Synthesis, characterization, and anticancer activity of dithiocarbamate ruthenium(II) complexes

Article abstract of DOI:10.1080/10426507.2017.1359594

Twelve arene and cyclopentadienyl ruthenium(II) dithiocarbamate complexes have been prepared and characterized by spectroscopicmethods. The structures of 3a and 3c have been determined by X-ray crystallography. Their in vitro antitumor activitieswere eval

Full text of DOI:10.1080/10426507.2017.1359594

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Synthesis, Characterization, and Anticancer
Activity of Dithiocarbamate Ruthenium(II)
complexes
Ye-Hong Dou, Shou-De Xu, Yi Chen & Xiang-Hua Wu
To cite this article: Ye-Hong Dou, Shou-De Xu, Yi Chen & Xiang-Hua Wu (2017): Synthesis,
Characterization, and Anticancer Activity of Dithiocarbamate Ruthenium(II) complexes,
Phosphorus, Sulfur, and Silicon and the Related Elements, DOI: 10.1080/10426507.2017.1359594
To link to this article: http://dx.doi.org/10.1080/10426507.2017.1359594
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Synthesis, Characterization, and Anticancer Activity of Dithiocarbamate Ruthenium(II)
complexes
Ye-Hong Dou, Shou-De Xu, Yi Chen, Xiang-Hua Wu*
College of Chemistry and Chemical Enginering, Yunnan Normal University, Kunming 650500,
P.R. China
*Corresponding Author, Email: chxhwu@sina.com
Abstract
Twelve arene and cyclopentadienyl ruthenium(II) dithiocarbamate complexes have been
prepared and characterized by spectroscopic methods. The structures of 3a and 3c have been
determined by X-ray crystallography. Their in vitro antitumor activities were evaluated by MTT
method against four tumor cells (SKOV-3, HepG-2, A549, as well as PC12) and two murine
cells (RAW246.7 and L6). Notably, the results in vitro indicated that the arene ruthenium(II)
complex 3e (N-methyl piperazine) displayed the highest activity and selectivity towards cancer
HepG-2 cells.
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Keywords
p-arene; Cyclopentadienyl; Ruthenium(II) complexes; Dithiocarbamates; Cytotoxic activity
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Introduction
Following the major clinical successes achieved with cisplatin toward a variety of cancers, the
search for other metal compounds with improved therapeutic properties has been extremely
active because some major drawbacks exist in the application of this drug.1,2 Therefore, a large
number of new and alternative metal complexes with considerable cytotoxic properties were
disclosed.3-8 In particular, ruthenium complexes have received increased attention in recent years
as potential anticancer agents, such as KP46, KP1019, NAMI-A which entered clinical trials
with promising results.9-12
In recent years, applications of ruthenium(II)-arene complexes in biology have received
increasing attention because of the lower toxicity, high selectivity and the potential synergism
that could be achieved by combining a metal ion and a bioactive ligand.13--20 Dithiocarbamates
are highly versatile ligands toward main group metals and their strong metal binding properties
are directly related to the possession of two donor sulfur atoms. Their derivatives are used
extensively as active antitumor, antibacterial and antifungal agents.21-33
It has been noted that tethering of biologically active ligands to the metal ion increases the
biological potency of the complexes, through a combination of increased solubility, altered
mechanisms of action, increased uptake, and improved cancer targeting properties.19,31-33 In this
paper, the biologically active groups dithiocarbamate are tethered to the arene and
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cyclopentadienyl ruthenium(II) units. In vitro anticancer activity of these complexes against
human cancer cell lines was described.
