Anticancer metallopharmaceutical agents based on mixed-ligand palladium(II) complexes with dithiocarbamates and tertiary organophosphine ligands

Article abstract of DOI:10.1002/aoc.2991

Mixed-ligand palladium(II) complexes of the type [(DT)Pd(PR ₃)Cl], where DT = diethyldithiocarbamate (1), dibutyldithiocarbamate (2,3), dipropyldithiocarbamate (4,5), bis(2-methoxyethyl)dithiocarbamate; PR₃ = benzyldiphenylphosphine (1,4), diphenyl-o-tolylphosphine (2), diphenyl-t-butylphosphine (3), P-chlorodiphenylphosphine (5) and triphenylphosphine (6), have been synthesized and characterized by elemental analyses and FT-IR, Raman and multinuclear NMR spectroscopy. The structures of compounds 1 and 2 were determined by single-crystal X-ray diffraction (XRD) measurements and these analyses showed that the complexes have pseudo square-planar geometry around the Pd(II) and that the dithiocarbamate ligand is bound in a bidentate fashion, while the remaining two positions are occupied by a tertiary organophosphine and a chloride ligand. The anticancer studies showed that the Pd(II) complexes are highly active against cisplatin-resistant DU145 human prostate carcinoma (HTB-81) cells with the highest activity shown by compound 6 (IC₅₀ = 2.12 μm). The redox behavior and ds-DNA-denaturing ability of the complexes were studied by cyclic voltammetry and two reduction and one oxidation waves were observed. The decrease in the reduction peak currents illustrated the consumption of the mixed-ligand drug by the DNA molecule. Copyright

Full text of DOI:10.1002/aoc.2991

Full Paper
Received: 21 November 2012
Revised: 23 January 2013
Accepted: 9 March 2013
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/aoc.2991
Anticancer metallopharmaceutical agents
based on mixed-ligand palladium(II)
complexes with dithiocarbamates
and tertiary organophosphine ligands
Hizbullah Khana,b,c, Amin Badshahb*, Muhammad Saidb,f, Ghulam Murtazab,
Jamil Ahmadd, Bertrand J. Jean-Claudee, Margarita Todorovae and
Ian S. Butlera
Mixed-ligand palladium(II) complexes of the type [(DT)Pd(PR3)Cl], where DT = diethyldithiocarbamate (1), dibutyldithiocarbamate
(2,3), dipropyldithiocarbamate (4,5), bis(2-methoxyethyl)dithiocarbamate; PR3 = benzyldiphenylphosphine (1,4), diphenyl-o-
tolylphosphine (2), diphenyl-t-butylphosphine (3), P-chlorodiphenylphosphine (5) and triphenylphosphine (6), have been
synthesized and characterized by elemental analyses and FT-IR, Raman and multinuclear NMR spectroscopy. The structures of
compounds 1 and 2 were determined by single-crystal X-ray diffraction (XRD) measurements and these analyses showed that
the complexes have pseudo square-planar geometry around the Pd(II) and that the dithiocarbamate ligand is bound in a
bidentate fashion, while the remaining two positions are occupied by a tertiary organophosphine and a chloride ligand. The
anticancer studies showed that the Pd(II) complexes are highly active against cisplatin-resistant DU145 human prostate
carcinoma (HTB-81) cells with the highest activity shown by compound 6 (IC50 = 2.12mM). The redox behavior and ds-DNA-
denaturing ability of the complexes were studied by cyclic voltammetry and two reduction and one oxidation waves were
observed. The decrease in the reduction peak currents illustrated the consumption of the mixed-ligand drug by the DNA
molecule. Copyright © 2013 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: anticancer activity; palladium(II) complexes; dithiocarbamates; tertiary organophosphines; X-ray diffraction; cyclic
voltammetry; DNA binding studies
complexes exhibit higher cytostatic activity than do their cis-
Introduction
analogues.1 Palladium(II) complexes are 105 times more labile
than are the analogous platinum(II) compounds,[17] and new
The field of metallodrugs has become a major research area for
medicinal inorganic chemists, after the discovery of cisplatin
(cis-PtCl2(NH3)2) as a DNA-modifying agent with high anticancer
activity.[1–3] Cisplatin is currently used for the treatment of tumors
of the ovaries, testes, and cancers of the head and neck
region.[4,5] Despite its wide spectrum of utility against tumors,
cisplatin has several drawbacks, viz. neurotoxicity, nephrotoxicity,
ototoxicity, gastrointestinal and bone marrow toxicity, and
acquired resistance after continued treatment.[6–9] The N-7 atom
of guanine in a DNA strand is generally considered to be the
main target for cisplatin antitumor action.[10]
charged species that interact with DNA are produced at an even
faster rate than with the platinum complexes.[18]
A suitable carrier ligand is crucial for the success of a cytostatic
drug,[19] as it plays an important role in stabilizing a specific oxidation
*
Correspondence to: A. Badshah, Department of Chemistry, Quaid-i-Azam
University, Islamabad 45320, Pakistan. E-mail: aminbadshah@yahoo.com
a Department of Chemistry, McGill University, Montreal, Quebec, Canada
H3A 2 K6
With the emergence of exciting antitumor activities of various
other transition metal complexes, the focus of research has
gradually been expanding beyond platinum.[11,12] Owing to the
structural resemblance of palladium(II) complexes to those of
platinum(II) and also because they exhibit promising antineoplas-
tic characteristics,[6,13,14] palladium(II) complexes are natural
candidates to be considered as anticancer drugs.[15,16] The pH
of normal body cells is 7.4, while tumor cells generally have
a lower pH value of about 6.8. Several palladium(II) complexes,
e.g. [(RO)CS2]2Pd] (R = Et, i-Pr, Cy), have been reported to show
antineoplastic activity at pH 6.8.[15] Moreover, trans-L2PdCl2
b Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan
c
Department of Chemistry, University of Science and Technology, Bannu 28100,
Pakistan
d Department of Chemistry, Government College University, Lahore 54000,
Pakistan
e Department of Medicine, Royal Victoria Hospital, Montreal, Quebec, Canada
H3A 1A1
f
Department of Chemistry, Abdul Wali Khan University, Mardan, KPK, Pakistan
Appl. Organometal. Chem. 2013, 27, 387–395
Copyright © 2013 John Wiley & Sons, Ltd.

