Ionic η5-Cp-Ruthenium (II) complexes as potential anticancer agents

Article abstract of DOI:10.1016/j.jorganchem.2018.08.027

Ionic organometallic ruthenium(II) complexes, [η⁵-CpRu(PPh₃) (1,10-phenanthroline)]⁺Cl^? 1, [η⁵-CpRu(PPh₃) (4,7-dimethyl, 1,10-phenanthroline)]⁺Cl^? 2, and [η⁵

Full text of DOI:10.1016/j.jorganchem.2018.08.027

Accepted Manuscript
5
Ionic η -Cp-Ruthenium (II) complexes as potential anticancer agents
André Delavault, Frank R. Fronczek, Wu Xu, Radhey S. Srivastava
PII:
S0022-328X(18)30746-0
10.1016/j.jorganchem.2018.08.027
JOM 20554
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 25 April 2018
Revised Date: 21 August 2018
Accepted Date: 28 August 2018
5
Please cite this article as: André. Delavault, F.R. Fronczek, W. Xu, R.S. Srivastava, Ionic η -Cp-
Ruthenium (II) complexes as potential anticancer agents, Journal of Organometallic Chemistry (2018),
doi: 10.1016/j.jorganchem.2018.08.027.
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ACCEPTED MANUSCRIPT
Ionic η5-Cp-Ruthenium (II) complexes as potential anticancer agents
André Delavault, Frank. R. Fronczek+, Wu Xu, Radhey S. Srivastava*
Department of Chemistry, University of Louisiana at Lafayette, Lafayette, LA 70504.
+ Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803
Abstract
Ionic organometallic ruthenium(II) complexes, [η5-CpRu(PPh3)(1,10-phenanthroline)]+Cl-
[η5-CpRu(PPh3)(4,7-dimethyl, 1,10-phenanthroline)]+Cl- 2, and [η5-CpRu(PPh3)(1,10-
1,
phenanthroline-5-amine)]+Cl- 3 have been synthesized and characterized. The molecular
structures of the complexes 1 and 2 were confirmed by single-crystal X-ray structure analysis.
Cytotoxicity assays demonstrated that these compounds show significant toxicity against
NIH3T3 and Raw 264 cancer cell lines at low concentration. These complexes have the
property of DNA binding cleavage.
+
N
reflux/N2
+
Ru
N
Cl-
Anhydrous toluene
PPh3
N
N
Ru
PPh3
Cl
PPh3
1
Keywords: Ruthenium arene complexes, Crystal structure, phenanthrolines, DNA binding
cleavage in vitro cytotoxicity.
______________________________________
To whom correspondence should be addressed. Email: rss@louisiana.edu
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1. Introduction.
The platinum derived complexes, in particular cisplatin and carboplatin are extensively utilized
for cancer treatment. However, drug resistance, the toxic side-effects, and lack of activity of
platinum compounds against several types of cancers are serious drawbacks [1]. The
shortcoming of platinum drugs inspired the search for anticancer activity of other transition metal
complexes. Ruthenium complexes including organometallic complexes has received immense
attention as anticancer agents [2, 3]. Early reports misconstrued that organometallic complexes
were unstable to normal conditions, and until recently organometallic compounds have never
been considered as suitable candidate as pharmaceuticals [4]. Consistent with recent studies,
organometallic compounds are promising therapeutic agents with novel mechanistic activity [5-
12], probably due to their great structural variety and by rational ligand design. Organometallic
complexes have tremendous advantage with their wide spectrum of coordination numbers,
coordination geometries, thermodynamic and kinetic preferences, redox activity, Lewis acidity,
electrophilicity, access to ionic/radical species, flexible bond order, unique geometries, easily
accessed structure/activity variations, and magnetic, spectroscopic, and radioactive signatures.