Results and discussion
The synthesis of ruthenium(II) complexes with dithiocarbamate was shown in Figure 1. The
formation of the target arene ruthenium(II) dithiocarbamate complexes 3a-3d was achieved by
reacting salts 2a-2d and arene ruthenium(II) 1 in acetone in good yields. The cyclopentadienyl
ruthenium(II) dithiocarbamate complexes were prepared according to literature methods. 34 The
structures of all the target compounds were characterized by NMR and EI-MS spectroscopy,
which are given in Supporting information. The multiplet observed in the region around δ
5.22--5.50 ppm in all the listed complexes have been assigned to the aromatic protons of the
phenyl group of p-cymene. The two isopropyl methyl protons of the p-cymene appeared as
doublet in the region of δ 1.23--1.30 ppm and the methine protons comes in the region of δ
2.85--2.87 ppm as a multiplet. Further, the methyl group of the p-cymene comes as singlet
around the region of δ 2.20--2.28 ppm. The five protons of the Cp-ring appeared as singlet in the
region of δ4.35--4.39 ppm. In addition, the crystal structures of 3a and 3c were determined by
X-ray diffraction analyses.
X-Ray Diffraction Studies
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Single crystals of complexes 3a and 3c suitable for X-ray analysis were obtained by slow
diffusion of hexane into solutions in CH2Cl2. The single-crystal X-ray structures of complexes 3a
and 3c are shown in Figures 2 and 3, respectively. The crystallographic details and selected bond
distances and angles are presented in Tables S 1 and S 2, respectively, which are given in
Supplemental Materials. The Ru-Cl bond distances are within the range of those reported for
other p-cymene Ru(II) complexes.34-40 The S1-Ru-S2 bond angles are 72.09(6) (3a) and
71.92(7)° (3c), which are smaller than those of N-Ru-S,39 N-Ru-C,40 and N-Ru-N.36
Biological evaluations
The in vitro anti-proliferative activity of complexes 3a-3d and 5a-5d was evaluated against
four human cancers (human ovarian cancer SKOV-3 cell line, human hepatoma carcinoma
HepG-2 cell line, the rat pheochromocytoma PC12 cell line, and human lung cancer A549 cell
line) and two murine cell lines (RAW246.7 and L6) by using the classical MTT assay. Cisplatin
(CDDP) was used as the reference drug. IC50 values of complexes 3a-3d and 5a-5d are listed in
Table S 3 (Supplemental Materials). Among the arene ruthenium(II) series, the complexes were
markedly less effective in SKOV-3, P12 and A549 cells in comparison to cisplatin, as shown in
Table S 3. However, only the complex 3e (N-methyl piperazine) is strongly cytotoxic against
HepG-2 cell line with the lowest IC50 of 7.7 µM, which is more cytotoxic than cisplatin (9.83
µM). Moreover, the IC50 values of 3e in the murine RAW246.7 and L6 cell lines are about 6 and
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8.3-fold higher than those of cisplatin, respectively. Importantly, it is found that the selectivity of
complex 3e is superior to that of cisplatin.
Compared to the arene ruthenium(II) series, when the dithiocarbamate moiety was introduced
into cyclopentadienyl ruthenium(II), the antitumor activities of the resulted complexes 5a-5f
were reduced significantly. Only complexes 5a (N,N-diethyl amine) and 5b (pyrrolidine) showed
high cytotoxic activity against SKOV-3 cells as compared to other cell lines, with IC50 values of
6.8 and 8.7 µM, respectively. In addition, the selectivity of complexes 5a and 5b is inferior to
that of 3e. Overall, complex 3e (N-methyl piperazine) is the most cytotoxic towards four tested
cancer cell lines and is also the most selective compound towards cancer cells.
Conclusions
In conclusion, twelve arene and cyclopentadienyl ruthenium(II) complexes bearing the
dithiocarbamate unit were synthesized and characterized. Based on the result of MTT assay, the
arene ruthenium(II) complex 3e substituted by N-methyl piperazine displayed the highest
activity and selectivity towards cancer HepG-2 cells. Notably, this study was initiated in the
frame of ongoing studies aimed at developing new organometallic ruthenium compounds as
potential anticancer agents.
Experimental
General Procedures
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All manipulations were carried out at room temperature under a nitrogen atmosphere using
standard Schlenk techniques, unless otherwise stated. All reagents were purchased from
commercial sources and were used without further purification. 1H, 13C, and 31P NMR spectra
were collected on a Bruker 500 MHz magnetic resonance spectrometer. 1H and 13C NMR
chemical shifts are relative to TMS, and 31P NMR chemical shifts are relative to 85% H3PO4.
