Two copper(II) complexes of curcumin derivatives: Synthesis, crystal structure and in vitro antitumor activity

Article abstract of DOI:10.1007/s11243-014-9831-z

Two Cu(II) complexes of curcumin derivatives, formulated as CuL ₂ ^a (1) and CuL ₂ ^b (2) [HL ^a = 1,7-bis(4-ethyloxy-3-methoxy-phenyl)-1,6-heptadiene-3,5-dione and HL^b = 1,7-bis(4-butyloxy-3-methoxy-phenyl)-1,6-heptadiene-3,5-dione] , have been synthesized and characterized by single-crystal X-ray diffraction, along with physicochemical and spectroscopic methods. In both complexes, each Cu(II) center is surrounded by four oxygen atoms from two β-diketone ligands in a square planar geometry. Complex 1 forms a 2D layer structure through intermolecular π-π stacking interactions, as well as weak coordination interactions between the Cu and O atoms of the solvent 1,4-dioxane molecules. Complex 2 displays a 1D column structure stabilized by intermolecular π-π stacking interactions. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide] assays were used to evaluate the cytotoxicities of these complexes against three human cancer cell lines. The results show that the Cu(II) complexes exhibit more potent inhibition tumor growth in comparison with the free ligands.

Full text of DOI:10.1007/s11243-014-9831-z

Transition Met Chem
DOI 10.1007/s11243-014-9831-z
Two copper(II) complexes of curcumin derivatives: synthesis,
crystal structure and in vitro antitumor activity
•
Jiafeng Wang Dong Wei Bo Jiang
•
•
•
Tao Liu Jia Ni Shuangsheng Zhou
•
Received: 12 February 2014 / Accepted: 28 April 2014
Ó Springer International Publishing Switzerland 2014
Abstract Two Cu(II) complexes of curcumin derivatives,
formulated as CuL2a (1) and CuLb2 (2) [HLa = 1,7-bis(4-
ethyloxy-3-methoxy-phenyl)-1,6-heptadiene-3,5-dione and
HLb = 1,7-bis(4-butyloxy-3-methoxy-phenyl)-1,6-hept-
adiene-3,5-dione], have been synthesized and characterized
by single-crystal X-ray diffraction, along with physico-
chemical and spectroscopic methods. In both complexes,
each Cu(II) center is surrounded by four oxygen atoms
from two b-diketone ligands in a square planar geometry.
Complex 1 forms a 2D layer structure through intermo-
lecular p–p stacking interactions, as well as weak coordi-
nation interactions between the Cu and O atoms of the
solvent 1,4-dioxane molecules. Complex 2 displays a 1D
column structure stabilized by intermolecular p–p stacking
rhizomes of turmeric (Curcuma Longa Linn.), which has
attracted interest in the fields of biology, medicine and
pharmacology over the past decades owing to its antitumor,
anti-inflammatory, antiviral, antibacterial and antioxidant
activities [1–4]. Ongoing clinical trials of curcumin,
including studies in colon cancer (phase I/II), pancreatic
cancer (phase II/III), cervical cancer (phase II/III), oral
cancer (phase II/III), rectal cancer (phase II) and multiple
myeloma, have shown that this compound exhibits anti-
proliferative activity against a variety of tumors via diverse
signaling pathways that affect tumor growth, involving
nuclear factor-jB (NF-jB), PI3K/Akt, activator protein-1
(AP-1) and cyclooxygenase-2 (COX-2) [5–9]. Importantly,
curcumin is very safe to humans even at 8,000 mg/day
dosage orally for 3 months [10]. Although curcumin pos-
sesses wide-spectrum and low-toxicity antitumor activity,
its clinical application in antitumor therapy has been
greatly limited by its rapid metabolism, low absorption and
poor stability in vivo [11]. In order to improve the bio-
availability and antitumor activity of curcumin, a large
number of curcumin derivatives and analogues have been
designed and synthesized through structural modifications
such as variation of the aromatic rings and their substitu-
ents and/or replacing the heptadiendione bridge chain of
curcumin with other linkers [12–17]. Because the poor
stability of curcumin is reported to mainly result from the
phenolic hydroxyl groups [18], our group has synthesized a
series of dialkoxyl substituted curcumin derivatives, such
as 1,7-bis(4-ethyloxy-3-methoxy-phenyl)-1,6-heptadiene-
3,5-dione (HLa) and 1,7-bis(4-butyloxy-3-methoxy-phe-
nyl)-1,6-heptadiene-3,5-dione (HLb), using the Williamson
ether reaction between halohydrocarbons and the phenolic
hydroxyl group of curcumin (Fig. 1). The introduction of R
groups to the hydroxyl positions not only increases the
stability of the derivatives but also retains the b-diketone
interactions.
