Synthesis, characterization and cytotoxicity of Pt(II), Pd(II), Cu(II) and Zn(II) complexes with 4'-substituted terpyridine

Article abstract of DOI:10.1002/aoc.2988

Eight novel Pt(II), Pd(II), Cu(II) and Zn(II) complexes with 4'-substituted terpyridine were synthesized and characterized by elemental analysis, UV, IR, NMR, electron paramagnetic resonance, high-resolution mass spectrometry and molar conductivity measur

Full text of DOI:10.1002/aoc.2988

Full Paper
Received: 11 December 2012
Revised: 26 February 2013
Accepted: 3 March 2013
Published online in Wiley Online Library: 21 May 2013
(wileyonlinelibrary.com) DOI 10.1002/aoc.2988
Synthesis, characterization and cytotoxicity
of Pt(II), Pd(II), Cu(II) and Zn(II) complexes with
4’-substituted terpyridine
Shuxiang Wanga,b*, Wenhao Chua, Yuechai Wanga, Siyuan Liua,
Jinchao Zhanga,b, Shenghui Lia, Haiying Weia, Guoqiang Zhoua
and Xinying Qina
Eight novel Pt(II), Pd(II), Cu(II) and Zn(II) complexes with 4’-substituted terpyridine were synthesized and characterized by elemental
analysis, UV, IR, NMR, electron paramagnetic resonance, high-resolution mass spectrometry and molar conductivity measurements.
The cytotoxicity of these complexes against HL-60, BGC-823, KB and Bel-7402 cell lines was evaluated by MTT assay. All the
complexes displayed cytotoxicity with low IC50 values (<20 mM) and showed selectivity. Complexes 3, 5, 7 and 8 exerted 9-, 5-,
12- and 7-fold higher cytotoxicity than cisplatin against Bel-7402 cell line. The cytotoxicity of complexes 3, 5, 6, 7 and 8 was higher
than that of cisplatin against BGC-823 cell line. Complexes 3, 7 and 8 showed similar cytotoxicity to cisplatin against KB cell line.
Complex 7 exhibited higher cytotoxicity than cisplatin against HL-60 cell line. Among these complexes, complex 7 demonstrated
the highest in vitro cytotoxicity, with IC50 values of 1.62, 3.59, 2.28 and 0.63 mM against HL-60, BGC-823, Bel-7402 and KB cells lines,
respectively. The results suggest that the cytotoxicity of these complexes is related to the nature of the terminal group of the ligand,
the metal center and the leaving groups. Copyright © 2013 John Wiley & Sons, Ltd.
Keywords: Pt(II), Pd(II), Cu(II) and Zn(II) complexes; 4’-substituted terpyridine; cytotoxicity
critical for numerous cellular processes, and may be a major regula-
Introduction
tory ion in the metabolism of cells.[16] The synthesis of new Zn(II)
Cisplatin is one of the most effective drugs in the treatment of
testicular, ovarian, small cell lung, bladder, cervical, head and
neck carcinomas.[1–5] Regardless of the achievements of current
platinum drugs, there are some major drawbacks, including
effectiveness against only a limited range of cancers, drug resis-
tance and severe side effects.[6,7] These problems provide an
incentive to discover new metal-based anticancer drugs.
complexes, study of their pharmacological properties and their
screening as antitumor agents constitute a matter of current inter-
est.[17] Stanojkovic et al.[18] reported several zinc(II) complexes
based on 2-acetylpyridine thiosemicarbazone derivatives, with
IC50 values ranging from 26 to 90 nM, against HeLa (cervical
adenocarcinoma), K562 (chronic myelogenous leukemia), and
MDA-MB-361 and MDA-MB-453 (breast cancer) cell lines.
Transition metal complexes as antitumor agents have been
extensively used following the success of cisplatin.[8] Among
the non-platinum compounds for cancer treatment, palladium
(II) derivatives have been reported to possess antitumor activity
Coordination chemistry of multidentate a-tpy-based ligands is
one of the most interesting research subjects because of their
application in molecular probes for biochemical research.[4] Metal
complexes of tpy can efficiently intercalate into nucleic acid to be
effectively performed as potential antitumor agents.[5] Modifica-
tion of tpy generated a variety of derivatives and structural
variation of tpy may have a significant impact on the antitumor
activity of their complexes.[13–19] In order to further explore the
structure–activity relationships and discover new metal-based
at least comparable to cisplatin, while they exhibit less kidney
[7]
toxicity.[9–11] Khan et al.
reported a series of mixed-ligand
dithiocarbamate Pd(II) complexes. The antitumor screening of
these compounds showed them to be highly active against
cisplatin-resistant DU145 human prostate cancer cells. Ulukaya
et al.[8] reported a Pd(II) complex based on terpyridine (tpy) and
saccharin, which exhibited a more powerful antigrowth effect than
its Pt(II) analog and cisplatin against human non-small cell lung
cancer cells. Copper(II) is known to be involved in many biological
processes and its role in increasing antitumor efficacy of organic
molecules has been established.[12,13] Roy et al.[14] synthesized
copper(II) complexes with terpyridyl and phenanthroline bases
in a distorted square-pyramidal coordination geometry; these
copper(II) complexes showed significant cytotoxicity with low IC50
value. Patel et al.[15] reported some copper(II) complexes based
on tpy and norfloxacin, and all the complexes exhibited good
cytotoxic activity. Zinc(II) is a vital component, an essential cofactor,
*
Correspondence to: Shuxiang Wang, Key Laboratory of Chemical Biology of
Hebei Province, College of Chemistry and Environmental Science, Hebei
University, Baoding 071002, Hebei, People’s Republic of China. Email:
wsx@hbu.edu.cn
a Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry
and Environmental ScienceHebei University, Baoding 071002, People’s Republic
of China
b Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of
Education, Hebei University, Baoding 071002, People’s Republic of China
Appl. Organometal. Chem. (2013), 27, 373–379
Copyright © 2013 John Wiley & Sons, Ltd.

