Synthesis, characterization and cytotoxicity of the Au(III) complexes with cyclic amine-based dithiocarbamate ligands

Article abstract of DOI:10.1016/j.inoche.2013.02.010

Seven new Au(III) complexes ([(PipDTC)AuCl₂] (1), [(MoDTC)AuCl₂] (2), [(BzoPizDTC)AuCl₂] (3), [(TsPizDTC)AuCl₂] (4), [(PizDTC)Au₂Cl₄] (5), [(MePizDTC)Au₂Cl₅] (6) and [(EtPizDTC)Au ₂Cl₅] (7)) with cyclic amine-based dithiocarbamate have been synthesized, characterized and evaluated in vitro. The results indicate that these complexes exert selective cytotoxic effects against HL-60, BGC-823, Bel-7402 and KB cells lines. Complex 1 shows 11-, 5- and 1-folds higher cytotoxicity than cisplatin against KB, BGC-823 and Bel-7402 cell lines. Complex 2 exhibits higher cytotoxicity than cisplatin against BGC-823 and Bel-7402 cell lines. Complexes 3 and 4 display higher cytotoxicity than cisplatin against BGC-823 cell line. The nature of cyclic amine and the number of metal centers have important effects on cytotoxicity of these Au(III) complexes.

Full text of DOI:10.1016/j.inoche.2013.02.010

Inorganic Chemistry Communications 30 (2013) 178–181
Contents lists available at SciVerse ScienceDirect
Inorganic Chemistry Communications
journal homepage: www.elsevier.com/locate/inoche
Synthesis, characterization and cytotoxicity of the Au(III) complexes with cyclic
amine-based dithiocarbamate ligands
a
Yanan Shi a, Wenhao Chu a, Yuechai Wang a, Shuxiang Wang a,b, , Jianlong Du , Jinchao Zhang
⁎
a,b,⁎⁎
,
Shenghui Li a, Guoqiang Zhou a, Xinying Qin a, Chenliang Zhang a
a
Key Laboratory of Chemical Biology of Hebei province, College of Chemistry and Environmental Science, Hebei University, Baoding 071002, China
b
Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding 071002, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Seven new Au(III) complexes ([(PipDTC)AuCl2] (1), [(MoDTC)AuCl2] (2), [(BzoPizDTC)AuCl2] (3), [(TsPizDTC)
AuCl2] (4), [(PizDTC)Au2Cl4] (5), [(MePizDTC)Au2Cl5] (6) and [(EtPizDTC)Au2Cl5] (7)) with cyclic amine-based
dithiocarbamate have been synthesized, characterized and evaluated in vitro. The results indicate that these com-
plexes exert selective cytotoxic effects against HL-60, BGC-823, Bel-7402 and KB cells lines. Complex 1 shows 11-,
5- and 1-folds higher cytotoxicity than cisplatin against KB, BGC-823 and Bel-7402 cell lines. Complex 2 exhibits
higher cytotoxicity than cisplatin against BGC-823 and Bel-7402 cell lines. Complexes 3 and 4 display higher cy-
totoxicity than cisplatin against BGC-823 cell line. The nature of cyclic amine and the number of metal centers
have important effects on cytotoxicity of these Au(III) complexes.
Received 20 December 2012
Accepted 7 February 2013
Available online 14 February 2013
Keywords:
Au(III) complexes
Cyclic amine-based dithiocarbamate
Cytotoxicity
© 2013 Elsevier B.V. All rights reserved.
Nowadays, cisplatin and the follow-on drugs (carboplatin and
oxaliplatin) are widely used to treat cancers, such as testicular cancer,
ovarian cancer, esophageal cancer, bladder cancer, head and neck
cancers, and small-cell lung carcinomas [1]. However, the effective-
ness of cisplatin in the treatment cancer diseases is severely hindered
by the frequent occurrence of initial and acquired drug resistance
[2–5], and detrimental side effects, including nephrotoxicity, peripheral
neuropathy, and ototoxicity [6,7]. Thus, it is critical to design other
metal-based chemotherapeutic compounds to overcome tumor resis-
tance to cisplatin.
