Synthesis, characterization and anticancer activity of dinuclear ruthenium(II) complexes linked by an alkyl chain

Article abstract of DOI:10.1039/c5nj00582e

A series of 1,10-phenanthroline-based dinucleating bridging ligands BL^1-3 and their dinuclear ruthenium Ru(ii) complexes [(bpy)₂Ru(BL^1-3)Ru(bpy)₂](PF₆)₄ (bpy = 2,2′-bipyridine; PF₆

Full text of DOI:10.1039/c5nj00582e

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DOI: 10.1039/C5NJ00582E
Page 1 of 15
New Journal of Chemistry
Synthesis, characterization and anticancer activity of dinuclear ruthenium(II)
complexes linked by alkyl chain
a
b
a
a
a
Yan Zhang , Lu Lai , Ping Cai *, Gong-Zhen Cheng *, Yi Liu
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
1
-3
A series of 1,10-phenanthroline-based dinucleating bridging ligands BL and
1
-3
their dinuclear Ru(Ⅱ) complexes [(bpy) Ru(BL )Ru(bpy) ](PF ) (bpy =
2
2
6 4
2
,2′-bipyridine) have been synthesized and characterized by elemental analysis,
IR, NMR and mass spectrometry methods. Their photophysical and
electrochemical properties have been studied. The symmetric nature of the
bridging ligands enabled the formation of dinuclear Ru(Ⅱ) complexes 1-3 with
1
0
equivalent metal centers. The complexes 1-3 exhibited the spin-allowed
1
MLCT (d -π*) transition at approximate 460 nm and Ru(Ⅱ) metal centered
π
emission at around 600 nm in solution at room temperature. The emission
profile and emission maxima are similar and independent of the excitation
wavelength for each complex. The complexes 1-3 undergo metal centered
oxidation and the E1/2 values for the Ru(Ⅱ)/Ru(Ⅲ) redox couple are 0.9 and
1
5
1
.4 V versus SCE. The cytotoxicity of these complexes in vitro was evaluated
by MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide)
assay. The result indicated that the Ru(Ⅱ) complexes 1-3 exhibited significant
dose-dependent cytotoxicity to cervical cancer(Hela), gastric cancer(SGC-7901)
and gastric cancer (BGC823) tumour cell lines. It is worth noting that the
cytotoxicity of the complexes 1-3 increased with the increase of methylene of
bridging ligands. The DNA-quenching constants were determined to be
2
0
5
5
5
-1
2
5
1.34×10 , 1.46×10 and 2.98×10 mol ·L for 1, 2 and 3, respectively,
1
indicating that the different interactions between complexes 1-3 with DNA.
1
a:College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, China E-mail:caiping@whu.edu.cn
b: College of Chemistry and Environmental Engineering, Yangtze University, Jingzhoun, 434023, China
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1
. Introduction
Ruthenium complexes as antitumor agents are
very promising in the field of non-platinum 35 of these complexes depend to a large extent on
ligands to assemble dinuclear and polynuclear
1
8
supramolecular. The shape, size and functions
complexes showing activity in tumors which
developed resistance to cisplatin
the nature of the bridging ligands which connect
the metal centers. The crucial role played by
bridging ligands in determining the ground state
5
0
5
0
5
(
cis-[PtCl (NH ) ]) or in which cisplatin is
2
3 2
1
-5
19
inactive.
Up to now, a large number of
metal-metal interaction is well recognized. The
ruthenium complexes have been synthesized and 40 flexibly linked species show an enhanced affinity
6
-11
tested for therapeutic potential.
For example,
as torsional rotation and allow the second metal
center to position and bind (although less
strongly) in the minor groove at a duplex region
adjacent to the non-duplex feature, rather than
being extra-helical as is the case in the
rigidly-linked species. Here, we reported a series
1
1
2
2
two Ru(Ⅲ) complexes have entered clinical
1
2-13
trials: KP1019 and NAMI-A.
The design and
construction of new ruthenium complexes have
been the subject of considerable attention by
many research groups over the past decade. In
particular, much attention is devoted to
4
5
of
new
phenanthroline-based
flexible
1
-3
dinucleating bridging ligands (BL ) and their
dinuclear Ru( Ⅱ ) complexes 1-3 with
2
,2′-bipyridine (bpy) due to its high complexing
affinity with a variety of metal ions and
interesting photophysical, photochemical, and 50 2,2′-bipyridine as ancillary ligands. The
electron transfer properties of its metal
cytotoxicity in vitro of the complexes was
evaluated by MTT assay and the interaction of
Ruthenium( Ⅱ ) complexes with DNA was
studied by electronic emission titration.
14
complexes. Ru(Ⅱ) complexes of polypyridine
1
5
ligands, because of their unique combination of
chemical stability, redox properties,
luminescence intensity and cytotoxicity, have 55 2. Experimental
been
used
extensively
to
construct
the
2.1 Materials and instrumentation
1
6
supramolecular
systems.
Since
All reagents and solvents were of commercial
origin and were used without further purification
unless otherwise noted. Ultrapure Milli-Q water
was used in all experiments. Dimethyl sulfoxide
luminescence, redox behavior and cytotoxicity of
Ru(Ⅱ) complexes are strongly ligand-dependent,
considerable research interest has been dedicated
to fine-tune these properties by changing the
60
(DMSO) and RPMI 1640 were purchased from
1
7
Sigma. Hela (human cervical carcinoma),
BGC823 (Human gastric carcinoma) and
SGC-7901 (Human gastric carcinoma) cell lines
3
0
commonly employed polypyridyl ligands. The
convenient features of pyridine as a coordinating
molecule was introduced in various bridging
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New Journal of Chemistry
were purchased from the American Type Culture
Collection. RuCl ·3H O, 2,2′-bipyridyl (bpy),
2.2 Synthesis
1
-3
3
2
2.2.1 Synthesis of the bridging ligands BL
5
1
-amino-1,10-phenanthroline, 1,2-ethyl bromide, 35 Stage-1: Synthesis of dialdehyde
,3-dibromopropane, 1,4-dibromobutane, The dialdehyde were synthesized according to
2
1
5
0
5
4-hydroxybenzaldehyde were purchased from the
the method reported by Donahoe et al.