Mass spectrometry was recorded with a Bruker (micrOTOF II). [Ru(η6-p-cymene)Cl2]2 was
purchased from Alfa Aesar. Others reagents were commercially sourced and used as received
unless mentioned otherwise. The starting materials dithiocarbamates and Ru(η-C5H5)Cl(PPh3)2
were prepared by the reported in literature method.41,42
General synthesis of complexes 3a-3f
[Ru(η6-p-cymene)-Cl2]2 (0.18 g, 0.3 mmol) and sodium dithiocarbamates (2a-2f) (0.6 mmol)
were dissolved in acetone (30 mL). Then the resulting solution was refluxed for 6 h and the
progress of the reaction was monitored by TLC. The solid product was filtered, and the filtrate
was removed under reduced pressure. The residues were purified by neutral alumina column
chromatography (eluent: CH2Cl2/CH3OH, 50:1, V/V) to offer complexes 3a-3f.
3a: orange red solid, 0.103 g (Yield: 82%). 1H NMR (500 MHz, CDCl3) δ 5.46 (d, J = 5.9 Hz,
2H, -PhH), 5.27 (d, J = 5.9 Hz, 2H, -PhH), 3.68 (dq, J = 14.3, 7.2 Hz, 2H, -NCH2-), 3.51 (dq, J =
14.3, 7.2 Hz, 2H, -NCH2-), 2.85 (m, 1H, -CHCH3CH3), 2.26 (s, 3H, -PhCH3), 1.28 (d, J = 6.9
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Hz, 6H, -CHCH3CH3), 1.21 (t, J = 7.2 Hz, 6H, -CH2CH3, -CH2CH3). 13C NMR (125 MHz,
CDCl3) δ 128.9 (NCS), 126.2, 102.5, 99.2, 83.5, 82.6, 77.2, 76.7, 43.7, 31.6, 24.0, 22.6, 19.0,
12.3. ESI-MS(+): m/z found 384.0369 [M−Cl]+, calcd for C15H24ClNRuS2 419.0082.
3b: red solid, 0.109 g (Yield: 87%).1H NMR (500 MHz, CDCl3) δ 5.48 (d, J = 5.8 Hz, 2H,
-PhH), 5.28 (t, J = 11.6 Hz, 2H, -PhH), 3.58 (dd, J = 10.4, 6.4 Hz, 4H, -NCH2-, -NCH2-), 2.87
(m, 1H, -CHCH3CH3), 2.28 (s, 3H, -PhCH3), 2.02--1.89 (m, 4H, -CH2CH2-, -CH2CH2-), 1.28 (t,
J = 11.8 Hz, 6H, -CHCH3CH3). 13C NMR (125 MHz, CDCl3) δ 129.0 (NCS), 126.3, 103.1, 98.4,
83.5, 82.2, 77.2, 76.7, 48.8, 31.5, 24.6, 22.7, 19.1. ESI-MS(+): m/z found 382.0220 [M−Cl]+,
calcd for C15H22ClNRuS2 416.9926.
3c: orange red solid, 0.099 g (Yield: 76%). 1H NMR (500 MHz, CDCl3) δ 5.42 (d, J = 5.9 Hz,
2H, -PhH), 5.22 (t, J = 4.8 Hz, 2H, -PhH), 3.75 (ddd, J = 14.4, 7.4, 3.2 Hz, 2H, -OCH2-), 3.66
(td, J = 7.7, 2.9 Hz, 4H, -NCH2-), 3.62-3.56 (m, 2H, -OCH2-), 2.78 (m, 1H, -CHCH3CH3), 2.20
(s, 3H, -PhCH3), 1.23 (d, J = 6.9 Hz, 6H, -CHCH3CH3). 13C NMR (125 MHz, CDCl3) δ 129.0
(NCS), 126.3, 103.4, 99.0, 83.8, 82.6, 77.3, 76.8, 65.8, 46.3, 31.7, 24.1, 22.8, 21.0, 19.2.