These variations in organometallic compounds may overcome the cellular resistance problem
common in platinum-related drugs and may suggest improvements in the discovery and
development of new cancer drugs. Biological activity of Ru complexes is becoming increasingly
important in both bioinorganic chemistry and anticancer chemotherapy [13-18]. Sadler’s piano-
stool organometallic compounds have contributed in the understanding of the mechanism of the
interaction between the target biomolecule and the ruthenium complex [19,20]. Also, transition
metal complexes are investigated comprehensively for biomedical applications [21]. In fact, the
rapid development of ruthenium compound’s in the field in the medicinal chemistry, especially
in the development of chemotherapeutics with minimal side effects and immunity to drug
resistance [22]. The most promising ruthenium complexes, NAMI-A and KP-1019, have
successfully reached clinical trials [23]. Recently, Chi et al. reported the antitumor activity and
cellular
pharmacology
of
various
metallacycles
composed
of
arene-Ru
acceptors and various pyridyl donors [24]. The studies on Ru-metallocycle suggested that larger
metallacyles show higher activity in comparison with small metallacycles. This is probably in
agreement with the hypothesis that a large macromolecules are more likely to be retained inside
cancer cells. A recent review describing potential application of ferrocenyl secondary natural
product conjugates in medicinal chemistry such as antimicrobial, antiparasite and anticancer
agents [25, 26].
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The ruthenium-based drugs seem to be a good alternative to platinum drugs, and
significant advances have been made in this regard [27-29]. Ru(III) complexes preferably bind to
Fe(III) sites of the proteins lactoferrin and transferrin [30 ,31], which are responsible for the
delivery of Ru(III) to cancer cells where they are taken up via receptor-mediated endocytosis
[32]. The protein which delivers iron to cells, and transferrin receptors are overexpressed in
cancer cells [29]. It is hypothesized that the Ru(III) complexes are reduced to Ru(II) in vivo,
being kinetically more reactive than Ru(III) [2]. Nonetheless ruthenium(II) compounds also
exhibit a low general toxicity, and since cancer cells can also become oxidizing at certain stages
of their growth cycle, oxidation of the ruthenium cannot be excluded [33].
Ligands such as arenes and cyclopentadienyl may provide control of the hydrophilicity
and hydrophobicity of the faces of the coordination complex (which influence cell uptake and
targeting) [34]. Metallodrugs are mainly prodrugs, and control over ligand substitution is vital if
the complex is to reach and react with its target site. The low-spin d6 metal complexes are
attractive for drug design since they are often kinetically inert. A number of organometallic
compounds bearing η5-cyclopentadienyl ligand capable of binding to the metal center through π
interactions exhibit promising anticancer activity. Cyclopentadienyl rhodium [35, 36] and
ruthenium complexes with potential therapeutic applications have also been reported.
In this paper we report synthesis of ionic cyclopentadienyl-ruthenium complexes with
bidentate nitrogen donor ligands. All these complexes were isolated as chloride salts. These
complexes (1, 2) were fully characterized by X-ray diffraction and spectroscopic studies. These
complexes were further studied for cytotoxicity and DNA binding.
2. Experimental
2.1 Materials and general methods. All reagents were of analytical grade. 1, 10-
phenanthroline,
4,7-dimethyl,
1,10-phenanthroline,
1,10-phenanthroline-5-amine
and
CpRuCl(PPh3)2 and solvents were purchased from Sigma-Aldrich. All reactions were performed
under inert atmosphere.
The IR spectra were measured on a CARY 630 FT- infrared spectrophotometer (Agilent
Technology). UV-vis spectra were obtained on an Agilent 8453 spectrophotometer. Elemental
analysis was performed by Atlantic Microlab, Norcross, Georgia. The diffraction data were
collected at low temperature on a Bruker Kappa Apex-II DUO diffractometer equipped with Mo
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Kα (λ = 0.71073 Å) radiation, a focusing monochromator, and an Oxford Cryostream low-
temperature device. Data were measured at 100K for 1 and 180K for 2. Absorption corrections
were made by the multi-scan method. For 2, disordered dichloromethane solvent contribution
was removed using the SQUEEZE procedure. Crystal data and details of data collection and
refinement are given in Tables 1-2. The NMR spectra were measured 400 MHz Varian/Joel
spectrophotometer in a CDCl3 solvent
2.2 Biological studies.
Plasmid DNA isolation and gel electrophoresis. pUC19 plasmid was introduced into DH5·
competent cells based on manufacturer's protocol (Invitrogen Corporation, Carlsbad, CA). A
single colony was selected from LB plate and cultured in 5.0 ml of LB medium at 37˚C in a
shaker at a speed of 300 rpm for overnight. This starter cell culture was diluted 1:500 using
freshly prepared LB medium and grew at 37˚C in a shaker at a speed of 300 rpm for 16-18 h.