A
.
Wu han Shen shi Hua gong, Ru(bpy) Cl 2H O
solution of sodium hydroxide (8 g, 200 mmol) in
water (40 mL) was added to a solution of
40 4-hydroxybenzaldehyde(24.4 g, 200 mmol) in
ethanol (40 mL) , warmed, and then 1,
2-dibromoalkane (100 mmol) was added
followed by ethanol (40 mL) to get a
homogeneous solution. The solution was
2
2
2
(bpy = 2,2′-bipyridyl) was synthesized and
2
0
purified according to the literature methods.
Microanalysis (C, H, O and N) were conducted
with a PerkinElmer 240Q Elemental Analyzer.
Electrospray Ionization Mass Spectra were
recorded with an LCQ system (Finnigan MAT,
1
USA) using CH OH as the mobile phase. 300 45 refluxed under nitrogen atmosphere for 20 h,
3
1
MHz H NMR spectroscopic measurements were
cooled to 0 °C, and the colorless needles that
separated out was filtered, washed with water,
and recrystallized in ethanol.
1
performed on
a
Bruker AM-300 NMR
spectrometer, using CDCl and d -DMSO as
3
6
solvent and TMS (SiMe ) as an internal
4,4'-(ethane-1,2-diylbis(oxy))dibenzaldehyde:
4
reference at 25C. Infrared spectra were recorded 50
on a Perkin-Elmer Spectrum FT-IR Spectrometer
using KBr pellets. Solution electronic absorption
spectra and emission spectra in acetonitrile were
recorded on Shimadzu 3100 spectrophotometer
C H O (0.25 g, 92 %). Anal. Calc: C, 71.11; H,
16 14 4
5.18; O, 23.71. Found: C, 71.08; H, 5.21; O,
1
2
2
3
0
5
0
23.66%. H NMR(300 MHz; CDCl
3
; 298 K):
), 7.06 (d, 4H, J=6.0 Hz, Ph),
7.86 (d, 4H, J=6.0 Hz, Ph), 9.91 (s, 2H, -CHO).
4.45 (s, 4H, -O-CH
2
and Shimadzu RF-5301 PC spectrofluorometer, 55 4,4'-(propane-1,3-diylbis(oxy))dibenzaldehyde:
respectively. Cyclic voltammetry (CV) were
obtained with CHI 630E instrument in a
three-electrode cell with a pure Ar gas inlet and
outlet. The working electrode and counter
C H O (0.24 g, 85 %). Anal. Calc: C, 71.83; H,
17 16 4
5.63; O, 22.54. Found: C, 71.85; H, 5.61; O,
1
22.60%. H NMR(300 MHz; CDCl
; 298 K):
3
2.35(m, 2H, -CH
), 4.27 (m, 4H, -O-CH ), 7.01
2
2
electrode were Pt electrode, and the reference 60 (d, 4H, J=9.0 Hz, Ph), 7.83 (d, 4H, J=9.0 Hz, Ph),
electrode was a saturated calomel electrode
9.89 (s, 2H, -CHO).
(SCE).The experiments were carried out in the
4,4'-(butane-1,4-diylbis(oxy))dibenzaldehyde:
presence of CH CN and scan rate was 100
C H O (0.27 g, 90 %). Anal. Calc: C, 72.48; H,
18 18 4
3
-1
6
.04; O, 21.48. Found: C, 72.45; H, 6.07; O,
mVs .
1
65
21.51%. H NMR(300 MHz; CDCl ; 298 K):
3
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2
4
9
.05(s, 4H, -CH ), 4.14 (s, 4H, -O-CH ), 6.99 (d,
7.58-7.67 (m, 4H, H , H ), 7.99 (d, 4H, J = 9.0
3 8
2
2
H, J=9.0 Hz, Ph), 7.83 (d, 4H, J=9.0 Hz, Ph), 35 Hz, H ), 8.19 (d, 2H, J = 9.0 Hz, H ), 8.62 (s,
11
7
.89 (s, 2H, -CHO).
2H, H ), 8.76 (d, 2H, J = 9.0 Hz, H ), 9.11 (d,
1
0
4
1
-3
Stage-2: Synthesis of Schiff base L
To a solution of 5-amino-1,10-phenanthroline
0.39 g, 2 mmol) was added a solution of
dialdehyde (1 mmol) in methanol (10 mL), 40 4.90; N, 12.91%. IR (cm , KBr): 2930(C-H),
2H, J = 3.0 Hz, H
9
), 9.22 (d, 2H, J = 3.0 Hz, H
2
).
