Synthesis, characterization, antibacterial and cytotoxic activity of new palladium(II) complexes with dithiocarbamate ligands: X-ray structure of bis(dibenzyl-1-S:S′-dithiocarbamato)Pd(II)

Article abstract of DOI:10.1016/j.jorganchem.2007.03.019

Six palladium(II) dithiocarbamates of general formula Pd(AmDTC)₂, where HAmDTC = aminedithiocarbamic acid, [Pd(II) piperidinedithiocarbamate (1), Pd(II) 4-methylpiperidinedithiocarbamate (2), Pd(II) N-methylbenzyldithiocarbamate (3), Pd(II) dibenzyldithiocarbamate (4), Pd(II) dicyclohexyldithiocarbamate (5), Pd(II) N-cyclohexyl-N-methyldithiocarbamate (6)] have been synthesized and characterized by elemental analyses, FT-IR, ¹H and ¹³C NMR. The X-ray structure of Pd(II), compounds 3 and 4, showed that the ligands are chelated by both sulfur atoms with bond angles S1-Pd-S4 = 179.24(2)° and S2-Pd-S3 = 179.09(5)°, with a distorted square planar geometry around Pd. All these complexes were screened for cytotoxic and antibacterial effects and showed significant antibacterial activity and no substantial in vitro cytotoxicity indicating specificity of the compounds.

Full text of DOI:10.1016/j.jorganchem.2007.03.019

Journal of Organometallic Chemistry 692 (2007) 3019–3026
www.elsevier.com/locate/jorganchem
Synthesis, characterization, antibacterial and cytotoxic activity
of new palladium(II) complexes with dithiocarbamate ligands:
X-ray structure of bis(dibenzyl-1-S:S0-dithiocarbamato)Pd(II)
a
a
b,
c
Farkhanda Shaheen , Amin Badshah , Marcel Gielen *, Michal Dusek ,
c
d
e
Karla Fejfarova , Dick de Vos , Bushra Mirza
a
Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan
Vrije Universiteit Brussel, Faculty of Engineering, HNMR Unit, B-1050 Brussels, Belgium
b
c
Institute of Physics, Na Slovance, 182 21 Praha 8, Czech Republic
Pharmachemie BV, P.O. Box 552, 2003 RN Haarlem, The Netherlands
Department of Biology, Faculty of Biological Science, Quaid-I-Azam University, Islamabad 45320, Pakistan
d
e
Received 23 January 2007; received in revised form 15 March 2007; accepted 15 March 2007
Available online 21 March 2007
Abstract
Six palladium(II) dithiocarbamates of general formula Pd(AmDTC)2, where HAmDTC = aminedithiocarbamic acid, [Pd(II) piper-
idinedithiocarbamate (1), Pd(II) 4-methylpiperidinedithiocarbamate (2), Pd(II) N-methylbenzyldithiocarbamate (3), Pd(II) dib-
enzyldithiocarbamate (4), Pd(II) dicyclohexyldithiocarbamate (5), Pd(II) N-cyclohexyl-N-methyldithiocarbamate (6)] have been
1
synthesized and characterized by elemental analyses, FT-IR, H and 13C NMR. The X-ray structure of Pd(II), compounds 3 and 4,
showed that the ligands are chelated by both sulfur atoms with bond angles S1–Pd–S4 = 179.24(2)ꢀ and S2–Pd–S3 = 179.09(5)ꢀ, with
a distorted square planar geometry around Pd. All these complexes were screened for cytotoxic and antibacterial effects and showed
significant antibacterial activity and no substantial in vitro cytotoxicity indicating specificity of the compounds.
ꢁ 2007 Elsevier B.V. All rights reserved.
Keywords: Dithiocarbamate; Palladium; Anti-bacterial activity; Cytotoxicity
1. Introduction
metallocyclation [9] due to strong bonds with dithiocarba-
mate, which prevent or at least limit the reactions with
other sulfur-containing renal proteins [10]. Dithiocarba-
mate/dithioester complexes of Pt2+ and Pd2+ are known
to exhibit antitumor properties [11,12] and cytotoxic activ-
ities against some tumor cells, such as lung, ovarian [13],
melanoma, colon, renal, prostate and breast cancer [14].