S. Wang et al.
4’-(4-Carboxymethylphenyl)-2,2’,6’,2”-terpyridine (Lb)
anticancer drugs, the synthesis, characterization and cytotoxicity
of eight new metal (Pt(II), Pd(II), Cu(II) and Zn(II)) complexes with
4’-substitued tpy are described in the present work for the first time.
The results of the cytotoxicity experiments indicated that the metal
(Pt(II), Pd(II), Cu(II) and Zn(II)) complexes with 4’-substitued tpy
exerted cytotoxic effects against HL-60 (immature granulocyte
leukemia), BGC-823 (gastrocarcinoma), Bel-7402 (liver carcinoma)
and KB (nasopharyngeal carcinoma) cell lines.
The synthesis of Lb was carried out in a similar manner to La starting
from chloroacetic acid (3.2 g, 32 mmol),4-hydroxybenzaldehyde
(4.88 g, 40 mmol), 2-acetylpyridine (2.03 g, 16.8 mmol) and aqueous
NH3 (40 ml, 25%). White solid; yield 1.04 g, 32.4%; m.p. > 250ꢂC;
UV (methanol, nm) 206, 227, 251, 285; IR (KBr, cmꢁ1) 3059–3029
(CꢁH), 1521 (C¼N); 1H NMR (CD3OD, 600 MHz) d/ppm: 8.76
(d, 2H, J = 4.8 Hz, 6,6”-H, tpy), 8.67 (s, 2H, 3’,5’-H, tpy), 8.65 (dd, 2H,
J = 7.8, 1.2 Hz, 3,3”-H), 8.02 (td, 2H, J = 7.8, 1.2 Hz, 4,4”-H, tpy),
7.87 (d, 2H, J = 9.0 Hz, 3,5-H, ph), 7.52 (ddd, 2H, J = 7.8, 4.8,
1.2 Hz, 5-5”-H, tpy), 7.13 (d, 2H, J = 9.0 Hz, 2,6-H, ph), 4.79
(s, 2H, CH2);13C NMR (CD3OD, 150 MHz) d/ppm: 174.8 (COOH),
160.1 (1-C, ph), 156.1 (2C, 2’,6’-C, tpy), 155.7 (2C, 2,2”-C, tpy),
150.0 (4’-C, tpy), 148.7 (2C, 6,6”-C, tpy), 137.4 (2C, 4,4”-C, tpy),
130.1 (4-C, ph), 127.8 (2C, 3,5-C, ph), 124.0 (2C, 3,3”-C, tpy),
121.6 (2C, 5,5”-C, tpy), 117.8 (2C, 3’,5’-C, tpy), 115.1 (2C, 2,6-C, ph),
67.1 (CH2); Anal. Calcd for C23H17N3O3: C, 72.05; H, 4.47;
N, 10.96. Found: C, 72.09; H, 4.47; N, 10.95; HRMS (+)-ESI
m/z [M + H]+ calcd for [C23H18N3O3]+: 384.1343; found: 384.1343.
Experimental
Materials and Measurements
All chemicals and reagents were of analytical grade. DMSO-d6 was
purchased from Separation (Beijing) Technology Co. Ltd. RPMI-1640
medium, trypsin and fetal bovine serum were purchased from Gibco.
3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT),
benzyl penicillin and streptomycin were from Sigma. Four different
human carcinoma cell lines – HL-60, BGC-823, Bel-7402 and KB – were
obtained from Peking University Health Science Center.
4’-(4-(2-Morpholinoethoxy)phenyl)-2,2’,6’,2”-terpyridine (Lc)
Elemental analyses were determined on an Elementar Vario EL III
elemental analyzer. The UV spectra were measured using a TU-1901
double-beam UV-visible spectrophotometer (Beijing Purkinje
General Instrument Co. Ltd). The IR spectra were recorded using
KBr pellets and a PerkinElmer Model-683 spectrophotometer. The
far-IR spectra were recorded on NICOLET 750. The 1H NMR spectra
were recorded on a Bruker AVIII 600 NMR spectrometer. Electron
paramagnetic resonance (EPR) was recorded on Bruker E500.
Electrospray ionization (ESI) high-resolution mass spectrometry
(HRMS) was performed by apex ultra 7.0T US+. Molar conductance
at room temperature was measured in 1ꢀ 10ꢁ3 M methanol or DMF
solution using a DDS-12DW type conductivity meter. Optical
density (OD) was measured on a microplate spectrophotometer
(Bio-RadModel 680, USA).