3
5
0
5
0
5
0
L : C H N O (0.41 g, 63 %). Anal. Calc: C,
42
32
6
2
(
77.30; H, 4.91; N, 12.88. Found: C, 77.28; H,
-1
glacial acetic acid was added dropwise with
stirring in nitrogen atmosphere, refluxed for 5 h,
cooled to room temperature, a pale yellow
precipitate separated out. The product was
1599(C=N), 1418(C=C), 1226 (C-O-C), 1061
(C-O-C), 802 (C-H) (pyridine), 731(β-ring)
1
1
1
2
2
3
(pyridine), 614(C-C). H NMR(300 MHz; CDCl ;
3
298 K): 2.10(s, 4H, -CH ), 4.19 (s, 4H, -O-CH ),
2
2
filtered, washed with large portions of ethanol, 45 7.05 (d, 4H, J=9.0 Hz, H ), 7.29 (s, 2H, H ),
1
2
6
and dried in vacuo.
7.56-7.65 (m, 4H, H , H ), 7.99 (d, 4H, J = 9.0
3 8
1
L : C H N O (0.47 g, 75 %). Anal. Calc: C,
Hz, H ), 8.20 (d, 2H, J = 6.0 Hz, H ), 8.62 (s,
11 7
40
28
6
2
76.92; H, 4.49; N, 13.46. Found: C, 76.88; H,
2H, H ), 8.77 (d, 2H, J = 9.0 Hz, H ), 9.11 (d,
10 4
-
1
4
1
.45; N, 13.41%. IR (cm , KBr): 2936(C-H),
2H, J = 3.0 Hz, H ), 9.22 (d, 2H, J = 3.0 Hz, H ).
9 2
1
-3
598 (C=N), 1423 (C=C), 1230 (C-O-C), 1062 50 Stage-3: Synthesis of bridging ligands BL
1
-3
(C-O-C), 801 (C-H) (pyridine), 734(β-ring)
To a solution of L (1 mmol) in ethanol (40 mL)
1
(
pyridine), 617(C-C). H NMR(300 MHz; CDCl ; was added a solution of sodium borohydride
3
298 K): 4.50 (s, 4H, -O-CH ), 7.12 (d, 4H, J=9.0
(0.076 g, 2 mmol) in ethanol (10 mL). The
solution was refluxed under nitrogen atmosphere
2
Hz, H ), 7.30 (s, 2H, H ), 7.59-7.68 (m, 4H, H ,
1
2
6
3
H ), 8.02 (d, 4H, J = 9.0 Hz, H ), 8.21 (d, 2H, J 55 for 4 h, cooled to room temperature, a pale
8
11
=
6.0 Hz, H ), 8.64 (s, 2H, H ), 8.78 (d, 2H, J =
yellow precipitate separated out. The product
was filtered, washed with large portions of
ethanol and dried in vacuo.
7
10
6
.0 Hz, H ), 9.12 (d, 2H, J = 3.0 Hz, H ), 9.23 (d,
4 9
2H, J = 3.0 Hz, H2).
2
1
L : C H N O (0.46 g, 72 %). Anal. Calc: C,
BL : C H N O (0.37 g, 59 %). Anal. Calc: C,
41
30
6
2
40 32
6
2
7
4
1
7.12; H, 4.70; N, 13.17. Found: C, 77.15; H, 60 76.43; H, 5.09; N, 13.38. Found: C, 76.42; H,
-1
-1
.69; N, 13.16%. IR (cm , KBr): 2935(C-H),
601(C=N), 1420(C=C), 1228 (C-O-C), 1060
5.11; N, 13.32%. IR (cm , KBr): 3321(N-H),
2936(C-H), 1599(C=C), 1498 (C=C), 1229(C-N),
(C-O-C), 805 (C-H) (pyridine), 735(β-ring)
1045(C-O-C), 818(C-H) (pyridine), 734(β-ring)
1
1
(
pyridine), 615(C-C). H NMR(300 MHz; CDCl ; (pyridine), 624(C-C). H NMR(300 MHz; CDCl ;
3
3
2
7
98 K): 2.38(t, 2H, -CH ), 4.31 (t, 4H, -O-CH ), 65 298K): 4.37 (s, 4H, -O-CH ), 4.52(s, 4H,
2
2
2
.08 (d, 4H, J=9.0 Hz, H ), 7.28 (s, 2H, H ),
-N-CH ), 4.71(s, 2H, -NH), 6.75(s, 2H, H ), 6.99
1
2
6
2
6
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New Journal of Chemistry
(
d, 4H, J=9.0 Hz, H ), 7.41 (d, 4H, J=9.0 Hz,
AgNO (0.17 g, 1.0 mmol) was added to an
3
13
H ), 7.47-7.51 (m, 2H, H ), 7.61-7.65(m, 2H, 35 ethanol solution of Ru(bpy) Cl ·2H O (0.26 g,
1
2
3
2
2
2
H ), 7.99 (d, 2H, J = 6.0 Hz, H ), 8.27 (d, 2H, J =
0.5 mmol). After refluxing for 30 min and
filtering to remove the deposited AgCl, the
filtrate was added to an ethanol solution of
8
4
9
.0 Hz, H ), 8.90 (d, 2H, J = 3.0 Hz, H ), 9.19 (d,
7 2
5
0
5
0
5
0
2H, J = 3.0 Hz, H9).