Complexes of dithiocarbamate also exhibited antitumor
activities against pam.ras cells [15]. Among them, the
dithiocarbamate complexes [M(S2CNEt2)(L)]NO3 (M = Pd,
Pt; L = 2,20-bipyridyl or 1,10-phenanthroline) showed anti-
Dithiocarbamates are known to display both mono and
bi-dentate co-ordination to transition metal centers. Tran-
sition metal complexes of dithiocarbamates present a wide
range of applications in agriculture, medicine, industry, in
analytical and organic chemistry [1–4], as fungicides, pesti-
cides [5]. They were also used as molecular precursors in
CVD processes [6]. Recently, palladium(II) complexes have
attracted significant attention due to their biological [7] as
well as catalytic applications [8], and also play a role in
tumor activities against leukaemic cells [16]. Many Pd2+
/
Pt2+ complexes with dithioesters and dithiocarbamates
exhibit in vitro cytostatic activities against KB tumor cells
[17,18]. Furthermore the diethylthiocarbamato complexes
*
Corresponding author. Tel.: +32 2 629 32 79; fax: +32 2 629 32 81.
E-mail addresses: fshaheenpk@yahoo.com (F. Shaheen), mgielen@
vub.ac.be (M. Gielen).
0022-328X/$ - see front matter ꢁ 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2007.03.019

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F. Shaheen et al. / Journal of Organometallic Chemistry 692 (2007) 3019–3026
Scheme 1. Structures of compounds 1–6.
1
of Pt2+ and Pd2+ exhibiting high anticancer activity
together with a reduced toxicity, with respect to cisplatin
and analogous compounds [19]. Recently we have reported
the crystal structure of analogous complexes, bis(piperi-
dine-1-dithiocarbamato)Pd(II), bis(4-methylpiperidine-1-S:
S0-dithiocarbamato)Pd(II) and chloro[(4-methylpiperidine-
1-S:S0-dithiocarbamato)(PPh3)]Pd(II) [20,21].
In this paper, we report the synthesis and characteriza-
tion of six palladium(II) aminedithiocarbamates of general
formula Pd(AmDTC)2, where H(AmDTC) = aminedithio-
carbamic acid: [Pd(II) piperidinedithiocarbamate (1), Pd(II)
4-methylpiperidinedithiocarbamate (2), Pd(II) N-methyl-
benzyldithiocarbamate (3), Pd(II) dibenzyldithiocarbamate
(4), Pd(II) dicyclohexyldithiocarbamate (5), Pd(II) N-cyclo-
hexyl-N-methyldithiocarbamate (6) (see Scheme 1).
a frequency of 300 MHz with H broad band decoupling
and are given relative to TMS.
2.2. Synthesis of substituted dithiocarbamic acids
Substituted dithiocarbamates were synthesized accord-
ing to the literature method [22]. Typically, to a 4.0 ml
solution of amines in methanol at 0 ꢀC, carbon disulfide
was added drop wise in a 1:1 molar ratio with constant stir-
ring during 1 h. The solid product thus obtained was
washed with an excess of methanol and dried in open air.
It was re-crystallized from dichloromethane/n-hexane.
2.3. Synthesis of the complexes
To a suspension of PdCl2 in dichloromethane (15 cm3),
a stoichiometric amount of substituted dithiocarbamic
acids in dichloromethane (15 cm3) was slowly added in a
1:2 metal:ligand molar ratio. The mixture was refluxed
for 2 h with constant stirring. The clear solution then
obtained was evaporated under reduced pressure 50–30%.
Crystalline products were obtained after a slow evapora-
tion of the solvent at room temperature. The general chem-
ical reaction is shown by the following equation:
2. Experimental
2.1. Materials and methods
PdCl2, substituted amines and all solvents, dichloro-
methane, diethyl ether, n-hexane, methanol were purchased
from E-Merck, Germany and Aldrich. The compounds
were characterized by elemental analyses, FT-IR, single
crystal X-ray diffraction, H and 13C NMR spectroscopy.
