Synthesis, characterization and anticancer activity of a series of curcuminoids and their half-sandwich ruthenium(II) complexes

Article abstract of DOI:10.1002/aoc.3685

A series of curcuminoids (L¹–L⁷) and their corresponding (η⁶-p-cymene)Ru^II(Cur)Cl complexes (1–7) were synthesized and characterized using ¹H NMR spectroscopy, elemental analysis and high-resolution e

Full text of DOI:10.1002/aoc.3685

Received: 4 October 2016
DOI 10.1002/aoc.3685
Accepted: 18 October 2016
F U L L PA P E R
Synthesis, characterization and anticancer activity of a series of
curcuminoids and their half‐sandwich ruthenium(II) complexes
Peiyuan Li1 | Wei Su2,3 | Xiaolin Lei2 | Qi Xiao2 | Shan Huang2
1 College of Pharmacy, Guangxi University of
A series of curcuminoids (L1–L7) and their corresponding (η6‐p‐cymene)RuII(Cur)
Cl complexes (1–7) were synthesized and characterized using H NMR spectros-
Chinese Medicine, Nanning, China
2 Key Laboratory of Environment Change and
1
Resources Use in Beibu Gulf (Guangxi Teachers
copy, elemental analysis and high‐resolution electrospray ionization mass
spectrometry. The molecular structures of L2, L4, 1 and 4 were determined using
Education University), Ministry of Education, China
3 Department of Chemistry, Guangxi Teachers
single‐crystal X‐ray diffraction analysis. The stability of 1–7 was investigated by
monitoring their UV profiles. The compounds were further evaluated for their
in vitro antiproliferative activities against the HepG2 human liver and HeLa human
Education University, Nanning, China
Correspondence
Wei Su, Key Laboratory of Environment Change
and Resources Use in Beibu Gulf (Guangxi
Teachers Education University), Ministry of
Education, China; Department of Chemistry,
Guangxi Teachers Education University, Nanning,
China.
cervical cancer cell lines and HEK‐293 T noncancerous cell line.
KEYWORDS
anticancer activity, arene, curcuminoids, ruthenium
Email: suwmail@163.com
Funding information
Guangxi Colleges and Universities Key Labora-
tory of Synthetic; Guangxi Natural Science Foun-
dation, Grant/Award Number:
2016GXNSFCA380013, 2014GXNSFBA118243;
National Natural Science Foundation of China,
Grant/Award Number: 51263002, 21261005;
Natural Functional Molecular Chemistry and
Guangxi Teachers Education University; State Key
Laboratory for Chemistry and Molecular Engineer-
ing of Medicinal Resources; Guangxi Normal Uni-
versity, Grant/Award Number: CMEMR 2016‐B16.
1
|
INTRODUCTION
anticancer activity. The vanadyl, gallium and indium com-
plexes of curcuminoids have been reported, and some of
them have shown cytotoxicity for anticancer applications.[5–8]
Among the transition metals, ruthenium appears to be the
most promising candidate, since the redox chemistry of
ruthenium is rich and compatible with biological media. In
addition, the low overall toxicity of ruthenium allows a high
dose of treatment.[9] Ruthenium‐based complexes have
attracted extensive interest for their potential in cancer
treatment.[10] For instance, the Ru(III) complexes [HIm]
[trans‐RuCl4(DMSO)(Im)] (NAMI‐A) and [ImH][trans‐
RuCl4(Im)2] (KP1019) have been undergoing clinical evalua-
tion with very promising results.[11] Recently, organometallic
ruthenium(II) arene complexes, with a half‐sandwich type of
structure, have been studied as a new source of anticancer
metallodrugs.[12] For instance, ruthenium(II) arene com-
plexes with ethylenediamine as the ligand can bind to DNA
and thus lead to cytotoxicity towards cancer cells.[13] In
Curcumin, 1,7‐bis(4‐hydroxy‐3‐methoxyphenyl)‐1,6‐heptadien‐
3,5‐dione, is the primary bioactive compound isolated from
turmeric.[1] Curcumin has a wide spectrum of pharmacologi-
cal effects including antioxidant, anti‐inflammatory, antiviral,
antimicrobial and antiproliferative activities.[2] In spite of its
promising biological effects, the therapeutic applications of
curcumin are restricted because of its low aqueous solubility,
slow dissolution rate, instability and poor bioavailability.[3]
To address these issues and to improve the systemic bioavail-
ability of curcumin, numerous strategies have been devel-
oped, including the use of adjuvants, liposomal curcumin
and the design of curcumin derivatives, the so‐called curcu-
minoids.[4] Moreover, curcumin and its analogues can bind
to transition metal ions and form metal‐based complexes,
which offer a promising opportunity for improving the
stability and tuning the biological properties such as
Appl Organometal Chem 2016; 1–8
wileyonlinelibrary.com/journal/aoc
Copyright © 2016 John Wiley & Sons, Ltd.