The synthesis of Lc was carried out in a similar manner to La starting
from 4-hydroxybenzaldehyde (2.44 g, 20 mmol),N-(2-Chloroethyl)
morpholine hydrochloride (3.68 g, 20 mmol), 2-acetylpyridine
(4.2 g, 40 mmol) and aqueous NH3 (40 ml, 25%). White solid; yield
2.94 g, 33.6%; m.p. 165–166.1ꢂC; UV (methanol, nm) 203, 227, 251,
1
285; IR (KBr, cmꢁ1) 3059–3039 (CꢁH), 1521 (C¼N); H NMR (CDCl3,
600 MHz) d/ppm: 8.71 (d, 2H, J= 4.8 Hz, 6,6”-H, tpy), 8.69 (s, 2H,
3’,5’-H), 8.64 (d, 2H, J= 7.8 Hz, 3,3”-H, tpy), 7.84 (m, 4H, 4,4”-H, tpy,
3,5-H, ph), 7.31 (dd, 2H, J= 7.8, 4.8 Hz, 5,5”-H, tpy), 7.01 (d, 2H,
J= 8.4 Hz, 2,6-H, ph), 4.15 (t, 2H, J=3.0 Hz, O-CH2), 3.75 (t, 4H,
J = 3.0 Hz, O-CH2, morpholine), 2.81 (t, 2H, J = 3.0 Hz, N-CH2),
2.60 (t, 4H, J = 3.0 Hz, N-CH2, morpholine); 13C NMR (CDCl3, 150
MHz) d/ppm: 159.7 (1-C, ph), 156.4 (2C, 2’,6’-C, tpy), 155.9 (2C,
2,2”-C, tpy), 149.7 (4’-C, tpy), 149.1 (2C, 6,6”-C, tpy), 136.8 (2C,
4,4”-C, tpy), 131.0 (4-C, ph), 128.6 (2C, 3,5-C, ph), 123.8 (2C,
3,3”-C, tpy), 121.4 (2C, 5,5”-C, tpy), 118.3 (2C, 3’,5’ -C, tpy), 115.0
(2C, 2,6-C, ph), 67.0 (2C, OꢁCH2, morpholine), 66.0 (OꢁCH2),
57.7 (NꢁCH2), 54.2 (2C, NꢁCH2, morpholine); Anal. Calcd for
Synthesis of Ligands
4’-(4-Hydroxyphenyl)-2,2’,6’,2”-terpyridine (La)
C
27H26N4O2: C, 73.95; H, 5.98; N, 12.78. Found: C, 73.93; H, 5.95;
4-Hydroxybenzaldehyde (2.44 g, 20 mmol) was dissolved in 100 ml
of 95% ethanol solution, following addition of 2-acetylpyridine
(4.84 g, 40 mmol) and KOH (4.2 g). After stirring for a few minutes,
aqueous NH3 (50 ml, 25%) was added to the solution and the
mixture was stirred at 50ꢂC overnight. A large amount of green solid
was obtained when the pH of the solution was changed to 3–4
followed by evaporation of ethanol in the solution. The precipitate
was filtrated and washed with ethanol (3 ꢀ 10 ml) and recrystallized
with methanol. A green solid was obtained after drying. Yield 2.23 g,
34.3%; m.p. > 250ꢂC; UV (methanol, nm) 203, 229, 251, 285; IR
(KBr, cmꢁ1) 3435 (OH), 3071–3039 (CꢁH), 1521 (C¼N); 1H NMR
(CD3OD, 600 MHz) d/ppm: 9.08 (m, 4H, 6,6”-H, 3,3”-H, tpy), 8.91
(s, 2H, 3’,5’-H, tpy), 8.72 (td, 2H, J= 7.8, 1.2 Hz, 4,4”-H, tpy), 8.14
(td, 2H, J= 7.8, 1.2 Hz, 5,5”-H, tpy), 8.02 (d, 2H, J=9.0 Hz, 3,5-H, ph),
7.05 (d, 2H, J = 9.0 Hz, 2,6-H, ph); 13C NMR (CD3OD, 150 MHz)
d/ppm: 160.5 (1-C, ph), 156.3 (2C, 2’,6’-C, tpy), 155.9 (2C, 2,2”-C, tpy),
149.8 (4’-C, tpy), 149.1 (2C, 6,6”-C, tpy), 136.8 (2C, 4,4”-C, tpy),
131.7 (4-C, ph), 129.4 (2C, 3’,5’-C, tpy), 123.7 (2C, 3,3”-C, tpy), 121.2
(2C, 5,5”-C, tpy), 118.4 (2C, 3’,5’-C, tpy), 116.5 (2C, 2,6-C, ph); Anal.
Calcd for C21H15N3O: C, 77.52; H, 4.65; N, 12.91. Found: C, 77.54; H,
4.63; N, 12.88; HRMS (+)-ESI m/z [M+ H]+ calcd for [C21H16N3O]+:
326.1288; found: 326.1287.
N, 12.76; HRMS (+)-ESI m/z [M + H]+ calcd for [C27H27N4O2]+:
439.2129; found: 439.2128.
4’-(4-(2-(Piperidin-1-yl)ethoxy)phenyl)-2,2’,6’,2”-terpyridine) (Ld)
The synthesis of Ld was carried out in a similar manner to La starting
from 4-hydroxybenzaldehyde (2.44 g, 20 mmol), N-(2-chloroethyl)
piperidine hydrochloride (3.68 g, 20 mmol), 2-acetylpyridine
(4.2 g, 40 mmol) and aqueous NH3 (40 ml, 25%). White solid; yield
3.13 g, 35.9%; m.p. 134.7–135.3ꢂC; UV (methanol, nm) 203, 227,
1
251, 285; IR (KBr, cmꢁ1) 3059–3039 (CꢁH), 1590 (C¼N); H NMR
(CDCl3, 600 MHz) d/ppm: 8.76 (d, 2H, J = 4.8 Hz, 6,6”-H, tpy), 8.67
(s, 2H, 3’,5’-H, tpy), 8.65 (d, 2H, J = 7.8 Hz, 3,3”-H, tpy), 8.03 (t, 2H,
J = 7.8 Hz, 4,4”-H, tpy), 7.87 (d, 2H, J = 8.4 Hz, 3,5-H, ph), 7.52 (dd,
2H, J = 7.8, 4.8 Hz, 5,5”-H, tpy), 7.13 (d, 2H, J = 8.4 Hz, 2,6-H, ph),
4.13 (t, 2H, J = 6.0 Hz, OꢁCH2), 2.68 (t, 2H, J = 6.0 Hz, N-CH2),
2.44 (s, 4H, NꢁCH2, piperidine), 1.50 (m, 4H, ꢁCH2, piperidine),
1.38 (s, 2H, ꢁCH2, piperidine); 13C NMR (CDCl3, 150 MHz) d/ppm:
159.8 (1-C, ph), 156.4 (2C, 2’,6’-C, tpy), 155.9 (2C, 2,2”-C, tpy), 149.8
(4’-C, tpy), 149.1 (2C, 6,6”-C, tpy), 136.8 (2C, 4,4”-C, tpy), 130.8
(4-C, ph), 128.5 (2C, 3,5-C, ph), 123.7 (2C, 3,3”-C, tpy), 121.4
(2C, 5,5”-C, tpy), 118.3 (2C, 3’,5’-C, tpy), 115.0 (2C, 2,6-C, ph),
wileyonlinelibrary.com/journal/aoc
Copyright © 2013 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. (2013), 27, 373–379

Pt, Pd, Cu and Zn complexes with 4’-substituted terpyridines
Zn(II)Lb(CH3COO)2 (4)
66.2 (OꢁCH2), 57.9 (NꢁCH2), 55.1 (2C, NꢁCH2, piperidine), 26.0
(2C, 2,4-C, piperidine), 24.2 (3-C, piperidine); Anal. Calcd for
C28H28N4O: C, 77.04; H, 6.46; N, 12.83. Found: C, 77.09; H, 6.49; N,
12.79; HRMS (+)-ESI m/z [M+ H]+ calcd for [C28H29N4O]+: 437.2336;
found: 437.2335.
