New dimeric and supramolecular mixed ligand Palladium(II) dithiocarbamates as potent DNA binders

Article abstract of DOI:10.1016/j.poly.2012.02.025

Five Pd(II)-based potential potent metallopharmaceuticals (1-5) of the general formula [(DT)Pd(PR₃)Cl], where DT = dibutyldithiocarbamate (1,2), dipropyldithiocarbamate (3), bis(2-methoxyethyl)-dithiocarbamate (4), dimethyldithiocarbamate (5);

Full text of DOI:10.1016/j.poly.2012.02.025

Polyhedron 39 (2012) 1–8
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Polyhedron
journal homepage: www.elsevier.com/locate/poly
New dimeric and supramolecular mixed ligand Palladium(II) dithiocarbamates
as potent DNA binders
a
a
a
a
Hizbullah Khan a,b, Amin Badshah a, , Zia-ur- Rehman , Muhammad Said , Ghulam Murtaza , Afzal Shah ,
⇑
Ian S. Butler b, Safeer Ahmed a, Frédéric-Georges Fontaine c
a Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan
b Department of Chemistry, McGill University, 801 Sherbrooke St., W. Montreal, Quebec, Canada H3A 2K6
c Département de Chimie, Université Laval, 1045 Avenue de la Médecine, Québec, Canada G1V 0A6
a r t i c l e i n f o
a b s t r a c t
Article history:
Five Pd(II)-based potential potent metallopharmaceuticals (1–5) of the general formula [(DT)Pd(PR3)Cl],
where DT = dibutyldithiocarbamate (1,2), dipropyldithiocarbamate (3), bis(2-methoxyethyl)-dithiocar-
bamate (4), dimethyldithiocarbamate (5); PR3 = triphenylphosphine (1), diphenyl-p-tolylphosphine (2),
diphenyl-t-butylphosphine (3), diphenyl-2-methoxyphenylphosphine (4), p-cholorodiphenylphosphine
(5), have been synthesized and characterized using FT-IR, Raman, and multinuclear-NMR spectroscopy.
The X-ray single crystal analysis (1 and 2) reveals the Pd(II) moiety is in a distorted square–planar
arrangement with two positions being occupied by the bidentate dithiocarbamate ligand, while the other
two positions are occupied by a phosphine ligand and a chloro group. The packing diagrams confirmed
that the intermolecular Clꢀ ꢀ ꢀH interactions are not only the main cause of deviation from an ideal square
planar geometry, but are also responsible for the Pd–S bond lengths variation. The DNA binding ability of
the complexes was examined by cyclic voltammetry (CV). The cyclic voltammograms of the synthesized
metallopharmaceuticals followed irreversible electrochemical behavior, which indicate the high reactiv-
ity of the reduced form of complexes. The results obtained from CV evidenced the catalytic role of DNA in
enhancing the electron transfer processes of the complexes. The DNA binding studies are expected to pro-
vide useful insights about the unexplored mechanism by which anticancer drugs exert their biochemical
action.
Received 29 November 2011
Accepted 13 February 2012
Available online 1 March 2012
Keywords:
DNA binding study
Palladium
Mixed ligand
Dithiocarbamate
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
to the (NH3)Pt+ moiety, causing ammonia release [6]. Thiocarbonyl
donorshavealsodemonstratedchemoprotectantpropertiesinmod-
Cisplatin is an important anticancer drug, but it suffers from
acquired resistance, neuro-, nephro-, oto-, gastrointestinal and bone
marrow toxicity [1]. In the previous two decades, there has been a
continuous interest in the synthesis of more potent drug complexes
containing S- and N-donor ligands that should have higher cytotoxic
activity with minimum or no side effects as compared to cisplatin
[2]. After extensive experimental screening, Das and Livingstone
postulated that sulfur containing palladium(II) complexes are more
effective anticancer drugs [3]. The aminothiol (NH2–(CH2)3–NH–
(CH2)2–S–PO3H2) was foundto protect against chemoand radiother-
apy side-effects, potentially because of the release of the tridentate
N, N, S aminothiol [4]. In combined therapy, glutathione has also
shown an evident reduction in the nephrotoxicity of cisplatin and
carboplatin [5]. It has been reported that thiols and glutathione bind
ulating the nephrotoxicity of cisplatin [7].
Cleare and Hoeshele suggested some prominent structure/
activity rules: trans-compounds, charged ones and those having
only one leaving group are inactive while complexes having two
amine ligands with at least one H atom are active [8]. However,
some complexes, like trans-[PtCl2(L)(L0)] with L and/or L0 = pyri-
dine-like ligands, L = alkyl substituted amine and L0 = isopropyl
amine, and L and/or L0 = iminoether, violate these criteria [9].
Dithiocarbamates have shown promising results in reversing
the renal cellular damage caused by cisplatin in several animal
models [10]. These ligands selectively remove the platinum metal
from the enzyme-thiol complex without reducing the antitumor
effect of the drug [11a]. Trevisan and co-workers found Pd(II)
dithiocarbamates to have anticancer activity like cisplatin with
the additional advantage of no cross-resistance [11a,b].
Keeping in view the objective of synthesizing palladium
complexes having maximal antitumor activity and little toxic
side effects when compared to cisplatin, we synthesized and
⇑
Corresponding author. Tel.: +92 051 90642131; fax: +92 05190642241.
E-mail addresses: aminbadshah@yahoo.com (A. Badshah), frederic.fontaine@
chm.ulaval.ca (F.-G. Fontaine).