H. Khan et al.
state of the metal ion, imparting substitution inertness, modifying
reactivity and lipophilicity and facilitating positive impacts on the
target site.[20] Sulfur-containing ligands like thiocarbonyls and thiols
are currently under investigation as chemoprotectants in platinum-
based chemotherapy[21] and the aminothiol molecule [NH2(CH2)
3NH(CH2)2SPO3H2] exhibits protective characteristics against
chemo- and radiotherapy.[22] Dithiocarbamates have the capability
to stabilize transition metals in a variety of oxidation states.[23] These
ligands selectively remove platinum metal from the enzyme–thiol
complex by nucleophilic attack of the sulfur atoms on the
platinum moiety and have been evaluated for their efficacy to inhibit
cisplatin-induced nephrotoxicity without undermining their
antiproliferative activity.[24] Marzano and co-workers have reported
a class of mixed ligands palladium(II) and platinum (II) complexes
with dithiocarbamate and various amines, exhibiting greater cytotox-
icity than does cisplatin,[25] very low in vitro and in vivo nephrotoxicity
and zero cross-resistance with cisplatin.[26]
Stimulated by the promising earlier results of palladium(II)
complexes with dithiocarbamate ligands against DU145 hu-
man prostate carcinoma (HTB-81) cells,[27] it was decided to
synthesize some novel mixed-ligand palladium(II) complexes
with dithiocarbamates and organophosphine ligands. In this
article we report the synthesis, characterization and antitumor
activities of six complexes of the general formula [(DT)Pd(PR3)Cl]
(DT = diethyldithiocarbamate, dibutyldithiocarbamate, dipropyld
ithiocarbamate, and bis(2-methoxyethyl)dithiocarbamate; PR3 =
benzyldiphenylphosphine, diphenyl-o-tolylphosphine, diphenyl-t-
butylphosphine, chlorodiphenylphosphine and triphenylphos
phine). The antitumor activities of the synthesized complexes have
been evaluated by testing against DU145 human prostate
carcinoma (HTB-81) cells. To further investigate the mode of action
of these complexes, the interaction with DNA has been studied by
cyclic voltammetry (CV).
dibutylamine, bis(2-methoxyethyl)amine, carbon disulfide, benzyl
diphenylphosphine, diphenyl-o-tolylphosphine, diphenyl-t-butyl
phosphine and chlorodiphenylphosphine were purchased from
Aldrich Chemical Co. and were used without further purification.
Palladium(II) chloride was obtained from Fluka and used as
received. All solvents were purified and dried by the reported
standard methods.
Solution Phase Synthesis of Mixed-Ligand Palladium(II)
Compounds (1–6)
A series of palladium(II) complexes was synthesized by reacting
dithiocarbamate ligands with (PR3)2PdCl2 in CH2Cl2 (Scheme 1)
and proved to be stable under ambient conditions and soluble
in common organic solvents.
The organophosphine solution in dry acetone (2M ratio) was
added to the palladium(II) chloride (1M ratio) solution in acidified
methanol and the reaction mixture was stirred under reflux condi-
tions for 6 h. The solid product, palladium phosphine complex, was
filtered, dried at room temperature, dissolved in dichloromethane
and added to the dithiocarbamic acid/sodium salt solution (1:1M
ratio). The reaction mixture was heated under reflux overnight.
The solvent was removed under reduced pressure; an orange-red
solid product was obtained, which was dissolved in a mixture of
dichloromethane and petroleum ether (4:1) for recrystallization at
room temperature. Orange-red, block-shaped crystals of 1 and 2
were obtained, while the other complexes could not be crystallized.
[Pd(diethyldithiocarbamate)(PPh2-benzyl)Cl] (1)
Quantities used were 0.06 g (0.40 mmol) diethyldithiocarbamate and
0.29 g (0.40 mmol) Pd(PPh2-benzyl)2Cl2 in 30 ml dichloromethane.
Yield 0.19 g (83%) orange-red crystals; m.p. 185–186 ꢁC. FT-IR and
1
Raman (cmꢀ1): 3051, 2981, 1518, 907, 693, 428, 324, 234. H NMR
(300 MHz, CDCl3, 291.9K) d (ppm): 7.52–7.17 (m, 15H, ArH),: 4.00 (d,
2
3
2H, PCH2, JP–H =12Hz), 3.69 (q, 2H, NCH2, JH–H = 7.2 Hz), 3.53 (q,
Experimental
2H, NCH2, 3JH–H = 7.2 Hz), 1.25 (t, 3H, -CH3, 3JH–H = 7.2 Hz), 1.15 (t, 3H,
3
CH3, JH–H =7.2Hz),. 13C NMR (75.46MHz, CDCl3, 290.5 K) d (ppm):
The experiments were carried out under the conditions of temper-
ature and pressure specified. Complexes 1 and 2 were analyzed on
a STOE IPDS image plate detector diffractometer, equipped with
206.1 (SCS), 133.7, 131.5, 130.7, 128.5, 128.1, 127.1, 126.7, 125.6
(18C, Ar-C), 43.8, 43.6 (2C, NCH2), 32.7 (PCH2), 12.4, 12.3 (2C, CH3),
31P NMR (121.4 MHz, CDCl3, 300.0K) d (ppm): 26.9. Anal. Calcd (%)
for C24H27ClNPPdS2: C, 50.89; H, 4.80; N, 2.47; S, 11.32. Found: C,
50.81; H, 4.76; N, 2.43; S, 11.37.
