Synthesis, characterization and cytotoxic activity of palladium (II) dithiocarbamate complexes with α,ω-diamines

Article abstract of DOI:10.1016/j.ica.2011.07.031

The polymeric [PdCl(dithiocarbamate)]_n complexes, in which the ligand ion is dimethyldithiocarbamate (DMDT), pyrrolidine dithiocarbamate (PyDT, (CH₂)₄NCS₂^-) and sarcosine ethyl ester dithiocarbamate (ESDT, EtO₂CCH₂N(CH ₃)CS₂^-), have been reacted with chelating diamines, like ethylenediamine (en) or 1,3-diaminopropane (dap) and long chain diamines, like 1,4-diaminobutane (dab) or 1,7-diaminoheptane (dah). The reaction products depend on either diamine chain length or molar ratio. By operating at PdCl(dithiocarbamate)/diamine molar ratio 1:1 chelating diamines yielded the ionic [Pd(dithiocarbamate)(diamine)]Cl species (diamine = en or dap), whereas with long chain diamines species of the type [Pd(dithiocarbamate)(diamine)] _nCl_n (diamine = dab or dah) were obtained, in which each Pd(dithiocarbamate)⁺ unit binds to the NH₂ group of two different molecules, in a network of bridging diamines. At molar ratio 1:0.5, the long chain diamines yielded the binuclear [Pd₂Cl ₂(dithiocarbamate)₂(diamine)] complexes (diamine = dab or dah), whereas exchange reactions take place generally in the presence of en or dap. The reaction trend is described on the basis of IR and proton NMR spectra. The new dithiocarbamate complexes were preliminarily tested for their cytotoxicity on human cancer cells.

Full text of DOI:10.1016/j.ica.2011.07.031

Inorganica Chimica Acta 376 (2011) 574–580
Contents lists available at SciVerse ScienceDirect
Inorganica Chimica Acta
journal homepage: www.elsevier.com/locate/ica
Synthesis, characterization and cytotoxic activity of palladium (II)
dithiocarbamate complexes with
a
,x
-diamines
b
b
Diego Montagner a, , Cristina Marzano , Valentina Gandin
⇑
a Dipartimento di Scienze Chimiche dell’ Università, Via Marzolo 1, 35131 Padova, Italy
b Dipartimento di Scienze Farmaceutiche dell’ Università, Via Marzolo 5, 35131 Padova, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 May 2011
Received in revised form 12 July 2011
Accepted 20 July 2011
Available online 28 July 2011
The polymeric [PdCl(dithiocarbamate)]n complexes, in which the ligand ion is dimethyldithiocarbamate
(DMDT), pyrrolidine dithiocarbamate (PyDT, (CH2)4NCS2ꢀ) and sarcosine ethyl ester dithiocarbamate
(ESDT, EtO2CCH2N(CH3)CS2ꢀ), have been reacted with chelating diamines, like ethylenediamine (en) or
1,3-diaminopropane (dap) and long chain diamines, like 1,4-diaminobutane (dab) or 1,7-diaminoheptane
(dah). The reaction products depend on either diamine chain length or molar ratio. By operating at
PdCl(dithiocarbamate)/diamine molar ratio 1:1 chelating diamines yielded the ionic [Pd(dithiocarba-
mate)(diamine)]Cl species (diamine = en or dap), whereas with long chain diamines species of the type
[Pd(dithiocarbamate)(diamine)]nCln (diamine = dab or dah) were obtained, in which each Pd(dithiocarba-
mate)+ unit binds to the NH2 group of two different molecules, in a network of bridging diamines. At
molar ratio 1:0.5, the long chain diamines yielded the binuclear [Pd2Cl2(dithiocarbamate)2(diamine)]
complexes (diamine = dab or dah), whereas exchange reactions take place generally in the presence of
en or dap. The reaction trend is described on the basis of IR and proton NMR spectra. The new dithiocar-
bamate complexes were preliminarily tested for their cytotoxicity on human cancer cells.
Ó 2011 Elsevier B.V. All rights reserved.
Dedicated to Dr. Elena Bertacco, a Ph. D.
student of our group recently deceased.
Keywords:
Palladium complexes
Diamines
Dinuclear complexes
Cytotoxicity
1. Introduction
[4]. Kinetics of ligand replacement by ethylenediamine in palla-
dium complexes containing either 2,20-bipyridine and substituted
Recent advances on platinum-based drugs concern the improve-
ment of the antitumour properties of cisplatin and carboplatin by
appropriate changes in either leaving or N-donor groups, which
could influence DNA interactions and drug metabolism [1]. Several
series have been synthesized, in which the non-leaving ligands are
generally mono- or diamines, the leaving groups being chloride ions
or carboxylates, whereas reports on the palladium analogues are
scanty. The main purpose of several researches is to overcome tox-
icity and cross resistance induced by cisplatin and analogues. Small
changes in ligand substituents can influence the biological activity
of the complexes, as for the chain length in N-alkyl-ethylenedia-
mine derivatives of the type [cis-PtCl2{H2NCH2CH2NH(CH2)nCH3}]
(n = 8–15) and [{cis-PtCl2(H2NCH2CH2NH)}2(CH2)n] (n = 6–12), the
latter containing a bridging aliphatic chain between the PtCl2N2
centres [2]. Propanediamine derivatives of the type [PtCl2(N-
benzyl-1,3-propanediamine)2] have been reported as potential
antitumour agents [3], whereas platinum complexes with 2,20-
bipyridines, in which have been inserted acridine tails, allow to
examine the combination of covalent attack to DNA (through the
PtCl2N2 moiety) and intercalation effect (by the tail chromophore)
ethylenediamines depends on the alkyl groups at the N-atom,
which influence the hydrogen bond network with water oxygen [5].
Dinuclear species like [M2(diamine)(triazolopyrimidinato)2]2+
(M = Pd or Pt; diamine = 2,20-bipyridil or 1,10-phenantroline) con-
tain two nearly parallel [M(diamine)]2+ units, the M atoms being
linked by two nitrogen atoms of each bridging pyrimidinato anion
[6]. Binuclear and trinuclear platinum complexes are actually un-
der study as potent second generation drugs, whose interaction
with DNA differs from that of cisplatin and depends on geometry,
leaving groups and bridging ligands, generally polyamines [7].