The synthesis of 4 was carried out in a similar manner to 3 starting
from Lb (38 mg, 0.1 mmol) and Zn(CH3COO)2.2H2O (22 mg,
0.1 mmol) in methanol. White solid; yield 34 mg, 61.2%; UV
(water, nm) 233, 265, 284 (IL), 326 (LMCT); IR (KBr, cmꢁ1
)
)
3071–3049 (CꢁH), 1594 (C¼N); far-IR (Nujol mull, cmꢁ1
Synthesis of Metal Complexes
413.2 (ZnꢁN); 1H NMR (DMSO-d6, 600 MHz) d/ppm: 8.77
(d, 2H, J = 4.8 Hz, 6,6”-H, tpy), 8.67 (m, 4H, 3,3”-H, tpy, 3’,5’-H,
tpy), 8.04 (t, 2H, J = 4.8 Hz, 4,4”-H, tpy), 7.83 (d, 2H, J = 9.0
Hz, 3,5-H, ph), 7.53 (t, 2H, J = 4.8 Hz, 5,5”-H, tpy), 7.01 (d, 2H,
J = 9.0 Hz, 2,6-H, ph), 4.20 (s, 2H, CH2), 1.67 (s, 6H, CH3); 13C
NMR (DMSO-d6, 150 MHz) d/ppm: 179.0 (2C, C¼O), 174.6
(ꢁCOOH), 160.2 (1-C, ph), 157.2 (2C, 2’,6’-C, tpy), 156.6
(2C, 2,2”-C, tpy), 149.8 (4’-C, tpy), 148.9 (2C, 6,6”-C, tpy),
137.8 (2C, 4,4”-C, tpy), 130.1 (4-C, ph), 127.7 (2C, 3,5-C, ph),
124.5 (2C, 3,3”-C, tpy), 121.7 (2C, 5,5”-C, tpy), 117.5 (2C, 3’,
5’-C, tpy), 115.1 (2C, 2,6-C, ph), 67.2 (CH2), 21.7 (2C, CH3);
Anal. Calcd for Zn(II)Lb(CH3COO)2: C, 57.21; H, 4.09; N, 7.41.
Found: C, 57.48; H, 3.85; N, 7.91; HRMS (+)-ESI m/z [M ꢁ Acꢁ]+
calcd for [C25H20N3O5Zn]+: 506.0694; found: 506.0698; Λm
(DMF, S m2 molꢁ1) 26.2.
[Pt(II)LaCl]Cl (1)
To 42 mg (0.1 mmol) K2PtCl4 dissolved in 10 ml water, 33 mg
(0.1 mmol) La was added, the mixture was stirred at 30ꢂC for
3 h before filtering, and the residue was washed with water. An
orange solid was obtained after drying; yield 32 mg, 54.2%; UV
(water, nm) 268, 324, 338 (IL), 386 (LMCT); IR (KBr, cmꢁ1
)
3139–3049 (CꢁH), 1602 (C¼N), 3447 (OH); far-IR (Nujol mull,
cmꢁ1) 423.1 (PtꢁN); 1H NMR (DMSO-d6, 600 MHz) d/ppm:9.12
(d, 2H, J = 4.8 Hz, 6,6”-H, tpy), 8.99 (d, 2H, J = 4.8 Hz, 3,3”-H,
tpy), 8.90 (s, 2H, 3’,5’-H, tpy), 8.57 (t, 2H, J = 4.8 Hz, 4,4”-H,
tpy), 8.02 (d, 2H, J = 8.4 Hz, 3,5-H, ph), 7.98 (t, 2H, J = 4.8 Hz,
5,5”-H, tpy), 7.01 (d, 2H, J = 8.4 Hz, 2,6-H, ph); 13C NMR
(DMSO-d6, 150 MHz) d/ppm: 160.4 (1-C, ph), 159.5 (2C, 2’,6’-C, tpy),
158.4 (2C, 2,2”-C, tpy), 151.3 (4’-C, tpy), 149.8 (2C, 6,6”-C, tpy),
136.8 (2C, 4,4”-C, tpy), 131.6 (4-C, ph), 129.5 (2C, 3’,5’-C, tpy), 124.5
(2C, 3,3”-C, tpy), 121.4 (2C, 5,5”-C, tpy), 119.3 (2C, 3’,5’-C, tpy), 116.4
(2C, 2,6-C, ph); Anal. Calcd for [Pt(II)LaCl]Cl ꢃ 3.5H2O: C, 38.54; H, 3.39;
N, 6.42. Found: C, 38.02; H, 3.49; N, 6.33; HRMS (+)-ESI m/z [M ꢁ Clꢁ]+
calcd for [C21H15ClN3OPt]+: 555.0547; found: 555.0552; Λm
(DMF, S m2 molꢁ1) 69.2.