1
graphite monochromated MoKa radiation. H, 13C and 31P NMR
spectra were recorded on Mercury 300 and VNMRS500 spectrome-
ters: 1H NMR (300.05 or 499.89MHz): internal standard solvent
CDCl3 (7.26 ppm from tetramethylsilane (TMS)) and DMSO-d6
(2.49 ppm from TMS), internal standard TMS; 13C NMR (75.44 or
125.69 MHz), internal standard TMS. The splittings of the proton
and phosphorus resonances are defined as s = singlet, d = doublet,
t = triplet and m = multiplet (showing a complex spectrum). FT-IR
spectra were recorded on Nicolet 6700 FT-IR instrument in the
range 4000–400 cmꢀ1. Raman spectra were measured on a
Rensihaw In Via instrument. Elemental analyses were conducted
on a LECO-183 CHNS analyzer and melting points were measured
on a Stuart SMP10 apparatus. Diethylamine, dipropylamine,
[Pd(dibutyldithiocarbamate)(PPh2-o-tolyl)Cl] (2)
Quantities used were 0.08 g (0.40 mmol) dibutyldithiocarbamate and
0.29 g (0.40 mmol) Pd(PPh2-o-toly)2Cl2 in 30 ml dichloromethane.
Yield 0.19 g (78%) orange-red crystals; m.p. 265–266 ꢁC. FT-IR and
Raman (cmꢀ1): 3050, 2960, 1517, 1026, 693, 380, 315, 262. 1H NMR
(300 MHz, CDCl3, 291.9 K) d (ppm): 7.82–7.25 (m, 14H, ArH), 3.63
(t, 2H, CH2CH2CH2CH3, 3JH–H = 7.8 Hz), 3.57 (t, 2H, CH2CH2CH2CH3,
3JH–H =7.8Hz), 2.66 (s, 3H, Ar-CH3), 1.65–1.54 (m, 4H, CH2CH2CH2CH3),
1.45–1.25 (m, 4H, CH2CH2CH2CH3), 0.96 (t, 3H, CH2CH2CH2CH3,
Scheme 1. Synthesis of dithiocarbamate palladium(II) complexes 1–6.
wileyonlinelibrary.com/journal/aoc
Copyright © 2013 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2013, 27, 387–395

Mixed ligand Pd(II) complexes as potent anticancer agents
3JH–H = 7.5 Hz), 0.90 (t, 3H, CH2CH2CH2CH3, 3JH–H = 7.5Hz). 13C NMR
(75.47MHz, CDCl3, 290.5K) d (ppm): 206.3 (SCS), 142.6, 142.3,
141.9, 138.3, 137.7, 137.2, 135.9, 133.8, 132.7, 128.5, (18C, Ar-C),
48.8 (CH2CH2CH2CH3), 47.7 (CH2CH2CH2CH3), 29.2 (CH2CH2CH2CH3),
29.1 (CH2CH2CH2CH3), 23.7 (Ph-CH3), 20.1 (CH2CH2CH2CH3), 20.0
[Pd(bis(2-methoxyethyl)-dithiocarbamate)(PPh3)Cl] (6)
Quantities used were 0.14 g (0.57 mmol) bis(2-methoxyethyl)-
dithiocarbamate and 0.40 g (0.57 mmol) Pd(PPh3)2Cl2 in 30 ml
dichloromethane. Yield 0.28 g (80%) golden-yellow solid; m.p.
165–166 ꢁC. FT-IR and Raman (cmꢀ1): 3053, 2929, 1524, 1094,
690, 380, 279, 203; 1H NMR (400.89 MHz, CDCl3, 298.1 K)
(CH2CH2CH2CH3), 13.7 (CH2CH2CH2CH3), 13.6 (CH2CH2CH2CH3), 31
P
NMR (121.4MHz, CDCl3, 287.8K) d (ppm): 20.6. Anal. Calcd (%) for
C28H35ClNPPdS2: C, 54.02; H, 5.67; N, 2.25; S, 10.30. Found: C,
54.08; H, 5.66; N, 2.25; S, 10.29.
d
(ppm): 7.65–7.38 (m, 15H, ArH), 4.00 (t, 2H, CH2CH2OCH3,
3JH–H = 7.6Hz), 3.85 (t, 2H, CH2CH2OCH3, 3JH–H = 7.6Hz), 3.64 (t, 2H,
CH2CH2OCH3, 3JH–H = 7.6 Hz), 3.52 (t, 2H, CH2CH2OCH3,
3JH–H = 7.6Hz), 3.33 (s, 3H, CH2CH2OCH3), 3.30 (s, 3H, CH2CH2OCH3).
13C NMR (125.7 MHz, CDCl3, 298.1 K) d (ppm): 206.1 (SCS), 134.2,
132.1, 128.5, 127.6 (18C, Ar-C), 70.1 (CH2CH2OCH3), 70.0
(CH2CH2OCH3), 60.1 (CH2CH2OCH3), 59.9 (CH2CH2OCH3), 50.4
(CH2CH2OCH3), 50.3 (CH2CH2OCH3). 31P NMR (125.7 MHz, CDCl3,
298.1 K) d (ppm): 30.6. Anal. Calcd (%) for C25H29ClNO2PPdS2: C,
49.02; H, 4.77; N, 2.29; S, 10.47. Found: C, 49.10; H, 4.75; N, 2.28;
S, 10.44.
[Pd(dibutyldithiocarbamate)(PPh2-t-butyl)Cl] (3)
Quantities used were 0.12 g (0.58 mmol) dibutyldithiocarbamate and
0.39 g (0.58 mmol) Pd(PPh2-t-butyl)2Cl2 in 25 ml dichloromethane.