ESI-MS(+): m/z found 398.0175 [M−Cl]+, calcd for C15H22ClNRuS2 432.9875.
3d: red solid, 0.100 g (Yield: 77%). 1H NMR (500 MHz, CDCl3) δ 5.46 (d, J = 5.9 Hz, 2H,
-PhH), 5.27 (d, J = 5.9 Hz, 2H, -PhH), 3.94--3.86 (m, 2H, -NCH2-), 3.52--3.44 (m, 2H, -NCH2-),
2.85 (m, 1H, -CHCH3CH3), 2.26 (s, 3H, -PhCH3), 1.64 (dd, J = 18.4, 15.2 Hz, 4H, -CH2CH2-,
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-CH2CH2-), 1.54 (d, J = 4.6 Hz, 2H, -CH2CH2-), 1.29 (d, J = 6.9 Hz, 6H, -CHCH3CH3). 13C
NMR (125 MHz, CDCl3) δ 129.0 (NCS), 126.3, 103.0, 99.02, 83.7, 82.6, 77.3, 76.8, 47.3, 31.6,
25.2, 24.1, 24.0, 22.8, 20.9, 19.1. ESI-MS(+): m/z found 396.0374 [M−Cl]+, calcd for
C15H22ClNRuS2 431.0082.
3e: red solid, 0.114 g (Yield: 85%). 1H NMR (500 MHz, CDCl3) δ 5.48 (d, J = 5.8 Hz, 2H,
-PhH), 5.27 (d, J = 5.8 Hz, 2H, -PhH), 3.87--3.79 (m, 2H, -NCH2-), 3.72 (s, 2H, -NCH2-), 2.85
(m, 1H, -CHCH3CH3), 2.47 (d, J = 3.8 Hz, 2H, -NCH2-), 2.37 (s, 2H, -NCH2-), 2.32--2.24 (m,
6H, -PhCH3, -NCH3), 1.29 (d, J = 6.9 Hz, 6H,-CHCH3CH3). 13C NMR (125 MHz, CDCl3) δ
129.0 (NCS), 126.3, 103.2, 90.0, 83.8, 82.5, 77.3, 76.8, 53.7, 45.8, 31.6, 24.1, 22.8, 19.2.
ESI-MS(+): m/z found 411.0477 [M−Cl]+, calcd for C16H25ClN2RuS2 446.0191.
3f: red solid, 0.122 g (Yield: 80%). 1H NMR (500 MHz, CDCl3) δ 7.29 (dd, J = 7.0, 1.6 Hz, 2H,
-PhH), 6.99--6.86 (m, 3H, -PhH), 5.50 (d, J = 5.9 Hz, 2H, -PhH), 5.30 (d, J = 5.8 Hz, 2H, -PhH),
4.03 (ddd, J = 13.1, 6.2, 3.4 Hz, 2H, -NCH2-), 3.81 (ddd, J = 13.0, 7.8, 3.4 Hz, 2H, -NCH2-),
3.37-3.24 (m, 2H, -NCH2-), 3.18--3.07 (m, 2H, -NCH2-), 2.86 (m, 1H, -CHCH3CH3), 2.27 (s,
3H, -PhCH3), 1.30 (d, J = 6.9 Hz, 6H, -CHCH3CH3). 13C NMR (125 MHz, CDCl3) δ 129.25
(NCS), 120.8, 116.7, 103.2, 98.9, 83.7, 82.5, 77.2, 76.7, 48.6, 45.8, 31.6, 22.7, 19.1. ESI-MS(+):
m/z found 473.0647 [M−Cl]+, calcd for C21H27ClNRuS2 508.0348.
General synthesis of complexes 5a-5f
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Ru(η-C5H5)Cl(PPh3)2 (0.36 g, 0.5 mmol) and sodium dithiocarbamates (2a-2f) (0.65 mmol) were
dissolved in methanol 30 mL. Then the resulting solution was refluxed for about 16 h and the
progress of the reaction was monitored by TLC. The solid product was filtered, and washed with
methanol. The residues were purified by column chromatography on silica gel (eluent:
CH2Cl2/CH3OH, 100:1, V/V) to offer complexes 5a-5f.