1

2
LI ET AL.
addition, related complexes that contain the 1,3,5‐triaza‐7‐
phosphatricyclo[3.3.1.1]decane (PTA) ligand, e.g. [(η6‐p‐
cymene)RuII(PTA)Cl2] (RAPTA‐C), have exhibited activity
against metastases.[14] Moreover, ruthenium–arene complexes
incorporating steroidal,[15] picolinamide[16] or carbohy-
drate[17] ligands have demonstrated promising pharmacologi-
cal activities particularly antiproliferative effects, making
them viable candidates for further biological study.
Recently, ruthenium(II) arene anticancer complexes
containing curcumin ligands have been shown to exhibit
exciting cytotoxic profiles against selective human cancer
cell lines.[18] Dyson and co‐workers have shown that
ruthenium(II)–arene PTA‐type complexes containing
curcumin and bisdemethoxycurcumin display potent and
selective anticancer activity.[19] In continuation of our
previous exploration of ruthenium(II) arene complexes with
curcuminoids,[20] and considering the promising biological
effects of curcuminoids, we report here the chemical
characterization of a series of half‐sandwich‐type ruthenium
(II) complexes (Scheme 1). Furthermore, we present a com-
parison of the antiproliferative results of these complexes
and the corresponding curcuminoid ligands with various can-
cer cell types.
acetylacetone (0.5 g, 0.05 mol) and boric oxide (0.25 g,
7.5 mmol) were added and, after stirring the reaction mix-
ture, n‐butylamine (0.4 ml) was added dropwise over a
period 30 min. After stirring for 12 h, the reaction mixture
was left overnight at room temperature. Dilute hydrochloric
acid (0.4 M, 7.5 ml) was added and the mixture was stirred
in an oil bath at 60 °C for 1 h. The organic layer was sep-
arated after cooling and the aqueous layer was extracted
several times with ethyl acetate. The combined organic
layer was washed with water, dried over anhydrous MgSO4
and evaporated to yield a gummy product which crystal-
lized from cold methanol. The crude curcuminoid was ana-
lyzed using TLC (ethyl acetate–petroleum ether, 1:2) and
further purified by flash chromatography using the same
eluents.