Yield 0.29 g (83%) golden-yellow solid; m.p. 150–151 ꢁC. FT-IR and Ra-
1
man (cmꢀ1): 3074, 2953, 1531, 1095, 694, 378, 298, 259; H NMR
(300.13 MHz, CDCl3, 291.9 K) d (ppm): 8.06–7.41 (m, 10H, ArH), 3.37
(t, 2H, CH2CH2CH2CH3, 3JH–H = 7.8 Hz), 3.58 (t, 2H, CH2CH2CH2CH3,
3JH–H = 7.8 Hz), 1.53 (s, 9H, C(CH3)3), 1.53–1.44 (m, 4H, CH2CH
2CH2CH3), 1.36–1.17 (m, 4H, CH2CH2CH2CH3), 0.93 (t, 3H, CH2
3
X-Ray Diffraction Studies
CH2CH2CH3, JH–H = 6.0 Hz), 0.83 (t, 3H, CH2CH2CH2CH3,
3JH–H = 6.0Hz), 13C NMR (75.46 MHz, CDCl3, 290.5K) d (ppm): 206.3
(SCS), 135.0, 130.1, 127.6, 126.9 (12C, Ar-C), 48.9 (CH2CH2CH2CH3),
48.6 (CH2CH2CH2CH3), 39.2 (C(CH3)3), 30.0 (CH2CH2CH2CH3), 29.9
(CH2CH2CH2CH3), 28.3 (3C, C(CH3)3), 20.1 (CH2CH2CH2CH3), 20.0
(CH2CH2CH2CH3), 13.7 (CH2CH2CH2CH3), 13.6 (CH2CH2CH2CH3).
31P NMR (121.4 MHz, CDCl3, 300.0 K) d (ppm) 45.1. Anal. Calcd
(%) for C25H37ClNPPdS2: C, 51.82; H, 6.52; N, 2.32; S, 10.64. Found:
C, 51.78; H, 6.55; N, 2.30; S, 10.60.
Suitable orange-red crystals of complexes 1 and 2 were obtained
by dissolving the product in a mixture of dichloromethane and
petroleum ether (4:1, v/v), and dichloromethane and n-hexane
(4:1, v/v) respectively. The solvents were slowly evaporated at
room temperature in an open atmosphere and orange-red crys-
tals were obtained. The block crystals of 1 and 2 were mounted
on glass fiber using epoxy glue. Measurements were made at
293(2) K on a STOE IPDS image plate detector diffractometer,
equipped with graphite monochromated MoKa radiation. The
program used for retrieving cell parameters, data collection and
data integration was STOE X-AREA.[28] Multiscan absorption cor-
rections were performed using SADABS.[29] The structures were
solved and refined using SHELXS-97 and SHELXL-97[30] and all
non-H atoms were refined anisotropically, with the hydrogen
atoms placed at idealized positions. Various crystallographic pa-
rameters of the two crystals are shown in Table 4.
[Pd(dipropyldithiocarbamate)(PPh2-benzyl)Cl] (4)
Quantities used were 0.10 g (0.56 mmol) dipropyldithiocarbamate
and 0.40 g (0.55 mmol) Pd(PPh2-benzyl)2Cl2 in 30 ml dichlorometh-
ane. Yield 0.28 g (85%) golden-yellow solid; m.p. 191–192 ꢁC. FT-IR
1
and Raman (cmꢀ1): 3053, 2960, 1523, 1099, 692, 378, 302, 219. H
NMR (400 MHz, CDCl3, 298.1 K) d (ppm): 7.70–7.06 (m, 15H, ArH),
2
4.00 (d, 2H, PCH2, JP–H = 12 Hz);, 3.58 (t, 2H, CH2CH2CH3,
3JH–H = 7.5 Hz) 3.42 (t, 2H, CH2CH2CH3, 3JH–H = 7.5 Hz), 1.67–1.65 (m, 2H,
CH2CH2CH3), 1.60–1.56 (m, 2H, CH2CH2CH3), 0.99 (t, 3H, CH2CH2CH3,
Antineoplastic Assay
3
3JH–H = 7.5Hz), 0.92 (t, 3H, CH2CH2CH3, JH–H = 7.5Hz).13C NMR
(125.67 MHz, CDCl3, 290.5 K) d (ppm): 207.2 (SCS), 134.0, 131.2,
132.7, 130.6, 129.0, 128.7, 126.8, 125.6 (18C, Ar-C), 50.8 (CH2CH2CH3),
50.7 (CH2CH2CH3), 38.3 (PCH2), 20.5 (CH2CH2CH3), 20.4 (CH2CH2CH3),
11.3 (CH2CH2CH3), 11.1 (CH2CH2CH3). 31P NMR (80.9MHz, CDCl3,
300.0 K) d (ppm): 27.9. Anal. Calcd (%) for C26H31ClNPPdS2: C, 52.53;
H, 5.26; N, 2.36; S, 10.79. Found: C, 52.48; H, 5.23; N, 2.34; S, 10.76.
DU145 human prostate carcinoma (HTB-81) cells were obtained from
the American Type Culture Collection (ATCC catalogue number). The
cells were maintained in Roswell Park Memorial Institute (RPMI-1640)
medium (Wisent Inc., St Bruno, Canada) and were supplemented
with 10% fetal bovine serum, 10 mM HEPES, 2 mML-glutamine and
100 g mlꢀ1 penicillin/streptomycin (GibcoBRL, Gaithersburg, MD,
USA). All assays cells were plated 24 h before drug treatment.
50 mmol stock concentrations of the compounds were prepared in
DMSO. Nine serial dilutions of the compounds were used to treat
the cells and the final concentration of DMSO on cells did not exceed
0.05%. In the growth inhibition assay, DU145 prostate cancer cells
were plated at 5000 cells per well in 96-well flat-bottom microtiter
plates (CostarW, CorningW, NY, USA). After 24 h incubation, cells were
exposed to different concentrations of each compound continuously
for 4 days. The remaining live cells were fixed using 50 ml cold trichlo-
roacetic acid (50%) for 60 min at 4 ꢁC, washed with water, stained
with 0.4% sulforhodamine B (SRB) for 4 h at room temperature,
rinsed with 1% acetic acid and allowed to dry overnight. The
resulting colored residue was dissolved in 200 ml Tris base (10mM,
pH 10.0) and optical density was recorded at 490 nm using a
microplate reader ELx808 (BioTek Instruments). The results were
analyzed by Graph Pad Prism (Graph Pad Software, Inc., San Diego,
CA, USA) and the sigmoidal dose–response curve was used to
[Pd(dipropyldithiocarbamate)(PPh2Cl)Cl] (5)
Quantities used were 0.11 g (0.62 mmol) dipropyldithiocarbamate
and 0.38 g (0.62 mmol) Pd(PPh2Cl)2Cl2 in 30 ml dichloromethane.