2
1-3
BL : C H N O (0.41 g, 64 %). Anal. Calc: C,
BL (0.25 mmol).The mixture was refluxed
4
1
34
6
2
7
5
2
6.64; H, 5.29; N, 13.08. Found: C, 76.71; H, 40 under the protection of nitrogen atmosphere for
-1
.31; N, 13.06%. IR (cm , KBr): 3285(N-H),
936(C-H), 1607(C=C), 1500(C=C), 1327(C-N),
24 h. After most of the solvent was removed
under a reduced pressure, an orange-red
precipitate was obtained by the dropwise
1
1
2
2
3
1046 (C-O-C), 823(C-H) (pyridine), 736(β-ring)
1
(
pyridine), 622(C-C). H NMR(300 MHz; CDCl ; addition of a 4-fold excess of saturated aqueous
3
2
4
2
98K): 2.29(m, 2H, -CH ), 4.21 (m, 4H, -O-CH ), 45 KPF solution. The purification was carried out
2
2
6
.49(s, 4H, -N-CH ), 4.70 (s, 2H, -NH), 6.75(s,
by column chromatography on neutral
2
H, H ), 6.95 (d, 4H, J=9.0 Hz, H ), 7.39 (d, 4H,
aluminium oxide with CH CN-H O-saturated
6
13
3
2
J=9.0 Hz, H ), 7.47-7.51 (m, 2H, H ),
aqueous KNO (10:3:1, v/v/v) as eluent followed
12
3
3
7
.60-7.64(m, 2H, H ), 7.99 (d, 2H, J = 9.0 Hz,
by reprecipitation with a saturated KPF aqueous
8
6
H ), 8.26 (d, 2H, J = 9.0 Hz, H ), 8.89 (d, 2H, J = 50 solution. Orange-red powder was obtained
4
7
3
.0 Hz, H ), 9.18 (d, 2H, J = 3.0 Hz, H ).
in >60% yields.
2
9
3
1
BL : C H N O (0.39 g, 59 %). Anal. Calc: C,
[Ru(bpy) -BL -Ru(bpy) ](PF ) , complex 1:
4
2
36
6
2
2
2
6 4
76.83; H, 5.49; N, 12.80. Found: C, 76.85; H,
Yield: 65%. Anal. Calcd for C H N O Ru
80 64 14 2 2
-1
5
2
1
.44; N, 12.90%. IR (cm , KBr): 3329(N-H),
(PF ) : C, 47.20; H, 3.15; N, 9.64. Found: C,
6 4
-1
936(C-H), 1593(C=C), 1500(C=C), 1291(C-N), 55 47.26; H, 3.14; N, 9.66. IR (cm , KBr):
032 (C-O-C), 816(C-H) (pyridine), 729(β-ring)
3329(N-H), 2936(C-H), 1593(C=C), 1500(C=C),
1
(
pyridine), 622(C-C). H NMR(300 MHz; CDCl ; 1291(C-N), 1032 (C-O-C), 816(C-H) (pyridine),
3
1
298K): 2.03(s, 4H, -CH ), 4.08 (s, 4H, -O-CH ),
729(β-ring) (pyridine), 622(C-C). H NMR (300
2
2
4
2
.50(s, 4H, -N-CH ), 4.64 (s, 2H, -NH), 6.77(s,
MHz; DMSO-d ; 298K): 4.00(s, 2H, -NH),
2
6
H, H ), 6.94 (d, 4H, J=9.0 Hz, H ), 7.40 (d, 4H, 60 4.26 (s, 4H, -O-CH ), 4.57(s, 4H, -N-CH ),
6
13
2
2
J=9.0 Hz, H ), 7.50-7.54 (m, 2H, H ),
6.87(s, 2H, H ), 6.94 (d, 4H, J=6.0 Hz, H ), 7.27
6 13
12
3
7
.60-7.64(m, 2H, H ), 8.00 (d, 2H, J = 6.0 Hz,
(d, 4H, J=9.0 Hz, H ), 7.37-7.44 (m, 4H, H , H ),
12 3 8
8
H ), 8.26 (d, 2H, J = 9.0 Hz, H ), 8.91 (d, 2H, J =
7.77-7.82(m, 12H, bpy), 7.95 (d, 2H, J = 9.0 Hz,
4
7
3
.0 Hz, H ), 9.19 (d, 2H, J = 3.0 Hz, H ).
H ), 8.08(m, 4H, bpy), 8.15(m, 4H, bpy), 8.19(d,
4
2
9
2
.2.2 Synthesis of dinuclear Ruthenium 65 4H, J = 9.0 Hz, bpy ), 8.26 (d, 2H, J = 9.0 Hz,
complexes 1-3
H ), 8.27(m, 4H, bpy), 8.81 (d, 2H, J = 3.0 Hz,
7
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H ), 8.84(m, 4H, bpy), 9.05(d, 2H, J = 3.0 Hz,
2
(s, 4H, -O-CH ), 4.00(s, 2H, -NH), 4.56(s, 4H,
2
5
H9). UV-vis in CH CN: λ/nm (ε/10 35 -N-CH ), 6.89(s, 2H, H ), 6.92 (d, 4H, J=6.0 Hz,
3
2
6
3
−1
−1
dm ·mol · cm ): 286 (1.42); 362 (0.23); 460
H ), 7.16-7.24 (m, 4H, H , H ), 7.42 (d, 4H,
13 3 8
4
+
(
0.26). ESI-MS: m/z 363.7 [M-4PF6] (calcd:
363.5)
Ru(bpy) -BL -Ru(bpy) ](PF ) , complex 2:
J=9.0 Hz, H ), 7.57-7.59 (m, 12H, bpy), 7.83 (d,
12
5
0
5
0
5
0
2H, J = 9.0 Hz, H ), 8.08(m, 4H, bpy), 8.13(m,
4
2
[
4H, bpy), 8.19(d, 4H, J = 9.0 Hz, bpy ), 8.26 (d,
2
2
6 4
Yield: 60%. Anal. Calcd for C H N O Ru 40 2H, J = 9.0 Hz, H ), 8.27(m, 4H, bpy), 8.67 (d,
8
1
66 14
2
2
7
(
PF ) : C, 47.46; H, 3.22; N, 9.57. Found: C,
2H, J = 3.0 Hz, H ), 8.82(m, 4H, bpy), 9.05(d,
6
4
2
-1
4
7.44; H, 3.18; N, 9.56. IR (cm , KBr):
2H, J = 9.0 Hz, H ). UV-vis in CH CN: λ/nm
9
3
5
3
−1
−1
1
1
2
2
3
3325(N-H), 2930(C-H), 1579(C=C), 1495(C=C),
(ε/10 dm ·mol ·cm ): 286 (2.41); 353 (0.41);
4
+
1
237(C-N), 1032 (C-O-C), 835(C-H) (pyridine),
464 (0.45). ESI-MS: m/z 371.2 [M-4PF6]
1
3+
7
81(β-ring) (pyridine), 637(C-C). H NMR (300 45 (calcd: 370.5), 542.8[M-3PF ] (calcd: 542.3),
6
2+
MHz; DMSO-d ; 298K): 2.13(m, 2H, -CH ),
887.2[M-2PF ] ( calcd: 886.0).
