(II) complexes with different
bridging ligands [20], the different substituents on bridging ligands in these polymeric

1-D copper(II) coordination polymer
947
copper(II) complexes result in differences in the space configuration and electron density
distribution, thus changing the DNA-binding abilities and in vitro anticancer activities
through varying the hydrophobicity. The in vitro anticancer activities of these polymeric
copper(II) complexes are in accord with their DNA-binding abilities. These results imply
that the anticancer activities of these polymeric copper(II) complexes may be associated
with their ability to intercalate the base pairs of DNA. The DNA-binding abilities and
in vitro anticancer activities could be tuned through changing the hydrophobicity of bridg-
ing ligands in these polymeric copper(II) complexes. Such strategy should be valuable for
understanding the mechanism of anticancer drugs binding to DNA, and for laying a founda-
tion for the rational design of highly effective agents for probing and targeting nucleic acids
and proteins.
Supplementary material
CCDC 917219 contains the supplementary crystallographic data for this article. Copies of
this information can be obtained for free from the Director, CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK (Fax: C44 1233 336 033; E-mail: deposit@ccdc.cam.ac.uk).
Funding
This project was supported by the National Natural Science Foundation of China [grant number 51273184], [grant
number 81202399]; the Program for Science and Technology of Shandong Province [grant number
2011GHY11521]; the key laboratory open funds of marine biological active substances and modern analytical tech-
nology of the state oceanic administration [MBSMAT-2012-05]; the Natural Science Foundation of Qingdao City
[grant number 12-1-3-52-(1)-nsh], [grant number 12-1-4-16-(7)-jch].
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