Yield 0.30 g (85%) golden-yellow solid; m.p. 185–186 ꢁC. FT-IR and
Raman (cmꢀ1): 3020, 2933, 1510, 1100, 690, 394, 284, 252.
1H NMR (400.89 MHz, CDCl3, 298.1K) d (ppm): 7.70–7.32 (m, 10H,
3
ArH), 3.58 (t, 2H, CH2CH2CH3, JH–H = 8.0 Hz), 3.54 (t, 2H,
3
CH2CH2CH3, JH–H = 8.0Hz), 1.81–1.76 (m, 2H, CH2CH2CH3), 1.67–
3
1.59 (m, 2H, CH2CH2CH3), 0.92 (t, 3H, CH3, JH–H = 7.5Hz) 0.89 (t,
3
3H, CH2CH2CH3, JH–H = 7.5Hz). 13C NMR (125.7MHz, CDCl3,
298.1 K) d (ppm): 207.9 (SCS), 131.4, 130.3, 127.9, 126.8 (12 C,
Ar-C), 54.7 (CH2CH2CH3), 51.9 (CH2CH2CH3), 20.5 (CH2CH2CH3),19.3
(CH2CH2CH3), 11.3 (CH2CH2CH3), 11.2 (CH2CH2CH3). 31P NMR
(125.7MHz, CDCl3, 298.1 K) d (ppm): 84.4. Anal. Calcd (%) for
C19H24Cl2NPPdS2: C, 43.45; H, 4.74; N, 2.53; S, 11.60. Found: C,
43.40; H, 4.73; N, 2.53; S, 11.63.
Appl. Organometal. Chem. 2013, 27, 387–395
Copyright © 2013 John Wiley & Sons, Ltd.
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H. Khan et al.
determine 50% cell growth inhibitory concentration (IC50). The
growth inhibition assay was performed once in triplicate.
nitrogen bond, which is further confirmed by X-ray crystallography
(see below). The IR bands normally observed for a C-N and a C¼N
bond are in the 1250–1350 and 1690–1640 cmꢀ1 regions, respec-
tively.[34,35] The appearance of a single IR-active bending mode in
the 1100–1026 cmꢀ1 region ascertain that the dithiocarbamate
species is symmetrically bonded to Pd in a bidentate fashion. The
disappearance of the S-H stretching mode in the 2500–2700 cmꢀ1
region in the metal complexes is another indication of bond forma-
tion between the palladium atom and the dithiocarbamate ligand.
There are no conspicuous differences in the 1H NMR spectra of
the complexes and the precursor ligands. The aromatic protons
have signals in the range of 8.06–7.06 ppm, as reported in the lit-
Cyclic Voltammetric Analysis
Cyclic voltammetric measurements were carried out using an Eco
Chemie Autolab PGSTAT 302 potentiostat/galvanostat (Utrecht,
Netherlands) along with the software GPES 4.9. All the experimen-
tation was made in a double-walled electrochemical cell (model
K-64 PARC) and conventional three-electrode system, using SCE
as reference electrode, a thin Pt wire as a counter electrode and
bare glassy carbon of 0.071 cm2 area as working electrode.
The glassy carbon electrode surface was polished before each
measurement. All the measurements were performed in DMSO
(99.5%, LAB-SCAN/Analytical) using 0.1 M tetrabutylammonium
perchlorate (TBAP ≥ 98%, Fluka) at 25 ꢂ 1 ꢁC under argon atmo-
sphere. Sample concentration was kept at 1 mM in each sample.
Electrochemical studies were made to assess the antitumor ac-
tivity of the synthesized complexes. Cyclic voltammograms of the
six complexes were performed in the absence and presence of
DNA (obtained from chicken blood) in DMSO.
To quantify the heterogeneous electron transfer kinetics, the
effect of scan rate was also studied and diffusion coefficients
were calculated to estimate the heterogeneous rate constants.
Voltammetric behavior of all compounds was studied on the
glassy carbon electrode at various scan rates (50–1000 mV sꢀ1).
The Randles–Sevcik equation for an irreversible process was
employed to plot ip vs. square root of scan rate and to determine
the diffusion coefficient (Dꢁ) values:[31]
1
erature.[36] An interesting feature of the H NMR spectra is the
asymmetry in the alkyl groups attached to the nitrogen atom of
the dithiocarbamate ligand, caused by the restricted rotation
around the C¼N bond, which is known to have an energy barrier
of 65–95 kJ mol .
ꢀ1 [37] 13C NMR spectra of the complexes show the
presence of all the carbon atoms in the compounds. The SCS
carbon atom has a signal in the 206.1–207.9 ppm region. The
slight upfield displacement of the SCS signal in complexes
demonstrates the coordination between the Pd atom and dithio-
carbamate ligand, which may be attributed to the higher electron
density on the SCS carbon after complexation. Like the protons of
the dithiocarbamate alkyl groups, the carbon atoms of the alkyl
groups are also asymmetric in nature. 31P NMR spectra show a
single resonance for the phosphorus atom, which is generally
observed at about 25–30 ppm downfield in the complexes, in
comparison with the precursor organophosphines.