Polyamines are present in human cells and in tumours, and they
can influence RNA expression through polyamine-dependent
protein [8,9]. The trinuclear complex [Pt(NH3)2Cl{NH2(CH2)6
NH2}Pt(NH3)2{NH2(CH2)6NH2}Pt(NH3)2Cl]4+, which contains three
trans-diaminoplatin units linked by two diaminohexane molecules,
is now in clinical trial, owing to the ability to overcome cisplatin
resistance [10]. In order to enhance the therapeutic index, dinucle-
ar complexes in which the bridging ligands are spermidine, or ana-
logues containing carbamato groups, have been studied, obtaining
species of remarkable activity [11]. Substitution of ammonia with
pyridine or picolines in dinuclear alkyldiamine platinum com-
plexes causes lower cytotoxicity, notwithstanding a DNA binding
kinetics superior to cisplatin [12]. Attempts toward more effective
⇑
Corresponding author. Tel.: +39 49 8275172; fax: +39 49 8275161.
E-mail address: diego.montagner@unipd.it (D. Montagner).
0020-1693/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.ica.2011.07.031

D. Montagner et al. / Inorganica Chimica Acta 376 (2011) 574–580
575
O
and 20F Far-IR spectrometers, as either Nujol mulls between KBr
and polyethylene discs or KBr pellets. NMR spectra were measured
using a Bruker DRX 300 (ppm; internal standard, TMS). Thermo-
gravimetric data in air were obtained on Netzsch STA 449 thermo-
H3C
H3C
S
S
S
S
S
S
N
N
N
H3CH2CO
H3C
analytical equipment (flux rate, 50 cm3 minꢀ1
; heating rate,
DMDT
PyDT
ESDT
5 °C minꢀ1; reference material Al2O3). The weight of the samples
Chart 1.
in the crucible was about 15–25 mg.
polynuclear drugs consist in the insertion of functionalized groups
in bridging polyamines, as amido-residues in bimetallic palladium
and platinum complexes [13].
2.1. Reagents
Palladium chloride, NBu4Cl, ethylenediamine (en), 1,3-diamino-
propane (dap), 1,4-diaminobutane (dab), and 1,7-diaminoheptane
(dah) and DMSO-d6 were used as supplied (Aldrich products).
As a general remark, the interaction mode of polynuclear com-
plexes with DNA could follow a different way than cisplatin, whose
attack occurs preferentially between the N7 atom of two adjacent
guanine residues. The fact that many S-donor sites are also present
could suggest competition among N and S sites as determinant in
drug behaviour, metal coordination to sulfur inducing possibly
the formation of a drug reserve in the cell [14]. Sulfur donors, gen-
erally thiols, are administered in combination with cisplatin, in or-
der to reduce renal damages [15–20]. The chemoprotective action
of sulfur containing molecules explains the attention to their effect
on Pd–N and Pt–N bonds. Glutathione has been found to be the
strongest nucleofile toward palladium complexes with tridentate
N-donors, whereas diethyldithiocarbamate was the most effective
rescue agent against cisplatin in respect to thiourea, thiosulfate or
glutathione [21,22].
An alternative way to modulate activity and toxicity of
platinum-based drugs concerns the design of new molecules con-
taining both N and S donor sites [23–25]. As regards dithiocarba-
mates, the mixed complexes [M(S2CNEt2)(L)]NO3 (M = Pd or Pt;
L = 2,20-bipyridil or 1,10-phenantroline) were found active toward
leukemic cells [26]. In this line we reported various palladium and
platinum complexes containing either dithiocarbamate and amine
moieties, of general formula [MCl(dithiocarbamate)(amine)] and
2.2. Starting materials
The [PdCl(ESDT)]n complex (ESDT = EtO2CH2N(CH3)CS2ꢀ) was
prepared by thermal degradation of solid samples of [PdCl2-
(ESDTM)] (ESDTM = EtO2CH2N(CH3)CS2CH3) in oil bath (120 °C)
under reduced pressure [36,37]. The [PdCl(PyDT)]n analogue was
obtained by heating the parent [PdCl2(PyDTM)] species
(PyDTM = (CH2)4NCS2CH3) in oil bath at 210 °C [38]. Evolution of
methyl chloride takes place, the orange initial product turning into
a pink powder, the colour being common to all the examined inter-
mediates. The [PdCl(DMDT)]n intermediate was prepared either by
thermal degradation of [PdCl2(DMDTM)] (DMDTM = (CH3)2NCS2-
CH3; oil bath at 150–170 °C) [39], or by reaction of PdCl2 with
DMDTB (DMDTB = (CH3)2NCS2-Ph) in dichloromethane [38].
The [PdCl2(dap)] complex has been prepared by reacting PdCl2
(1.0 mmol) and dap (1.0 mmol) in CH3CN/CHCl3 (3:1 vol/vol, 1
day with stirring). Yield, 61%. The pale yellow solid was filtered,
washed with CHCl3 and dried under reduced pressure. The
[Pd(dap)2]Cl2 species has been prepared by reaction of PdCl2
(1.0 mmol) with dap (4.0 mmol) in CHCl3 (15 cm3; 8 days). Yield,
95%. The white solid was washed with CHCl3 and n-pentane and
dried in vacuo.
[M(dithiocarbamate)(amine)2]Cl [27,28]. Among them, some spe-
ꢀ
cies in which dithiocarbamate was ESDT (EtO2CCH2(CH3)NCS2
)
(Chart 1), an ion containing the sarcosine moiety, gave interesting
results when tested against human cancer cells [29], the most
efficacy being the [PtCl(ESDT)(pyridine)] complex [30,31]. This
compound has shown cytotoxic efficacy, ability to overcome cis-
platin resistance and low toxicity [30,31] whereas [PdCl(ESDT)]n
was toxic and scarcely active [30]. We thought then of interest to
extend the study to polynuclear diamino-bridged complexes con-
taining MCl(dithiocarbamate) residues. As a first study, this paper
reports the interaction of the polymeric [PdCl(dithiocarbamate)]ꢀn
species with diamines. Dithiocarbamate ions were Me2NCS2
The NBu4[PdCl2(DMDT)] salt was prepared by reaction of
[PdCl(DMDT)]n (0.5 mmol) with NBu4Cl (0.55 mmol) in CH2Cl2
(5 cm3). An orange solution formed initially, which, on standing
(8 h), separated an orange solid. The compound was filtered,
washed with CH2Cl2 and dried under reduced pressure. Yield,
88%. The NBu4[PdCl2(PyDT)] complex synthesis was reported pre-
viously in Ref. [38].