2.3 | Synthesis of complexes
2.3.1
|
Complex (η6‐p‐cymene)Ru(L1)Cl (1)
[(η6‐p‐cymene)RuCl2]2 (31.5 mg, 0.05 mmol), L1 (27.6 mg,
0.1 mmol) and C2H5ONa (10.2 mg, 0.15 mmol) were
dissolved in 6 ml of ethanol. The reaction mixture was
stirred at room temperature. After 1 h, the mixture was
dried in vacuum, the residue was redissolved in dichloro-
methane (10 ml) and the mixture was filtered to remove
sodium chloride. Removal of the solvent gave a red solid
which was further purified by recrystallization from
ethanol and hexane. Yield: 32.8 mg, 60%. HR‐ESI‐MS
(MeOH): m/z found (calcd): 511.1212 (511.1219) (100%)
[(η6‐p‐cymene)Ru(L1)]+. 1H NMR (300 MHz, CDCl3,
25 °C, δ, ppm): 1.31 (d, 6H, J = 6.9 Hz, p‐cym
CH(CH3)2), 2.37 (s, 3H, p‐cym CCH3), 3.00 (m, 1H,
p‐cym CH(CH3)2), 5.33(d, 2H, J = 6.0 Hz, p‐cym
phenyl‐H), 5.51 (s, 1H, ─CH1), 5.60 (d, 2H,
2
| EXPERIMENTAL
2.1 | Materials
Ruthenium(III) chloride hydrate, curcumin (L7) and other
reagents were purchased from J&K Chemical Co. (China).
All reagents and solvents were of high purity and used with-
out further purification. The starting material [(η6‐p‐cymene)
RuCl2]2 was prepared according to previously reported
procedures.[20]
J
=
6.0 Hz, p‐cym phenyl‐H), 6.60 (d, 2H,
J = 15.7 Hz, 2× ═CH3,3′), 7.37–7.47 (m, 6H, 4×
─ArH7,7′,9,9′ and 2× ─ArH8,8′), 7.52–7.55 (m, 4H, 4×
─ArH6,6′,10,10′), 7.64 (d, 2H, J = 15.9 Hz, 2× ═CH4,4′).
Anal. Calcd for C29H29O2RuCl⋅3/4CH2Cl2 (%): C, 58.60;
H, 5.04; N, 0. Found (%): C, 58.88; H, 4.83; N, <0.30.
2.2 | General procedure for synthesis of curcuminoids
All of the curcuminoid analogues (L1–L6) were prepared
using literature methods.[21] Aromatic aldehyde (0.01 mol)
and tributylborate (4.6 g, 0.02 mol) were dissolved in dry
ethyl acetate (0.5 ml). After stirring for
5
min,
2.3.2
|
Complex (η6‐p‐cymene)Ru(L2)Cl (2)
This complex was synthesized as for 1. Yield: 78%. HR‐ESI‐
MS (MeOH): m/z found (calcd): 547.1035 (547.1031)
(100%) [(η6‐p‐cymene)Ru(L2)]+. 1H NMR (300 MHz, CDCl3,
25 °C, δ, ppm): 1.41 (d, 6H, J = 6.9 Hz, p‐cym CH(CH3)2),
2.36 (s, 3H, p‐cym CCH3), 2.99 (m, 1H, p‐cym CH(CH3)2),
5.32 (d, 2H, J = 6.0 Hz, p‐cym phenyl‐H), 5.47 (s, 1H,
─CH1), 5.59 (d, 2H, J = 6.0 Hz, p‐cym phenyl‐H), 6.50 (d,
2H, J = 15.7 Hz, 2× ═CH3,3′), 7.04–7.10 (m, 4H, 2×
─ArH7,7′ and 2× ─ArH9,9′), 7.48–7.53 (m, 4H, 2× ─ArH6,6′
and 2× ─ArH10,10′), 7.58 (d, 2H, J = 15.7 Hz, 2× ═CH4,4′).
Anal. Calcd for C31H27O2F2RuCl⋅3/4CHCl3 (%): C, 54.82;
H, 4.02; N, 0. Found (%): C, 54.78; H, 4.23; N, <0.30.
SCHEME
1
Curcuminoids and corresponding Ru–arene complexes
(L7: curcumin)

LI ET AL.
3
2.3.3
|
Complex (η6‐p‐cymene)Ru(L3)Cl (3)
(s, p‐cym phenyl‐C), 97.64 (s, C1 of curc), 99.55 (s, C3’ of
curc), 101.88 (s, C3 of curc), 109.59 (s, C6,6′ of curc),
111.16 (s, C9,9′ of curc), 121.97 (s, C10,10′ of curc), 125.78
(s, C5,5′ of curc), 138.53 (s, C4,4′ of curc), 149.16 (s, C8,8′
of curc), 150.36 (s, C7,7′ of curc), 178.38 (s, C2,2′ of curc).