MTT
[3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyltetrazolium bromide] assays were used to evaluate
the cytotoxicities of these complexes against three human
cancer cell lines. The results show that the Cu(II) com-
plexes exhibit more potent inhibition tumor growth in
comparison with the free ligands.
Introduction
Curcumin, 1,7-bis(4-hydroxyl-3-methoxyphenyl)-1,6-hept-
adiene-3,5-dione, is a naturally occurring yellow pigment
with a symmetric b-diketone unit extracted from the
J. Wang ꢀ D. Wei ꢀ B. Jiang ꢀ T. Liu ꢀ J. Ni ꢀ S. Zhou (&)
Department of Pharmacy, Anhui University of Chinese
Medicine, Hefei 230031, China
e-mail: zshuangsheng@126.com
J. Wang
Anhui Province Key Laboratory of Environment-friendly
Polymer Materials, Anhui University, Hefei 230601, China
123

Transition Met Chem
Fig. 1 Synthesis route of
curcumin derivatives and their
Cu(II) complexes (HLa: R
=CH2CH3; HLb: R
=CH2CH2CH2CH3)
fragment which can act as a good O-donor chelating
ligand. It has been demonstrated that the coordination of
curcumin with various metals can enhance the antitumor
activity [19–25]. Metal complexes have attracted consid-
erable attention as new anticancer therapeutic candidates in
recent years because metal ions are essential in many
natural biological processes. Moreover, metal complexes
can offer mechanisms of action that are unavailable to
organic compounds. However, to the best of our knowl-
edge, the coordination chemistry of curcumin derivatives
has been little explored [26, 27]. Considering that Cu(II) is
an essential micronutrient participating in many biological
processes such as mitochondrial respiratory reaction,
energy generation, cellular stress response, antioxidant and
antitumor defense [28], in this paper, we have used our
curcumin derivatives HLa and HLb as ligands to prepare
two new Cu(II) complexes, formulated as CuLa2 (1) and
CuLb2 (2), respectively (Fig. 1). It is hoped that the conju-
gation of Cu(II) with these curcumin derivatives may
enhance their antitumor activity. Herein, we report the
synthesis, crystal structures and in vitro antitumor activities
of the two complexes.
(0.18 g, 1.0 mmol) in ethanol (10 mL) were added into the
solution sequentially at room temperature. The reaction
mixture was stirred at 80 °C for 6 h. After cooling to room
temperature, the complex was filtered off, washed thor-
oughly with water and ethanol and then dried under vac-
uum. Yellow green crystals; Yield 0.65 g (65 %). FTIR
(KBr, cm-1): 2,979 (CH3), 1,623 (C=O), 1,510 (C=C),
1,598, 1,577, 1,477 (Ar), 1,257 (=CH), 543 (Cu–O); Anal.
Calcd. for C54H62CuO14: C 65.0, H 6.2, Cu 6.4 %; Found:
1
C 64.5, H 6.0, Cu 6.2 %; H-NMR (d6-DMSO, 400 MHz)
d: 1.63 (t, 12H, J = 8 Hz, CH3), 4.0 (s, 12H, –OCH3),
4.14–4.21 (q, 16H, J = 8 Hz, OCH2), 5.96 (s, 2H, O=C–
CH–C=O), 6.61–6.70 (d, 4H, J = 16 Hz, =CH), 7.07–7.31
(m, 12H, Ar–H), 7.57–7.63 (d, 4H, J = 16 Hz, =CH–Ar).