Cells were harvested at 4,000 rpm for 5 min. The plasmid DNAs were purified from the cell
culture using a Qiagen plasmid purification column based on manufacturer's protocol (Qiagen
Inc., Valencia, CA). LB medium and plates contained 100
plasmid DNA was determined by the absorbance at 260 nm using UV-Vis spectrophotometry.
1.0 g of pUC19 plasmid DNA was incubated with the ruthenium complexes at the specified
concentrations in a total 20 l in a 37˚C water bath for 2-32 h. At the end of incubation,
bromophenol blue loading buffer was added. The samples were then loaded on a 1.0% agarose
gel containing ~2.0 g/ml ethidium bromide. Gel electrophoresis was carried out at 150 V for
µg/ml ampicillin. The concentration of
µ
µ
µ
~20 min in Tris-Borate-EDTA (TBE) buffer. Bands were visualized by UV light and
photographed by a Bio-Rad gel documentation system (Bio-Rad Laboratories, Hercules, CA)
[37].
Culture of cell lines and cytotoxicity test.
The murine cell lines: NIH3T3 and Raw 264 were maintained in either T25 or T75 flasks
containing DMEM medium supplemented with 10% fetal bovine serum, 1% glutamine, and 1%
penicillin and streptomycin (Invitrogen) in the standard 3T3 protocol. The cells were grown at
37 ̊
C in a 5% CO2 incubator. 1.0 x 105 cells (cell culture day 0) were plated in T25 flasks for
investigating effects of the ruthenium complexes on the murine cell lines. Specifically, the
ruthenium complexes dissolved in DMSO, filter-sterilized, were added into a growth medium
using 1:1000 dilution to avoid the toxic effects of DMSO after the cells were plated for 24 h (cell
culture day 1). At the end of incubation with ruthenium complexes from 0 h (day 1), 24 h (day 2),
48 h (day 3), 72 h (day 4), and 96 h (day 5), cells were removed from flasks by trypsin-EDTA
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solution (Invitrogen). Cell viability was determined by the trypan blue staining, and cell number
was counted using a haemocytometer [38]. The experiment was independently repeated for four
times. IC50 values for each ruthenium complexes were calculated by normalizing survival rate of
the treated cells to that of control (DMSO treated) cells.
As stated earlier, the cells were incubated with the compounds for 0, 1, 2, 3, 4 and 5 days. At
the end of incubation with the compound each day, cell viability was determined by the trypan
blue staining, and cell number was counted using a haemocytometer. At the longest incubation
(5 days), nearly all cells were killed by 10.0 µM of the compounds, the highest concentration in
our study. Significant fraction of the cells were still alive in the culture media with low
concentration, for example 0.080 µM, of the compounds.
3. Synthesis of complexes
3.1 Synthesis of [η
5-CpRu(PPh3)(1,10-phenanthroline)]+Cl- 1. In a 100 mL Schlenk flask
provided with magnetic stirrer and a condenser under nitrogen, CpRuCl(PPh3)2 (0.1g, 0.138
mmol) and anhydrous 1,10-phenanathroline (0.027g, 0.151 mmol) were dissolved in anhydrous
toluene (6 mL) and was stirred for 3 h at room temperature to get a thick red solution. An
orange solid was obtained on cooling at -200C, which was filtered and vacuum dried. Yield 45
mg, 45 %. Anal. Calcd. for C35H28N2PRuCl·CH2Cl2·H2O (747.03): C, 57.88; H, 4.32; N, 3.75.
Found: C, 58.50; H, 4.15; N, 3.86. Selected IR absorption bands (cm-1): νSO1096 (S-TMSO) and,
νC=N (pyz) 1401. UV-vis (H2O): 364 nm (ε = 3260 L.mol-1.m-1); 426 nm (ε = 1060 L.mol-1.m-1). 1H
NMR (400MHz ,CDCl3) δ = 9.66 (d, J = 5.5 Hz, 2 H), 8.34 (d, J = 8.2 Hz, 2 H), 7.87 - 7.83 (m, 2
H), 7.75 (dd, J = 5.3, 8.0 Hz, 2 H), 7.23 - 7.18 (m, 3 H), 7.14 - 7.07 (m, 6 H), 6.90 - 6.83 (m, 6
H), 4.85 (s, 5 H).