Anal. Calcd for C33H37O6RuCl⋅5/4CH2Cl2 (%): C, 53.26; H,
5.16; N, 0. Found (%): C, 53.43; H, 5.30; N, <0.30.
See Pettinari et al.[19]
2.3.4
|
Complex (η6‐p‐cymene)Ru(L4)Cl (41)
This complex was synthesized as for 1. Yield: 65%.
HR‐ESI‐MS (MeOH): m/z found (calcd): 571.1628
(571.1431) (100%) [(η6‐p‐cymene)Ru(L4)]+. 1H NMR
(300 MHz, CDCl3, 25 °C, δ, ppm): 1.41 (d, 6H, J = 6.9 Hz,
p‐cym CH(CH3)2), 2.36 (s, 3H, p‐cym CCH3), 3.01 (m, 1H,
p‐cym CH(CH3)2), 3.86 (s, 6H, 2× ─OCH3), 5.31 (d, 2H,
J = 6.0 Hz, p‐cym phenyl‐H), 5.45 (s, 1H, ─CH1), 5.58 (d,
2.3.7
|
Complex (η6‐p‐cymene)Ru(L7)Cl (7)
See Caruso et al.[18]
2.4 | Methods and instrumentation
2H,
J = 6.0 Hz, p‐cym phenyl‐H), 6.47 (d, 2H,
J = 15.7 Hz, 2× ═CH3,3′), 6.91 (d, 4H, J = 8.8 Hz, 2×
─ArH7,7′ and 2× ─ArH9,9′), 7.48 (d, 4H, J = 8.7 Hz, 2×
─ArH6,6′ and 2× ─ArH10,10′), 7.59 (d, 2H, J = 15.7 Hz, 2×
═CH4,4′). Anal. Calcd for C31H33O4RuCl⋅5/4CH2Cl2: C,
54.38; H, 5.02; N, 0. Found (%): C, 54.54; H, 4.93; N, <0.30.
NMR spectra were recorded with a Bruker AV‐300 spectrom-
eter at a working frequency of 300 MHz. Chemical shifts (δ)
are expressed in parts per million and coupling constants (J)
in hertz. Mass spectra for the complexes were recorded with a
Waters UPLC XEVO G2 TOF mass spectrometer using an
electrospray ionization (ESI) probe. Elemental analyses were
carried out using an Elementar Vario EL Cube.
2.3.5
|
Complex (η6‐p‐cymene)Ru(L5)Cl (5)
This complex was synthesized as for 1. Yield: 67%. HR‐ESI‐
MS (MeOH): m/z found (calcd): 571.1464 (571.1431)
(100%) [(η6‐p‐cymene)Ru(L5)]+. 1H NMR (300 MHz,
CDCl3, 25 °C, δ, ppm): 1.46 (d, 6H, J = 6.9 Hz, p‐cym
CH(CH3)2), 2.37 (s, 3H, p‐cym CCH3), 3.07 (m, 1H, p‐cym
CH(CH3)2), 3.92 (s, 6H, 2× ─OCH3), 5.31 (d, 2H,
J = 6.2 Hz, p‐cym phenyl‐H), 5.52 (s, 1H, ─CH1), 5.60 (d,
2.5 | X‐ray crystallographic determination
All reflection data were collected with a Bruker SMART CCD
instrument using graphite monochromatic Mo Kα radiation
(λ = 0.71073 Å) at room temperature. A semiempirical
absorption correction using the SADABS program was
applied, and raw data frame integration was performed with
SAINT.[22] The crystal structures were solved by the direct
method using the SHELXS‐97 program[23] and refined by
the full‐matrix least‐squares method on F2 for all non‐hydro-
gen atoms using SHELXTL‐97[24] with anisotropic thermal
parameters. All hydrogen atoms were located in calculated
positions and refined isotropically, except the hydrogen atoms
of water molecules that were fixed in a difference Fourier map
and refined isotropically. The details of the crystal data are
summarized in Table 1, and selected bond lengths and angles
for L2, L4, 1 and 4 are listed in Table 2. Crystallographic data
for the structural analysis have been deposited with the Cam-
bridge Crystallographic Data Center, with reference numbers:
1486215 (L2), 1486216 (L4), 1486213 (1) and 1486214 (4).
