Two new coordination polymers containing dicyanidoargentate(I) and dicyanidoaurate(I): Synthesis and characterization, and a detailed in vitro investigation of their anticancer activities on some cancer cell lines

Article abstract of DOI:10.3906/kim-1412-13

Two novel cyanido-bridged bimetallic polymeric complexes, [Ni(edbea)Ag₃ (CN)₅ ]_n (C1) and [Ni(bishydeten) Au₂ (CN)₄]_n (C2), where edbea = [2,2′-(ethylenedioxy)bis(ethylamine)] and bishydeten = [(N ,N′-bis(2-hydroxyethyl) ethylenediamine)] are ligands, were synthesized and characterized by elemental, infrared, and thermal measurement techniques and investigated for their biological activity in cultured cancer cell lines. The results show that both compounds and free anions, [Ag(CN)₂]^- and [Au(CN)₂]^- , exhibited very high antiproliferative activity compared to the anticancer drug 5FU against the cancer cell lines tested. The antiproliferative and cytotoxic activities of C1 and C2 were significantly lower than those of free anions, indicating that the extreme cytotoxicity of free anions decreased to safe levels in C1 and C2. In conclusion, the results show that these novel compounds possess anticancer activities.

Full text of DOI:10.3906/kim-1412-13

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Turk J Chem
Turkish Journal of Chemistry
(2015) 39: 532 – 549
¨
http://journals.tubitak.gov.tr/chem/
˙
c
⃝ TUBITAK
doi:10.3906/kim-1412-13
Research Article
Two new coordination polymers containing dicyanidoargentate(I) and
dicyanidoaurate(I): synthesis and characterization, and a detailed in vitro
investigation of their anticancer activities on some cancer cell lines
2
1
2
Ali AYDIN1,∗, Ahmet KARADAG , S¸aban TEKIN , Nesrin KORKMAZ ,
˘
˙
2
¨
˙
Aslıhan OZDEMIR
1Department of Molecular Biology, Science and Arts Faculty, Gaziosmanpa¸sa University, Tokat, Turkey
2Department of Chemistry, Science and Arts Faculty, Gaziosmanpa¸sa University, Tokat, Turkey
Received: 06.12.2014
•
Accepted/Published Online: 16.02.2015
•
Printed: 30.06.2015
Abstract:Two novel cyanido-bridged bimetallic polymeric complexes, [Ni(edbea)Ag3 (CN)5 ]n (C1) and [Ni(bishydeten)
Au2 (CN)4 ]n (C2), where edbea = [2,2′ -(ethylenedioxy)bis(ethylamine)] and bishydeten = [(N ,N′ -bis(2-hydroxyethyl)
ethylenediamine)] are ligands, were synthesized and characterized by elemental, infrared, and thermal measurement
techniques and investigated for their biological activity in cultured cancer cell lines. The results show that both
compounds and free anions, [Ag(CN)2 ]− and [Au(CN)2 ]− , exhibited very high antiproliferative activity compared
to the anticancer drug 5FU against the cancer cell lines tested. The antiproliferative and cytotoxic activities of C1 and
C2 were significantly lower than those of free anions, indicating that the extreme cytotoxicity of free anions decreased
to safe levels in C1 and C2. In conclusion, the results show that these novel compounds possess anticancer activities.
Key words: Dicyanidoargentate(I), dicyanidoaurate(I), coordination polymers, anticancer activity, apoptosis
1. Introduction
The use of metals in medicine dates back to antiquity, with various complexes being used to treat different
ailments. Even today, metal complexes and their application in medicine have been studied extensively.1,2 The
use of metal complexes as a chemotherapeutic agent in the treatment of cancer may lead to alternatives to the
anticancer agents presently being used.3,4
From this perspective, Kelland et al.5 reported the first metal-based anticancer drug, cisplatin, which is
used in the treatment of ovarian cancer. Metal complexes such as silver, gold, and platinum are metabolized in
the body to form complexes with the amino and carboxyl groups in RNA, DNA, and proteins. For example,
the platinum center in cisplatin is known to coordinate DNA, thereby disrupting DNA replication. In recent
years, silver and gold complexes have been reported to have anticancer activity in vitro.6 Various silver and
gold compounds with interesting antitumor activity have been reported. For example, Zachariadis et al.7 found
that Ag(I) complexes of heterocyclic thioamide 2-mercapto-3,4,5,6-tetrahydropyrimidine derivatives possess
anticancer activity against certain types of cancer. El-din et al.8 reported [SnMe3 (bpe)][Ag(CN)2 ].2H2 O,
where bpe is 1,2-bis(4-pyridyl)ethane and SnMe3 is a ligand that possesses anticancer activity against human
carcinoma cells. Liu et al.9 showed that Au(I) and Ag(I) bidendate pyridyl phosphine complexes possess
∗Correspondence: aliaydin.bio@gmail.com
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AYDIN et al./Turk J Chem
anticancer activity against cisplatin-resistant human cancer cells (CH1-cisR, 41M-cisR, and SKOV-3) based on
their lipophilicity. Moreover, Au(III) compounds possess certain promising anticancer activities, as observed by
Sun et al.10
Many anticancer drugs kill normal growing cells together with cancerous cells. This damage to normal cells
causes side effects. Hence, the major drawback of using old anticancer agents is adverse effects such as nausea,
bone marrow suppression, and kidney toxicity, which are experienced by patients receiving chemotherapy.11
Another major drawback of old anticancer agents is the drug resistance that usually occurs.11 There are various
types of cancers that are inherently resistant to anticancer agents, with drugs having no effect. Therefore, there
is a need for new approaches to address these drawbacks.