6
2
6
4
.01(s, 2H, -NH), 4.07 (m, 4H, -O-CH ), 4.56(s,
2.3 Methods
2
4H, -N-CH ), 6.89(s, 2H, H ), 6.94 (d, 4H, J=6.0
2.3.1 MTT assays
2
6
Hz, H ), 7.39 (d, 4H, J=9.0 Hz, H ), 7.42-7.51
Standard MTT(3-(4, 5-dimethylthiazol-2-yl)-2,
1
3
12
(
m, 4H, H , H ), 7.79-7.84(m, 12H, bpy), 7.97 (d, 50 5-diphenyltetrazolium
bromide)
assay
3
8
2
2
2
4
H, J = 9.0 Hz, H ), 8.09(m, 4H, bpy), 8.15(m,
procedures were used. Cells were placed in
4
3
H, bpy), 8.19(d, 4H, J = 9.0 Hz, bpy ), 8.26 (d,
96-well microassay culture plates (8×10 cells
2H, J = 9.0 Hz, H ), 8.27(m, 4H, bpy), 8.81 (d,
per well) and grown overnight at 37 °C in a 5%
7
2
2
H, J = 3.0 Hz, H ), 8.84(m, 4H, bpy), 9.07(d,
CO incubator. The complexes tested were then
2
2
H, J = 3.0 Hz, H ). UV-vis in CH CN: λ/nm 55 added to the wells to achieve final concentrations
9
3
5
3
−1
−1
-6
-4
-1
(
ε/10 dm ·mol ·cm ): 286(1.33); 360(0.23);
ranging from 0.39×10 to 10 µmol·L . Control
61(0.23). ESI-MS: m/z 367.2 [M-4PF ] (calcd: wells were prepared by addition of culture
4+
4
6
367.0)
Ru(bpy) -BL -Ru(bpy) ](PF ) , complex 3:
medium (200 µL). The plates were incubated at
3
[
37 °C in a 5% CO incubator for 48 h. On
2
2
6 4
2
Yield: 62%. Anal. Calcd for C H N O Ru 60 completion of the incubation, stock MTT dye
8
2
68 14
2
2
-
1
(
PF ) : C, 47.72; H, 3.30; N, 9.51. Found: C,
solution (20 µL, 5 mg·mL ) was added to each
well. After 4 h, 150 mL dimethylsulfoxide
(DMSO) was added to solubilize the MTT
formazan. The optical density of each well was
6
4
-1
4
7.70; H, 3.28; N, 9.46. IR (cm , KBr):
3415(N-H), 2939(C-H), 1600(C=C), 1507(C=C),
1
7
377(C-N), 1025 (C-O-C), 758(C-H) (pyridine),
1
22(β-ring) (pyridine), 657(C-C). H NMR (300 65 then
measured
with
a
microplate
MHz; DMSO-d ; 298K): 1.83(s, 4H, -CH ), 3.99
spectrophotometer at a wavelength of 490 nm.
6
2
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New Journal of Chemistry
1
1
The IC values were determined by plotting the
CDCl . The H NMR spectrum of L shown ten
5
0
3
percentage viability versus the concentration and 35 sets of signals in the aromatic region, as
reading off the concentration at which 50 % of
the cells remained viable relative to the control.
Each experiment was repeated at least three
times to obtain the mean values. Three different
illustrated in Supporting Information Fig. 2. The
signal assignment was rather straightforward by
the comparison of chemical shifts with those of
similar Schiff-base ligands, the resonances at
5
0
5
0
5
0
tumor cell lines were the subjects of this study: 40 9.23, 9.12, 8.78, 8.21, 7.65, 7.59 and 7.27 ppm
Hela (human cervical carcinoma), BGC823 were assigned to the H , H , H , H , H , H and
human gastric carcinoma), and
SGC-7901(human gastric carcinoma).
.3.2 Fluorescence spectra
2
9
4
7
3
8
(
H protons, respectively, of the phenanthroline
6
1
1
2
2
3
ring. The resonances at 8.02 and 7.12 ppm were
assigned to the H11 and H12 protons, respectively,
2
Fluorescence measurements were carried out by 45 of the phenyl spacer. The H13 (methylene)
keeping the concentration of complexes constant
10 μM) and varying the concentration of
protons of the linker moiety resonated at 4.47
ppm. It’s worth noting that there was a singlet at
8.64 ppm, which indicated formation of -C=N in
(
CT-DNA from 20 to 100 μM. The complexes
were excited at 465 nm and the fluorescence
spectra were recorded between 500 and 800 nm.
1
-3
the Schiff base. The bridging ligands BL were
1
-3
50 synthesized by reducing the L in the presence
3
3
. Results and discussion
of sodium borohydride.