2H,
J = 5.9 Hz, p‐cym phenyl‐H), 6.67 (d, 2H,
J = 15.9 Hz, 2× ═CH3,3′), 6.91–6.98 (m, 4H, 2× ─ArH7,7′
and 2× ─ArH8,8′), 7.33 (m, 2H, 2× ─ArH9,9′), 7.54 (d, 2H,
J = 7.7 Hz, 2× ─ArH10,10′), 7.98 (d, 2H, J = 15.9 Hz, 2×
═CH4,4′). 13C NMR (150 MHz, CDCl3, δ, ppm): 17.72 (s,
p‐cym CCH3), 22.47 (s, p‐cym CH(CH3)2), 30.82 (s, p‐cym
CH(CH3)2), 55.56 (s, OCH3 of curc), 79.31, 83.12 (s, p‐cym
phenyl‐C), 97.29 (s, C1 of curc), 99.49 (s, C3’ of curc),
102.21 (s, C3 of curc), 111.14 (s, C7,7′ of curc), 120.72 (s,
C9,9′ of curc), 124.99 (s, C8,8′ of curc), 128.08 (s, C5,5′ of
curc), 130.34 (s, C10,10′ of curc), 133.73 (s, C4,4′ of curc),
158.01 (s, C6,6′ of curc), 178.86 (s, C2,2′ of curc).
2.3.6
|
Complex (η6‐p‐cymene)Ru(L6)Cl (6)
This complex was synthesized as for 1. Yield: 72%. HR‐ESI‐
MS (MeOH): m/z found (calcd): 631.1633 (631.1643)
(100%) [(η6‐p‐cymene)Ru(L6)]+. 1H NMR (300 MHz,
CDCl3, 25 °C, δ, ppm): 1.38 (d, 6H, J = 6.9 Hz, p‐cym
CH(CH3)2), 2.35 (s, 3H, p‐cym CCH3), 2.98 (m, 1H, p‐cym
CH(CH3)2), 3.91 (d, 12H, J = 6.8 Hz, 4× ─OCH3), 5.30
(d, 2H, J = 5.9 Hz, p‐cym phenyl‐H), 5.48 (s, 1H, ─CH1),
5.56 (d, 2H, J = 5.9 Hz, p‐cym phenyl‐H), 6.46 (d, 2H,
J = 15.6 Hz, 2× ═CH3,3′), 6.85 (d, 2H, J = 6.8 Hz, 2×
─ArH9,9′), 7.03 (s, 2H, 2× ─ArH6,6′), 7.08 (m, 2H,
J = 7.7 Hz, 2× ─ArH10,10′), 7.54 (d, 2H, J = 15.6 Hz, 2×
═CH4,4′). 13C NMR (150 MHz, CDCl3, δ, ppm): 18.11 (s,
p‐cym CCH3), 22.46 (s, p‐cym CH(CH3)2), 30.87 (s, p‐cym
CH(CH3)2), 55.90, 55.97 (s, OCH3 of curc), 79.07, 83.04
2.6 | Cell culture and assay for cell viability
HeLa (cervical carcinoma), HepG2 (liver carcinoma) and
HEK‐293 T human embryonic kidney (a model for healthy
cells) cell lines were obtained commercially. Cells were grown
in RPMI‐1640 supplemented with 10% cosmic calf serum
(Hyclone) and antibiotics in a humidified atmosphere of 5%
CO2 at 37 °C. The viability of these cells was determined using
the colorimetric Cell Titer 96 aqueous cell proliferation assay
(MTT) according to the instructions provided by the manufac-
turer (Promega, Madison, WI). Briefly, cells (1 × 104–3 × 104
cells per well) were seeded in 96‐well plates. One day after
seeding, the cells were treated with or without various concen-
trations of each compound and re‐incubated for 72 h. After the

4
LI ET AL.