ꢀ
ꢀ
2.3. Synthesis of the en complexes
(DMDT), (CH2)4NCS2 (PyDT) and EtO2C(CH2)N(CH3)CS2 (ESDT)
and the amines were ethylenediamine (en), 1,3-diaminopropane
(dap), 1,4-diaminobutane (dab) and 1,7-diaminoheptane (dah).
Although recent studies are focused on the interaction of
multinuclear platinum complexes linked by flexible diamino al-
kanes, mixed platinum and palladium complexes of the type
The [Pd(PyDT)(en)]Cl complex was prepared by reaction of
[PdCl(PyDT)]n (0.8 mmol) and en (0.93 mmol) in CHCl3 (8 cm3)
with vigorous stirring (24 h). The pink suspension turned into a
pale yellow solid, which was filtered, washed with CHCl3 and
n-pentane and dried under reduced pressure. Yield, 83%. The
[Pd(ESDT)(en)]Cl and [Pd(DMDT)(en)]Cl analogues were
prepared by reaction of the appropriate [PdCl(dithiocarbamate)]n
intermediate with en, as reported in Refs. [28,40]. The
[Pd(DMDT)(en)][PdCl2(DMDT)] complex was obtained by reaction
of [PdCl(DMDT)]n (1.1 mmol) with en (0.55 mmol) in CHCl3
(5 cm3; 2 days with vigorous stirring). The beige solid was
separated by centrifugation, washed with CHCl3 and n-pentane
and dried under reduced pressure. Yield, 72%. By operating in the
same conditions, the reaction of [PdCl(PyDT)]n with en at molar
ratio 1:0.5 yielded a mixture of [Pd(PyDT)(en)][PdCl2(PyDT)],
[Pd(PyDT)2] and [PdCl2(en)]. Physical data, elemental analyses,
IR and NMR data of the products are collected in Tables 1, 2
and 3, respectively.
[{trans-PtCl(NH3)2}2-l-{trans-Pd(NH3)2-(H2N(CH2)nNH2)2}]Cl4 (n =
4–7) have been found to exhibit significant anticancer activity
against ovarian cancer cell lines [32–35]. Those species contain a
central trans-Pd(NH3)2 unit, which is bound to two trans-Pt(NH3)2
units by bridging diamines, the trinuclear complex assuming a +4
charge. For this reason either neutral or ionic species, containing
dithiocarbamate and chelating or bridging diamines, were evalu-
ated for their cytotoxicity on human tumour cell lines.
2. Experimental
Elemental analyses were carried out on a Fisons EA1108 CHNS-
O microanalyser. IR spectra were recorded on Nicolet 5SXC FT-IR

576
D. Montagner et al. / Inorganica Chimica Acta 376 (2011) 574–580
2.4. Synthesis of the dap complexes
and dried in vacuo. Yield, 75% and 73% for dah and dab adducts,
respectively. The chloroform amount in the samples was estimated
by thermogravimetry. At contrary, chloroform was absent in sam-
ples of [Pd(ESDT)(dab)]nCln, which were obtained by reaction of
equimolar [PdCl(ESDT)]n and dab (molar ratio 1:1) in CHCl3 (1
day with stirring). Yield, 70%. Elemental analyses, IR and NMR data
of the products are collected in Tables 1, 2 and 3, respectively.
[Pd(PyDT)(dah)]nCln and [Pd(PyDT)(dab)]nCln have been obtained
without CHCl3 heating the samples under vacuum as suggested
by thermograms, in order to obtain compounds suitable for bio-
logic investigation.
The [Pd(PyDT)(dap)]Cl complex separated as a pale yellow pow-
der by reaction of [PdCl(PyDT)]n (0.95 mmol) with equimolar dap
in CHCl3 (8 cm3; 1 day with stirring). The solid was centrifugated
and dried in vacuo. Yield, 80%. The [Pd(DMDT)(dap)]Cl [40] and
[Pd(ESDT)(dap)]Cl samples were prepared following the same
method. Particular attention should be paid to the reaction time,
especially for the [PdCl(ESDT)]n/dap system. If [PdCl(ESDT)]n and
dap (molar ratio 1:1; 0.45 mmol in 8 cm3 of CHCl3) are allowed
to react for 5 days, the solid obtained is mainly [Pd(dap)2]Cl2, im-
pure for [Pd(ESDT)2], which is isolated by evaporating to dryness
the mother solution. The reaction of [PdCl(dithiocarbamate)]n sam-
ples with dap in CHCl3 at molar ratio 1:0.5 yielded always a mix-
ture of [PdCl2(dap)] and [Pd(dithiocarbamate)2]. For example, the
yellow powder obtained by reaction of [PdCl(PyDT)]n (0.34 mmol)
with dap in CHCl3 (0.18 mmol in 6 cm3; 2 days with stirring) is a
mixture of [Pd(PyDT)2] (IR: 1511s, 346s, 334s) and [PdCl2(dap)]
(IR: 3243, 3204, 3121, 1595, 319w, 297s), both insoluble in chloro-
form. The exchange is particularly evident for the [PdCl(ESDT)]n/
dap system (molar ratio 1:0.5), the solid reaction product being
essentially [PdCl2(dap)]. Elemental analyses, IR and NMR data of
the products are collected in Tables 1, 2 and 3, respectively.
2.6. Experiments with human tumour cells
Dithiocarbamate complexes were dissolved in dimethyl sulfox-
ide just before the experiments; calculated amounts of drug solu-
tion were added to the growth medium containing cells to a final
solvent concentration of 0.5% which had no discernible effect on
cell killing. Cisplatin was dissolved in 0.9% NaCl solution.
MTT
(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide) and cisplatin were obtained from Sigma Chemical Co.,
St. Louis, USA.
2.6.1. Cell cultures
2008 human ovarian cancer cell line and its cisplatin resistant
variant, C13⁄ cells, were kindly provided by Prof. G. Marverti
(Department of Biomedical Science of Modena University, Italy)
and A431 human cervix carcinoma were kindly provided by Prof.