During the last few years, there has been a renewed interest in the
application of Au(III) compounds in cancer chemotherapy [8,9]. At-
tention was directed towards Au(III) compounds for two reasons:
(1) Au(III) center is isoelectronic to Pt(II) compounds and adopt
square-planar configuration; (2) Au(III) compounds have displayed
strong tumor cell growth inhibition effects by a non-cisplatin-like
mode of action. However, the high redox potential and poor stability
of Au(III) compounds make their use rather problematic under phys-
iological conditions. In recent years, by implementation of appropri-
ate ligand selection strategies, a number of Au(III) compounds have
been obtained, exhibiting sufficient stability under physiological-like
conditions and manifesting cytotoxic properties towards several tumor
cell lines [10,11]. The main types of Au(III) complexes endowed with
improving stability and encouraging pharmacological properties are
summarized as follows: coordination compounds with N-polydentate
[12,13], macrocyclic ligands [14], chelating phosphines [15,16], and
organometallic compounds with an Au–C bound or CNC-pincer back-
bone [17,18].
There has been a continuous interest in the synthesis of more potent
Au(III) complexes containing S- and N-donor ligands that should have
higher cytotoxic activity with minimum or no side effects compared
to cisplatin [19]. In former work, we reported the synthesis and cyto-
toxicity of new Au(III) complexes with 5-aryl-3-(pyridin-2-yl)-4,5-
dihydropyrazole-1-carbothioamide derivatives, which showed higher
cytotoxicity than cisplatin against HeLa cell [20]. It was also reported
that Au(III)-dithiocarbamato complexes displayed antitumor proper-
ties and no nephrotoxic side-effects [21]. Fregona and co-workers
reported Au(III) complexes [Au(DMDT)X2] and [Au(ESDT)X2], which
exhibited much more cytotoxic in vitro than cisplatin, with 1- to
4-folds higher cytotoxicity than reference drug, even toward human
tumor cell lines intrinsically resistant to cisplatin itself [21–25]. Cyclic
amine (such as piperidine, morpholine or piperazine) was able to select
for improving activity in drug design [26]. In order to further explore the
structure–activity relationships and discover new metal-based antican-
cer drugs, the synthesis, characterization and cytotoxicity of seven new
Au(III) complexes with cyclic amine-based dithiocarbamate ligands are
described in this paper.
⁎
Correspondence to: S. Wang, Key Laboratory of Chemical Biology of Hebei province,
College of Chemistry and Environmental Science, Hebei University, Baoding 071002,
China. Tel./fax: +86 312 507 9359.
⁎⁎ Correspondence to: J. Zhang, Key Laboratory of Chemical Biology of Hebei province,
College of Chemistry and Environmental Science, Hebei University, Baoding 071002,
China. Tel./fax: +86 312 507 9005.
The ligands L1–L7 were prepared through reaction of the corre-
sponding cyclic amine with CS2 in a basic medium (NaOH), following
the method as described in literature [27]. Au(III) complexes:
[(PipDTC)AuCl2] (1), [(MoDTC)AuCl2] (2), [(BzoPizDTC)AuCl2] (3),
E-mail addresses: wsx@hbu.cn (S. Wang), jczhang6970@yahoo.com.cn (J. Zhang).
1387-7003/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.inoche.2013.02.010

Y. Shi et al. / Inorganic Chemistry Communications 30 (2013) 178–181
179
[(TsPizDTC)AuCl2] (4), [(PizDTC)Au2Cl4] (5), [(MePizDTC)Au2Cl5] (6)
and [(EtPizDTC)Au2Cl5] (7) have been prepared as described in the
experimental section (as shown in Scheme 1). Treatment of the
cyclic-amine-based (such as piperidine, morpholine, N-benzoyl pipera-
zine or N-(p-toluenesulfonyl)piperazine) dithiocarbamate ligands
(L1–L4) with K[AuCl4]·H2O afford complexes (1–4) in 65–70% yields
(Scheme 1, Route 1). Reaction of piperazine bis-dithiocarbamate (L5)
with K[AuCl4]·H2O affords complex 5 in ~70% yield (Scheme 1,
Route 2). Using N-alkyl piperazine dithiocarbamates (L6 or L7) as li-
gands afford complexes (6, 7) in 51–56% yields (Scheme 1, Route 3).