TABLE 1 Crystal data and details of data collection for L2, L4, 1 and 4
3
|
RESULTS AND DISCUSSION
L2
L4
1
4
3.1 | Synthesis and characterization
Formula
Mr
C19H14F2O2 C21H20O4 C29H29ClO2Ru C31H33ClO4Ru
312.30
Monoclinic Monoclinic
P21/c C2/c
336.37
546.04
Triclinic
P‐1
606.09
Triclinic
P‐1
For the study at hand, a series of curcuminoid ligands
(L1–L6) were synthesized as reported in the literature.[20]
Curcumin (L7) was purchased commercially. Subsequently,
the corresponding half‐sandwich (η6‐p‐cymene)Ru(L)Cl
complexes (L = L1–L7) were prepared via reaction of each
of L1–L7 with [(η6‐p‐cymene)RuCl2]2 (Scheme 1). All com-
Crystal system
Space group
a (Å)
36.350(5) 11.804(3)
5.7608(14) 10.836(2)
7.4088(12) 13.835(2)
8.2192(17)
9.980(2)
16.913(3)
96.513(4)
102.675(4)
109.297(4)
1251.1(4)
2
7.6052(6)
11.1063(7)
17.0498(11)
87.248(5)
77.073(6)
78.602(6)
1375.92(16)
2
b (Å)
c (Å)
1
plexes were characterized using H/13C NMR spectroscopy,
α (°)
90.00
91.308(12) 100.440(19)
90.00 90.00
1551.0(5) 1740.3(6)
90.00
β (°)
high‐resolution (HR)‐ESI‐MS and elemental analysis. In
addition, crystal structures were obtained for compounds
L2, L4, 1 and 4.
γ (°)
V (Å3)
The X‐ray crystal structures of L2 and L4 are shown in
Figure 1, with the crystal data being presented in Table 1
and selected bond lengths and angles being presented in
Table 2. The structures of L2 and L4 are solved in the mono-
clinic space group P2/c and C2/c, respectively, and the frame-
works of both molecules are in a plane. In the structure of L2,
the distances C2─O1 and C2′─O1′ are 1.2760(39) and
1.2902(43) Å, respectively, which are shorter than C─O sin-
gle bond length (1.43 Å) but longer than double bond length
(1.23 Å); and the bond lengths of C1─C2 and C1─C2′ are
1.4015(32) and 1.3838(41) Å, respectively, between C─C
single bond length (1.54 Å) and double bond length
(1.34 Å), which indicates the enol/keto resonance forms of
L2 (Scheme 2). An intramolecular hydrogen bond between
O1 and the proton of O1′ is shown, O1⋅⋅⋅H─O1′, the length
of which is 1.7827(16) Å and the O1⋅⋅⋅H⋅⋅⋅O1′ angle is
148.4°. Interestingly, L4 shows a unique C─C (C1─C2 and
Z
4
4
Dcalcd (Mg m−3
F(000)
)
1.337
648
1.284
712
1.449
1.463
560.0
624
μ (mm−1
)
0.102
0.0684
0.088
0.0781
0.757
0.701
Rint
0.0300
0.0200
θ range (°)
6.72 to
50.04
5.62 to
50.04
4.42 to 50.04
6.1 to 52.74
Reflections
collected
7900
2694
1.082
5991
1540
1.111
17 212
4387
11 641
5636
Independent
reflections
GOF (S)
1.055
1.045
R1/wR2
[I ≥ 2σ(I)]
0.0561/
0.1364
0.1085/
0.3226
0.0239/0.0574 0.0258/0.0654
R1/wR2
(all data)
0.0928/
0.1757
0.1602/
0.3696
0.0298/0.0600 0.0292/0.0679
cells were washed with sterile phosphate buffer saline, 190 μl
of RPMI‐1640 and 10 μl of MTT dye solution (5 mg ml−1
)
were added to each well, and the cells were incubated for an
additional 4 h. The medium was discarded; 200 μl of
dimethylsulfoxide (DMSO) was added to dissolve the purple
formazan crystals formed. The absorbance at 492 nm was
measured using a Thermo Scientific Multiskan MK3.