0277-5387/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.poly.2012.02.025

2
H. Khan et al. / Polyhedron 39 (2012) 1–8
characterized mixed ligand palladium(II) complexes of the
general formula [(DT)Pd(II)(PR3)Cl] (DT = dibutyldithiocarbamate,
dipropyldithiocarbamate, bis(2-methoxyethyl) dithiocarbamate
or dimethyldithiocarbamate; PR3 = triphenylphosphine, diphenyl-
p-tolylphosphine, diphenyl-t-butylphosphine, diphenyl-2-meth-
oxyphenylphosphine, or p-cholorodiphenylphosphine). Moreover,
the DNA binding ability of the palladium drugs were investigated
by cyclic voltammetry (CV) with the objective of adding effective
chemotherapeutic agents to the arsenal of weapons used against
cancer.
2.2. Structural study of complexes 1 and 2
The molecular structures and selected distances and angles of
compounds 1 and 2 are shown in Figs. 1 and 3, respectively. Com-
plex 1 crystallizes in the triclinic crystal system (P1), whereas 2
ꢀ
crystallizes in the P21/c monoclinic system. Both complexes exhibit
a similar pseudo square-planar geometry, with the S atoms of the
dithiocarbamate ligand occupying two adjacent coordination sites
and with the chloride and the phosphine binding to the two
remaining sites. The largest distortion from the normal geometry
comes from the bidentate ligand (S(1)–Pd(1)–S(2) of 75.41(3)
and 75.48(2)° for 1 and 2, respectively), which causes the trans
S(2)–Pd(1)–Cl(1) and P(1)–Pd(1)–S(1) angles to be between
167.75(3) and 171.53(2)°, smaller than the expected value of
180°. The increase in the trans S–Pd–Cl angle can also be attributed
to the involvement of the chloro group in intermolecular non-cova-
lent interactions. The high trans angle of 2 compared to 1 is possi-
bly due to stronger Clꢀ ꢀ ꢀH intermolecular interactions (Figs. 2 and
4) in 2 (2.830 Å) than 1 (2.849 Å). Moreover, this also confirms the
idea that the intermolecular Clꢀ ꢀ ꢀH interaction is a main cause of
the deviation of the square planar geometry from its ideal value.
The dissymmetry observed in the Pd–S distances is typical for
square-planar systems and reflects the trans influence of the li-
gands in play. In both complexes, the Pd(1)–S(1) bond lengths trans
to the phosphine ligand are longer (2.3302(7) and 2.3566(5) Å for 1
and 2, respectively) than the Pd(1)–S(2) bond lengths trans to the
chloride (2.2966(7) and 2.2793(6) Å for 1 and 2, respectively).
The largest discrepancy in the Pd–S bond lengths for complex 2
2. Results and discussion
2.1. Synthesis of the dithiocarbamate palladium(II) complexes and
their characterization in solution
Complexes 1–5 were synthesized by reacting the appropriate
dithiocarbamic acid and (PR3)2PdCl2 in CH2Cl2 (Scheme 1). The
complexes are soluble in common organic solvents and are stable
under normal conditions of temperature and pressure.
In addition to the absorption bands associated with the phos-
phine ligands, complexes 1–5 display IR stretching modes at mmax
values of 1512–1530 (CN), 995–1096 (SCSasym), 701–689 (SCSsym
)
and 380–388 cmꢁ1 (Pd-S), suggesting coordination of the dithiocar-
bamate ligand to the metal. The diagnostic band in the 1450–
1580 cmꢁ1 range is attributable to the C–N stretching mode and is
highly characteristic of dithiocarbamate complexes [12]. This C–N
vibration appears at a value between that normally found for a sin-
gle bond (1250–1350 cmꢁ1) and a double bond (1640–1690 cmꢁ1).
This intermediate bond length was also confirmed using X-ray crys-
tallography (vide infra) [13], suggesting that the resonance structure
I is dominant compared to the others (Scheme 2) and that the C–N
bond strength is increased compared to that of the free ligand
[14]. The absence of an S–H absorption band in the 2550–
2700 cmꢁ1 region indicates that in all cases replacement of the
hydrogen atom of the SH group by a metal ion has occurred. The
appearance of a single absorption band for the SCS moiety in the
900–1100 cmꢁ1 (SCSasym) region and one in the 680–705 cmꢁ1 re-
gion (SCSsym) shows the complete symmetrically bonded nature of
the dithiocarbamate ligand in a bidentate fashion [15].
(DPd–S of 0.077 Å for 2 compared to 0.034 Å for 1) reflects the bet-
ter donating capability of the PPh2-p-tolyl ligand compared to tri-
phenylphosphine. In addition to this, packing diagrams (Figs. 3 and
5) show stronger Clꢀ ꢀ ꢀH intermolecular interactions in 2 (2.830 Å)
compared to 1 (2.849 Å), and as a consequence the Pd–Cl bond is
longer in 2 (2.3277 Å) than 1 (2.3226 Å). This allows the S atom
trans to the chloro group to approach comparatively closely and
to undergo a strong interaction with the Pd atom, thus causing
the higher discrepancy in the Pd–S bond lengths in 2. The S–C dis-
tances in 1 and 2 of 1.711(3) and 1.732(3) Å, respectively, are inter-
mediate between normal C–S (1.82 Å) and C@S (1.60 Å) distances.
Similarly, the C(1)–N(1) bond lengths of 1.312(3) Å for 1 and
1.318(3) Å for 2 are significantly shorter than a normal C–N bond
(1.47 Å) and longer than a C@N bond (1.28 Å) [17]. These bond val-
ues clearly demonstrate the resonance phenomenon in the SCS
moiety, as reported in the previous section.