1
MeOH
FT-IR spectra were recorded on a Perkin–Elmer FTIR
1000 spectrophotometer using KBr pellets in the 4000–
400 cmꢀ1 range, NMR measurements were carried out on
a Bruker ARX 250 FT NMR spectrophotometer at
297 K in CDCl3. The 13C NMR spectra were obtained at
PdX2 þ 2HðAmDTCÞ ! PdðAmDTCÞ2 þ 2HX
All these crystalline solids are soluble in dichlorometh-
ane and chloroform. The elemental analyses of the com-
plexes are given in Table 1.

F. Shaheen et al. / Journal of Organometallic Chemistry 692 (2007) 3019–3026
3021
Table 1
Elemental analysis of the [PdII(AmaDTC)2] complexes
Complexes [PdII(AmDTC)2]
Elemental analysis (%), observed (calculated)
M.p. (ꢀC)
Molecular formula weight
C
H
N
S
[PdII(pipDTC)2] (1)
[PdII(MpipDTC)2] (2)
[PdII(MBzDTC)2] (3)
[PdII(DBzDTC)2] (4)
[PdII(DCyDTC)2] (5)
[PdII(CyMDTC)2] (6)
a
39.0 (39.4)
35.9 (36.5)
43.3 (43.2)
69.9 (71.0)
52.3 (52.4)
39.5 (39.7)
5.3 (5.4)
5.2 (5.2)
4.1 (4.0)
5.4 (5.5)
7.5 (7.4)
5.5 (5.7)
7.6 (7.5)
6.0 (6.1)
5.5 (5.6)
5.2 (5.5)
4.5 (4.7)
5.5 (5.7)
35.1 (35.0)
27.8 (27.8)
25.5 (25.6)
25.4 (25.2)
21.7 (21.5)
26.6 (26.5)
328–330(dec.)
260–261(dec.)
145–147
301–302(dec.)
300–302
365.31
459.31
499.00
507.00
595.00
483.00
287–289
Am = piperidine, 4-methylpiperidine, dibenzylamine, N-methylbenzylamine, dicyclohexylamine, N-methylcyclohexylamine.
2.4. X-ray data collection and structure determination of
complexes 3 and 4
counting statistics w = 1/(r2(I) + 0.0009I2), C–H distances
were constrained at 0.96 A to their ideal position, their iso-
˚
tropic displacement parameter were kept as 1.2 multiple of
equivalent displacement parameter of the atoms to which
the hydrogen is bonded. A final differences map showed
no significant features.
Orange X-ray quality crystal of complex-3 was selected
with a dimension 0.25 · 0.10 · 0.08 mm and mounted on
˚
a Philips PW 1100 diffractometer (Mo Ka; k = 0.71073 A).
Reflection data were collected by using limits ꢀ7 6 h 6 5,
ꢀ9 6 k 6 4, ꢀ12 6 l 6 12, out of 1830 reflections 1698
were considered observed with [I > 2r(I)]. Empirical
absorption correction was applied using the local program
based on Walker and Stuart [23]. The structure was solved
by direct methods (SIR-97) [24] and refined with full-matrix
least-squares (SHELXL-97) [25], using the wingx software
package [26]. The program ORTEP for window was also
used. Cell dimension were obtained by least-squares refine-
ment of the setting angles of 25 accurately centered reflec-
tions: 1830 independent reflection (to h 6 25ꢀ) were
measure using by h–2h scans, background scans being
taken on each side of the peak (Rint = 0.000). Atomic scat-
tering factors were taken from International Tables for
X-ray Crystallography (1974).
An yellow crystal of complex 4 ca. 0.259 · 0.138 ·
0.061 mm was mounted on Oxford Diffraction CCD-
calibur2/Sapphire2 [27], at angle 2.5ꢀ, Mo Ka radiation fil-
tered by graphite crystal monochromator, using diffraction
detector mean area of resolution 8.3438, cell dimensions
and their standard deviations derived by rotation method
data acquisition using x–2h scans, densities of 28577 reflec-
tions (h < 26.71ꢀ) measured by x–2h scans and background
counts taken on each side of the peak, intensities of three
standard reflection measured 9000 s showed no significant
change during data collection. Integration of the CCD
images was done by program CrysAlis RED (Oxford index
diffraction 2004) [28]. The same program was used for
indexing of the crystal shape, its refinement and absorption
correction. Reflection data were collected by using limits
ꢀ17 < h > 14, ꢀ17 < k > 17, ꢀ20 < l > 20, out of 11397
reflections 8044 were considered observed with I > 3r(I).