1
1-3
.1 H NMR of the bridging ligands BL
1
-3
The synthetic route of the bridging ligands BL
and the complexes 1-3 was depicted in Scheme 1.
The precursors dialdehyde were synthesized by
modifying the procedure reported by Donahoe et
2
1 1
a. ( H NMR of dialdehyde in Supporting
1
-3
Information Fig.1).The Schiff bases L were
obtained as yellow powder by reacting the
dialdehyde and 5-amino-1,10-phenanthroline in
the presence of glacial acetic acid in methanol.
1-3
Scheme 1 Synthetic route of the bridging ligands BL
and the complexes 1-3.
55
R=CH CH (1),(CH ) (2),(CH ) (3)
2
2
2 3
2 4
1
-3
The ligands were polyaromatic bridging ligands
containing two equivalent chelating sites of
phenanthroline ring. In the ligands, the two
phenanthroline moieties were bridged by a
The L gave satisfactory elemental analysis, the
IR spectra of all the three ligands shown the
-1
presence of any band around 1600 cm , which
indicated the formation of C=N in the Schiff base,
1
1-3
60 flexible alcoxyphenyl spacer moiety. They were
and the H NMR spectra of L were recorded in
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1
.
characterized by IR, H NMR and elemental
Ru(bpy) Cl 2H O in ethanol. The complexes
2 2 2
1
1
analysis. In the H NMR spectrum of BL (in
were isolated as hexafluorophosphate salt and
Fig.1), the signal of Schiff base at 8.64 ppm 30 stable in air and in solution. The elemental
disappeared and at 4.71 ppm a new weak signal
analyses suggested the formation of the dinuclear
1
-3
1
5
0
5
0
appeared, which indicated the -C=N of L were
ruthenium complexes. H NMR spectra of
reduced into -CH -NH. The resonances at 9.19,
complexes 1-3 were recorded in d -DMSO, since
2
6
8
.90, 8.27, 7.99, 7.61, 7.47 and 6.75 ppm were
the electronic environments of many aromatic
assigned to the H , H , H , H , H , H and H 35 hydrogen atoms were very similar, their signals
9
2
7
4
8
3
6
protons, respectively, of the phenanthroline ring.
The resonances at 7.41 and 6.99 ppm were
assigned to the H and H protons, respectively,
may appear in a narrow chemical shift
range(7.2-9.0 ppm). In fact, the aromatic regions
of the spectra were complicated, however, the
number of the aromatic proton signals were
1
1
2
1
3
14
of the phenyl spacer. The H15 (methylene)
protons of the linker moiety resonate at 4.37 ppm. 40 consistent with the number of protons of
The H12 protons of the methylene resonate at
4.52 ppm and the NH proton at 4.71 ppm. The
molecular formula. The partial overlapping of the
signals made it difficult to assign all the
2
3
1
resonances of BL and BL were analogous to
individual signals respectively. The detailed H
1
1
BL , and the detailed H NMR information of
NMR information of complexes 1-3 were shown
2
3
BL and BL were shown in the Supporting 45 in the Supporting Information Fig. 4. The
1
Information Fig. 3, all H NMR data indicated
structures of dinuclear complexes were further
established by electrospray mass spectrometry
that -C=N were reduced to -CH -NH.
2
(
ESI-MS) in DMSO-CH OH. This technique has
3
proven to be very helpful for identifying
polynuclear metal complexes with high
molecular masses. In the ESI-MS of the complex
5
5
6
0
5
0
1
, the peak at m/z 363.7 was due to the dinuclear
4
+
species 1 ; in the ESI-MS of the complex 2, the
4
+
peak at m/z 367.2 was due to the species 2 ; in
the ESI-MS of the complex 3, the peaks at m/z
1
1
Fig.1 H NMR of BL in the CDCl
3
3
.2 Synthesis and characterization of
8
87.2, 542.3 and 371.2 were due to the species
Ruthenium complexes 1-3
.
2+
.
3+
4+
[
3 2PF ] , [3 PF ] and 3 , respectively(See
6 6
2
5
The dinuclear complexes 1-3 were prepared by
the reaction of the preformed double-N,
Supporting Information Fig. 5). All of these
information indicates that the dinuclear
ruthenium complexes are stable in the solution.
1
-3
N-bidentate bridging ligands BL
with
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New Journal of Chemistry
2
+
3
.3 Electronic absorption spectra studies
that of [Ru(bpy) ] (λmax = 451 nm) which can be
3
The electronic absorption spectral data of the 15 attributed to the extended structural framework
2
4
dinuclear complexes 1-3 were presented in Table
. The complexes exhibited intense absorption
of the bridging ligands. The Ru(Ⅱ) complexes
1
were dark red in solution and in the solid state
1
5
bands at 286 and 360 nm due to the spin-allowed
due to the strong MLCT absorption band at 460
1
ligand centered ( LC) π-π* transition of the
nm.