The 1H NMR data show the disappearance of the SH frequency,
once more suggesting coordination of the dithiocarbamate moiety
to the metal center by abstraction of H+ from the dithiocarbamic
acid. Another characteristic feature of the 1H NMR spectra is the
asymmetry in the alkyl groups attached to the nitrogen atom of
the dithiocarbamate moiety, caused by the restricted rotation
around the CN bond which is known to have an energy barrier of
65–92 kJ molꢁ1 [16]. The SCS carbon shift appeared in the range
206.2–208.5 ppm in the 13C NMR spectra of the complexes. A slight
decrease in the chemical shift of the SCS carbon atom compared to
dithiocarbamic acid suggests complexation of the ligand to the
palladium center. Similarly to the features observed by 1H NMR
spectroscopy, the carbon atoms of the substituents of the dithiocar-
bamate moiety are non-equivalent.
The packing diagrams (Figs. 2 and 4) attribute a supramolecular
ladder structure to complex 1, mediated by Bu–Hꢀ ꢀ ꢀCl and Ph–
Hꢀ ꢀ ꢀCl intermolecular interactions, whereas complex 2 exhibits a
dimeric structure due to the presence of intermolecular Clꢀ ꢀ ꢀH
interactions.
3. Cyclic voltammetry (CV)
3.1. Electrochemical characterization and DNA binding studies
The synthesized compounds were screened for their anticancer
activity by a cyclic voltammetric based assay. Although easy to
implement, this assay cannot be applied to electro-inactive com-
pounds. Moreover, the method is limited to compounds exerting
their anticancer effect through a direct interaction with DNA. In
spite of these obvious limitations, this technique can differentiate
the binding strength and modes of action of DNA-binding
compounds.
SH
R'2N
PR3
Cl
S
S
S
R'2N
Pd
(PR3)2PdCl2
Δ,
CH2Cl2, 24 hr
PR3 = PPh3 (1), PPh ( -tolyl) (2), PPh ( Bu) (3), PPh ( OMe-Ph) (4), PPh Cl (5)
2 p 2 t 2 o-
2
Electrochemical studies of the synthesized Pd(II)-based potential
anticancer compounds (1–5) were carried out with the objective of
getting insight into their redox behaviour and DNA binding modes.
1 2
3
4
5
R' = butyl ( , ), propyl ( ), 2-methoxyethyl ( ), methyl ( )
Scheme 1. Synthesis of the mixed ligand Pd(II) complexes.

H. Khan et al. / Polyhedron 39 (2012) 1–8
3
S
S
S
S
S
S
N
C
N
C
N
C
N
C
S
S
I
III
IV
II
Scheme 2. Resonance structures of the dithiocarbamate moiety.
Fig. 1. Ball and stick representation of complex 1. Selected bond lengths (Å) and angles (°): Pd(1)–P(1) 2.2926(7); Pd(1)–Cl(1) 2.3226(7); Pd(1)–S(1) 2.3302(7); Pd(1)–S(2)
2.2966(7); S(1)–C(1) 1.711(3); S(2)–C(1) 1.732(3); C(1)–N(1) 1.312(3); P(1)–Pd(1)–Cl(1) 96.47(3); P(1)–Pd(1)–S(2) 95.63(3); S(2)–Pd(1)–S(1) 75.41(3); Cl(1)–Pd(1)–S(1)
92.58(3); S(2)–Pd(1)–Cl(1) 167.75(3); P(1)–Pd(1)–S(1) 170.64(2); C(1)–N(1)–C(2) 119.7(3); C(1)–N(1)–C(6) 122.2(2); C(6)–N(1)–C(2) 118.2(2); S(1)–C(1)–S(2) 110.57(15).
Typical cyclic voltammograms of the synthesized complexes 1 and 3
are depicted in Fig. 5. The relevant electrochemical parameters are
assembled in Table 1.
were recorded at various scan rates. The corresponding data of the
complexes are listed in Table 1. The effect of scan rate on complex
3 is shown in Fig. 6. The shift in peak potential with the increase in
scan rate manifests the irreversibility of the reduction process.
However, the emergence of an oxidation hump at higher scan rates
points to quasi-reversible behavior. The relatively large D° values
also suggest quasi-reversible kinetics [20]. The values of ksh are
of the magnitude expected for intermediate kinetic processes [21].