Synthesis of complex 2
CuLb2 (2) was synthesized by a similar procedure to com-
plex 1, except using ligand HLb instead of HLa. Yellow
crystals; Yield 0.60 g (59 %). FTIR (KBr, cm-1): 2,957
(CH3), 1,624 (C=O), 1,510 (C=C), 1,598, 1,579, 1,466
(Ar), 1,262 (=CH), 533 (Cu–O); Anal. Calcd. for C58H70-
CuO12: C 68.1, H 6.9, Cu 6.2 %; Found: C 68.4, H 6.6, Cu
1
6.5 %; H-NMR (d6-DMSO, 400 MHz) d: 1.32 (t, 12H,
Experimental
J = 8 Hz, CH3), 3.15–3.34 (m, 16H, -CH2), 3.87 (s, 12H,
–OCH3), 4.10–4.19 (m, 8H, OCH2), 5.88 (s, 2H, O=C–CH–
C=O), 6.56–6.64 (m, 4H, =CH), 6.82–7.16 (m, 12H, Ar–
H), 7.42–7.53 (m, 4H, =CH–Ar).
Materials and instruments
All reagents were purchased commercially and used
directly without further purification. The curcumin deriv-
atives, HLa and HLb, were prepared by the method we
reported in Ref. [29]. Elemental analyses were obtained on
a Perkin-Elmer 240 analyzer. Infrared spectra were recor-
ded on a Nicolet FT-IR 170 SX spectrophotometer with
KBr pellets in the 4,000–400 cm-1 region.
Crystal structure determination
Single crystals, suitable for X-ray analyses, were obtained
by slow evaporation of ethyl acetate/1,4-dioxane solutions
at room temperature. Single-crystal X-ray diffraction data
were collected on a Bruker SMART APEX CCD diffrac-
tometer equipped with graphite monochromated Mo Ka
˚
Synthesis of complex 1
radiation (k = 0.71073 A) at ambient temperature. All
independent reflections were collected in a range of
0.94–25.00° for complex 1 and 1.52–24.97° for complex 2
(determined in the subsequent refinement). The structures
were solved by direct methods with SHELXS-97 and
CuLa2 (1) was prepared as follows. HLa (0.85 g, 2.0 mmol)
was dissolved in ethanol (30 mL), then solid sodium
hydroxide (0.09 g, 2.2 mmol) and a solution of Cu(OAc)2
123

Transition Met Chem
riding model. In the final difference map, the residual
maximum and minimum were 0.354 and -0.718 e A-3 for
Table 1 Crystal data and structure refinement parameters for 1 and 2
˚
Complex
1
2
-3
1, 0.305 and -0.365 e A for 2, respectively. Crystallo-
˚
Empirical formula
Formula weight
Temp (K)
C54H62CuO14
998.58
C58H70CuO12
1,022.68
298 (2)
graphic data and experimental details for complexes 1 and
2 are summarized in Table 1. Selected bond lengths and
angles are listed in Table 2.
296 (2)
0.71073
Monoclinic
P21/c
˚
k (A)
0.71073
Monoclinic
C2/m
Crystal system
Space group
Cell lines and culture conditions
˚
a (A)
21.86 (2)
16.453 (16)
7.184 (7)
97.643 (11)
2,561 (4)
2
15.556 (5)
34.764 (5)
8.546 (5)
110.882 (5)
4,318 (3)
2
Three different human cancer cell lines were used: ASPC-1
(pancreatic carcinoma), MCF-7 (breast cancer) and HeLa
(cervical cancer). All cell lines were purchased from the
Cell Culture Center of China Pharmaceutical University.
The cell lines were cultured in RPMI 1,640 medium sup-
plemented with 10 % (v/v) fetal bovine serum (FBS) and
antibiotics (100 U/mL of penicillin and 100 lg/mL of
streptomycin) in cell culture incubators at 37 °C in a
humidified atmosphere containing 5 % (mass fraction)
CO2.
˚
b (A)
˚
c (A)
b (°)
3
˚
V (A )
Z
Dc (g cm-3
l (mm-1
)
1.295
0.787
)
0.492
0.291
F (000)
1,054
1,086
Crystal size (mm)
h range (°)
Limiting indices
0.30 9 0.20 9 0.20 0.30 9 0.20 9 0.20
0.94–25.00
-25B h B25
-18B k B19
-8B l B8
1.52–24.97
MTT cytotoxicity assay
-18 B h B18
-41 B k B40
-10 B l B8
13,453
The effects of the free ligands and their complexes on cell
proliferation were determined using the MTT [3-(4,5-
Reflections collected
Reflections unique
17,861
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide]
4,510 (0.0247)
3,783 (0.0967)
assay. The cells were seeded in 96-well plates at a con-
centration of 2 9 104 cells/well. Subsequently, the cells
were treated with graded concentrations of reagents in
triplicate. After 48 h of incubation, 40 lL of MTT (5 mg/
mL) was added to each well, which was then incubated for
an additional 4 h. After discarding the medium, the cells
were dissolved in DMSO (150 lL/well) and the absor-
bance was recorded at 570 nm. The cell lines without any
drug treatment were used as a blank control in all experi-
ments. The cell survival rates were calculated as a per-
centage by comparison of the treated cells with the
untreated control. The maximal inhibitory concentration at
50 % cell survival rate of each reagent (IC50) was deter-
mined from the curve or regression equation of the survival
rate versus drug concentration.