Complexes 1–4 are mononuclear complexes, whereas complexes 5–7
are binuclear complexes [28].
Fig. 1. Molecular structure for the complex 1.
The mode of coordination of complex 1 was confirmed by X-ray dif-
fraction. The crystal was obtained by recrystallization complex 1 in ace-
tonitrile and evaporating the solvent supernatant for a few weeks.
Complex 1 crystallized in a monoclinic unit cell, space group P212121
(as shown in Fig. 1). Crystallographic data [29], selected bond lengths
and angles for complex 1 are shown in Tables 1 and 2. The crystal
data reveal that the dithiocarbamate ligands take place through the
two sulfur atoms in an approximately square-planar geometry around
the gold atom, while the other two coordination positions are occupied
by the chlorine atoms, the -NCSS moiety acting as a symmetrical
bidentate chelating group. The angle between planar S(1)–Au(1)–S(2)
and planar Cl(1)–Au(1)–Cl(2) is 0.879(132)°, which indicates that
the Au(1)–Cl(1)–Cl(2)–N(1)–N(2) plane is slightly distorted. The two
Au–S bond lengths are 2.2821(19) and 2.290(3)Å. And, it is in good ar-
rangement with the structure of [Au(MSDT)Br2] obtained from GGA
calculation reported by Fregona [22].
compounds. The presence of the band in 1425–1456 cm−1 region is
due to the v(N-CSS). The bands present in the 1026–1087 cm−1 region
are attributed to v(C–S) vibration. The bands in the 391–420 cm−1 re-
gion are associated with v(Au–S) vibration [32,33]. In addition, the
most important change is that the peak of ligands due to the v(N-CSS)
vibration are shifted to higher frequency by about 20–25 cm−1 after
coordination with Au(III) atom [34].
In comparison the 1H NMR of the Au(III) complexes with those of
free ligands, the δ of \CH2NCS2 shifts 0.3–0.5 ppm to the down field.
For example, the proton signal at 3.55 ppm attributed to \CH2NCS2
(2H) of L1 shift 0.37 ppm in complex 1. This down field shift is caused
by the lower electron density existing on theses protons in the com-
plexes, in which the -NCSS moiety is neutral than in the free ligands,
in which such a dithiocarbamic group is anionic.
13C NMR of complexes 1–7 are recorded in DMSO-d6, the δ of
-NCS2 carbon of all the complexes shifts 5–10 ppm to the down
field in comparison to free ligands. This result is consistent with
Fregona reported [35].
Complexes 1–7 are evaluated for their cytotoxic potency against
four cell lines carried out by MTT assay [36], and the IC50 values are
listed in Table 3. It can be seen that complexes 1–7 exert cytotoxic
effect and selectivity against HL-60, BGC-823, Bel-7402 and KB cells
lines. Complex 1 exhibits 11-, 5- and 1-folds higher cytotoxicity
than cisplatin against KB, BGC-823 and Bel-7402 cell lines. Complex 2
shows higher cytotoxicity than cisplatin against BGC-823 and
Bel-7402 cell lines. Complexes 1 and 2 display similar cytotoxicity to cis-
platin against HL-60 cell line. Complexes 3 and 4 display higher cytotox-
icity than cisplatin against BGC-823 cell line. In general, Complexes 1–4
The elemental analysis data of 1–7 are in good agreement with the
calculated values. All the complexes 1–7 are nonelectrolytes, as their
molar conductance values (Λm) recorded in acetonitrile at 25.0 °C are
in the range of 18.6–30.3 S m2 mol−1 [30].