For the evaluation of the interaction parameters of Pd-based
complexes with DNA, cyclic voltammetric measurements were
performed, keeping the concentration of the complex constant
(5 mM) and varying the concentration of DNA from 10 to
200 nM. Typical CVs of samples 1 and 3 with and without DNA
are presented in Fig. 7. For both complexes, the reduction peak in-
creased in height accompanied by a slight shift in the peak poten-
tial upon incremental addition of DNA. A dramatic change in the
voltammetric response of complexes 1 and 3 was encountered in
the presence of 35–50 nM DNA, when the reduction peak leveled
off and another cathodic peak emerged exactly at the potential va-
lue of the small hump observed in the CV of the pure complexes. A
literature survey regarding drug-DNA binding in solution has re-
vealed three modes of interaction: (i) a decrease in peak current
with no shift in peak potential value, ascribed to the consumption
of the drug by DNA [22], (ii) a negative shift rationalized as electro-
static interactions between the anionic phosphate of DNA and the
cationic moiety of the drug [23], and (iii) a positive shift related to
the intercalation of the drug into the stacked base pairs of DNA
[24]. The present novel situation (i.e., peak current enhancement
of the complexes in the presence of DNA) can be attributed to
the catalytic role of DNA in inducing an electron transfer to the
The cyclic voltammograms of all five complexes registered a
single broad cathodic peak corresponding to irreversible reduction
of the analyte. The absence of a peak in the reverse scan indicates
the instability of the reduced form of the complexes. The relatively
difficult reduction of compounds 1–4, as evident from their catho-
dic peaks at more negative potentials, can be linked to the low
electron affinity of the electrophore due to the more nucleophilic
nature of the electron-donating phosphine and dithiocarbamate
attached to the metal. The reduction potential of the complexes
followed the expected tendency of Tolman’s electronic parameter
(m
, cmꢁ1) of phosphines (PPh2-tBu < PPh2-p-tolyl < PPh3 < PPh2Cl)
[18]. The facile electro-reduction of compound 5 (Table 1) can be
attributed to the presence of a strongly electron-withdrawing
chloro group at the phosphine moiety. The peak current data of
complex 5 was not so strong as to allow the calculation of the dif-
fusion coefficient, D°, and heterogeneous rate constant, ksh. The
rationale behind the comparatively low peak current of complex
5 may be its interaction with the solvent due to the presence of
an additional chloro group. The small hump at ꢁ1.14 and
ꢁ1.15 V, noticed in the CV of complexes 1 and 2, before the appear-
ance of a prominent reduction peak can be related to inner sphere
(within the complex molecule) and outer sphere (due to the sol-
vent effect) rearrangements of the complexes, as reported previ-
ously for organometallic complexes [19].
The dependence of the current function Ip on the scan rate, m, is
an important diagnostic criterion for establishing the type of
mechanism. For achieving this objective, the CVs of the complexes

4
H. Khan et al. / Polyhedron 39 (2012) 1–8
Fig. 2. Supramolecular chain structure of compound 1 mediated by Bu–Hꢀ ꢀ ꢀCl and Ph–Hꢀ ꢀ ꢀCl intermolecular interactions of 2.787 and 2.849 Å, respectively.
Fig. 3. Ball and stick representation of complex 2. Hydrogen atoms have been omitted for clarity. Selected bond lengths (Å) and angles (°): Pd(1)–P(1) 2.2699(5); Pd(1)–Cl(1)
2.3277(6); Pd(1)–S(1) 2.3566(5); Pd(1)–S(2) 2.2793(6); S(1)–C(1) 1.717(2); S(2)–C(1) 1.731(2); C(1)–N(1) 1.318(3); P(1)–Pd(1)–Cl(1) 91.48(2); P(1)–Pd(1)–S(2) 96.412(19);
S(2)–Pd(1)–S(1) 75.48(2); Cl(1)–Pd(1)–S(1) 96.81(2); S(2)–Pd(1)–Cl(1) 170.80(2); P(1)–Pd(1)–S(1) 171.53(2); C(1)–N(1)–C(2) 121.25(19); C(1)–N(1)–C(6) 120.70(19);
C(6)–N(1)–C(2) 117.16(19); S(1)–C(1)–S(2) 110.79(12).

H. Khan et al. / Polyhedron 39 (2012) 1–8
5
Fig. 4. Dimeric structure of compound 2 mediated by Clꢀ ꢀ ꢀH interactions (2.830 Å).
4
(b)
2
(a)
5
0
0
-2
-5
-4
-6
-8
-10
-12
-14
-10
-15
-20
-25
-30
-1.8 -1.6 -1.4 -1.2 -1.0 -0.8 -0.6
E (V)
-1.8 -1.6 -1.4 -1.2 -1.0 -0.8 -0.6
E (V)
Fig. 5. Representative cyclic voltammograms of a 5 mM concentration of (A) 1 and (B) 3 in dichloromethane with a 0.1 M concentration of MTBAP at 25 °C on a glass carbon
electrode vs. SCE at a 0.150 Vsꢁ1 scan rate.
Table 1
Voltammetric and kinetic parameters of the complexes in dichloromethane at 25 °C on GC vs. SCE.
Substrate
Epc (V)
Ipc
(lA)
Ecp ꢁ Ec (V)
D° ꢂ 105 (cm2/s)
ksh ꢂ 104 (cm/s)
p/2
1
2
3
4
5
ꢁ1.387
ꢁ1.412
ꢁ1.463
ꢁ1.331
ꢁ0.899
17.79
11.58
9.87
11.27
1.08
0.076
0.056
0.044
0.042
0.130
5.1
4.9
4.3
4.3
–
5.8
4.7
4.6
6.9
–
Pd(II) complex. The increase in peak current intensity with the
generation of no new peak has also been assigned to catalytic
behavior by previous electrochemists [25]. An examination of the
packing diagrams demonstrates that the chloro groups may be in-
volved in hydrogen bonding with DNA bases in the same fashion as
depicted in Figs. 2 and 4. Consequently, the electronic density in
the vicinity of Pd will be lowered, which may lead to the enhance-
ment of the electron transfer process, as evidenced from the in-
crease in peak current intensity. The argument is further
supported by the presence of two chloro groups in complex 5,
which has the highest DNA-binding affinity (Table 2). The lowest
binding constant of complex 4 can be attributed to the presence
of the more polar methoxy groups having a lower affinity for the
DNA less polar interior. The high DNA-binding affinity of complex
1 may be due to the more hydrophobic butyl groups. The leveling
off of the major reduction peak points to the unavailability of the
free drug, resulting in the culmination of the catalytic effect of
DNA.