3.2 Synthesis of [
prepared following a method analogous to that described for 1 starting from compound
CpRuCl(PPh3)2 (0.1g, 0.138 mmol) and 4,7-dimethyl-1,10-phenanthroline (0.031 g, 0.151
η
5-CpRu(PPh3)(4,7-dimethyl-1,10-phenanthroline)]+Cl- 2. This compound was
mmol) in anhydrous toluene except that the reaction mixture were reflux for 3 h. The flask was
placed in a refrigerator overnight. An orange colored crystalline compound was obtained. Yield:
66 mg 62%. Anal. Calcd. for C35H32N2PRuCl·H2O·CH2Cl2 (775.127): C, 58.88; H, 4.68; N, 3.61.
Found: C, 58.08; H, 4.04; N, 3.51. Selected IR absorption bands (cm-1): νSO1113 (S-TMSO), νSO
880 (O-TMSO) and, νC=N (pyz) 1401. UV-vis (H2O): 364 nm (ε = 3260 L.mol-1.m-1); 426 nm (ε =
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1060 L.mol-1.m-1). 1H NMR (400MHz ,CDCl3) δ = 9.48 (d, J = 5.1 Hz, 2 H), 7.94 (s, 2 H), 7.55 (d,
J = 5.5 Hz, 2 H), 7.6 (5,4 Hz, 2H), 7.21 - 7.15 (m, 2 H), 7.11 - 7.04 (m, 6 H), 6.91 - 6.82 (m, 6 H),
4.78 (s, 5 H), 2.80 (s, 6 H).
3.3 Synthesis of [η
5-CpRu(PPh3)(1,10-phenanthroline-5-amine)]+Cl- 3. This compound was
prepared following a method analogous to that described for 2 starting from compound
CpRuCl(PPh3)2 (0.1g, 0.138 mmol) and 1,10-phenanthroline-5-amine (0.031 g, 0.151 mmol) in
anhydrous toluene. The flask was placed in the refrigerator for overnight. A orange colored
crystalline compound was obtained. Yield: 66 mg 62%. Anal. Calcd. for C35H28N3PRuCl
(658.094): C, 63.87; H,4.28; N, 6.38. Found C, 64.17; H, 4.04; N, 6.62. Selected IR absorption
bands (cm-1): νSO1113 (S-TMSO), νSO 880 (O-TMSO) and, νC=N (pyz) 1401. UV-vis (H2O): 364
nm (ε = 3260 L.mol-1.m-1); 426 nm (ε = 1060 L.mol-1.m-1). 1H NMR (400MHz ,CDCl3) δ = 9.32-
9.30 (d, J = 5.1 Hz, 2 H), 8.94 (d, 2 H), 7.72-7.27 (m, J = 5.5 Hz, 2 H), 7.25 (d, 2H), 7.4-6.96
(m, 3 H), 6.83 – 6.81 (m, 6 H),6.79 - 6.38 (m, 6 H), 4.68 (s, 5 H), 1.80 (s, 3 H).
4. Results and Discussion
4.1 Synthesis of complexes. The reaction of CpRuCl(PPh3)2 with phenanthrolines in
anhydrous toluene at room temperature to refluxing temperature gave ionic complex [η5-
CpRu(PPh3)(1,10-phenanthroline)]+Cl- 1, η5-CpRu(PPh3)(4,7-dimethyl, 1,10-phenanthroline)]+Cl-
2, and [η5-CpRu(PPh3)(1,10- phenanthroline-5-amine)]+Cl- 3 as microcrystalline orange solids
(Scheme 1). The elemental analysis, IR, and NMR analysis support the proposed structure for
1, in which a ruthenium atom is coordinated to a η5-Cp, 1,10-phenanthroline and triphenyl
phosphine ligands, acting as an cation and Cl- as anion.