TABLE 2 Selected bond lengths (Å) and angles (°) in L2, L4, 1 and 4
L2
L4
1
4
C2–O1
1.2760(39)
1.2902(43)
1.3223(31)
1.4607(38)
1.4015(32)
1.3838(41)
1.4672(36)
1.3171(38)
1.2966(69)
1.2966(69)
1.3300(75)
1.4326(71)
1.4020(57)
1.4020(57)
1.4326(71)
1.3300(75)
1.2815(21)
1.2748(21)
1.3158(35)
1.4637(49)
1.3900(32)
1.3923(31)
1.4717(32)
1.3221(33)
1.6460(3)
1.2790(23)
1.2759(23)
1.3129(30)
1.4682(27)
1.3920(29)
1.3914(27)
1.4657(28)
1.3186(27)
1.6514(2)
C2′–O1′
C3–C4
C3–C2
C2–C1
C1–C2′
C2′–C3′
C3′–C4′
Ru1–centroid
Ru1–Cl1
Ru1–O1
FIGURE 1 ORTEP plots of L2and L4; thermal ellipsoids are drawn at 50%
probability
2.4179(9)
2.4177(8)
2.0678(14)
2.0609(16)
88.724(60)
85.665(52)
84.168(52)
2.0745(13)
2.0579(14)
89.309(58)
85.331(45)
84.369(45)
Ru1–O1′
O1–Ru1–O1′
O1–Ru1–Cl1
O1′–Ru1–Cl1
SCHEME 2 Resonance forms of curcuminoids with O1′ protonated

LI ET AL.
5
C1─C2′) distance of 1.2966(69) Å, and the whole molecule
presents a twofold symmetry that lies on the central carbon
atom (C1), which are also described to the enol/keto reso-
nance forms of L4 (Scheme 2).
Different from free ligands, the curcuminoid ligands of 1
and 4 are twisted with torsion angles about the coordina-
tion sphere O1–Ru1–O1′–C1′ of 7.960(182)° and 8.063
(168)°, respectively, whereas the angles between the
planes of the two phenyl rings in the curcuminoid ligands
are 50.328(91)° and 6.781(76)°, respectively (see the pro-
file views of the complexes in Figure 4).
Intermolecular hydrogen bonds are also found in the crys-
tal lattices of 1 and 4. In the crystal structure of compound 1,
two molecules are interlinked to form a dimer in the unit cell,
through a pair of intermolecular hydrogen bonds between
N1─H protons and the coordinated chloride ion of another
molecule, with a distance of 2.8230(4) Å (Figure 5). Simi-
larly, in compound 4, dimers are also formed in the unit cell
via an intermolecular hydrogen bonding interaction,
N1─H⋅⋅⋅Cl, the length of the hydrogen bond being 3.0369
(2) Å (Figure 6).
Intermolecular hydrogen bonds are formed in the crystal
lattices of both L2 and L4, and the molecular topology and
the presence of hydrogen bonding centers play essential roles
in the number of such bonds per molecule. In L2, the benzene
ring (R = C5/C6/C7/C8/C9/C10) and C9′─H proton show
intramolecular CH/π interactions with the C9─H proton and
the benzene ring (R = C5′/C6′/C7′/C8′/C9′/C10′) of another
molecule, distances being 2.8589(4) and 2.8271(4) Å,
respectively (Figure 2). In addition, the intermolecular
hydrogen bond is found between C7′─H and F1′ of the
neighboring molecule (C7′─H⋅⋅⋅F1′, 2.7283(15) Å). In
crystal structure of L4, the hydrogen bonding interaction is
found between two neighboring molecules (C─H⋅⋅⋅O,
2.6136(40) Å) (Figure 3).