5a: yellow solid, 0.190 g (Yield: 66%). 1H NMR (500 MHz, CDCl3) δ 7.52 (m, 6H, -PhH),
7.32--7.26 (m, 7H, -PhH), 7.26--7.24 (m, 2H, -PhH), 4.35 (d, J = 4.5 Hz, 5H, -CpH), 3.34 (m,
4H, -NCH2-, -NCH2-), 0.97 (t, J = 7.2 Hz, 6H, -CH2CH3, -CH2CH3). 13C NMR (125 MHz,
CDCl3) δ 138.12 (NCS), 137.8, 133.9, 133.8, 132.9, 132.1, 132.1, 131.9, 131.9, 128.5, 128.5,
128.4, 127.2, 127.1, 77.3, 76.8, 76.2, 76.2, 42.9, 29.7, 12.5. 31P NMR (200 MHz, CDCl3) δ
53.79. ESI-MS(+): m/z found 577.0603 [M], calcd for C28H30NPRuS2 577.0601.
5b: yellow solid, 0.193 g (Yield: 67%). 1H NMR (500 MHz, CDCl3) δ 7.56 (m, 6H, -PhH),
7.34--7.26 (m, 9H, -PhH), 4.37 (s, 5H, -CpH), 3.31 (dd, J = 10.9, 5.8 Hz, 2H, -NCH2-), 2.96 (dd,
J = 11.3, 6.0 Hz, 2H, -NCH2-), 1.79--1.69 (m, 4H, -CH2CH2-, -CH2CH2-). 13C NMR (125 MHz,
CDCl3) δ 137.5 (NCS), 137.2, 134.2, 134.1, 132.15, 132.1, 131.9, 131.9, 128.5, 128.4, 126.9,
126.8, 77.2, 76.7, 75.5, 75.5, 47.8, 24.8. 31P NMR (200 MHz, CDCl3) δ 54.92. ESI-MS(+): m/z
found 575.0456 [M], calcd for C28H28NPRuS2 575.0444.
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5c: yellow solid, 0.163 g (Yield: 55%). 1H NMR (500 MHz, CDCl3) δ 7.53 (m, 6H, -PhH),
7.33--7.28 (m, 9H, -PhH), 4.38 (s, 5H, -CpH), 3.50 (s, 4H, -OCH2-, -OCH2-), 3.49--3.44 (m, 2H,
-NCH2-), 3.29 (s, 2H, -NCH2-). 13C NMR (125 MHz, CDCl3) δ 137.6 (NCS), 137.4, 134.0,
128.7, 127.1, 77.2, 76.7, 76.0, 65.7, 44.7, 38.1, 31.9, 31.2, 29.7, 29.4, 22.7, 14.1. 31P NMR (200
MHz, CDCl3) δ 54.16. ESI-MS(+): m/z found 591.0412 [M], calcd for C28H28NOPRuS2
591.0393.
5d: yellow solid, 0.156 g (Yield: 53%). 1H NMR (500 MHz, CDCl3) δ 7.58 -- 7.53 (m, 6H,
-PhH), 7.35--7.30 (m, 9H, -PhH), 4.39 (s, 5H, -CpH), 3.43 (d, J = 24.1 Hz, 4H, -NCH2-,
-NCH2-), 1.57 (s, 4H, -CH2CH2-, -CH2CH2-), 1.54 (s, 2H, -CH2CH2-). 13C NMR (125 MHz,
CDCl3) δ 137.6 (NCS), 137.3, 134.1, 134.0, 128.7, 128.7, 127.1, 127.1, 77.3, 76.8, 76.1, 76.0,
65.7, 59.5, 44.7, 38.1, 31.9, 31.2, 29.7, 29.7, 29.4, 22.7, 14.1. 31P NMR (200 MHz, CDCl3) δ