Optical electronic absorption spectra in acetonitrile generally show a
similar pattern for all these complexes. Band I (226–228 nm) assign
⁎
to an intraligand π→π transition located in the -NCSS moiety or
intraligand d→p transition between levels originated by sulfur
atoms. Bands II (266–275 nm) and Bands III (315–322 nm) show
⁎
and correspond to π→π intraligand transitions mainly located in
the -NCS and -CSS moieties, respectively [31].
Three regions in the IR spectrum of 1–7 are valuable in arguments
concerning the electronic and structural characteristics of these
Route 1 For mononuclear Au(III) complexes with cyclicamine-based dithiocarbamate
SNa
Cl
S
S
20 oC
X
N
KCl
+
+
NaCl
K[AuCl4]
+
Au
X
N
S
Cl
X = CH2 , O, N-COPh, N-SO2PhCH3
X = CH2, O, N-COPh, N-SO2PhCH3
L1 L2 L3 L4
1
2
3
4
Route 2 For Au(III) complexes with piperazine bis-dithiocarbamate
SNa
S
Cl
Cl
S
S
Cl
S
20 o
C
2K[AuCl4] +
N
N
Au
Au
+
2KCl+2NaCl
N
N
Cl
S
S
NaS
5
L5
Route 3 For Au(III) complexes with N-alkyl piperazine dithiocarbamate
Scheme 1. The synthetic routines of the complexes 1–7.

180
Y. Shi et al. / Inorganic Chemistry Communications 30 (2013) 178–181
Table 1
Table 3
Selected bond lengths and angles for complex 1.
The cytotoxicity of the complexes 1–7 against HL-60, BGC-823, KB and Bel-7402 cell
lines.
Length/Å or angle/°
Complexes
IC50 (μM)
Au(1)–S(2)
Au(1)–S(1)
2.2821 (19)
2.290 (3)
HL-60
BGC-823
KB
0.64 0.12
Bel-7402
Au(1)–Cl(1)
Au(1)–Cl(2)
2.299 (3)
2.309 (3)
75.58 (7)
171.01 (13)
95.45 (13)
94.39 (10)
169.96 (10)
94.57 (15)
1
2
3
4
5
6
7
2.88 0.22
2.85 0.19
3.60 0.35
12.89 1.52
18.60 1.27
17.90 1.42
28.28 1.45
2.89 0.34
1.05 0.26
3.22 0.25
3.35 0.29
5.86 0.48
22.91 1.68
14.25 1.17
26.91 0.64
6.48 0.81
1.18 0.16
1.67 0.35
9.46 0.24
5.56 0.48
4.93 0.50
12.85 0.75
22.19 1.42
2.65 0.33
8.52 0.46
11.85 0.85
17.01 1.25
15.24 0.46
55.65 1.85
59.74 1.88
8.12 0.97
S(2)–Au(1)–S(1)
S(2)–Au(1)–Cl(1)
S(1)–Au(1)–Cl(1)
S(2)–Au(1)–Cl(2)
S(1)–Au(1)–Cl(2)
Cl(1)–Au(1)–Cl(2)
Cisplatin [37]
show better cytotoxicity than cisplatin against BGC-823 cell line. It indi-
cates that complexes 1–4 maybe exhibit selectivity cytotoxicity against
BGC-823 cell line.