Zn(II)Lc(CH3COO)2 (5)
The synthesis of 5 was carried out in a similar manner to 3
starting from Lc (44 mg, 0.1 mmol) and Zn(CH3COO)2.2H2O
(22 mg, 0.1 mmol) in methanol. White solid; yield 34 mg, 54.7%;
yield 34 mg, 61.2%; UV (water, nm) 232, 264, 284 (IL), 326 (LMCT);
IR (KBr, cmꢁ1) 3083–3049 (CꢁH), 1594 (C¼N); far-IR (Nujol mull,
cmꢁ1) 413.2 (ZnꢁN); H NMR (DMSO-d6, 600 MHz) d/ppm: 8.88
1
[Pd(II)LbCl]Cl (2)
(s, 2H, 6,6”-H, tpy), 8.79 (m, 4H, 3,3”-H, 3’,5’-H, tpy), 8.19 (m, 4H,
4,4”-H, tpy, 3,5-H, ph), 7.75 (t, 2H, J = 5.4 Hz, 5,5”-H, tpy), 7.11
(d, 2H, J = 7.8 Hz, 2,6-H, ph), 4.21 (t, 2H, J = 5.4 Hz, ꢁOꢁCH2ꢁ),
3.63 (t, 4H, J = 5.4 Hz, ꢁOꢁCH2ꢁ, morpholine), 2.77 (t, 2H,
J = 6.0 Hz, NꢁCH2ꢁ), 2.53 (t, 4H, J = 5.4 Hz, NꢁCH2ꢁ, morpholine),
1.67 (s, 6H, CH3ꢁCOOꢁ); 13C NMR (CDCl3, 150 MHz) d/ppm: 179.0
(2C, C¼O), 161.0 (1-C, ph), 157.6 (2C, 2’,6’-C, tpy), 156.8 (2C, 2,2”-C,
tpy), 149.6 (4’-C, tpy), 149.2 (2C, 6,6”-C, tpy), 140.0 (2C, 4,4”-C, tpy),
131.4 (4-C, ph), 128.6 (2C, 3,5-C, ph), 126.4 (2C, 3,3”-C, tpy), 121.8
(2C, 5,5”-C, tpy), 117.9 (2C, 3’,5’-C, tpy), 114.8 (2C, 2,6-C, ph), 66.3
(2C, OꢁCH2, morpholine), 65.4 (OꢁCH2), 57.2 (NꢁCH2), 53.9
(2C, NꢁCH2, morpholine), 21.7 (2C, CH3); Anal. Calcd for Zn(II)Lc
(CH3COO)2 ꢃ 1.5H2O: C, 57.37; H, 5.44; N, 8.63. Found: C, 57.06;
H, 5.18; N, 8.69; HRMS (+)-ESI m/z [M ꢁ Acꢁ]+ calcd for
[C29H29N4O4Zn]+: 561.1474; found: 561.1483; Λm (methanol,
S m2 molꢁ1) 52.3.
To 33 mg K2PdCl4 (0.1 mmol) dissolved in 10 ml water, 38 mg Lb
(0.1 mmol) in 5 ml methanol was added, the mixture was stirred
at room temperature for 3 h before filtering, and the residue was
washed with water and methanol. A yellow solid was obtained
after drying; yield 35 mg, 57.1%; UV (water, nm) 244, 278, 349
(IL), 365 (LMCT); IR (KBr, cmꢁ1) 3071–3024 (CꢁH), 1602 (C¼N);
far-IR (Nujol mull, cmꢁ1) 438.5 (PdꢁN); 1H NMR (DMSO-d6,
600 MHz) d/ppm:8.79 (d, 2H, J = 4.8 Hz, 6,6”-H, tpy), 8.68 (d, 2H,
J = 4.8 Hz, 3,3”-H, tpy), 8.64 (s, 2H, 3’,5’-H, tpy), 8.01 (t, 2H, J = 4.8
Hz, 4,4”-H, tpy), 7.78 (d, 2H, J = 7.8 Hz, 3,5-H, ph), 7.46 (t, 2H,
J = 4.8 Hz, 5,5”-H, tpy), 7.10 (d, 2H, J = 7.8 Hz, 2,6-H, ph), 4.62
(s, 2H, CH2); 13C NMR (DMSO-d6, 150 MHz) d/ppm: 174.6 (COOH),
160.1 (1-C, ph), 158.9 (2C, 2’,6’-C, tpy), 157.9 (2C, 2,2”-C, tpy), 149.7
(4’-C, tpy), 149.1 (2C, 6,6”-C, tpy), 138.5 (2C, 4,4”-C, tpy), 130.2
(4-C, ph), 127.4 (2C, 3,5-C, ph), 125.8 (2C, 3,3”-C, tpy), 121.7
(2C, 5,5”-C, tpy), 117.8 (2C, 3’,5’-C, tpy), 115.2 (2C, 2,6-C, ph),
67.3 (CH2); Anal. Calcd for [Pd(II)LbCl]Cl ꢃ H2O: C, 47.73; H,
3.31; N, 7.26. Found: C, 48.09; H, 3.10; N, 7.18; HRMS (+)-ESI
m/z [M ꢁ Clꢁ]+ calcd for [C23H17ClN3O3Pd]+: 525.9992; found:
525.9997; Λm (DMF, S m2 molꢁ1) 68.1.