The X‐ray crystal structures of 1 and 4 were also deter-
mined. Both of them crystallize in the triclinic space group
P‐1. Their structures are shown in Figure 4, crystallographic
data are listed in Table 1 and selected bond lengths and angles
are presented in Table 2. In 1 and 4, Ru(II) adopts the familiar
piano‐stool geometry with the metal center being coordinated
by the p‐cymene aromatic ring, a terminal chloride and a
chelating β‐diketone curcuminoid ligand. The distances of
Ru–centroid are 1.6460(3) and 1.6514(2) Å, respectively.
The Ru─Cl bond lengths are almost equal (ca 2.418 Å)
and the Ru─O bond lengths vary over a small range
(2.0579(14)–2.0745(13) Å). All of the data are in agree-
ment with similar compounds reported elsewhere.[18,20]
3.2 | Stability studies
Since aqueous stability is important factor that affects the
bioavailability of Ru–arene complexes,[19,20] the stability of
1–7 was tested by monitoring their UV profiles. The
complexes were dissolved in DMSO and followed by water
solution, giving a final concentration of 1% (v/v) of
DMSO. The time‐dependent absorption spectra of 1–7
are presented in Figure 7. With absorption being moni-
tored for 72 h, a continued decrease is observed for the
FIGURE 2 Crystal packing of L2
FIGURE
4
Time‐dependent UV‐visible absorption spectra of 1–7
FIGURE 3 Crystal packing of L4
measured in DMSO–H2O

6
LI ET AL.
FIGURE 6 Crystal packing of 1
3.3 | Cytotoxicity
The cytotoxicity of the series of curcuminoid ligands L1–L7
and their corresponding ruthenium–arene complexes 1–7
was evaluated towards the HepG2 human liver and HeLa
human cervical cancer cell lines and HEK‐293 T human
embryonic kidney (a model for healthy cells) cell line, and
for comparison purposes the cytotoxicity of cisplatin was
evaluated under the same experimental conditions (Table 3).
Most of the curcuminoids are deemed inactive toward these
three cell lines (IC50 > 100 μM). It is worth noting that
curcumin (L7) shows moderate cytotoxicity against HepG2
with an IC50 value of 82.4 μM. Introducing methoxyl groups
at the phenolic hydroxyls (L6) or eliminating the substituent
group of the two terminal phenyls (L1) greatly contributes
to the antiproliferative activity in HepG2 cells with IC50
values of 15.3 and 12.6 μM, respectively. Most of the ruthe-
nium–arene complexes show moderate micromolar concen-
trations against cancer cell lines, with IC50 values in the
30–79 μM range for HepG2 cell line except 3 and in the
33–65 μM range for HeLa cell line. Towards HEK‐293 T
cells, comparable IC50 values are obtained (19–100 μM),
which suggests a lack of cancer cell selectivity. The
ruthenium–arene complexes containing curcuminoid ligands
have shown moderate activity towards several carcinoma cell
lines.[18] Our results show that most of the ruthenium–arene
complexes possess higher cytotoxicity in comparison to their
free ligands, indicating that the combination of ruthenium–
FIGURE 5 ORTEP plots of 1 and 4 (including front view and profile view);
thermal ellipsoids are drawn at 50% probability; hydrogen atoms have been
omitted for clarity
intensity of the absorption bands of these seven complexes
from 366 to 475 nm. This suggests the occurrence of
hydrolysis, which is essential in the biological functions
of these complexes.[13]
FIGURE 7 Crystal packing of 4

LI ET AL.
7
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