All calculations were carried out by using CrysAlis RED
(for cell refinement, data reduction). SIR-2002 was used to
solve the structure [29]. The structure was refined by using
Jana 2000 [30], refinement of non-H atoms was done aniso-
tropically and H atoms isotropically reduced R to a final
value of 0.0354, Rw = 0.0522, weighting scheme based on
2.5. Biological assays
2.5.1. Antibacterial assay
The antibacterial activity of all synthesized metal com-
plexes has been investigated against six strains of bacteria
(Escherichia coli, Bacillus subtilis, Shigella flexenari,
Staphylococcus aureus, Salmonella typhi, and Pseudomonas
aeruginosa) by the agar well diffusion method [31,32]. Imi-
penum was used as standard antibiotic. Three milligrams
of the complexes were dissolved in 1 ml of DMSO. Cen-
trifuged pellets of bacteria from a 24-h-old culture con-
taining approximately 104–106 colony forming unit
(CFU) per ml was spread on the surface of Muller Hinton
Agar (MHA) plates. Wells were created in medium with
the help of a sterile metallic borer and nutrients agar med-
ium were prepared by suspending nutrient agar (Merck)
20 g in one liter of distilled water (pH 7.0), autoclaved
and cooled down to 45 ꢀC. Then it was seeded with
10 ml of prepared inocula to have 106 CFU/ml. Peter
plates were prepared by pouring 75 ml of seeded nutrients
agar. Experimental plates were incubated for 24 h and
zones of inhibition (%) were measured and compared with
standard antibiotic imipenum with zone inhibition of 20
and 22 mm, respectively [33,34]. The results are shown
in Table 6.
2.5.2. Cytotoxicity screenings
The test and reference compounds were dissolved to a
concentration of 250 000 ng/ml in full medium, by 20-fold
dilution of a stock solution which contained 1 mg com-
pound/200 ll. The compounds were taken into dimethyl-
sulfoxide. Cytotoxicity was estimated by the microculture
sulforhodamine B (SRB) test [34]. The human cancer cell
lines examined in the present study were: A498, renal can-
cer; MCF-7, estrogen receptor (ER)+/progesterone recep-
tor (PgR) + breast cancer; EVSA-T, estrogen receptor
(ER)-/progesterone receptor (PgR)-breast cancer, H226,

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F. Shaheen et al. / Journal of Organometallic Chemistry 692 (2007) 3019–3026
non-small cell lung cancer; IGROV, ovarian cancer; M19
MEL, melanoma; and WIDR, colon cancer.
tiate between mono- and bidentate modes of binding of
dithiocarbamate ligands [37]. The position of the m(C–N)
absorption is at 1438–1410 cmꢀ1 in the free ligands and
complexes. The 1500–1470 cmꢀ1 region allows to identify
the nature of the resulting complexes [38]: in the complexes
showing an S–S chelate to metal coordination, the m(C–N)
stretching frequencies are shifted to higher frequency by
about ꢁ50 cmꢀ1 on coordination with palladium. The
energy of the dithiocarbamate m(C–N) band is intermediate
between the stretching frequencies associated with singly
and doubly bonded carbon and nitrogen, and the double
bond character is increased by electron delocalization
towards the metal center [39]. In the case of a singular
coordination with the thiocarbonyl sulfur, the shift is only
approximately 10–20 cmꢀ1 [40]. This suggests that the C–N
bonds in the complexes have some partial double bond
character. Partial double bond character for the C–N bond
would result in some partial double bond character for the
C–S bonds [41,42]. This band also defines a carbon-nitro-
gen bond order intermediate between a single bond-charac-
teristic frequency (1350–1250 cmꢀ1) and a double bond
(1680–1470 cmꢀ1) [43]. The presence of only one band in
the region 1061–940 cmꢀ1 is assumed to indicate a com-
pletely symmetrically bonding of the dithiocarbamate
ligand, acting in a bidentate fashion, while a split band
indicative of an unsymmetrically bound bidentate ligand
[38,44] (see Table 2).