Cu(II)Lc(CH3COO)2 (6)
The synthesis of 6 was carried out in a similar manner to 3
starting from Lc (44 mg, 0.1 mg) and Cu(CH2COO)2.H2O (20 mg,
0.1 mmol) in methanol. Blue solid; yield 41 mg, 66.1%; UV (water,
nm) 223, 266, 286 (IL), 334 (LMCT); IR (KBr, cmꢁ1) 3071–3049
(CꢁH), 1595 (C¼N); far-IR (Nujol mull, cmꢁ1) 419.6 (Cu ꢁ N);
Anal. Calc. for Cu(II)Lc(CH3COO)2.3H2O: C, 55.23; H, 5.68; N, 8.31.
Found: C, 54.90; H, 5.57; N, 8.24; HRMS (+)-ESI m/z [M ꢁ Acꢁ]+
calcd for [C29H29CuN4O4]+: 560.1485; found: 560.1478; Λm (meth-
anol, S m2 molꢁ1) 56.2.
Cu(II)LaCl2 (3)
To 17 mg (0.1 mmol) CuCl2.2H2O dissolved in 10 ml methanol, 33 mg
La was added, the mixture was stirred at room temperature for 3 h
before filtering, and the residue was washed with methanol. Green
solid; yield 31 mg, 67.4%; UV (water, nm) 223, 265, 286 (IL), 333
(LMCT); IR (KBr, cmꢁ1) 3105–3024 (CꢁH), 1595 (C¼N), 3401 (OH);
far-IR (Nujol mull, cmꢁ1) 419.6 (CuꢁN); Anal. Calcd for Cu(II)LaCl2: C,
54.85; H, 3.29; N, 9.14. Found: C, 54.86; H, 3.37; N, 8.95; HRMS (+)-ESI
m/z [M ꢁ Clꢁ]+ calcd for [C21H15ClCuN3O]+: 423.0200; found:
423.0194; Λm (DMF, S m2 molꢁ1) 32.4.
Cu(II)LcCl2 (7)
The synthesis of 7 was carried out in a similar manner to 3 starting
from Lc (44 mg, 0.1 mg) and CuCl2.2H2O (17 mg, 0.1 mmol) in
methanol. Green solid; yield 33 mg, 57.6%; UV (water, nm) 223,
Appl. Organometal. Chem. (2013), 27, 373–379
Copyright © 2013 John Wiley & Sons, Ltd.
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S. Wang et al.
265, 286 (IL), 334 (LMCT); IR (KBr, cmꢁ1) 3059–3039 (CꢁH), 1595
(C¼N); far-IR (Nujol mull, cmꢁ1) 419.6 (CuꢁN); Anal. Calcd for Cu
(II)LcCl2.2H2O: C, 53.25; H, 4.97; N, 9.20; Found: C, 53.42; H, 4.61; N,
8.96; HRMS (+)-ESI m/z [Mꢁ Clꢁ]+ calcd for [C27H26ClCuN4O2]+:
536.1040; found: 536.1035; Λm (methanol, S m2 molꢁ1) 58.6.
prepared 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.[20] Upon completion of the incubation
for 44 h, stock MTT dye solution (20 ml, 5 mg mLꢁ1) was added
to each well. After 4 h incubation, 2-propanol (100 ml) was added
to solubilize the MTT formazan. The OD of each well was mea-
sured on a microplate spectrophotometer at a wavelength of
570 nm. The IC50 value was determined from plot of percent
viability against dose of compounds added.
Cu(II)LdCl2 (8)
The synthesis of 8 was carried out in a similar manner to 3
starting from Ld (44 mg, 0.1 mmol) and CuCl2.2H2O (17 mg,
0.1 mmol) in methanol. Green solid; yield: 39 mg, 63.2%; yield
63.2%; UV (water, nm) 223, 265, 287 (IL), 332 (LMCT); IR (KBr,
cmꢁ1) 3059–3039 (CꢁH), 1595 (C¼N); far-IR (Nujol mull, cmꢁ1
)
Results and Discussion
419.6 (CuꢁN); Anal. Calc. for Cu(II)LdCl2.H2O: C, 57.10; H, 5.13;
N, 9.51. Found: C, 56.59; H, 4.66; N, 9.23; HRMS (+)-ESI m/z [M ꢁ
Clꢁ]+ calcd for [C28H28N4OClCu]+: 534.1248; found: 534.1243;
Λm (methanol, S m2 molꢁ1) 58.3.
Synthesis and Characterization
The ligands La–Ld were prepared following reported proce-
dures,[19,21] and their structures and purity were identified by
melting points, IR, NMR data, HRMS and element analysis.
All complexes were synthesized as described in the experimental
section (as shown in Scheme 1). Treatment of the free 4’-sustituted
tpy ligands (La–Ld) with corresponding salts in a methanol or meth-
anol/water mixture at different temperatures afforded complexes
(1–8) in ~60% yields. These complexes are air-stable powders
at room temperature. They can be dissolved in methanol, water,
DMF and DMSO. Attempts to obtain a single crystal suitable
for X-ray determination were unsuccessful. The structures of
the synthesized complexes were established with the help of
elemental analyses data, IR, UV, NMR, EPR and HRMS.
Cytotoxic Studies
Cell culture
Four different human carcinoma cell lines – HL-60, BGC-823, KB,
Bel-7402 – were cultured in RPMI-1640 medium supplemented
with 10% fetal bovine serum, 100 units mLꢁ1 penicillin and 100
mg mLꢁ1 streptomycin. Cells were maintained at 37ꢂC in a humid-
ified atmosphere of 5% CO2 in air.