ligand framework and a broad band at 460 nm
20
3.4 Luminescence spectra studies
The emission spectral data (wavelength of
excitation and emission) were presented in Table
3
-1
-1
3
-1
-1
(
ε/dm mol cm 26070), 461nm (ε/dm mol cm
3
-1
-1
2
2720) and 464 nm (ε/dm mol cm 45470),
1
0
respectively, assignable to the spin-allowed
1
. All measurements were made with solutions
1
23
MLCT (d -π*) transition. The MLCT band of
π
deoxygenated by purging argon. The excitation
the complexes 1-3 with bpy as ancillary ligands
25
spectra of the complexes 1-3 were monitored at
were bathochromically shifted with respect to
Table 1 Photophysical and electrochemical data of the complexes 1-3
complex
Absorption
(nm)
ε/10 dm ·mol ·cm
Excitation
λex(nm)
Emission
λ (nm)
em
λ
E (V)
1/2
max
5
3
−1
−
Metal
Ligand
centered
reductions
-0.81, -1.60
-1.86
1
centered
oxidation
0.92, 1.37
1
2
3
286(1.4), 362(0.2)
468
467
468
601
602
602
4
60(0.26)
286(1.3), 360(0.2)
61(0.23)
286(2.4), 353(0.4)
64(0.45)
0.94, 1.42
0.95, 1.44
-0.47, -1.62
-1.83
-0.52, -1.57
-1.81
4
4
emission maxima of each complex at room
excitation spectrum of complex 3 contained two
temperature. The excitation spectrum of the free 40 weak bands at 264 and 372 nm and one intense
1
-3
ligands BL contained bands at 286, 302 and
343 nm. The free ligands emitted at 426 nm upon
excitation onto the excitation maxima. This
fluorescence band of the ligand was no longer
band at 468 nm. The complexes 1-3 upon
excitation onto their excitation maxima exhibited
an emission band at 601, 602 and 602 nm,
respectively. The emission profile and emission
3
0
observed in its metal complex. The excitation 45 maxima were similar and independent of the
spectrum of complex 1 contained two weak
excitation wavelength. The electronic emission
spectral of the complexes 1-3 were presented in
Fig. 2.
3
5
bands at 268 and 373 nm and one intense band at
4
68 nm, the excitation spectrum of complex 2
contained two weak bands at 267 and 372 nm
and one intense band at 467 nm, while the
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2
2
1
1
50
00
50
00
place and adsorption of the complexes on the
electrode surface also occurred. However, the
30 first reduction potential was still safely measured
which was assigned to the reduction of the
bridging ligands although more precise
assignment could not be made. The first
reduction, usually expected to involve the ligand
35 having the most stable lowest unoccupied
1
2
3
5
0
0
5
00
550
600
650
700
Wavelength/nm
Fig. 2 The emission spectrum of complexes 1-3 in
-5
. -1
2
6
acetonitrile(1.0×10 mol L , λ =465nm)
ex
molecular orbital (LUMO), the other two
3
.5 Electrochemistry studies
successive reductions were characteristic of the
2
7
5
0
5
The redox behavior of the complexes 1-3 has
been investigated in acetonitrile solution to
complement the spectroscopic data. The
investigation of electrochemical behavior was
very useful to determine the extent of electronic
interaction between the metal centers. The cyclic
voltammetric data of the complexes were
presented in Table 1, and a representative was
shown in Fig. 3. All the three complexes
exhibited two oxidations in the range of 0-1.5 V.
Since the bridging ligands did not exhibit any
obvious peaks at the range of 0-1.5 V under the
same condition, these peaks of the complexes
bpy ligands. It was concluded that reduction of
the complexes occured first on the bridging
ligands and then on the bpy ligands.
4
0
0
.002
.000
1
0
-
0.002
-0.004
-
2
-1
0
1
2
E/V vs SCE
Fig. 3 Cyclic voltammograms (scan rate 100 mV/s) of
1
complex 1
3
.6 Cytotoxicity studies
45
The cytotoxicity of the complexes 1-3 in vitro
were assessed using the method of MTT
reduction, culture medium was used as a positive
control. After treatment of three cell lines for 48h
with complexes 1-3 in a range of concentrations
Ⅱ
were all assigned to the redox of the Ru
moieties. In Fig. 3, the oxidations at 0.92 and
2
0
1.37 V of complex 1 correspond to the couples
5
+
4+
6+ 5+
1
/1 and 1 /1 , respectively. Oxidation of
these complexes stabilized the metal d -orbital
. -1
π
50
(0.39-100 µmol L ), the percentage inhibition of
growth of the cancer cells was determined. The
cell viabilities (%) vs concentrations obtained
with continuous exposure for 48 h were depicted
in Fig. 4, the IC values were listed in Table 2.
directly and the ligand π*-orbital indirectly
through charge interactions. Subsequent d -π*
π
2
5
back bonding further stabilized the metal
2
5
dπ-orbital but destabilized the ligand π*-orbital.
5
0
On reduction, several ill-behaved processes took
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New Journal of Chemistry
3
5
Table 2 The IC of the complexes 1-3
cells.
50
.
-1
IC (µmol L )
5
0
(a)
Complex
1
00
1
2
3
Hela
SGC-7901
BGC823
1
2
3
18.39
16.04
13.09
21.60
15.86
10.38
16.14
13.83
9.21
8
6
0
0
The cytotoxicity of the complexes were found to
be concentration dependent. The cell viability
decreased with increasing concentrations of both
complexes. From Table 2, it is clear that complex
40
2
0
0
5
0
5
0
5
0
20
40
60
80
100
3
is generally the most active and exhibits low
Complexes Concentration (μmol/L)
3
0
IC values of 9.21 and 10.38 µM for BGC823
5
0
(b)
1
00
1
2
3
and SGC-7901 cells, and complex 1 is less active
than complex 2 in three cell lines. The
cytotoxicity of complex 3 toward Hela cells is
higher than that of [(bpy) Ru(L)Ru(bpy) ]Cl
4
8
6
4
2
0
0
0
0
0
1
1
2
2
2
2
(
L=1,6-bis(3-(1Himidazo[4,5-f][1,10]phenanthro
lin-2-yl)-9H-carbazol-9-yl)hexane) (IC50 >100
2
8
µM). The difference in cytotoxicity of these
complexes toward the Hela, SGC823 and
SGC-7901 cell lines may be caused by different
number of methylene groups in the flexible
alkane chain. The in vitro activity of anticancer
drugs can often be related in part to their
lipophilic character, the resulting hydrophobicity
may contribute to an increased uptake of the
complex by the cells, thereby enhancing the
0
20
40
60
80
100
Complexes Concentration (μmol/L)
(c)
100
1
2
3
80
60
40
20
0
0
20
40
60
80
100
Complexes Concentration (μmol/L)
2
9-33
antiproliferative activity.