The experiment was started on day 0. On day 0, 10000
cells per well were seeded into 96-wells flatbottom microti-
ter plates (falcon 3072, DB). The plates were incubated
overnight at 37 ꢀC, 5% CO2 to allow the cells to adhere
to the bottom. On day 1, a threefold dilution sequence of
10 steps was made in full medium, starting with the
250,000 ng/ml stock solution. Every dilution was used in
quadruplicate by adding 200 ll to a column of four wells.
This procedure results in a highest concentration of
625,000 ng/ml present in column 12. Column 2 was used
for the blank. After incubation of 3 days, the plates were
washed with PBS twice. Fluorescein diacetate (FDA) stock
solution was diluted to 2 lg/ml with PBS and 200 ll of this
solution was added to each of the control, experimental
and blank wells. The plates were incubated for 30 min at
37 ꢀC and the fluorescence generated from each well was
measured at an excitation wavelength of 485 nm and an
emission wavelength of 535 nm using an automated micro-
plate reader (Labsystems Multiskan MS). Data were used
for construction of concentration–response curves and
determination of the ID50 value by use of Deltasoft 3 soft-
ware. The variability of the in vitro cytotoxicity test
depends on inter alia the cell lines used and the serum
applied. With the same batch of cell lines and the same
batch of serum the inter-experimental CV (coefficient of
variation) is 1–11% depending on the cell line and the
intra-experimental CV is 2–4%. These values may be higher
with other batches of cell lines and/or serum. For details on
the in vitro cytotoxicity tests, see Refs. [34,35].
In the complexes reported in this paper, the presence of
only one band in the region of 1061–940 cmꢀ1, the m(CSS)
mode, suggests a symmetrical behavior of the bidentate
dithiocarbamate moiety. According to the literature
[37,41,45] for complexes, the Dm values m(CSS)asym
ꢀ
3. Result and discussion
m(CSS)sym are 120–137 cmꢀ1, indicating that the sulfur
atoms of the dithiocarbamate group are linked to the cen-
tral tin in a bidentate fashion. A new M-S band appeared
in the region 400–300 cmꢀ1 in the complexes due to (Pd–
S) stretching [46] (see Table 2).
3.1. Infrared spectroscopy
The most significant bands recorded in the IR spectra of
all synthesized complexes are listed in Table 2. Tentative
assignments are made according to the literature [36].
The absence of m(S–H) vibrations (which were observed
in the parent dithiocarbamates in the range of 2754–
2654 cmꢀ1), in the synthesized complexes indicate that
the S–H proton is replaced by a metal ion, and the C–N
and C–S stretching frequencies that can be used to differen-
3.2. X-ray structure
In compound 3 (see Table 3) the palladium(II) ion is
bonded to four sulfur atoms belonging to the two dithio-
carbamate ligands. The palladium metal is an inversion
centre of a square planar structure. The corresponding
S1–Pd–S2 angles are 180ꢀ, 94.98ꢀ and 85.02ꢀ, respectively.
The crystal is twinned and this probably affected some geo-
metric parameters such as the C–S bond distances of the
Table 2
Principal IR spectral data (cmꢀ1 a of [PdII(Am*DTC)2] complexes by
)
˚
dithiocarbamate fragments (ꢁ2 A). The bond distances of
using KBr pellets
Pd–S are not equal and lie in the range 2.299(3)–2.312(3)
Complexes [PdII(AmDTC)2]
IR (m, cmꢀ1
)
˚
A (see Fig. 1) (see Table 5).
(C–S)
(Pd–S)
(C–N)
(C@S)
The molecular structure of the compound 4 (see Table 4)
is depicted in Fig. 2. The geometry around the Pd(II) center
is a slightly distorted square plane. The corresponding
bond angles S(1)–Pd(1)–S(4) and S(2)–Pd(1)–S(3) are equal
to 179.24(2)ꢀ and 179.095ꢀ, respectively, The metal–ligand
[PdII(pipDTC)2] (1)
[PdII(MpipDTC)2] (2)
[PdII(MBzDTC)2] (3)
[PdII(DBzDTC)2] (4)
[PdII(DCyDTC)2] (5)
[PdII(CyMDTC)2] (6)
a
1530 br
1529 m
1535 m
1534 br
1545 m
1532 m
388 m
392 m
390 w
399 w
335 m
338 m
1485 s
1478 s
1470 s
1461 s
1467 s
1458 s
1030 m
1034 m
995 w
1020 w
1032 m
1012 m
˚
bond distances are Pd(1)–S(1) = 2.3290(6) A and Pd(1)–
˚
s = strong, m = medium, w = weak, br = broad.