54.13. ESI-MS(+): m/z found 589.0628 [M], calcd for C29H30NPRuS2 589.0601.
5e: yellow solid, 0.216 g (Yield: 72%). 1H NMR (500 MHz, CDCl3) δ 7.47 (m, 8H, -PhH),
7.30--7.28 (m, 7H, -PhH), 4.38 (s, 5H, -CpH), 3.61 (s, 2H, -NCH2-), 3.29 (s, 2H, -NCH2-), 2.25
(d, J = 4.9 Hz, 4H, -NCH2-, -NCH2-), 2.24 (s, 3H, -NCH3). 13C NMR (125 MHz, CDCl3) δ 137.8
(NCS), 137.5, 134.0, 133.0, 132.2, 132.1, 132.1, 131.9, 131.9, 128.6, 127.1, 77.2, 76.8, 76.1,
53.7, 44.3. 31P NMR (200 MHz, CDCl3) δ 53.90. ESI-MS(+): m/z found 605.0800 [M+H]+,
calcd for C29H31N2PRuS2 604.0710.
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5f: yellow solid, 0.218 g (Yield: 66%). 1H NMR (500 MHz, CDCl3) δ 7.53 (m, 6H, -PhH),
7.32-7.26 (m, 11H, -PhH), 6.88 (dd, J = 16.3, 8.0 Hz, 3H, -PhH), 4.39 (s, 5H, -CpH), 3.67 (s, 2H,
-NCH2-), 3.51 (s, 2H, -NCH2-), 3.02 (d, J = 20.5 Hz, 4H, -NCH2-, -NCH2-). 13C NMR (125
MHz, CDCl3) δ 137.7 (NCS), 137.4, 134.1, 133.9, 132.1, 132.1, 129.3, 128.7, 128.5, 128.4,
127.2, 127.1, 120.4, 116.5, 77.3, 76.7, 76.1, 76.1, 48.32, 44.30, 29.71, 14.13. 31P NMR (200
MHz, CDCl3) δ 54.06. ESI-MS(+): m/z found 667.0924 [M+H]+, calcd for C34H33N2PRuS2
666.0866.
Crystal structures determination for 3a and 3c
Single crystals of complexes 3a and 3c suitable for X-ray analysis were obtained by slow
diffusion of hexane into solutions in dichloromethane. Diffraction intensity data were collected
on a Nonius Kappa CCD diffractometer with Mo Kα radiation (0.71073 Å) at room temperature
(292 K). The structure was solved by direct methods (SHELXS-97) and refined by full matrix
least squares on F2 (SHELXL-97).43,44 All non-H atoms were refined anisotropically. The
hydrogen atoms were placed in geometric positions and refined using a riding model (then list
X-H distances and Uiso relative to parent atom).
Cytotoxicity assay in vitro
Cytotoxic activities were evaluated by the MTT [3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl
tetrazolium bromide] method in the SKOV-3, HepG-2, PC12, A549, RAW246.7, and L6 cell
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lines. Briefly, the cell suspensions (198 μL) were plated in 96 well microtiter plates at a density
of 5 × 104 cells/mL and incubated for 12 h at 37 C in a humidified incubator with 5% CO2. The
test compounds with different concentrations were added to each well and further incubated for
24 h under the same conditions. Then, 20 μL of the MTT solution was added to each well and
incubated for 4 h. The old medium (200 μL) containing MTT was then gently replaced by
DMSO and pipetted to dissolve any formazan crystals formed. Absorbance was then determined
on a Spectra Max Plus plate reader at 570 nm. Dose--response curves were generated and the
IC50 values were determined. Cisplatin (CDDP), a commonly approved agent for the treatment of
many tumors, was used as the positive control.
Acknowledgments
The authors acknowledge financial support from National Natural Science Foundation of China
(Nos. 21002086), and the Natural Science Foundation of Yunnan Province (No. 2010ZC071).
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Figure 1. Synthesis of ruthenium(II) dithiocarbamate complexes 3a-3f and 5a-5f
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Figure 2. Molecular structure of 3a with displacement ellipsoids drawn at the 30% probability
level.
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Figure 3. Molecular structure of 3c with displacement ellipsoids drawn at the 30% probability
level.
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