À
Á
1=2
ip ¼ 2:99 ꢃ 105 nðanÞ1=2ACðDvÞ
(1)
Structural Study of Compounds 1 and 2
The ORTEP representations of compounds 1 and 2, together with
selected bond distances and bond angles, are shown in Figs 1
and 2, respectively. Compound 1 crystallizes in a triclinic crystal
system (P ꢀ 1), whereas compound 2 crystallizes in a monoclinic
system (P2(1)/n). Both complexes display similar pseudo square-
planar geometry with the dithiocarbamate ligand, in bidentate
fashion, occupying two adjacent coordination sites, while a chlo-
ride and the organophosphine ligand are bonded to the two
remaining sites. The largest distortion from the normal geometry
arises from the bidentate ligand [S(1)-Pd-S(2) of 75.56(3)ꢁ and
where a is transfer coefficient, n is number of electrons trans-
ferred, A (cm2) is area of working electrode, n (V sꢀ1) is scan rate
and C (mol cmꢀ3) is bulk concentration of the sample. an = 47.7/
(EP ꢀ EP/2) was used.[32] To calculate the standard heterogeneous
rate constants, Gileadi’s method was used.[33] From the shift in
peak potential value while changing the scan rate, the critical
scan rate was obtained, which was subsequently used in the fol-
lowing equation to obtain ksh:
ꢀ
ꢁ
anFvcD∘
2:3RT
logksh ¼ ꢀ0:48a þ 0:52 þ log
(2)
To investigate the antitumor activity of the complexes, cyclic
voltammetric measurements were made, varying the DNA
concentration from 10 to 200 nM to the constant concentration
of the complex (5 mM).
Results and Discussion
Spectroscopic Characterization
FT-IR and Raman spectra of the complexes showed that the main
vibrational stretching modes were located at 3074–3020 (aro-
matic C-H), 2981–2929 (aliphatic C-H), 1531–1510 (C¼N), 428–378
(Pd-S), 324–279 (Pd-Cl) and 262–203 cmꢀ1 (Pd-P), while SCSasym
and SCSsym bending modes were observed at 1100–1026 and
694–690 cmꢀ1, respectively. The appearance of a Pd-S band in
the far-IR region confirms the complexation of Pd atom with
dithiocarbamate moiety. The C-N stretching mode observed at
about 1520 cmꢀ1 indicates the intermediate nature of the carbon–
Figure 1. Ball and stick diagram (50% probability) of compound 1.
Hydrogen atoms have been omitted for clarity. Selected bond lengths
(Å) and angles (ꢁ): Pd-P 2.2685(9); Pd-Cl 2.3436(8); Pd-S(1) 2.2720(8); Pd-
S(2) 2.357(1); S(1)-C(1) 1.728(4); S(2)-C(1) 1.714(3); C(1)-N 1.314(5); P-Pd-Cl
90.86(3); P-Pd-S(2) 170.96(3); S(2)-Pd-S(1) 75.56(3); Cl-Pd-S(1) 173.48(3) ;
S(2)-Pd-Cl 98.06(3); P-Pd-S(1) 75.56(3); C(1)-N-C(21) 120.8(3); C(1)-N-C
(23) 118.5(3); C(21)-N-C(23) 118.5(3) and S(1)-C(1)-S(2) 111.0(2).
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Copyright © 2013 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2013, 27, 387–395

Mixed ligand Pd(II) complexes as potent anticancer agents
Table 1. IC50 (mM) values of mixed ligand Pd(II) complexes against
DU145 human prostate carcinoma (HTB-81) cells
Compound
IC50
1
3
4
5
6
3.67
9.52
4.57
21.7
2.12
potential to form a hydrogen bond with the DNA bases. The lower
cytotoxicity of compound 5 may be attributed to the weak Pd-P
bond, due the presence of strong withdrawing chlorine and phenyl
groups in the organophosphine moiety. As a result, the complex
has a higher tendency to dissociate and react with other groups like
glutathione, cysteines and methionines in the cell before reaching
the target DNA.[44] The second lowest activity of compound 3
(IC50 9.52 mM) may derive from the presence of a bulky tertiary
butyl group, which renders movement of the complex to the target
DNA difficult. The activities of compounds 1 (3.67 mM) and 4
(4.57 mM) are close to each other; both of these complexes have a
similar benzyldiphenylphosphine ligand and their dithiocarbamate
ligands differ by only one methylene group (Fig. 3).
Figure 2. Ball and stick diagram (50% probability) of compound 2.
Hydrogen atoms have been omitted for clarity. Selected bond lengths
(Å) and angles (ꢁ): Pd-P 2.298(1); Pd-Cl 2.321(1); Pd-S(1) 2.319(1); Pd-S(2)
2.286(1); S(1)-C(1) 1.707(4); S(2)-C(1) 1.716(4); C(1)-N 1.313(5); P-Pd-Cl 92.94(4);
P-Pd-S(2) 99.99(3); S(2)-Pd-S(1) 75.25(4); Cl-Pd-S(1) 92.07(4) ; S(2)-Pd-Cl 166.60
(4); P-Pd-S(1) 173.87(4); C(1)-N-C(21) 120.3(4); C(1)-N-C(25) 122.0(3); C(21)-
N-C(25) 117.7(4) and S(1)-C(1)-S(2) 110.4(2).
Cyclic Voltammetric Analysis
Voltammetric measurements were carried out to study the redox
behavior of the compounds and also to investigate the possible
interaction mechanisms with ds-DNA obtained from chicken
blood. Representative cyclic voltammograms are presented in
Fig. 4 and the corresponding reduction potential data for the
compounds are tabulated in Table 2. The voltammograms repre-
sent one oxidation wave and two reduction waves sufficiently
apart from each other, with a difference of 0.430–0.573 V, indicat-
ing the independent electroreductions of the compounds. The
first reduction (with no corresponding oxidation) is irreversible,
while the presence of an oxidation wave for the second reduction
reveals its reversibility. The electrochemical irreversibility of the
first electron-transfer process shows the instability of the reduced
species, which in turn points to its high reactivity. The oxidation
peak in the reverse scan indicates the stability of the
electroreduced species generated in the second electron transfer
reaction. The small current values for the first reduction (1.457–
3.685 mA) illustrate the relatively slow electron transfer in com-
parison to the second one (current values 2.398–5.373 mA). The
appearance of two cathodic waves and one anodic wave in the
present work, conducted in DMSO, indicates the favorable reor-
ganization and involvement of the solvent molecules to affect
the electron transfer process. The late reduction, as indicated by
a sufficiently negative reduction potential, suggests the difficult
acceptability of the incoming electron by the reaction center
and could be attributed to the electron-donating nature of
the phosphine and dithiocarbamate ligands. The ΔEP2 values
in Table 2 portray the quasi-reversible behavior of the second
electron-transfer process.