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+
Ru
N
Cl-
PPh3
N
N
N
Anhydrous toluene
N2
1
+
Ru
N
N
N
Cl-
PPh3
N
Anhydrous toluene
reflux/N2
Ru
PPh3
Cl
PPh3
2
NH2
+
N
N
Ru
Cl-
Anhydrous toluene
reflux/N2
N
PPh3
N
H2N
3
Scheme 1. Synthetic scheme for
[
η
5-CpRu(PPh3)(1,10-phenanthroline)]+Cl- 1, η5
1,10-phenanthroline)]+Cl- 5-CpRu(PPh3)(1,10-
2, and
-
CpRu(PPh3)(4,7-dimethyl,
[η
phenanthroline-5-amine)]+Cl- 3
The asymmetric units of both 1 and 2 include one cationic complex, one chloride as a
counter-anion, one water molecule and one CH2Cl2 molecule, although the dichloromethane in 2
was removed by SQUEEZE. The structures of compounds 1 and 2 are represented in Fig. 1
and 2 respectively. Details of crystallographic data are given in Table 1, 2, and significant bond
lengths and bond angles are listed in Table 3. Cations of both compounds 1 and 2 consist of a
ruthenium atom coordinated to the cyclopentadienyl ligand, to the two nitrogen atoms of
bidentate 1,10-phenanthroline ligand or 4,7-dimethyl-1,10-phenanthroline, and one
triphenylphosphine, with chloride as counterion. In these complexes the coordination geometry
of ruthenium is pseudo-tetrahedral (piano-stool complexes). The Ru-C(Cp) distances are in the
range 2.158(2) - 2.2149(16) Å. The average value agrees with those of 2.177(5) and 2.185 A,
respectively, reported for the [CpRu(PMe3)(CH3CN)2]+ and [CpRu (PCy3)(CH3CN)2]+ monomeric
complex cations [39]. The Ru–N distances of compounds 1 and 2 agree well and are in the
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range 2.0858(18) - 2.1002(18) Å. Ru–P distances also agree well, having values of 2.2997(4) Å
in 1 and 2.3060(6) Å in 2. The presence of the N-coordinated phenanthroline is evidenced by
the characteristic IR spectrum absorption at 698 cm-1. The band detected at 1430 cm-1 are
characteristic of triphenylphosphine.
Figure 1. ORTEP diagram and labelling scheme of complex 1. 50% thermal ellipsoids plotted.
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Figure 2. ORTEP diagram and labelling scheme of complex 2. 50% thermal ellipsoids plotted.
5. Effects on cell viability by the ruthenium complexes 1, 2 and 3. A number of ruthenium
complexes were reported to have anti-metastatic activity. Specifically, certain ruthenium
complexes with heterocycles coordinated to the ruthenium center through nitrogen have been
shown to act as cytostatic and cytotoxic drugs on colorectal tumor cells both in vivo and in vitro.
In the present work, the effects of the ruthenium complexes on cell growth were investigated
using two murine cell lines (NIH3T3 and Raw264). Three compounds at high concentration
have cytotoxicity activities. Raw264 is more sensitive to ruthenium complexes than NIH3T3
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cells. There are measurable differences in cytotoxicity of these three complexes: 2 has a slightly
greater effect than 1, which has a higher effect than 3.
Effect of Ru Compound AD67
on Raw 264 Cells
Effect of Ru Compound AD63
on Raw 264 Cells
3
2
1
×
100 6
3 100 6
×
Control (DMSO)
0.08 µM AD67
0.40 µM AD67
2.0 µM AD67
4.0 µM AD67
10.0 µM AD67
2 100 6
×
×
100 6
Control (DMSO)
0.08 µM AD63
0.40 µM AD63
2.0 µM AD63
4.0 µM AD63
10.0 µM AD63
1 100 6
×
×
100 6
Effect of Ru Compound RS1038
on Raw 264 Cells
3
2
1
×
100 6
×
100 6
Control (DMSO)
0.08 µM RS1038
0.40 µM RS1038
2.0 µM RS1038
4.0 µM RS1038
10.0 µM RS1038
×
100 6
Figure 3. Effects of the Ru complexes 1, 2 and 3 on cell viability. The mouse Raw 264 and NIH
3T3 cell lines were incubated with varying concentrations [0 (control), 0.080. 0.40, 2.0, 4.0 and
10.0
µM] of the complexes.
5.1.