Alternatively, due
Fig.4 Cell viability of complexes 1-3 toward
proliferation of Hela (a), SGC-7901 (b) and BGC823 (c)
cells in vitro.
to the higher negative mitochondrial membrane
potential present in cancer cells, lipophilic
cations may preferentially cross the membrane
35
3
4
and accumulate in mitochondria,
thereby
leading to the observed higher uptake in cancer
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3
.7 DNA binding studies
The fluorescence measurement was performed to
clarify the interaction mode between the
complexes and DNA, CT-DNA was chosen as a
the interaction between naproxen and ds-DNA in
a groove binding mode cause a strong
3
9
fluorescence quenching.
emit 20 emission intensity of complexes also agrees with
the findings obtained with other
non-intercalators. The quenching constants
(K ) using the Stern-Volmer fluorescence
This decrease in
5
0
5
representative.
Complexes
1-3
luminescence in a buffer 10 mM Tris and 50 mM
NaCl, with a maximum wavelength of about 600
nm when excited at 465 nm. The emission
spectra of complexes with the increase in amount
4
0,41
SV
4
2
quenching equation, F /F = 1 + K [Q], were
0
SV
5
5
5
1
of CT-DNA are shown in Fig. 5. The observed 25 obtained 1.34×10 , 1.46×10 and 2.98×10
-1
luminescence quenching of complexes by
CT-DNA is consistent with a photoelectron
transfer from guanine base of DNA to the excited
MLCT state of the Ru(II) complex as reported in
mol ·L for 1, 2 and 3, respectively. DNA
binding studies by fluorescence spectroscopic
titrations reveal that complex 3 binds more
strongly to CT-DNA as compared to complexes
2
+
2+
1
the cases of [Ru(bzimpy) ] , [Ru(TAP) ] and 30 1 and 2. This result is consistent with
2 3
2
+ 36-38
[
Ru(bpz) ] .
In addition, it was found that
cytotoxicity.
3
6
5
4
3
2
1
00
00
00
00
00
00
0
1
40
20
4
.5
4
3
2
1
00
00
00
00
0
2.2
2.4
2.2
2.0
4.0
1
2
1
1
1
1
1
.0
.8
.6
.4
.2
.0
3.5
100
80
1.8
3.0
2.5
2.0
1.5
1.6
1.4
1.2
60
0
2
4
6
8
10
0
2
4
6
8
10
0
2
4
6
8
10
[DNA]x105
[DNA]x105
[
DNA]x10
5
4
0
0
0
2
5
00
550
600
650
700
750
800
500
550
600
650
700
750
800
500
550
600
650
700
750
800
Wavelength/nm
Wavelength/nm
Wavelength/nm
Fig.5 Changes in the fluorescence spectra of complexes 1-3 with increasing concentrations of CT-DNA. Inset:
changes of intensity with increasing concentrations of CT-DNA
3
5
4
. Conclusions
dinuclear complexes with equivalent metal
A
series of new phenanthroline-based 45 centers. Absorption spectra, luminescent
dinucleating bridging ligands and their dinuclear
properties and electrochemical behavior have
been studied and these properties of the Ru(Ⅱ)
species were dominated by MLCT transitions
and excited states. The results also showed that
Ru(Ⅱ) complexes have been synthesized and
4
0
characterized by elemental analysis, IR, ESI-MS
1
and H NMR techniques. The bridging ligands
readily formed dinuclear Ru(Ⅱ) complexes and 50 each metal-based subunit retained its own
spectroscopic properties in the dinuclear arrays.
their symmetric nature ensured the formation of
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New Journal of Chemistry
Cytotoxic assays in vitro of the complexes was
complexes. The interaction between complexes
and CT-DNA were studied using fluorescence
spectrometry. The addition of CT-DNA to
complexes solution resulted in a strong
fluorescence quenching. The interaction between
complexes and the CT-DNA may be a groove
binding mode.
studied, according to the studies, Ru( Ⅱ )
complexes showed significant dose-dependent
cytotoxicity to cervical cancer(Hela), gastric
cancer(SGC-7901) and gastric cancer(BGC823)
tumour cell lines, and the more of methylene of
bridging ligands, the higher cytotoxicity of the
10
5
1
5
Acknowledgements
[
[
8] E. Wachter, D. K. Heidary, B. S. Howerton,
This work was supported by the National Natural
Science Foundation of China (No. 21101121),
the Natural Science Fund (No. 2010CDB01301)
of Hubei Province.
S. Parkin and E. C. Glazer, Chem Commun.,
2
012, 48, 9649-9651.
9] A. Grau-Campistany, A. Massaguer, D.
Carrion-Salip, F. Barragan, G. Artigas, P.
Lopez-Senin, V. Moreno and V. Marchan,
Mol. Pharmaceutics., 2013,10, 1964-1976.
10]R. Pettinari, C. Pettinari, F. Marchetti, C. M.
Clavel, R. Scopelliti and P. J. Dyson,
Organometallics, 2013, 32, 309-316.
2
0
4
5
5
6
6
5
0
5
0
5
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