75.25(4)ꢁ for 1 and 2 respectively], which causes the trans S(2)-
Pd-P and S(1)-Pd-Cl angles to be 170.96(3)ꢁ and 173.48(3)ꢁ for 1,
and S(2)-Pd-Cl and S(1)-Pd-P angles to be 166.60(4)ꢁ and 173.87
(4)ꢁ for 2, respectively, i.e. smaller than the expected value
of 180ꢁ. The asymmetry observed in the Pd-S distances is
typical for square-planar systems and reflects the trans influence
of the organophosphine ligands. In both complexes, the Pd-S
bonds trans to the organophosphine ligand are longer (2.357
(1) Å and 2.319(1) Å for 1 and 2, respectively) than are the Pd-S
bonds trans to the chloride (2.2720(8) and 2.286(1) Å for 1
and 2, respectively). The larger divergence in the Pd-S bond
lengths for compound 1 (ΔPd-S = 0.085 Å) than compound 2
(ΔPd-S = 0.033 Å) reflects the better donating capability of the
(PPh2-benzyl) group compared to the (PPh2-o-tolyl) group. Both
S-C distances in 1 and 2 fall between 1.728(4)–1.714(3) Å (1) and
1.716(4)–1.707(4) Å (2) and are intermediate between normal C-S
(1.82 Å) and C¼S (1.60 Å) distances.[38] Similarly, the C(1)-N bond
lengths (1.314(5) for 1 and 1.313(5) for 2) are significantly shorter
than is a normal C-N bond (1.47 Å) and longer than a C¼N bond
(1.28 Å).[39] These bond values clearly demonstrate the resonance
phenomenon in the SCS moiety, as reported in the previous
section. This resonance phenomenon is not uncommon in
dithiocarbamate complexes, e.g. [Ni{S2CN(CH2CH2NEt)2}2],23
[Ni(S2CNC4H8NH2)(dppp)] (BF4)2.[40]
Anticancer Activity
The mixed-ligand Pd(II) complexes were tested for antitumor activ-
ity against DU145 human prostate carcinoma (HTB-81) cells. All the
complexes tested, were found to be highly active against these
cells. The 50% inhibitory concentrations (IC50) of compounds 1–6
are listed in Table 1. All the observed values are lower than are
the literature values reported for the standard drug cisplatin.[41–43]
Compound 6 is the most active, with an IC50 of 2.12 mM, while com-
pound 5 has the lowest antitumor activity (IC50 21.7 mM). The higher
cytotoxicity of compound 6 may be ascribed to the presence of
oxygen species in the dithiocarbamate ligand, which has the
To further probe the nature of the electron transfer process,
the scan rate was varied from 20 to 1000 mV sꢀ1. The effect of
scan rate is shown in Fig. 5 and corresponding data in Tables 2
and 3. It was observed that as the scan rate is increased there is
a systematic negative potential shift in the reduction waves with
the expected current increase, while the anodic peak shifts anod-
ically. These observations indicate the irreversibility of the elec-
trochemical charge transfer process; however, the shift is not
large enough to justify a totally irreversible process. To investi-
gate whether the process is adsorption controlled or diffusion
Appl. Organometal. Chem. 2013, 27, 387–395
Copyright © 2013 John Wiley & Sons, Ltd.
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H. Khan et al.
Figure 3. Cell growth of DU145 human prostate carcinoma (HTB-81) cells at various concentrations of Pd(II) complexes.
Figure 4. Representative cyclic voltammograms: (a) compound 1 and (b) compound 6 for 1 mM concentration in DMSO, in the presence of tetra-n-
butylammonium perchlorate (TBAP), 0.1 M, at 25 ꢂ 1 ꢁC on glassy carbon vs. SCE at 20 mV sꢀ1
.
Table 2. Reduction and oxidation potential data of the Pd(II) complexes
controlled the peak current value (ip) was plotted against the
square root of the scan rate (n½) in the presence and absence
of DNA, using the Randles–Sevcik equation[31] for an irreversible
process. The diffusion coefficient value (Do) of the electron-
transfer process was determined from the Randles–Sevcik plot
and thus, subsequently, the heterogeneous rate constant were
determined employing Gileadi’s method of critical scan rate.[33]
The Do values obtained suggest that the overall process is mainly
diffusion controlled but charge transfer is also affecting the rate
of overall electrochemical reaction. The ksh values are of a magni-
tude which falls in the range reported for intermediate kinetic
processes depicting a quasi-reversible process.[45]
on glassy carbon electrode vs. SCE at 25 ꢂ 1ꢁC at 20mVsꢀ1 scan rate
Compound
Peak 1
Peak 2
*EP1c (V)
EP2c (V)
EP2a (V)
ΔEP2 (V)
1
2
3
4
5
6
ꢀ0.888
ꢀ0.860
ꢀ0.903
ꢀ0.920
ꢀ0.953
ꢀ0.718
ꢀ1.345
ꢀ1.357
ꢀ1.388
ꢀ1.374
ꢀ1.383
ꢀ1.291
ꢀ1.250
ꢀ1.254
ꢀ1.291
ꢀ1.264
ꢀ1.283
ꢀ1.181
0.095
0.103
0.097
0.110
0.100
0.110
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Mixed ligand Pd(II) complexes as potent anticancer agents
Figure 5. Effect of scan rate on compound 6, for 1 mM concentration: (a) pure complex, (b) in the presence of DNA, in DMSO + TBAP (tetra-n-butyl
ammonium perchlorate) 0.1 M at 25 ꢂ 1 ꢁC on glassy carbon vs. SCE.