From the data listed in Table 2, it can be inferred that the K val-
ues are of the order of 106 for compounds 1, 2 and 5, while the K

6
H. Khan et al. / Polyhedron 39 (2012) 1–8
20
15
10
5
4. Conclusions
Five new palladium(II) dithiocarbamates have been successfully
synthesized and characterized by various analytical techniques.
The X-ray single crystal structures of compounds 1 and 2 show that
these species are pseudo square-planar with the dithiocarbamate
ligands bonding in a cis fashion and with the Pd–S bond trans to
the phosphine being longer than the Pd–S bond trans to the chlo-
ride. The involvement of the chloro group in secondary interactions
not only plays a key role in this deviation (see the packing dia-
grams) but also has a marked influence on the DNA binding ability
of complexes. The cyclic voltammograms of complexes 1–4 exhibit
a single irreversible scan rate dependent reduction peak at ꢁ1.33
to ꢁ1.46 V (versu SCE). In the presence of DNA, an increase in peak
current accompanied with a small cathodic shift in reduction po-
tential evidenced the catalytic role of DNA in enhancing the elec-
tron transfer process. At higher concentrations, the catalytic
20mV/s
0
-5
-10
-15
-20
-25
-30
1000mV/s
-1.8 -1.6 -1.4 -1.2 -1.0 -0.8 -0.6
E(V)
Fig. 6. Cyclic voltammograms of complex 3 (5 mM) in dichloromethane + 0.1MTBAP
at 25 °C on GC vs. SCE at different scan rates.
15
(a) 105
effect of DNA was culminated. The negative
DG° values indicate
the spontaneity of the complexes-DNA binding. The binding con-
stants varied in the sequence: K1 = K5 > K2 > K3 > K4. The values of
K for complexes 1, 2 and 5 are greater than most of the clinically
used anticancer drugs and these complexes may emerge as a
new class of anticancer drugs after further investigations.
0
-5
-10
0.0nM
7.0nM
-15
21.0nM
-20
35.0nM
-25
91.0nM
-30
-35
-40
5. Experimental
-45
-1.8 -1.6 -1.4 -1.2 -1.0 -0.8 -0.6
5.1. General comments
E(V)
All the experiments were performed under the normal condi-
tions of temperature and pressure. Dimethylamine, p-chlorodi-
phenylphosphine, dibutylamine, triphenylphosphine, diphenyl-
p-tolylphosphine, dipropylamine, diphenyl-t-butylphosphine,
bis(2-methoxyethyl)amine, HCl, CS2 and palladium(II) chloride were
purchased from Aldrich Chemical Co. and were used without further
purification. All the solvents were purified by the standard methods,
dried, saturated with nitrogen and stored over molecular sieves
(4 Å). NMR spectra were recorded on a Bruker 300 MHz spectrome-
ter. 1H NMR (300.13 MHz): CDCl3 (7.26 ppm from SiMe4) and
DMSO-d6 (2.49 ppm from SiMe4), internal standard SiMe4; 13C
NMR (75.46 MHz): internal standard TMS; the splitting of proton
resonances in the NMR spectra are shown as: s = singlet, d = doublet,
t = triplet and m = multiplet (showing a complex pattern). IR spectra
were recorded on a Perkin–Elmer system 2000 FT-IR spectrometer
(250–4000 cmꢁ1). The elemental analyses were conducted on a
LECO-183 CHNS analyzer.
20
(b)
10
0
-10
0.0nM
-20
7.0nM
14.0nM
-30
35.0nM
-40
141.0nM
-50
-1.8 -1.6 -1.4 -1.2 -1.0 -0.8 -0.6
E(V)
Fig. 7. Cyclic voltammograms depicting the effect of DNA concentration on the
complexes (a) sample
1 (b) sample 3 at a constant (5 mM) concentration in
dichloromethane + 0.1 M TBAP at 25 °C on GC vs. SCE at 0.150 Vsꢁ1 scan rate.
An Autolab PGSTAT 302 with software GPES (version 4.9, Eco
Chemie, Utrecht, Netherland) was used to perform the cyclic vol-
tammetry measurements. A standard calomel electrode was used
as the reference electrode, a thin Pt-wire as a counter electrode
and a bare glassy carbon (GC) electrode of 0.071 cm2 area as a
working electrode for all the measurements. All the measurements
were carried out in CH2Cl2 (99.5%, Riedel-de Haen) using 0.1 M
t-butyl ammonium perchlorate (TBAP P 98%, Fluka) at 25 1 °C
under an argon atmosphere. The sample concentration was
maintained at 5 mM in each case.
Table 2
Binding parameters for the compounds based upon cyclic voltammetric data.
Substrate
K (Mꢁ1
)
ꢁD )
G° (kJmolꢁ1
1
2
3
4
5
7.05 ꢂ 106
1.35 ꢂ 106
8.46 ꢂ 104
6.16 ꢂ 102
7.05 ꢂ 106
39
35
28
16
39
5.2. General synthesis of complexes 1–5
values of 3 and 4 are of the order of 104 and 102. The binding con-
stants of these complexes are higher than those normally reported
for drug molecules, i.e., 102–104 [26]. The DNA-binding affinity of
complexes 1, 2 and 5 are greater than K = 4.1 ꢂ 105 Mꢁ1 for the
The palladium(II) phosphine complexes were prepared by dis-
solving the appropriate amount of Pd(II) chloride in methanol in
the presence of 3 or 4 drops of concentrated HCl and by refluxing
the solution for 30 min. The desired phosphine was dissolved in
acetone and the solution was added to the Pd(II) chloride solution
in a 2:1 M ratio. The reaction mixture was stirred under reflux for
3 h. The solid product obtained was filtered off and dried at room
clinically used anticancer drug epirubicin [27]. The high
DG° values
of complexes 1 and 5 ensure greater conformational stability of
their DNA adducts.