Zunino (Division of Experimental Oncology B, Istituto Nazionale
dei Tumori, Milan, Italy). All cell lines were maintained in the log-
arithmic phase at 37 °C in a 5% carbon dioxide atmosphere using
RPMI-1640 medium (Sigma Chemical Co.) containing 10% foetal
bovine serum (Euroclone, Milano, Italy) and supplemented with
2.5. Synthesis of the dab and dah complexes
The binuclear complex [Pd2Cl2(PyDT)2(dab)] has been prepared
by reaction of [PdCl(PyDT)]n (0.82 mmol) with dab (0.41 mmol) in
CHCl3 (10 cm3). A pale yellow solid is formed within few minutes,
which is left on standing and then filtered, washed with CHCl3 and
n-pentane and dried in vacuo. Yield, 90%. The [Pd2Cl2(PyDT)2(dah)]
complex was obtained in good yield (93%) by reaction of
[PdCl(PyDT)]n and dah (molar ratio 1:0.5) in chloroform, whereas
the synthesis of the [Pd2Cl2(ESDT)2(diamine)] analogues (diami-
ne = dab or dah) was carried out in benzene/CH2Cl2. For example,
[PdCl(ESDT)]n (0.6 mmol) and dah (0.3 mmol) were allowed to re-
act in benzene/CH2Cl2 (5:1 vol/vol; 8 cm3; 3 days with stirring).
The yellow solid was filtered, washed with benzene and n-pentane
and dried in vacuo. Yield, 80%. If the solvent was CHCl3, the yield
was lower and the sample contained unidentified side products.
The reaction of [PdCl(PyDT)]n with dab (or dah) in CHCl3 at mo-
lar ratio 1:1 yielded ionic species of formula [Pd(PyDT)(diami-
ne)]nCln, which contained variable amounts of CHCl3 (from 0.3 to
1.0 for each polymer unit). For example, the [Pd(PyDT)
(dah)]nClnꢁnCHCl3 complex was prepared by reaction of
[PdCl(PyDT)]n (0.78 mmol) and dah (0.78 mmol) in CHCl3 (8 cm3).
The golden yellow solution separated on standing (1 day) yellow
crystals of the product, which were filtered, washed with CHCl3
L
-glutamine and with antibiotics (penicillin 50 U mLꢀ1 and strepto-
mycin 50
g mLꢀ1).
l
2.6.2. Cytotoxicity assay
The growth inhibitory effect towards tumour cell lines was
evaluated by means of MTT (tetrazolium salt reduction) assay
[41]. Briefly, between 3 and 5 ꢂ 10ꢀ3 cells, dependent upon the
growth characteristics of the cell line, were seeded in 96-well
microplates in growth medium (100 lL) and then incubated at
37 °C in a 5% carbon dioxide atmosphere. After 24 h, the medium
was removed and replaced with a fresh one containing the com-
pound to be studied at the appropriate concentrations. Quadrupli-
cate cultures were established for each treatment. Forty-eight
hours later, each well was treated with 10
(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)
l
L of a 5 mg mLꢀ1 MTT
Table 1
Analyticala and physical data for the complexes.
Compound
Formula
Colour
C
H
N
m
(CN) (cmꢀ1
)
Yield (%)
[Pd(PyDT)(en)]Cl
[Pd(PyDT)(dap)]Cl
C7H16ClN3PdS2
C8H18ClN3PdS2
pale yellow
pale yellow
nutmeg
pale yellow
beige
yellow
beige
orange
yellow
24.3 (24.1)
26.3 (26.5)
25.1 (25.3)
26.7 (26.9)
28.6 (28.9)
29.4 (29.0)
16.9 (16.4)
42.4 (42.3)
25.2 (25.4)
28.3 (28.4)
29.1 (28.6)
14.4 (14.3)
22.6 (22.1)
4.6 (4.7)
5.0 (5.0)
4.1 (4.2)
4.4 (4.9)
4.9 (4.8)
5.3 (5.1)
3.1 (3.4)
7.6 (7.8)
4.3 (4.3)
4.5 (5.2)
4.7 (4.8)
4.1 (4.0)
6.2 (6.2)
12.0 (12.1)
11.3 (11.6)
8.6 (8.4)
9.7 (10.0)
7.9 (7.9)
7.8 (7.8)
9.2 (9.6)
5.0 (5.2)
7.2 (7.4)
9.3 (9.3)
6.9 (7.0)
11.0 (11.1)
17.5 (17.2)
1526
1520
1544
1541
1534
1534
1569
1563
1536
1525
1521
83
80
90
73
93
75
72
88
80
70
75
61
95
[Pd2Cl2(PyDT)2(dab)]
[Pd(PyDT)(dab)]nClnꢁ1/3CHCl3
[Pd2Cl2(PyDT)2(dah)]
[Pd(PyDT)(dah)]nClnꢁCHCl3
[Pd(DMDT)(en)][PdCl2(DMDT)]
NBu4[PdCl2(DMDT)]
[Pd2Cl2(ESDT)2(dab)]
[Pd(ESDT)(dab)]nCln
[Pd2Cl2(ESDT)2(dah)]
[PdCl2(dap)]
C14H28Cl2N4Pd2S4
C9.33H20.33Cl2N3PdS2
C17H34Cl2N4Pd2S4
C13H27Cl4N3PdS2
C8H20Cl2N4Pd2S4
C19H42Cl2N2PdS2
C16H32Cl2N4O4Pd2S4
C10H22ClN3O2PdS2
C19H38Cl2N4O4Pd2S4
C3H10Cl2N4Pd
pale yellow
yellow
beige
[Pd(dap)2]Cl2
C6H20Cl2N4Pd
white
a
Calculated values (%) in parentheses.

D. Montagner et al. / Inorganica Chimica Acta 376 (2011) 574–580
577
Table 2
a
Selected IR frequencies (cmꢀ1
)
for the complexes.