Solutions
The complexes were dissolved in DMSO at a concentration of
5 mM as stock solution, and diluted in culture medium at concen-
trations of 1.0, 10, 100 and 500 mM as working solution. To avoid
DMSO toxicity, the concentration of DMSO was less than 0.1%
(v/v) in all experiments.
The elemental analysis data of the complexes are in agreement
with the calculated values. The molar conductance values in metha-
nol or DMF for the complexes 1 and 2 correspond to 1:1 electrolyte
type, while other complexes correspond to non-electrolyte.[22]
The UV-visible spectra of ligands in methanol and complexes
in water were measured at a concentration of 1 ꢀ 10ꢁ4 mol Lꢁ1
.
Cytotoxicity analysis
The essential absorption of prepared complexes appeared red
shifted compared with free ligands. The peaks of Pt(II) complex
1 at 324 and 338 nm were attributed to a p–p* intraligand (IL)
transition of tpy, whereas the peak at 386 nm was assigned to
The cells harvested from exponential phase were seeded equiva-
lently into a 96-well plate, and then the complexes were added
to the wells to achieve final concentrations. Control wells were
Scheme 1. Synthesis of the ligands and their complexes.
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Copyright © 2013 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. (2013), 27, 373–379

Pt, Pd, Cu and Zn complexes with 4’-substituted terpyridines
metal-to-ligand charge transfer (MLCT) transition. Peaks of Pd(II)
complex 2 at 244 and 278 nm were assigned to the p–p* IL
transition and the 349 and 365 nm absorptions were assigned
to MLCT transition.[23,24] The bands of Cu(II) and Zn(II) complexes
(3–8) between 223 and 286 nm were assigned to IL transition
and 326–334 nm absorption bands were assigned to MLCT
transition.[15,18,25] The red shift indicated that the metal coordi-
nated with the ligand through nitrogen atoms.
Comparison of the IR spectra of the ligands and complexes
provided information about the mode of bonding of the ligands
in complexes. The band of υC¼N at 1590 cmꢁ1 of free ligands
shifted to higher frequency by 4–12 cmꢁ1 after coordination.
far-IR spectra of the complexes were recorded, and bands
assigned to υMꢁN appeared at 413.2–438.5 cmꢁ1
, which
suggested the coordination of the metal ion with the nitrogen
atom of pyridyl.[17]
The 1H NMR and 13C NMR spectra of ligands (La–Ld) and
complexes 1, 2, 4 and 5 were recorded in DMSO-d6. The 1H
NMR spectra of the complexes showed down-field shift for
the 6,6”-tpyHs ( d 0.04, 0.03, 0.01 and 0.17 ppm, respectively)
compared to the ligands. The chemical shift for the 2’,6’-tpyCs
moved down-field by 3.2, 2.8, 1.1 and 1.2 ppm, respectively.
Similar situations were found for 2,2”-tpyCs (2.5, 2.2, 0.9 and
0.9 ppm, respectively) and 6,6”-tpyCs (0.7, 0.4, 0.1 and 0.1 ppm,
respectively). The results indicate the coordination of the ligands
with the metal ions.
Figure 1. EPR (X-band) spectrum of powdered sample of complex 7 at
room temperature (298 K) (υ = 9.689838 GHz).
The formation of complexes was further supported by positive
mode ESI-HRMS spectrometry, which documented a base peak
corresponding to the [M ꢁ Clꢁ]+ or [M ꢁ Acꢁ]+. The HRMS spectra
of Pt(II) complex 1, Pd(II) complex 2, Zn(II) complex 4 and 5 and
Cu(II) complexes 3 and 6–8 were recorded in MeOH. The molec-
ular ion peaks appeared (m/z) at 555.05525 [M ꢁ Clꢁ]+, 525.9997
[M ꢁ Clꢁ]+, 423.0194 [M ꢁ Clꢁ]+, 506.0698 [M ꢁ Acꢁ]+, 561.14838
[M ꢁ Acꢁ]+, 560.1478 [M ꢁ Acꢁ]+, 536.1035 [M ꢁ Clꢁ]+ and
534.1243 [M ꢁ Clꢁ]+ for complexes 1–8, respectively, which
indicated the formation of these complexes. As shown in Fig. 2,
the obtained experimental data of complex 3 perfectly match
theoretical expectations, therefore confirming our hypotheses
on the chemical structure.
Attempts to obtain a single crystal suitable for X-ray determination
were unsuccessful. The crystal structures of the analogues of title
complexes, ZnL1Cl2, ZnL1(CH3COO)2 (L1 = 4’-phenyl-terpyridine)[17]
and [Pt(II)L2Cl]+ (L2 =4’-(2-morpholinoethoxy)-2,2’,6’,2”-terpyridine,
4’-(2-(piperidin-1-yl)ethoxy)-2,2’,6’,2”-terpyridine)[32] have revealed
that the metals are coordinated by three nitrogen atoms
from ligands.
The 1H NMR spectra of complexes 4 and 5 provided information
about the bonding mode of acetate in Zn(II) complexes. The acetate
anion can act as a monodentate ligand or a bidentate ligand. These
Zn(II) complexes may choose a six-coordinate geometry around
metal ion through one tridentate tpy, one bidentate acetate and
one monodentate acetate ligand, or a five-coordinate geometry
around metal ion through one tridentate tpy and two monodentate
acetate ligands. Two peaks of methyl due to bidentate and
monodentate acetate ligands should be obvious at about 2.1 and
1.8 ppm for six-coordinate geometry.[26–29] However, only a single
peak (s, 6H, CH3) was found at 1.67 ppm for complexes 4 or 5, which
suggested the five-coordinate geometry around Zn(II) ion through
one tridentate tpy and two monodentate acetate ligands.