H. Khan et al. / Polyhedron 39 (2012) 1–8
7
temperature, dissolved in dichloromethane and reacted with the
5.2.4. [Pd(bis(2-methoxyethyl)-dithiocarbamate)(PPh2-o-OMe-Ph)Cl]
(4)
desired dithiocarbamate in a 1:1 M ratio. The reaction mixture
was heated under reflux for 24 h. The resulting solution was dec-
anted off and the solvent was removed under reduced pressure
to form a golden yellow solid, which was dissolved in 30 mL of a
mixture of dichloromethane, n-hexane and diethyl ether (2:1:1)
and kept for recrystallization at room temperature in a 100 mL
conical flask. Golden yellow crystals of 1 and 2 were obtained,
but the other products were not crystalline under these conditions.
Quantities used were 0.99 g (4.0 mmol) of bis(2-methoxyethyl)-
dithiocarbamate and 3.04 g (4.0 mmol) Pd(PPh2-o-tolyl)2Cl2 in
25 mL of dichloromethane. Yield: 90% (0.30 g) of a golden yellow
solid. M.p. 175–176 °C. FTIR (powder, cmꢁ1): 3060, 2962, 1520,
1412, 1257, 995, 790, 701, 385, 322. 1H NMR (300 MHz, CDCl3) d:
7.40–7.33 (m, 7H, ArH), 7.32–7.25 (m, 6H, ArH), 7.15 (t, 1H, ArH,
3
3JH–H = 7.6 Hz), 3.72 (t, 2H, –CH2CH2, JH–H = 6.9 Hz), 3.70 (t, 2H, –
3
CH2CH2, JH–H = 6.9 Hz), 3.30 (s, 6H, –CH2OCH3), 3.24 (t, 2H, –
3
3
NCH2, JH–H = 6.3 Hz), 3.22 (t, 2H, –NCH2, JH–H = 6.3 Hz), 1.82 (s,
3H, Ar-OCH3). 13C{1H} NMR (75.47 MHz, CDCl3) d: 206.2 (1C, -
CSS), 159.8 (1C, Ar), 135.6 (2C, Ar), 134.2 (5C, Ar), 128.2 (7C, Ar),
123.0 (1C, Ar), 121.0 (1C, Ar), 111.2 (1C, Ar), 69.9 (1C, –CH2OCH3),
69.4 (1C, –CH2OCH3), 55.9 (1C, –NCH2), 55.2 (1C, –NCH2), 50.1 (1C,
–NCH2CH2), 49.8 (1C, –NCH2CH2). 31P NMR (80.98 MHz, CDCl3) d:
22.6. Anal. Calc. for C26H31ClNO3PPdS2: C, 48.60; H, 4.86; N, 2.18;
S, 9.98. Found: C, 48.56; H, 4.83; N, 2.16; S, 10.01%.
5.2.1. [Pd(dibutyldithiocarbamate)(PPh3)Cl] (1)
Quantities used were 0.28 g (4.0 mmol) of dibutyldithiocarba-
mate and 2.80 g (4.0 mmol) Pd(PPh3)2Cl2 in 25 mL of dichloro-
methane. Yield 80% (0.24 g) of golden yellow crystals. M.p.
171–172 °C. FT-IR (powder, cmꢁ1): 3072, 2925, 1526, 1093, 798,
691, 388, 320. 1H NMR (300 MHz, CDCl3) d: 7.73–7.66 (m, 9H,
3
ArH), 7.47–7.40 (m, 6H, ArH), 3.63 (t, 2H, –NCH2, JH–H = 7.5 Hz),
3.48 (t, 2H, –NCH2, 3JH–H = 7.5 Hz), 1.68–1.50 (m, 4H, –CH2CH2CH3),
3
1.38–1.23 (m, 4H, -CH2CH2CH3), 0.94 (t, 3H, –CH2CH3, JH–H
5.2.5. [Pd(dimethyldithiocarbamate)(PPh2Cl)Cl] (5)
3
= 7.2 Hz), 0.88 (t, 3H, –CH2CH3, JH–H = 7.2 Hz). 13C{1H} NMR
Quantities used were 0.48 g (4.0 mmol) of dimethyldithiocarba-
mate and 2.47 g (4.0 mmol) of Pd(PPh2Cl)2Cl2 in 25 mL of dichloro-
methane. Yield: 84% (0.17 g) of a golden yellow solid. M.p.
195–196 °C. FTIR (powder, cmꢁ1) 3053, 2962, 1534, 1433, 1096,
727, 689, 485, 383, 320. 1H NMR (300 MHz, CDCl3) d: 7.73–7.66
(m, 6H, ArH), 7.38–7.35 (m, 4H, ArH), 3.25 (s, 3H, –NCH3), 3.23 (s,
3H, –NCH3). 13C{1H} NMR (75.47 MHz, CDCl3) d: 208.5 (1C, –CSS),
131.3 (2C, Ar), 131.0 (4C, Ar), 128.1 (6C, Ar), 39.1 (1C, –NCH3),
39.0 (1C, –NCH3). 31P NMR (121.49 MHz, CDCl3) d: 84.0. Anal. Calc.
for C15H16Cl2NPPdS2: C, 37.32; H, 3.34; N, 2.90; S, 13.29. Found: C,
37.00; H, 3.33; N, 2.91; S, 13.25%.