BzoPizDTC benzoylpiperazinedithiocarbamate
TsPizDTC tosyl piperazinedithiocarbamate
PizDTC piperazinedithiocarbamate
The structure–activity relationships are summarized as follows:
(1) The number of metal centers affects on cytotoxicity. In general,
mononuclear complexes 1–4 show higher cytotoxicity than binuclear
complexes 5–7. (2) The characteristic of cyclic amine has an impor-
tant effect on cytotoxicity. For example, the cytotoxicity of 1–4
against HL-60, BGC-823 and KB cell lines decreases in the sequence:
piperidine≥morpholine>N-benzoyl piperazine>N-(p-toluenesulfonyl)
piperazine. The cytotoxicity of 1–3 against Bel-7402 cell line decreases
in the sequence: piperidine>morpholine>N-benzoyl piperazine. It indi-
cates that the steric hindrance has an important effect on the cytotoxicity,
and the cytotoxicity decreases with increasing of the steric hindrance. In
summary, when the cyclic amine is piperidine or morpholine, Au(III)
complexes have better cytotoxicity.
MePizDTC N-methylpiperazinedithiocarbamate
EtPizDTC N-ethylpiperazinedithiocarbamate
DMDT
ESDT
GGA
N,N-dimethyldithiocarbamate
ethylsarcosinedithiocarbamate
generalized gradient approximation
MTT
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide
IC50
OD
half maximal (50%) inhibitory concentration (IC) of a
substance
optical density
Acknowledgments
Seven new potential anticancer Au(III) complexes with cyclic
amine-based dithiocarbamate ligands were synthesized and elucidat-
ed on the basis of elemental analysis, IR, UV, and NMR, conductivity
measurements and X-ray diffraction. The cytotoxicity results show
that the Au(III) complexes with cyclic amine-based dithiocarbamate
exert selective cytotoxicity against the tested cell lines. The nature
of cyclic amine and the number of metal centers have important
effects on cytotoxicity of the complexes. This study indicates that
Au(III) complexes with dithiocarbamate derivative might be a prom-
ising source of metal-based antitumor agent.
This work was supported by Natural Science Foundation of Hebei
Province (No. B2011201135), the Nature Science Foundation for Distin-
guished Young Scholars of Hebei Province (No. B2011201164), the Key
Basic Research Special Foundation of Science Technology Ministry of
Hebei Province (Grant Nos. 11966412D, 12966418D), the Key Research
Project Foundation of Department of Education of Hebei Province
(No. ZH2012041), the Pharmaceutical Joint Research Foundation of
the Natural Science Foundation of Hebei Province and China Shiyao
Pharmaceutical Group Co., Ltd (B2011201174), and the Science and
Technology Support Project of Hebei Province (No. 11276431).
Abbreviations
PipDTC piperidindithiocarbamate
MoDTC morfolindithiocarbamate
Appendix A. Supplementary data
Supplementary data to this article can be found online at http://
dx.doi.org/10.1016/j.inoche.2013.02.010.
Table 2
Crystallographic data for complex 1.
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C6H10AuCl2NS2
Fw
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a (Å)
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[27] C. Bolzati, M. Cavazza-Ceccato, S. Agostini, F. Refosco, Y. Yamamichi, S. Tokunaga,
D. Carta, N. Salvarese, D. Bernardini, G. Bandoli, Bioconjugate Chem. 21 (2010)
928–939.
[28] General Procedure for the synthesis of 1–7: Complexes were prepared by reaction
K[AuCl4]·H2O and L1–L7 (1:1) or (2:1) in aqueous solution. After further 2 h at
room temperature, the resulting yellow precipitate was filtered. The collected
solid was washed with cold CH3CN (3×1 mL) and dried to give 1. Complex 1:
Yellow solid, yield: 66.7% IR (KBr, cm−1): v(N-CSS) 1430, ν(S–C–S) 1026, ν(S–Au–S)
408; UV (acetonitrile, nm): 228 (-NCSS), 275 (-NCS), 318 (-CSS); 1H NMR
(600 MHz, DMSO-d6) δ 3.82 (m, 4H, CH2), 1.72 (m, 6H, CH2); 13C NMR (150 MHz,
DMSO-d6) δ 23.9, 25.4, 51.2, 192.3; Anal. Calc. for C6H10NS2AuCl2: C, 16.83; H,
2.35; N, 3.27. Found: C, 16.93; H, 2.16; N, 3.10; Λm (CH3CN)=18.6 S m2 mol−1
.