DNA binding activity by the ruthenium complexes 1, 2 and 3. Ruthenium (II)
complexes have been reported to have DNA binding properties. The observed cell growth
inhibition of complexes 1, 2 and 3 made us hypothesize that the complexes might have the
property of either DNA binding, or cross-linking, or cleavage. Our gel electrophoresis results
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show that intensity of plasmid forms I and II is proportionally decreased in dose-dependent
manner when DNAs were incubated with the compounds (Figure 4). This observation indicates
that ruthenium compounds especially at high concentration gradually replace ethidium bromide,
and cause decreased intensity under UV light. Taken all together, our DNA binding experiments
suggest that the complexes could function as intercalating agents.
Figure 4. Plasmid DNA binding by complexes 1, 2 and 3. Plasmid DNA (1.0 µg) was incubated
with varying concentrations (0.80, 40, 200, 400 and 1,000 µM) of the complexes in 1.0 mM Tris-
Cl buffer, pH 7.0 at 37˚C.
Supplementary material
Crystallographic data for the structure analyses have been deposited with the Cambridge
Crystallographic Data Center, CCDC 1584250 and 1584251 for compounds 1-2. Copies of this
may be obtained free of charge from the Director, CCDC, 12 Union Road, Cambridge, CB2
1EZ,
UK
(fax:
+44-1223-336-033;
email:
deposit@ccdc.cam.ac.uk
or
http://www.ccdc.cam.ac.uk).
Acknowledgement
We are grateful for the financial support of the Louisiana Board of Regents [LEQSF(2013-16)-
RD-B-06].
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Table 1. Crystallographic data and structure refinement for compounds 1, and 2.
_____________________________________________________________________
1
2
______________________________________________________________________
Formula
Formula weight
Crystal system
Space group
T (K)
C35H28N2PRuCl.CH2Cl2.H2O
C37H32N2PRu.Cl.H2O.CH2Cl2
747.03
775.08
Triclinic
PI
Triclinic
PI
100
180
a (Å)
9.8122 (3)
10.1176 (3)
16.8761 (4)
99.883 (2)
97.574 (2)
97.546 (2)
1615.67 (8)
2
9.9987 (3)
10.636 (3)
17.4832 (6)
100.284 (2)
92.954 (2)
91.062 (2)
1727.96 (9)
2
b (Å)
c (Å)
α (°)
β (°)
γ (°)
V (Å3)
Z
Dx (Mg m-3)
µ (mm-1)
Crystal size (mm)
R [F²>2σ(F²)]
Rint
1.536
1.490
0.82
0.77
0.18 x 0.11 x 0.09
0.093
0.20 x 0.19 x 0.09
0.035
0.039
0.025
wR(F²)
0.093
0.084
________________________________________________________________
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Table 2. Selected bond lengths (Å) and angles (°) for complexes 1and 2.
____________________________________________________________________________
1
2
____________________________________________________________________________
Ru1-N1
Ru1-N2
Ru1-C1
Ru1-C2
Ru1-C3
Ru1-C4
Ru1-C5
Ru1-P1
N1-Ru1-N2
N1-Ru1-C1
N2-Ru1-C1
N1-Ru1-C2
N2-Ru1-C2
N1-Ru1-P1
N2-Ru1-P1
2.0882(13)
2.0922(13)
2.1715(16)
2.1793(16)
2.1938(16)
2.2149(16)
2.2050(16)
2.2997(4)
77.52(5)
142.87(6)
139.56(6)
106.31(6)
163.11(6)
91.36(4)
Ru1-N1
Ru1-N2
Ru1-C15
Ru1-C16
Ru1-C17
Ru1-C18
Ru1-C19
Ru1-P1
N1-Ru1-N2
N1-Ru1-C18
N2-Ru1-C18
N1-Ru1-C17
N1-Ru1-C17
N1-Ru1-P1
N2-Ru1-P1
2.0858(18)
2.1002(18)
2.208(2)
2.203(2)
2.175(2)
2.158(2)
2.193(2)
2.3060(6)
77.45(7)
142.79(9)
139.61(9)
106.89(9)
159.94(9)
89.82(5)
912.45(5)
90.11(4)
____________________________________________________________________________
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Highlights
•
•
•
We have synthesized three new organometallic complexes.
All the complexes have half sandwich geometry.
All the complexes are significantly toxic against NIH3T3 and Raw 264 cancer cell lines at
low concentration.
•
These complexes have the property of DNA binding cleavage.