(75.47 MHz, CDCl3) d: 206.2 (1C, –CSS), 134.5 (3C, Ar), 130.7 (6C,
Ar), 128.8 (6C, Ar), 128.7 (3C, Ar), 48.9 (1C, –NCH2), 48.8 (1C, –
NCH2), 29.1 (1C, –CH2CH2CH3), 29.0 (1C, –CH2CH2CH3), 20.0 (1C,
–CH2CH3), 19.8 (1C, –CH2CH3), 13.7 (1C, –CH3), 13.6 (1C, –CH3).
31P{1H} NMR (121.49 MHz, CDCl3) d: 26.4. Anal.
Calc. for
27H33ClNPPdS2: C, 53.29; H, 5.47; N, 2.30; S, 10.54. Found: C,
C
53.31; H, 5.48; N, 2.33; S, 10.51%.
5.2.2. [Pd(dibutyldithiocarbamate)(PPh2-p-tolyl)] (2)
Quantities used were 0.28 g (4.0 mmol) dibutyldithiocarbamate
and 2.91 g (4.0 mmol) Pd(PPh2-o-tolyl)2Cl2 in 25 mL of dichloro-
methane. Yield: 82% (0.28 g) of golden yellow crystals. M.p. 195–
196 °C. FTIR (powder, cmꢁ1): 3049, 2930, 1512, 1433, 1095, 804,
747, 694, 380, 315. 1H NMR (300 MHz, CDCl3) d: 7.74–7.58 (m,
8H, ArH), 7.44–7.32 (m, 4H, ArH), 7.28–7.19 (m, 2H, ArH), 3.64 (t,
5.3. Structural studies
Crystals of complexes 1 and 2 were obtained by dissolving the
product in a mixture of dichloromethane, n-hexane, and diethyl
ether (2:1:1 v/v), and dichloromethane, n-hexane and petroleum
ether (2:1:1 v/v), respectively. The solvents were slowly evapo-
rated at room temperature in an open atmosphere and golden yel-
low crystals were obtained. The block crystals were mounted on a
glass fibre using Paratone N hydrocarbon oil. The measurements
were made at 200(2) K on a Bruker APEX II area detector diffrac-
3
3
2H, –NCH2, JH–H = 7.8 Hz), 3.49 (t, 2H, –NCH2, JH–H = 7.8 Hz),
1.73 (s, 3H, –CH3(p-tol)), 1.66–1.53 (m, 4H, –CH2CH2CH3), 1.38–
3
1.23 (m, 4H, –CH2CH2CH3), 0.94 (t, 3H, –CH2CH3, JH–H = 7.5 Hz),
3
0.89 (t, 3H, –CH2CH3, JH–H = 7.2 Hz). 13C{1H} NMR (75.47 MHz,
CDCl3) d: 206.3 (1C, –CSS), 137.3 (1C, Ar), 135.1 (9C, Ar), 134.0,
128.4 (8C, Ar), 49.0 (1C, –NCH2), 48.8 (1C, –NCH2), 29.2 (1C, –
CH2CH2CH3), 29.1 (1C, –CH2CH2CH3), 20.0 (1C, –CH2CH3), 19.8
(1C, –CH2CH3), 13.7 (1C, –CH3), 13.6 (1C, –CH3). 31P{1H} NMR
(121.49 MHz, CDCl3) d: 22.9. Anal. Calc. for C28H35ClNPPdS2: C,
54.02; H, 5.67; N, 2.25; S, 10.30. Found: C, 54.08; H, 5.68; N,
2.27; S, 10.34%.
tometer equipped with graphite monochromated Mo Ka radiation.
The program used for retrieving cell parameters and data collec-
tion was APEX-2 [28]. The data were integrated using the program
SAINT [29] and were corrected for Lorentz and polarization effects.
The multiscan absorption corrections were performed using SADABS
[30]. The structures were solved and refined using SHELXS-97 and
SHELXL-97 (Sheldrick, 1997) [31] and all non-H atoms were refined
anisotropically, with the hydrogen atoms placed at idealized
positions.
5.2.3. [Pd(dipropyldithiocarbamate)(PPh2-t-butyl)Cl] (3)
Quantities used were 0.70 g (4.0 mmol) of dipropyldithiocarba-
mate and 2.65 g (4.0 mmol) of Pd(PPh2-t-butyl)2Cl2 in dichloro-
methane. Yield: 85% (0.27 g) of a golden yellow solid. M.p.
155–156 °C. FTIR (powder, cmꢁ1): 3051, 2959, 1512, 1432, 1246,
1095, 742, 693, 382, 316. 1H NMR (300 MHz, CDCl3) d: 7.50–7.46
5.4. Anti-tumor potato disc assay
For the assay of anti-tumour potato discs, the procedure of
Mclaughlin et al. was followed [32]. Agrobacterium tumefecien (At
10) was grown for 48 h in lauria broth medium containing rifampi-
cin (50 mg/ml). Red skinned potatoes were surface sterilized in a
0.1% mercuric chloride solution for 10 min and thoroughly washed
with autoclaved distilled water. Potato discs (5 mm ꢂ 8 mm) were
made with a borer and placed on agar (1.5%) plates (10 discs per
3
(m, 6H, ArH), 7.44–7.40 (m, 4H, ArH), 3.93 (t, 2H, –NCH2, JH–H
3
= 7.5 Hz), 2.99 (t, 2H, –NCH2, JH–H = 7.5 Hz), 1.88–1.77 (m, 2H, –
CH2CH3), 1.74–1.66 (m, 2H, –CH2CH3), 1.00 (s, 9H, –C(CH3)3), 0.94
3
3
(t, 3H, –CH2CH3, JH–H = 7.5 Hz), 0.88 (t, 3H, –CH2CH3, JH–H
= 7.5 Hz). 13C{1H} NMR (75.47 MHz, CDCl3) d: 206.5 (1C, –CSS),
134.9 (4C, Ar), 129.9 (2C, Ar), 127.6 (6C, Ar), 55.5 (1C, –NCH2),
47.9 (1C, –NCH2), 30.0 (1C, C(CH3)3), 27.8 (1C, C(CH3)3), 20.3 (1C,
–CH2CH3), 19.0 (1C, –CH2CH3), 11.4 (1C, –CH3), 11.3 (1C, –CH3).