Research efforts are focused on developing novel antitumor drugs to ameliorate clinical effectiveness
and to minimize general toxicity and drug resistance.12 Silver and gold complexes are found to be promising
alternatives to old anticancer agents, showing activity on tumors that have developed resistance.13 The serious
limitations of cancer treatments have prompted many researchers to develop alternative strategies based on
different metals, ligands, and mechanisms for cancer.14 Transition metal complexes of this type have not been
extensively explored for their chemotherapeutic usage.
This paper shows a new class of silver and gold complexes denoted as C1 and C2, which were tested for
their anticancer activity against rat glioma (C6), human cervical cancer (HeLa), human colon cancer (HT29),
and African green monkey kidney (Vero) cell lines. In the present study, the use of different N - and O−donor
ligands, edbea [2,2′ -(ethylenedioxy)bis(ethylamine)] and bishydeten [(N ,N′ -bis(2-hydroxyethyl) ethylenedi-
amine)], led to various types of structures and different function of the cyanido groups (e.g., terminal or bridging),
reflected by the ν (CN) stretching vibration positions in the IR spectra of C1 and C2. Dicyanidoargentate(I)
{[Ag(CN)2 ]− } and dicyanidoaurate(I) {[Au(CN)2 ]− } are linear anions with considerable stability and simplic-
ity. These were used to successfully synthesize [Ni(edbea)Ag3 (CN)5 ]n (C1) and [Ni(bishydeten)Au2 (CN)4 ]n
(C2). Free [Ag(CN)2 ]− and [Au(CN)2 ]− are known to be highly cytotoxic. The newly synthesized silver and
gold complexes containing [Ag(CN)2 ]− and [Au(CN)2 ]− have anticancer properties but low cytotoxicity.
2. Results and discussion
2.1. Results
2.1.1. Structural description
X-ray single crystal analyses of C1 and C2 could not be performed as it was not possible to obtain suitable
crystals. C1 and C2 obtained as powder crystals are well soluble in DMSO and much less soluble in
water. Recrystallization in DMSO of the complexes is not possible due to its donor character. Furthermore,
recrystallization of the complexes in different solvents was not possible. Therefore, the characterization of the
complexes was conducted using some other techniques. The molecular structures of C1 and C2 were estimated
by taking advantage of the literature15−20 related to edbea and bishydeten ligands and using elemental, IR, and
thermal measurements. The neutral ligands edbea and bishydeten were observed to act as two, three, or four
dentate in our previous studies15−20 and it is known that the ligands behave as either two or three dentate
in the polymeric structure. On the other hand, thermal analysis data provide quite remarkable results about
the structures of the complexes. For example, thermal stability can be seen as an important criterion in the
structural description. Moreover, the exchange of cyanido stretching vibration peak values and numbers are
important for the structural definition of the complexes. C1 and C2 were formulated as [Ni(edbea)Ag3 (CN)5 ]n
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AYDIN et al./Turk J Chem
and [Ni(bishydeten)Au2 (CN)4 ]n, respectively, considering the results of elemental and thermal analysis. Hereby,
the molecular structures of C1 and C2 by taking into consideration IR, elemental, thermal analysis, and
literature data might be depicted as in the Scheme.
Scheme
2.1.2. Fourier transform-infrared spectra (FT-IR)
Cyanido complexes are easily identifiable owing to sharp cyanido stretching vibration peaks at 2200–2000
cm−1
21
.