(NH)
Compound
m
d(NH2)
Far IR (400–200 cmꢀ1
)
[Pd(PyDT)(dap)]Cl
[Pd(PyDT)(en)]Cl
[Pd(DMDT)(en)][PdCl2(DMDT)]
3255m,
3276m,
3290w,
3169w,
3176w,
3246m, 3208m,
3049sbr
3056sbr
3145w
1598vw
1595w, 1548w
1570vw
359s
364s
359w
335w
333w
348m
322w
254w
230mbr
226w
226m
322w
324w
279w
272m
304m
NBu4[PdCl2(DMDT)]
[Pd2Cl2(PyDT)2(dab)]
[Pd2Cl2(PyDT)2(dah)]
350w
366m
364m
301m
293m
297m
279m
3267m,
3274m,
3218w,
3232m,
3148w
3155w
1584vw
1581w
336w
340m
258mbr
237wbr
268ms
224wbr
232mbr
b
[Pd(PyDT)(dab)]nClnꢁ1/3CHCl3
3246w,
3210w,
3309m,
3126mbr,
3162w,
3232m,
3070w
3098mbr
3155w
1584w
1598w, 1578w
1591w
365m
359m
380m
336w
335w
350w
b
[Pd(PyDT)(dah)]nClnꢁCHCl3
[Pd2Cl2(ESDT)2(dab)]
291m
[Pd(ESDT)(dab)]nCln
[Pd2Cl2(ESDT)2(dah)]
3204sh,
3281m,
3151mbr,
3224m,
3080mbr
3150w
1596w, 1567w
1567w
379m
381m
352w
352w
319w
324w
284w
297s
258w
240w
293m
319m
[PdCl2(dap)]
[Pd(dap)2]Cl2
3243m,
3204w,
3121w
1595vw, 1563m
1598w
365m
365w
329sh
346w
248mbr
249mbr
3140mbr,
3060mbr
a
m
(Pd–Cl) underlined.
b
CHCl3, 751 cmꢀ1
.
Table 3
1H NMR data for the complexes in DMSO-d6 (ppm, T = 25°C).
Compound
NH2
a
CH2
b CH2
c
,d CH2
dithiocarbamate
[PdCl(PyDT)]n
[Pd(PyDT)(en)]Cl
[Pd(PyDT)(dap)]Cl
PyDT: (CH2)2N 3.66; (CH2)2 1.97
PyDT: (CH2)2N 3.59; (CH2)2 1.95
PyDT: (CH2)2N 3.59; (CH2)2 1.95
DMDT: (CH3)2N 3.23
5.06w, 4.88
4.54w, 4.37
2.54
2.55
1.63
NBu4[PdCl2(DMDT)]a
[Pd(DMDT)(en)][PdCl2(DMDT)]
[Pd2Cl2(PyDT)2(dab)]
[Pd2Cl2(ESDT)2(dab)]
4.90
4.42
4.54
4.40
2.52
2.64b
2.63b
2.64
2.63
2.38
2.36
2.40
DMDT: (CH3)2N 3.22
1.94c
PyDT: (CH2)2N 3.60; (CH2)2 1.94c
1.94
ESDT: OEt 1.21, 4.18; NCH3 3.22; NCH2 4.60
1.95c
PyDT: (CH2)2N 3.60; (CH2)2 1.95c
d
[Pd(PyDT)(dab)]nClnꢁ1/3CHCl3
[Pd(ESDT)(dab)]nCln
[Pd2Cl2(PyDT)2(dah)]
[Pd2Cl2(ESDT)2(dah)]
4.58
1.95
1.73w, 1.59
1.59
ESDT: OEt 1.21, 4.16; N(CH3) 3.23; N(CH2) 4.54w, 4.57s
PyDT: (CH2)2N 3.58; (CH2)2 1.93
ESDT: OEt 1.21, 4.16; N(CH3) 3.22; N(CH2) 4.50, 4.52
PyDT: (CH2)2N 3.61; (CH2)2 1.95
4.31, 4.11
4.57, 4.59
4.36
1.33w, 1.23
1.40
1.24w
d
[Pd(PyDT)(dah)]nClnꢁCHCl3
1.73, 1.60w
a
b
c
In CDCl3.
Weak signals at 2.4 ppm are also present.
The amine b CH2 resonance superimposes to the PyDT ring CH2 signal.
CHCl3 proton resonance at 8.31 ppm.
d
saline solution, and after 5 h of incubation, 100 lL of a sodium
S
S
Cl
Cl
S
NH2
NH2
S
S
NH2
NH2
dodecyl sulfate (SDS) solution in HCl 0.01 M were added. After over-
night incubation, the inhibition of cell growth induced by the tested
complexes was detected by measuring the absorbance of each well
at 540 nm using a Bio-Rad microplate reader. Mean absorbance for
each drug dose was expressed as a percentage of the control un-
treated well absorbance and plotted versus drug concentration.
IC50 values represent the drug concentrations that reduced the
mean absorbance at 540 nm to 50% of those in the untreated control
wells.
Pd
Pd
Pd
(CH2)n Cl
(CH2)n
S
n = 2 (en); 3 (dap)
Pd/en or dap 1:1
n = 2 (en); 3 (dap)
Pd/en or dap 1:0.5
n
(CH2)n
Cl
S
S
S
S
Cl
S
S
NH2
NH2
NH2
NH2
Pd
Pd
Pd
(CH2)n
NH2
NH2
(CH2)n
n
3. Results and discussion
n = 4 (dab); 7 (dah)
Pd/en or dap 1:1
n = 4 (dab); 7 (dah)
Pd/en or dap 1:0.5
By reaction of the [PdCl(dithiocarbamate)]n precursors with the
appropriate diamine either ionic or neutral species can be isolated
(Chart 2).
The [PdCl(dithiocarbamate)]n intermediates are probably di-
mers through chlorine bridges, as observed for di-l-chlorobis-
[di-n-butyldithiocarbamate]dipalladium [42]. Nevertheless, the
presence of polymeric species containing more than two units can-
not be excluded. In the [PdCl(mercaptonicotinic acid)]3 species the
single PdCl(mercaptonicotinic) units, in which the anion is S,N che-
lated to the metal, form a trimeric molecule held by sulfur bridges,
the chlorine atoms being terminal [43]. An unique and exotic pen-
tanuclear Pt5 structure has been recently reported by the author
where S atoms of PyDT ligands act as chelating and bridging donors
at the same time [44].
Chart 2.