31P{1H} NMR (121.49 MHz, CDCl3) d: 46.9. Anal. Calc. for
plate). Agrobacterium cultures (600 ll) mixed with 150 ll each of
10,000, 1000, 100, 10, and 1 ppm of the compounds inoculum (in
DMSO) were applied on the surface of each disc with the respective
concentrations mentioned. The petri plates were then kept at 28 °C
for 21 days. After 21 days, the discs were stained using Lugol’s
C23H33ClNPdS2: C, 52.17; H, 6.28; N, 2.65; S, 12.11. Found: C,
52.12; H, 6.26; N, 2.64; S, 12.16%.

8
H. Khan et al. / Polyhedron 39 (2012) 1–8
solution (10% KI and 5% I2) for 30 min and then observed under a
dissecting microscope to calculate the number of tumors.
tion may be obtained free of charge from the Director, CCDC, 12 Un-
ion Road, Cambridge, CB2 1EZ, UK (fax: +44 1223 336033; email:
deposit@ccdc.cam.ac.uk or www:http://www.ccdc.cam.ac.uk).
5.5. Cyclic voltammetric analysis
References
The cyclic voltammograms of the six complexes were per-
formed in the absence and presence of DNA in CH2Cl2. The effect
of scan rate was also studied and diffusion coefficients were calcu-
lated to estimate the heterogeneous rate constants. Voltammetric
behavior of all the compounds was studied on a glassy carbon elec-
trode at various scan rates (50–1000 mVsꢁ1). The Randles–Sevcik
equation for an irreversible process was employed for the determi-
nation of the diffusion coefficient (D°) values [33]
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1=2
Ip ¼ ð2:99 ꢂ 105Þnð
a
nÞ1=2ACðD
mÞ
ð1Þ
where
ferred, A (cm2) is area of working electrode,
and C (mol/cm3) is bulk concentration of the sample.
lated from the equation reported in literature.
[34]. To calculate the standard heterogeneous rate constant, Gile-
adi’s method was used [35]. From the shift in peak potential with
the change in scan rate, the critical scan rate was determined,
which was subsequently used in the following equation for the
evaluation of ksh
a
is transfer coefficient, n is number of electrons trans-
(Vsꢁ1) is scan rate
n was calcu-
n = 47.7/(Epc ꢁ Ep/2
m
a
a
)
ꢀ
ꢁ
a m
cDꢃ
nF
2:3RT
log ksh ¼ ꢁ0:48
a
þ 0:52 þ log
ð2Þ
To investigate the anti-tumor activity of the complexes, cyclic
voltammetric measurements were made by varying the DNA con-
centration from 10 to 200 nM while keeping the concentration of
the complex constant (5 mM). The complex-DNA binding constant
was calculated according to the following equation [27]:
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logð1=½DNAꢄÞ ¼ log K þ logfðIHꢁGÞ=ðIG ꢁ IHꢁGÞg
ð3Þ
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Applications, second ed., Wiley, New York, 2001. p. 274.
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127.
[28] Bruker (2005). APEX 2 Version 2.0.2. Bruker AXS Inc., Madison, Wisconsin,
USA.
[29] Bruker (2003). SAINT Version 7.07a. Bruker AXS Inc., Madison, Wisconsin, USA.
[30] G.M. Sheldrick, SADABS Version 2004/1, Bruker AXS Inc., Madison, Wisconsin,
USA, 2004.
[31] G.M. Sheldrick, SHELXS-97 and SHELXL-97, Programs for the refinement of crystal
structures, University of Gottingen, Germany, 1997.
where, K is the binding constant, IG and IH–G are the peak currents of
the free guest (G) and the complex (H–G), respectively.
Acknowledgements
Mr. Hizbullah Khan is highly grateful to the Higher Education
Commission (HEC) of Pakistan for providing a scholarship under
the programme ‘‘5000 Indigenous PhD Scholarships’’ at Quaid-i-
Azam University Islamabad and six months scholarship under
the ‘‘International Research Support Initiative programme (IRSIP)’’
as a Graduate Research Trainee, Department of Chemistry, Otto
Maass Building, McGill University, Montreal, Quebec, Canada.
F.-G. Fontaine would like to acknowledge CFI.
Appendix A. Supplementary material
[32] J.L. Mclaughlin, L.L. Rogers, J.E. Anderson, Drug Info. J. 32 (1998) 513.
[33] J.E.B. Randles, Trans. Faraday Soc. 44 (1948) 327.
[34] A.J. Bard, L.R. Faulkner, Electrochemical Methods: Fundamentals and
Applications, second ed., Wiley, New York, 2001. p. 236.
[35] E. Gileadi, V. Eisner, J. Electroanal. Chem. 28 (1970) 81.
Single crystal X-ray diffraction data for the structural analysis
have been deposited with the Cambridge Crystallographic Data
Centre, CCDC No. 813648 (1) and 813649 (2). Copies of this informa-