Complex 2: Yellow solid, yield: 65.2%; IR (KBr, cm−1): v(N-CSS) 1444, ν(S–C–S)
1072, ν(S–Au–S) 416; UV: (acetonitrile, nm) 226 (-NCSS), 273 (-NCS), 317 (-CSS);
1H NMR (600 MHz, DMSO-d6) δ 3.90 (q, 4H, CH2), 3.81 (m, 4H, CH2); 1C NMR
(150 MHz, DMSO-d6) δ 50.1, 65.3, 197.4; Anal. Calc. for C5H8NOS2AuCl2: C, 13.96;
[35] L. Ronconi, C. Maccato, D. Barreca, R. Saini, M. Zancato, D. Fregona, Polyhedron 24
(2005) 521–531.
[36] Four human carcinoma cell lines were used for cytotoxicity determination:
HL-60, BGC-823, KB and Bel-7402 cell lines. The cells harvested from exponential
phase were seeded equivalently into a 96-well plate, and then the complexes
were added to the wells to achieve final concentrations. Control wells were pre-
pared by addition of culture medium. Wells containing culture medium without
cells were used as blanks. All experiments were performed in quintuplicate.
The MTT assay was performed as described by Mosmann [30]. Upon completion
of the incubation for 44 h, stock MTT dye solution (20 mL, 5 mg/mL) was
added to each well. After 4 h incubation, 2-propanol (100 mL) was added to sol-
ubilize the MTT formazan. The OD of each well was measured on a microplate
spectrophotometer at a wavelength of 570 nm. The IC50 value was determined
from plot of % viability against dose of compounds added.
H, 1.87; N, 3.26. Found: C, 14.04; H, 1.81; N, 3.14; Λm(CH3CN)=24.0 S m2 mol−1
.
Complex 3: Yellow solid, yield: 68.7%; IR (KBr, cm−1): v(N-CSS) 1425, ν(S–C–S)
1083, ν(S–Au–S) 391; UV: (acetonitrile, nm) 227 (-NCSS), 271 (-NCS), 315 (-CSS);
1H NMR (600 MHz, DMSO-d6) δ 7.51 (m, 5H, ph), 3.88 (m, 4H, CH2), 3.68 (m, 4H,
CH2); 1C NMR (150 MHz, DMSO-d6) δ 46.0, 49.6,127.6, 129.0, 130.5, 135.4, 169.8,
194.7; Anal. Calc. for C12H13N2OS2Au2Cl2: C, 27.03; H, 2.46; N, 5.25. Found: C,
27.04; H, 2.88; N, 5.14; Λm(CH3CN)=23.2 S m2 mol−1. Complex 4: Yellow solid,
yield: 69.2%; IR (KBr, cm−1): v(N-CSS) 1436, ν(S–C–S) 1080, ν(S–Au–S) 399; UV:
(acetonitrile, nm) 228 (-NCSS), 274 (-NCS), 315 (-CSS); 1H NMR (600 MHz,
DMSO-d6) δ 7.78 (d, 2H, ph), 7.35 (d, 2H, ph), 3.81(m, 4H, CH2), 3.75 (m, 4H, CH2),
2.36 (s, 3H, CH3); 13C NMR (150 MHz, DMSO-d6) δ 22.8, 48.5, 52.1, 128.3, 129.3,
137.6, 143,3, 198.8; Anal. Calc. for C12H15N2O2S3AuCl2: C, 24.71; H, 2.59; N, 4.80.
Found: C, 24.45; H, 2.36; N, 4.54; Λm(CH3CN)=26.7 S m2 mol−1. Complex 5:
Yellow solid, yield: 70.1%. IR (KBr, cm−1): v(N-CSS) 1426, ν(S–C–S) 1078,
[37] J.C. Zhang, L.W. Li, L.W. Wang, F.F. Zhang, X.L. Li, Eur. J. Med. Chem. 45 (2010)
5337–5344.