EPR spectroscopy was used to further confirm the identity of the
Cu(II) complex. The X-band EPR spectrum of a powdered complex
7 recorded at room temperature (298 K) is shown in Fig. 1. It is accor-
dance with the existence around the Cu(II) ion of the square-
pyramidal geometry.[30,31] For complex 7, g|| (2.253) > g⊥(2.082) > 2,
and G value (G=(g|| ꢁ 2)/(g⊥ ꢁ 2)) falling in the range 2–4 is consis-
tent with a dx2–y2 ground state, which suggests the existence of
considerable exchange interaction in the solid complex.
Based on all the above physical and spectral studies, we propose
tentative structures for these complexes as shown in Fig. 3.
Cytotoxicity Study
As shown in Table 1, the complexes (1–8) display cytotoxic
effects with low IC50 values (<20 mM) and show selective
Figure 2. Experimental and theoretical high-resolution mass spectra of complex 3: (A) experimental spectrum; (B) theoretical spectrum.
Appl. Organometal. Chem. (2013), 27, 373–379
Copyright © 2013 John Wiley & Sons, Ltd.
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S. Wang et al.
Figure 3. Tentative structures of complexes 1–8.
Table 1. IC50 values of the complexes against HL-60, BGC-823, KB and Bel-7402 cell lines
Complex
HL-60
BGC-823
KB
Bel-7402
1
13.09 ꢄ 1.27
10.32 ꢄ 0.73
4.77 ꢄ 0.15
39.14 ꢄ 1.14
17.71 ꢄ 1.32
5.02 ꢄ 0.12
1.62 ꢄ 0.19
3.40 ꢄ 0.23
2.89 ꢄ 0.34
9.93 ꢄ 0.52
15.24 ꢄ 1.26
4.54 ꢄ 0.24
21.26 ꢄ 1.26
2.12 ꢄ 0.23
4.34 ꢄ 0.21
3.59 ꢄ 0.16
3.73 ꢄ 0.26
6.48 ꢄ 0.81
6.71 ꢄ 0.38
7.57 ꢄ 0.27
2.74 ꢄ 0.16
11.87 ꢄ 0.82
5.99 ꢄ 0.36
7.70 ꢄ 0.52
2.28 ꢄ 0.27
2.37 ꢄ 0.18
2.65 ꢄ 0.33
3.66 ꢄ 0.14
5.58 ꢄ 0.24
0.89 ꢄ 0.12
16.23 ꢄ 1.36
1.42 ꢄ 0.28
4.43 ꢄ 0.25
0.63 ꢄ 0.08
1.09 ꢄ 0.12
8.12 ꢄ 0.97
2
3
4
5
6
7
8
Cisplatin[33]
cytotoxicity against HL-60, BGC-823, Bel-7402 and KB cell lines.
The cytotoxicity of these complexes against Bel-7420 cell line is
better than that against the other three cell lines. Complexes
1–3 and 5–8 exhibit better cytotoxicity than cisplatin against
Bel-7402 cell line. Complexes 3, 5, 7 and 8 demonstrate 9-,
5-, 12- and 7-fold higher cytotoxicity than cisplatin, respec-
tively. The cytotoxicity of complexes 3, 5, 6, 7 and 8 is also
higher than that of cisplatin against BGC-823 cell line. Com-
plex 7 exerts higher cytotoxicity than cisplatin against HL-60
cell line. Complexes 3, 7 and 8 show similar cytotoxicity to
cisplatin against KB cell line. Among these complexes, com-
plex 7 displays the highest in vitro cytotoxicity, with IC50
values of 1.62, 3.59, 2.28 and 0.63 mM against HL-60, BGC-
823, Bel-7402 and KB cells lines, respectively.
cytotoxicity than complexes (3, 8 or 4) with the other three termi-
nal groups. (ii) The metal center of the complexes has an impor-
tant effect on the cytotoxicity. For example, with the same ligand
La, the cytotoxicity of complexes 1 and 3 against the four cell
lines decreases in the sequence Cu > Pt. In addition, with the
same ligand Lc, the cytotoxicity of complexes 5 and 6 against
HL-60 cell lines decreases in the sequence Cu > Zn; the cytotoxi-
city against BGC-823, Bel-7402 and KB cell lines decreases in the
sequence Zn > Cu. (iii) The leaving group of the complexes also
plays an important role in cytotoxicity. For example, with the
same metal center and the same carrying group, the cytotoxicity
of complexes 6 and 7 against the four cell lines decreases in the
sequence: Clꢁ > Acꢁ.
The structure–activity relationships are summarized as follows.
(i) The terminal group of the complex plays an important role in
the cytotoxicity. For the tested cell lines, complex 7 demonstrates
higher cytotoxicity than complexes 3 and 8; complex 5 exhibits a
higher cytotoxicity than complex 4. It was shown that complex
5 or 7 with morpholinyl as the terminal group has higher
Conclusion
Eight new complexes with 4’-substitued tpy have been synthesized
and characterized, and their cytotoxicity against four human cell lines
has been investigated. All the complexes display high cytotoxicity
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Copyright © 2013 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. (2013), 27, 373–379

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Acknowledgments
This work was supported by Hebei Province Nature Science Fund for
Distinguished Young Scholars (Grant No. B2011201164), the Nature
Science Fund of Hebei Province (Grant No. B2011201135), the Key
Basic Research Special Foundation of Science Technology Ministry
of Hebei Province (Grant No. 11966412D, 12966418D), the Key
Research Project Foundation of the Department of Education of
Hebei Province (Grant 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 Technology Research and Development
Foundation of Hebei Province (No. 11276431).
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