Table 3. Values of diffusion coefficient (Do) and heterogeneous rate constant (ksh) for Pd(II) complexes from the second reduction peak in the
absence and presence of DNA
Compound
Do ꢃ 106 cm2 sꢀ1
ksh ꢃ 103 cm sꢀ1
Before DNA addition
After DNA addition
Before DNA addition
After DNA addition
1
2
3
4
5
6
1.61
1.06
1.68
1.62
1.37
1.32
0.96
0.79
0.97
1.03
0.93
0.84
4.39
4.28
5.32
4.63
4.72
4.28
3.68
3.67
3.70
4.00
3.49
3.53
Figure 6. Cyclic voltammograms depicting the effect of DNA concentration on the complexes; (a) compound 1, (b) compound 2 and (c) compound 6,
having 1 mM constant concentration in DMSO + 0.1 M TBAP at 25 ꢁC on glassy carbon vs. SCE at 20 mV sꢀ1 scan rate.
Appl. Organometal. Chem. 2013, 27, 387–395
Copyright © 2013 John Wiley & Sons, Ltd.
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H. Khan et al.
Table 4. Crystallographic data
1
2
Formula
FW
C24H27ClNPPdS2
566.45
C28H35ClNPPdS2
622.56
Crystal system
Space group
a (Å)
Triclinic
Monoclinic
P2(1)/n
(P ꢀ 1)
10.9056(3)
11.2073(3)
12.9279(3)
66.4820(10), 89.1410(10),
62.4860(10)
1256.79(6)
2
9.3010(2)
20.0610(5)
15.9196(4)
90.00, 95.9120(10),
90.00
b (Å)
c (Å)
a, b, g (ꢁ)
V (Å3)
2954.60(12)
4
Z
Cell measurement temperature
Diffraction radiation type
F000
293(2) K
296(2) K
MoKa
1280
MoKa
576.0
Goodness-of-fit on F2
R indices (all data)
Reflections collected
Max. 2θ
1.131
0.994
R1 = 0.0234, wR2 = 0.0893
26 944
R1 = 0.0589, wR2 = 0.1010
34 381
56.73
56.69
Interaction with DNA
corresponding heterogeneous rate constant data also showed
the slowness of the charge transfer process across the electrode
solution interface for the DNA-bound complexes.
To explore the denaturing ability of the complexes, cyclic
voltammetric measurements were carried out for varying DNA
concentrations (20–2000 nM) against a constant concentration
of the test compound (1 mM). The behavior of compounds 1, 2
and 6 are presented in Fig. 6.
Conclusion
Similar responses were observed in all cases and these can be
generalized into three major outcomes: (i) the systematic addi-
tion of DNA caused a significant decrease in the peak current of
the first reduction; (ii) the effect on the current decrease in the
second reduction remained either very small or practically con-
stant; (iii) the anodic wave remained unaffected. The systematic
decrease in the reduction peak current(s) can be attributed to
the consumption of the test compound by DNA, which becomes
denatured, as reported in the literature.[45] The complexes
contain electron-donating ligands that make the Pd(II) center
more electronegative and also reactive.[46] Upon DNA addition
a complex–DNA adduct is formed and the process is linearly
dependent on concentration. The same situation obtains in the
case of testing the complexes against the cancer cell line. The
major decrease was found in the first reduction, which corre-
sponds to an irreversible process, and remained irreversible after
the DNA addition. The overall process corresponds to an EiCi type
mechanism, i.e. irreversible electron transfer followed by an
irreversible chemical reaction, as expected. In a few cases, a very
small negative shift in the potential value indicates a possible
electrostatic interaction between the positive metal center and
the negative oxygen atoms of the phosphate groups in DNA.[47]
To support the above qualitative hypothesis about the com-
plex–DNA interaction, the process was studied from another
point of view which includes the calculation of diffusion coeffi-
cients (Do) of the electron-transfer process before and after
DNA addition. The data obtained are collected together in
Table 3. The smaller values of diffusion coefficient in the presence
of DNA implies that the complex–DNA adduct formed diffuses at
a slower rate than does the pure complex. Hence a decrease in
the diffusion coefficient exhibits the effect of complex–DNA
adduct formation on the electron transfer process. The
Six new palladium(II) complexes with dithiocarbamates and
phosphine ligands have been successfully synthesized and char-
acterized by various spectroscopic techniques. The crystal struc-
tures of 1 and 2 illustrate the attachment of dithiocarbamate in
a cis fashion. The geometry around the palladium moiety is
pseudo square-planar with the Pd-S bond trans to the phosphine
being longer than Pd-S bond trans to the chloride atom. All the
compounds synthesized have shown excellent to good
antitumor activity against cisplatin-resistant DU145 human pros-
tate carcinoma (HTB-81) cells lines, with the highest activity
shown by compound 6 (IC50 2.12 mM). Cyclic voltammograms
show the two independent electroreductions of the compounds.
The first electron transfer is an irreversible process, while transfer
of the second electron is a quasi-reversible process. The decrease
in peak current with no shift in peak potential upon addition of
DNA in all the cases describes the consumption of the complexes
by DNA. The successive decrease in diffusion constant (Do) upon
addition of DNA also describes the interaction of synthesized
compounds with DNA.
Supplementary Material
The crystallographic data for the structural analyses of compounds
1 and 2 (Table 4) have been deposited with the Cambridge Crystal-
lographic Data Centre, CCDC No. for 1 is CCDC 833826 and for 2 is
CCDC 833827. A copy of this information may be obtained free of
charge from the Director, CCDC, 12 Union Road, Cambridge, CBZ
1EZ, UK (fax: +44 1223 336 033; e-mail: deposit@ccdc.cam.ac.uk or
www: http://www.ccdc.cam.ac.uk).
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Mixed ligand Pd(II) complexes as potent anticancer agents
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Acknowledgments
Mr H. Khan is highly indebted to the Higher Education Commis-
sion (HEC) of Pakistan for providing scholarship under the pro-
gram 5000 Indigenous PhD Scholarships at Quaid-i-Azam
University in Islamabad and for a 6-month scholarship under
the International Research Support Initiative program (IRSIP) as
a Graduate Research Trainee in the Department of Chemistry,
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