The [PdCl(dithiocarbamate)]n intermediates have been pre-
pared by thermal decomposition of the parent dithioester com-
plexes at the appropriate temperature as reported in Section 2.
The trend of the [PdCl(dithiocarbamate)]n complex reaction with
diamines depends on either stoichiometric ratio or diamine chain
length. When [PdCl(PyDT)]n is reacted with ethylenediamine (en)
or 1,3-diaminopropane (dap) in chloroform at molar ratio 1:1,
the ionic [Pd(PyDT)(en)]Cl and [Pd(PyDT)(dap)]Cl species are ob-
tained (Chart 2, Table 1), as for the ESDT and DMDT analogues
[28,40]. Sample purity depends on reaction time. For example, if
[PdCl(ESDT)]n and dap (molar ratio 1:1) are kept under stirring in
chloroform for 5 days, the main reaction products are [Pd(ESDT)2]

578
D. Montagner et al. / Inorganica Chimica Acta 376 (2011) 574–580
and [Pd(dap)2]Cl2, supporting a rearrangement in the initial prod-
uct, [Pd(ESDT)(dap)]Cl, to give the symmetrical bis-chelated spe-
cies. The process can be followed by infrared spectra of samples
drawn out at different reaction times. The exchange process is
particularly evident when [PdCl(dithiocarbamate)]n and dap are
reacted at molar ratio 1:0.5. In this case a mixture of [Pd(dithiocar-
bamate)2] and [PdCl2(dap)] is formed, the initial N attack to metal
being followed by formation of the diamine chelate ring (Chart 3).
The infrared spectrum of the final reaction mixture contains
with time ligand rearrangement to form [Pd(dithiocarbamate)2]
and [Pd(diamine)2]Cl2. When the reaction is carried out at molar
ratio 1:0.5, the reaction products are [PdCl2(amine)] and the appro-
priate bis-dithiocarbamate (dithiocarbamate = PyDT or ESDT),
except for the PdCl(DMDT)/en system, in which ethylenediamine
chelation to the Pd(DMDT)+ moiety causes the transfer of the chlo-
rine ion to another PdCl(DMDT) unit yielding the [Pd(DMDT)(en)]
[PdCl2(DMDT)] complex (Chart 3).
The reactions of [PdCl(dithiocarbamate)]n with diamines con-
taining longer chains, as 1,4-diaminobutane (dab) and 1,7-diami-
noheptane (dah), follow a totally different trend (Chart 2). When
[PdCl(PyDT)]n is allowed to react with either dab or dah at molar
ratio 1:0.5, the binuclear complexes [Pd2Cl2(PyDT)2(diamine)] are
obtained, in which the diamine nitrogen atoms bind two different
PdCl(PyDT) moieties. By operating at molar ratio 1:1, species of
general formula [Pd(PyDT)(diamine)]nClnꢁxCHCl3 are obtained, in
which each Pd(PyDT)+ unit binds to the nitrogen atom of two dif-
ferent diamines, the whole arrangement leading to a polymeric
structure of bridging diamines. The samples contain always vari-
able amount of chloroform (from 0.3 to 1.0). As shown in Fig. 1
the thermogram of a [Pd(PyDT)(dah)]nClnꢁnCHCl3 sample shows
CHCl3 release in the 60–125 °C temperature interval (DTA endo-
therm, 122 °C; weight loss of 21.5% against a calculated value of
22.2%). The desolvated sample is stable up to 250 °C, successive
pyrolysis yielding palladium (total weight loss of 79.7% against cal-
culated 80.2%). The degradation process ends at ca. 500 °C. The
weight increase in the 500–800 °C range is caused by oxygen up-
take on the metal surface to form PdO, which decomposes to give
palladium at 812 °C.
essentially the bands of the components. In the
spectrum shows three well resolved bands at 3243, 3204 and
3121 cmꢀ1, the d(NH2) absorption being observed at 1563 cmꢀ1
In the Pd–Cl region two strong absorptions are present (319 and
297 cmꢀ1), which coincide with those of [PdCl2(dap)]. The
(CN)
m(NH) region the
.
m
band of PyDT is at 1511 cmꢀ1, as for [Pd(PyDT)2] and at lower en-
ergy with respect to the corresponding value in [PdCl(PyDT)]n
(1548 cmꢀ1) or [PdCl(PyDT)(DMSO)] (1554 cmꢀ1) [38]. Moreover,
the far infrared spectrum contains two strong bands at 345 and
334 cmꢀ1, characteristic of [Pd(PyDT)2] [38]. When [PdCl(PyDT)]n
and dap are reacted at molar ratio 1:1, the initial product is
[Pd(PyDT)(dap)]Cl, whose spectrum shows three absorption in
the 3300–3000 cmꢀ1 region, the stronger one at 3049 cmꢀ1 being
characteristic of ionic species, as observed for the en analogues
(Table 2). If the solid is kept in the mother solution for several days
with stirring, the amount of the [Pd(PyDT)2] and [Pd(dap)2]Cl2 spe-
cies increases, as indicated by the [Pd(PyDT)2] bands at 1511, 345
and 334 cmꢀ1. A similar behaviour is observed for the PdCl(DMDT)/
dap and PdCl(ESDT)/dap systems in the same solvent (molar ratio
1:0.5). In particular, being [Pd(ESDT)2] slightly soluble in chloro-
form, the main product of the reaction of [PdCl(ESDT)]n with dap
is [PdCl2(dap)], containing small amounts of [Pd(ESDT)2]. The reac-
tion of [PdCl(PyDT)]n with ethylenediamine at molar ratio 1:1
yields the usual [Pd(PyDT)(en)]Cl species, whereas at molar ratio
1:0.5 a mixture of [Pd(PyDT)2] and [PdCl2(en)] is obtained, as for
1,3-diaminopropane. In the same conditions the PdCl(DMDT)/en
system forms probably the [Pd(DMDT)(en)][PdCl2(DMDT)] com-
plex (Chart 3). In order to clarify the product nature we have syn-
thesized the NBu4[PdCl2(DMDT)] salt, characterized by two Pd–Cl
The IR spectra of the polynuclear species contain one
m(CN)
band in the 1545–1530 cmꢀ1 interval. The binuclear
[Pd2Cl2(PyDT)2(diamine)] complexes contain one Pd–Cl band at
ca. 295 cmꢀ1, which is absent in the polymeric [Pd(PyDT)(diami-
ne)]nCln samples. The PdCl(ESDT)/diamine (diamine = dab or dah)
system gave analogous results, binuclear complexes like
[Pd2Cl2(ESDT)2(diamine)] or polymeric species as [Pd(ESDT)(dia-
mine)]nCln being isolated. The IR spectra follow the trend observed
for the PyDT analogues, the binuclear species showing one Pd–Cl
absorption at ca. 292 cmꢀ1, which is absent in [Pd(ESDT)(dab)]nCln.