(Rint
)
Parameters
Goodness of fit on F2
317
165
1.095
0.934
Final R indices [I [2 r R1 = 0.0503,
wR2 = 0.1420
R1 = 0.0836,
wR2 = 0.2191
(I)]a
R indices (all data)a
R1 = 0.0629,
wR2 = 0.1557
R1 = 0.1524,
wR2 = 0.2523
Largest diff. peak and
´
0.354 and -0.718
0.305 and -0.365
-3
˚
hole (eꢀ A
)
.
2
a
x ¼ 1 ½r2ðF02Þ þ ð0:0881PÞ þ 1:2757Pꢁ for
1
and x ¼
.
ꢀ
2
1
½r2ðF02Þ þ ð0:1216PÞ þ 0:0000Pꢁ for 2, where P ¼ ðF02 þ 2FC2 Þ 3
a
˚
Table 2 Selected bond lengths (A) and angles (°) for 1 and 2
1
2
Cu1-O3
Cu1-O4
O3-Cu1-O4
O3-Cu1-O4#2
a
1.929 (2)
1.903 (2)
Cu1-O3
1.988 (3)
93.28 (18)
86.72 (18)
Results and discussion
O3-Cu1-O3#2
O3-Cu1-O3#3
93.68 (11)
86.32 (11)
Crystal structures of the complexes
Symmetry transformations used to generate equivalent atoms:
complex 1 #2 -x ? 2, -y ? 2, -z ? 1; complex 2 #2 -x ? 2, y, -
z ? 3 and #3 x, -y ? 2, z
As shown in Fig. 2a, complex 1 has a neutral mononuclear
structure, composed of one copper(II) center and two
anionic (La)- ligands, being formulated as CuLa2. The
central Cu atom is four-coordinated by two oxygen atoms
of the carbonyl groups and two oxygen atoms of enolic
hydroxyl groups from two b-diketone ligands, which adopt
the chelating coordination modes in their enol forms. The
refined by full-matrix least-squares methods on F2 with
SHELXL-97 software. All non-hydrogen atoms were
refined anisotropically, while hydrogen atoms were added
at the calculated positions and refined isotropically using a
123

Transition Met Chem
Fig. 3 a ORTEP drawing of the molecular structure of 2 with atomic
labeling scheme (50 % thermal ellipsoids probability,. symmetry
code: #1 -x ? 2, -y ? 2, -z ? 3; #2 -x ? 2, y, -z ? 3; #3 x, -
y ? 2, z). b View showing the 1D column structure of 2 formed by p–
p stacking interactions (Hydrogen atoms are omitted for clarity)
the coordination plane composed of one Cu(II) atom and
four oxygen atoms are 3.33° and 1.42°, respectively,
showing that they are nearly coplanar. In complex 1, an
infinite 1D column arrangement along the c-axis is
observed. This 1D column structure is formed by weak
coordination interactions between the Cu and the O atoms
of the 1,4-dioxane molecules, with a distance of 2.726
˚
(2) A (Fig. 2b). The CuꢀꢀꢀCu separation across the 1,4-
˚
dioxane bridge is 7.184 A, and all Cu(II) atoms are in a
straight line. The 1D columns are further extended into a
2D layer structure extending along the ab plane through
two kinds of alternant p–p interactions between almost
parallel benzene rings P1 and P1 (centroid–centroid sepa-
˚
ration 3.846 A with a dihedral angle of 5.62°, described as
M in Fig. 2c), and between P2 and P2 rings (centroid–
Fig. 2 a ORTEP drawing of the molecular structure of 1 with atomic
labeling scheme (50 % thermal ellipsoids probability, symmetry
code: #1 -x ? 2, -y, -z; #2 -x ? 2, -y ? 2, -z ? 1). b View
showing the 1D column structure of 1 along c-axis formed through
weak coordination interactions between the Cu and the O atoms of the
1,4-dioxane molecules. c View showing the 2D layer structure of 1 on
the ab plane stabilized by p–p stacking interactions (Hydrogen atoms
are omitted for clarity)
˚
centroid separation 3.897 A with a dihedral angle of 8.13°,
described as N in Fig. 2c) from different mononuclear
units.