Characteristic cyanido stretching vibration peaks of C1 and C2 (peak at 2161 cm−1 and peaks
at 2194, 2173, and 2150 cm−1 , respectively) were observed at higher frequencies than those belonging to
K[Ag(CN)2 ] (2136 cm−1) and K[Au(CN)2 ] (2140 cm−1) complexes. This suggests C1 could be a complex
in which all cyanide groups behaved as a bridge because there is only one strong single cyanido peak at 2150
cm−1 . Moreover, the three cyanido peaks observed at 2194, 2173, and 2150 cm−1 for C2 indicate the presence
of both terminal and bridging cyanido groups.
Other prominent peaks in the IR spectra of C1 and C2 are the stretching vibration peaks belonging to
the NH2 , CH2 , and CO groups of neutral edbea ligand and the OH, NH2 , and CH2 groups of neutral bishydeten
ligand.15−20 Four peaks at 2906 and 2865 cm−1 with 1101 and 1031 cm−1 were attributed to –CH2 and –CO
groups, respectively, while –NH2 stretching vibrations of edbea were observed at 3342 and 3276 cm−1 . On the
other hand, the ν (OH), ν (NH), and ν (CH) vibrational frequencies of bishydeten appeared at 3446, 3255 and
3220, and 2938 and 2881 wave numbers, respectively.
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2.1.3. Thermal analyses
The thermal stability and decomposition behavior of C1 and C2 were studied by thermogravimetry-differential
thermal analysis (TG-DTA) in flowing atmosphere of N2 . The general way of the thermal decomposition of
cyanido complexes is characterized by leaving of N -donor ligands and then decomposition of all cyanido groups
in one step.22−24 Thermal decompositions of C1 and C2 are three- to four-stage processes. Moreover, DTA
curves show that the complexes have no melting points. Thermal analysis data for C1 and C2 are given in
Table 1.
Table 1. Thermoanalytical data for C1 and C2.
Temperature
range (°C)
DTGmax
(°C)
Mass loss, m (%)
Total mass loss, m (%)
Removed
group
Stage
1
Complex
Found.
8.33
Calc.
Found.
8.33
Calc.
140–338
305
22.44
22.44
edbea
C11H16N7O2Ag3Ni (C1)
MA: 660.59
2
3
1
2
3
4
338–455
455–982
221–308
308–418
418–486
486–570
397
952
263
378
452
510
14.85
19.81
16.17
10.54
4.11
23.18
42.99
16.17
26.71
30.82
33.55
19.69
33.52
42.13
33.52
5CN
C10H16N6O2NiAu2 (C2)
MA:704.90
bishydeten
4CN
2.73
The first process in the thermal decomposition of C1 is the release of edbea in the 140–338 ◦ C temperature
range with an endothermic process (found 23.18% calc. 22.44%). The observed total weight loss of 19.81%
corresponds to the liberation of all five cyanido molecules in the 455–982 ◦ C temperature range (calc. 19.69%).
The most probable thermal decomposition scheme of C1 is given below:
140−455◦C
−−−−−−−→
−edbea
445−982◦C
−−−−−−−→
−5CN
[Ni(edbea)Ag3(CN)5]
[NiAg3(CN)5]
Ni + 3Ag
In the 221–570 ◦ C temperature range, four processes are observed for C2. In the 221–570 ◦ C temperature
range, the release of bishydeten and four cyanido molecules is observed with the total weight loss of 33.55%
(calc. 33.52%). The most probable thermal decomposition scheme of C2 is given below:
221−570◦C
−bishydeten,4CN
−−−−−−−−−−−−→
[Ni(bishydeten)Au2(CN)4]
NiO + 2Au
2.1.4. Antiproliferative effect of C1, C2, [Ag(CN)2 ]− , and [Au(CN)2 ]− against HT-29, HeLa,
C6, and Vero cells
In vitro evaluation of the target coordination polymers (C1 and C2) and linear ions {[Ag(CN)2 ]− and
[Au(CN)2 ]− } for their cytotoxic properties was performed by means of BrdU cell proliferation ELISA assays
against three cancer cell lines and one noncancerous cell line for the first time. In contrast to the control
compound, 5FU, each coordination polymer significantly inhibited proliferation of HeLa (P < 0.05), C6 (P <
0.05), HT-29 (P < 0.05), and Vero (P < 0.05) cells (Figure 1).
It was seen that C2 coordination polymer was five-fold more active than C1 coordination polymer. As
shown in Figure 1, each coordination polymer was significantly more antiproliferative against Hela, HT29, and
C6 tumor cell lines with lower IC50 concentrations (P < 0.05) than the control anticancer drug 5FU. Among
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