The proton NMR spectra of the complexes in deuterated di-
methyl sulfoxide are reported in Table 3. In this solvent the
[PdCl(PyDT)]n complex shows two signals at 3.66 and 1.97 ppm,
assigned to methylene groups bound to nitrogen and to ring meth-
ylene groups, respectively. Those resonances are nearly unchanged
in the PyDT complexes, whereas the position of the NH2 signals
supports diamine coordination in all the reported compounds.
The spectra of the simple [PdCl2(dap)] and [Pd(dap)2]Cl2 species
contain the NH2 proton signal of the chelated diamine at ca.
4.35 ppm, very close to the value observed for the related com-
plexes of Table 3. In all compounds the NH2 proton signals fall in
absorptions at 301 and 279 cmꢀ1
1563 cmꢀ1. Accordingly, the spectrum of the [Pd(DMDT)(en)]
, the m(CN) band being at
[PdCl2(DMDT)] complex contains one m(CN) absorption for both
ionic moieties (1569 cmꢀ1), the Pd–Cl bands at 304 and 272 cmꢀ1
having the shape and relative intensities of those observed for
the tetrabutylammonium salt.
As a general observation, ethylenediamine and 1,3-diaminopro-
pane assume the stable chelate arrangement yielding ionic species
of the type [Pd(dithiocarbamate)(diamine)]Cl, which can undergo
Cl
Cl
NH
S
S
S
S
n = 3 (dap)
Pd
Pd
Pd
+
(CH2)n
PyDT
DMDT
ESDT
NH2
Pd/en or dap 1:0.5
S
Cl
Cl
S
S
NH2
NH2
DMDT
n = 2 (en)
Pd
(CH2)n
NH
S
S
S
Cl
Pd
n = 2 (en)
3 (dap)
S
PyDT
DMDT
ESDT
2
Pd
(CH2)n
Cl
S
NH2
Pd/en or dap 1:1
2
H2N
H2N
NH
S
S
S
PyDT
ESDT
n = 3,
Pd
Pd
+ (CH2)n
(CH2)n
2 Cl
NH2
S
long stirring
Chart 3.
Fig. 1. Thermograms of [Pd(PyDT)(dah)]nClnꢁCHCl3.

D. Montagner et al. / Inorganica Chimica Acta 376 (2011) 574–580
579
the 4.3–5 ppm range, no evidence of free NH2 groups being ob-
A 100
2
served. The mixed species [PdCl(ESDT)(amine)] (amine = n-propyl-
amine or cyclobutylamine) showed the NH2 signal of the
monodentate ligand at ca. 4.2 ppm, whereas ligand release in
[Pd(DMDT)(n-propylamine)2]Cl solutions to form the parent
[PdCl(DMDT)(n-propylamine)] species was clearly evident by the
free NH2 signal at 1.5 ppm. The spectra have been registered
immediately after sample dissolution. Aged solution (4 days) pres-
ent weak side peaks for the diamine proton signals, particularly
evident for the binuclear species, in which the diamines acts as
monodentate toward each metal centre. A similar trend has been
observed previously for [PdCl(dithiocarbamate)(amine)] samples,
the solvent interacting more easily with monodentate amines than
for chelating diamines [28,40].
The new palladium (II) complexes were preliminarily tested for
their cytotoxic properties on two human cancer cell lines, 2008 and
A431, from ovarian and cervix carcinoma, respectively. For com-
parison purpose, the cytotoxicity of cisplatin was evaluated under
the same experimental conditions. IC50 values, calculated from the
dose-survival curves obtained after 48 h drug treatment by MTT
test, are shown in Table 4.
[Pd2Cl(ESDT)2(dah)]
2
[Pd2Cl(ESTD)2(dab)]
[Pd(ESDT)(dab)]nCln
cisplatin
80
60
40
20
0
0
20
40
60
80
100
Concentration (µM)
B100
2
[Pd2Cl2 (ESDT)2(dah)]
[Pd2Cl2 (ESDT)2(dab)]
2
Both ionic [Pd(dithiocarbamate)(diamine)]Cl (dithiocarbamate
being PyDT; diamine being en or dap) and the dap complexes
[Pd(dap)Cl2] and [Pd(dap)2]Cl2 proved to be quite ineffective
against 2008 and A431 tumour cell lines (Table 4). These results
are in line with those previously reported for [Pd(ESDT)(en)]Cl,
which showed a lower cytotoxicity than cisplatin toward HeLa
80
60
40
20
0
[Pd(ESDT)(dab)]nCln
cisplatin
cells (IC50, 77.0 and 6.33 lM for [Pd(ESDT)(en)]Cl and cisplatin,
respectively) [28], as well as for [Pd(DMDT)(en)]Cl and the analo-
gous dap derivative which have been found inactive toward KB cell
line [40]. The total ineffectiveness showed by [Pd(PyD-
T)(en)][PdCl2(PyDT)] and Bu4N[PdCl2(DMDT)] derivatives, con-
firmed that ionic species containing chelating either diamine or
dithiocarbamate were generally inactive, a certain activity being
observed when the sulfur donor was ESDT [28].
0
20
40
60
80
100
Concentration (µM)
Binuclear and polynuclear Pd derivatives elicited a cytotoxicity
that was dependent on the nature of either dithiocarbamate type
or diamine chain length. Among PyDT derivatives, dinuclear
[Pd2Cl2(PyDT)2(dab)] was totally inactive whereas dinuclear
[Pd2Cl2(PyDT)2(dah)] complex elicited a rather similar cell death
induction over two cancer cells, with an average IC50 value of
Fig. 2. Sensitivity of 2008 (A) and A431 (B) cells to Pd complexes [Pd2Cl2(ESDT)2-
(dah)] (s), [Pd2Cl2(ESDT)2(dab)] (}), [Pd(ESDT)(dab)]nCln (N) or cisplatin (j). Drug
exposure with the indicated compounds was for 48 h. Cytotoxicity was evaluated
by the MTT test. Values are the mean ( SD) of three independent experiments.