The crystal structure of complex 2 is shown in Fig. 3a.
The asymmetric unit contains one Cu(II) atom and two Lb
ligands, the complex being formulated as CuLb2. The Cu
atom is located on an inversion center and four-coordinated
by four crystallographically equivalent oxygen atoms from
two chelating b-diketone ligands in their enol form. The
˚
Cu–O bond lengths are 1.929 (2) and 1.903 (2) A, which
are a little shorter than those in other copper diketonate
complexes [30, 31]. The O–Cu–O bond angles are 93.68
(11) and 86.32 (11)°, and the sum of them is 180°, indi-
cating the Cu(II) center adopts a square planar configura-
tion. The dihedral angle between the two benzene rings P1
and P2 is 4.09°, while the dihedral angles they form with
˚
Cu–O bond lengths are all 1.988 (3) A. The O–Cu–O bond
angles are 93.28 (18) and 86.72 (18)°, respectively, and
their sum is also 180°, revealing the Cu(II) center adopts a
square planar geometry in this complex also. The dihedral
123

Transition Met Chem
activities. Complex 1 exhibits higher antiproliferative
activity against three human cancer cell lines tested than
complex 2, suggesting that increased steric hindrance in the
R groups will bring down the antitumor activity. Both
complexes show significantly enhanced antitumor activity
in comparison with the free ligands, which suggests that
exploring the coordination chemistry of curcumin deriva-
tives is an effective method to improve their antitumor
activity. Further studies on the in vivo antitumor activities
of these complexes are in progress.
Table 3 IC50 values of the free ligands and their Cu(II) complexes
against three cancer cell lines
Compound
IC50 (lM)
ASPC-1
MCF-7
HeLa
CuLa2 (1)
CuLb2 (2)
HLa
6.52
7.45
3.22
4.43
11.48
13.34
40.69
43.26
22.90
24.68
14.96
18.06
HLb
angle between benzene ring P1 and the coordination plane
composed of one Cu(II) atom and four oxygen atoms is
6.01°, and the dihedral angle between two benzene rings in
each ligand is 9.23°, which are both slightly larger than
those in complex 1, indicating that complex 2 is twisted
slightly to reduce steric hindrance. The structure is exten-
ded into a 1D column by p–p stacking interactions between
the benzene rings, with a centroid–centroid separation of
Supplementary material
CCDC reference numbers 972326 (CuLa2) and 937711
(CuLb2) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html or from the
Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: ?44 1223/336 033; e-mail:
deposit@ccdc.cam.ac.uk.
˚
3.888 A and dihedral angle of 9.23° (Fig. 3b).
In vitro antitumor activities
Acknowledgments This research was financially supported by the
Opening Foundation of Anhui Province Key Laboratory of Environ-
ment-friendly Polymer Materials (No. 2013KF001), the National
Natural Science Foundation of China (No. 21071001), the Natural
Science Foundation of Anhui Province (No. 1208085MH173), and
the Youth Foundation of Anhui University of Chinese Medicine (No.
2011qn027).
We evaluated the cytotoxicities of the free ligands and their
Cu(II) complexes against three cell lines, ASPC-1, MCF-7
and HeLa. MTT assays were performed to detect cell
survival rates following exposure to the tested compounds
during 48 h of incubation. Table 3 summarizes IC50 values
from a series of individual experiments. It can be observed
that both complexes significantly enhanced the inhibition
activity of tumor growth in contrast to the two ligands. The
cytotoxicities of complexes 1 and 2 were about three–
fivefold higher than the corresponding free ligands against
every cancer cell tested. The increased growth-suppressive
activity of the complexes may be associated with the DNA-
binding interactions of copper ions [32–35]. The IC50
levels of complex 1 against all three cancer cells were a
little lower than those of complex 2, and the same phe-
nomenon was also observed for the free ligands, which
may be a result of a spacer effect. When HLb was used in
place of HLa, the increased steric hindrance of the R groups
would influence the efficient transmembrane transportation
and penetration of the compounds into tumor cells,
resulting in the decrease in cytotoxicity.
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