56.52
lM.
tency comparable to that of cisplatin (average IC50 of 19.9, 15.3
ESDT Pd derivatives showed a significant in vitro antitumour
activity which was dose-dependent against both tumour cell lines
(Fig. 2A and B). In particular, despite [Pd2Cl2(ESTD)2(dab)] was less
effective than cisplatin in inhibiting cancer cell growth, the ionic
polynuclear [Pd(ESDT)(dab)]nCln species and the neutral binuclear
[Pd2Cl2(ESDT)2(dah)] complex displayed an antiproliferative po-
and 15.7 lM for [Pd(ESDT)(dab)]nCln, [Pd2Cl2(ESDT)2(dah)] and cis-
platin, respectively).
Among binuclear Pd complexes, the antiproliferative activity
against both cell lines increases when the diamine was 1,7-diami-
noeptane, the effect being, also in this case, more evident for the
ESDT complex (Fig. 2 and Table 4). The importance of the chain
length of the bridging diamine was pointed out in various multi-
charged polynuclear complexes, the most active species containing
1,6-diaminoexane [10].
Table 4
Cytotoxic activity.
Additionally, the most promising derivatives [Pd(ESDT)
(dab)]nCln and [Pd2Cl2(ESDT)2(dah)], were also tested against a cis-
platin-resistant human ovarian carcinoma subline, C13⁄ cells, in
order to assess their cross-resistance with cisplatin. In C13⁄ cells,
cisplatin resistance has been correlated to a reduced cell drug up-
take, high cellular thioredoxin reductase and glutathione levels,
and enhanced repair of DNA damage [45]. The cytotoxicity of Pd
derivatives was assessed in sensitive and resistant cells after 48-
h drug exposure by the MTT test; for comparison purposes, the
cytotoxicity of cisplatin was also evaluated under the same exper-
imental conditions. Cross-resistance profiles were evaluated by
means of the resistance factor (RF), which is defined as the ratio
between IC50 values calculated for calculated for cisplatin-resistant
cell lines and those arising from the sensitive parental ones (see
Table 5).
Compound
2008
A431
[Pd2Cl2(PyDT)2(dah)]
[Pd2Cl2(PyDT)2(dab)]
[Pd2Cl2(ESDT)2(dah)]
[Pd2Cl2(ESDT)2(dab)]
[Pd(ESDT)(dab)]nCln
[Pd(PyDT)(en)]Cl
[Pd(PyDT)(dap)]Cl
[Pd(PyDT)(en)][PdCl2(PyDT)]
Bu4N[PdCl2(DMDT)]
[Pd(dap)Cl2]
52.91 3.32
>100
16.36 1.14
42.47 2.72
18.40 1.81
>100
>100
>100
>100
>100
60.14 0.42
>100
14.32 1.23
36.55 2.86
21.50 2.63
>100
>100
>100
>100
>100
[Pd(dap)2]Cl2
Cisplatin
>100
12.24 2.15
>100
19.53 1.75
SD = standard deviation. IC50 values were calculated by probit analysis (P < 0.05, v2
test). Cells (3–5 ꢂ 104 mlꢀ1) were treated for 48 h with increasing concentrations of
tested compounds. Cytotoxicity was assessed by MTT test.

580
D. Montagner et al. / Inorganica Chimica Acta 376 (2011) 574–580
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Cisplatin cross-resistance profiles.
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Compound
IC50
(lM) SD
2008
C13⁄
RF
[Pd2Cl2(ESDT)2(dah)]
[Pd(ESDT)(dab)]nCln]
Cisplatin
16.36 1.14
18.40 1.81
12.24 2.15
14.48 0.95
17.58 2.04
95.45 2.05
0.9
0.9
7.8
SD = standard deviation. IC50 values were calculated by probit analysis (P < 0.05, v2
test). Cells (3 ꢂ 104 mlꢀ1) were treated for 48 h with increasing concentrations of
tested compounds. Cytotoxicity was assessed by MTT test.
Remarkably, both ESTD derivatives exhibited a different cross-
resistance profile from that of cisplatin, being the RF values calcu-
lated for [Pd(ESDT)(dab)]nCln and [Pd2Cl2(ESDT)2(dah)] about 8
times lower than that of cisplatin. These results, besides attesting
for derivatives [Pd(ESDT)(dab)]nCln and [Pd2Cl2(ESDT)2(dah)] the
ability to circumvent the acquired cisplatin resistance, support
the hypothesis of a different cytotoxic mechanisms of action for
these poly- and binuclear Pd ESDT complexes than that of the ref-
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Reaction between dithiocarbamate complexes of the type
[PdCl(dithiocarbamate)]n and different diamines like ‘‘en’’, ‘‘dap’’,
‘‘dab’’ and ‘‘dah’’ have been investigated. The reactions products
depend on either diamine chain length or molar ratio. With the
longer ‘‘dab’’ and ‘‘dah’’ the products obtained are dinuclear species
of the type [Pd2Cl2(dithiocarbamate)2(amine)] or polynuclear spe-
cies [PdCl(dithiocarbamate)(amine)]nCln (Pd/amine molar ratio
1:0.5 and 1:1, respectively) while anionic species like [Pd(dithio-
carbamate)(diamine)]Cl or exchange ligand reactions occur with
the shorter ‘‘en’’ and ‘‘dap’’. An appreciable in vitro antiproliferative
activity toward two different cancer cell lines have been obtained
with the dinuclear [Pd2Cl2(dithiocarbamate)2(amine)] (amine
‘‘dah’’ or ‘‘dab’’; dithiocarbamate ESDT and PyDT) and polynuclear
species. Interestingly, [Pd(ESDT)(dab)]nCln and [Pd2Cl2(ESDT)2-
(dah)] showed a remarkable cytotoxic activity also toward cis-
platin-resistant C13⁄ cells, thus strengthening the prospective of
further studies on this class of non-covalent polynuclear metal
complexes.
ˇ
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