S(2) = 2.3385 A.

F. Shaheen et al. / Journal of Organometallic Chemistry 692 (2007) 3019–3026
3023
Table 3
Crystal data and structure refinement for compound 3
Table 4
Crystal data and structure refinement for compound 4
Empirical formula
Formula weight
Temperature (K)
C18H20N2PdS4
499.00
293(2)
Empirical formula
Formula weight
Temperature (K)
C30H28N2PdS4
651.2
293(2)
˚
˚
Wavelength (A)
0.71073
Wavelength (A)
0.71073
ꢀ
Crystal system
Space group
Triclinic
Crystal system, space group
Unit cell dimensions
Triclinic, P1
ꢀ
P1
˚
Unit cell dimensions
a A
13.8787(10)
14.3656(10)
16.4788(10)
64.337(6)
72.330(6)
83.290(6)
2821.3(4)
4
˚
˚
a (A)
6.526(5)
8.155(7)
10.567(7)
89.55(7)
78.50(7)
71.44(6)
521.5(7)
1
b A
˚
˚
b (A)
c A
˚
c (A)
a (ꢀ)
b (ꢀ)
c (ꢀ)
a (ꢀ)
b (ꢀ)
c (ꢀ)
3
˚
V (A )
3
˚
V (A )
Z
Z
Dcalc (Mg/m3)
1.5327
0.977
1328
Dcalc (Mg/m3)
1.589
1.294
252
Absorption coefficient (mmꢀ1
F(000)
)
Absorption coefficient (mmꢀ1
F(000)
)
Crystal size (mm)
h Range for data collection (ꢀ)
Limiting indices
0.25 · 0.13 · 0.06
2.48–26.49
Crystal size (mm)
h Range for data collection (ꢀ)
Limiting indices
0.25 · 0.10 · 0.08
3.20–25.00
ꢀ7 6 h 6 5, ꢀ9 6 k 6 4,
ꢀ12 6 l 6 12
1830/1830 (0.0000)
99.5
ꢀ17 6 h 6 14, ꢀ17 6 k 6 17,
ꢀ20 6 l 6 20
Reflections collected/unique (Rint
Completeness to h = 26.71 (%)
Absorption correction
Maximum and minimum
transmission
)
28577/11397 (0.0190)
99.5
Reflections collected/unique (Rint
Completeness to h = 25.00ꢀ (%)
Absorption correction
Maximum and minimum
transmission
)
Analytical
Empirical
1.000 and 0.861
0.812 and 0.689
Refinement method
Full-matrix least-squares on
F2
Refinement method
Full-matrix least-squares on F2
1830/0/116
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2r(I)]
R indices (all data)
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 3r(I)]
R indices (all data)
28577/0/667
1.074
0.94
R1 = 0.0561, wR2 = 0.1386
R1 = 0.0605, wR2 = 0.1426
1.070 and ꢀ0.975
R1 = 0.0206, wR2 = 0.0498
R1 = 0.0354, wR2 = 0.0522
0.21 and ꢀ0.15
Largest difference in peak and hole
Largest difference in peak and hole
ꢀ3
ꢀ3
˚
˚
(e A
)
(eA
)
3.3. NMR study
Generally, the absence of S–H protons and a slight
downfield shift of the protons in the NMR spectra of all
complexes were observed, which indicates that the ligands
are coordinated to palladium through sulfur atoms [47].
The mode of coordination has also been confirmed by sin-
gle crystal X-ray diffraction. In the piperidinedithiocarba-
mate complex 1, the methylene protons belonging to the
(CH2)3 moiety exhibit downfield shifts in the range of
1.09–2.63 ppm and two signal appeared around 3.73–
3.87 ppm for the NCH2 methylene protons of N(CH2)2
originated from the different position (syn or anti) with
respect to the thiocarbonyl group in the square planar mol-
ecule, the separation being larger than in the free dithiocar-
bamic acids due to coordination. The appearance of two
signals is related to the barrier of rotation about the C–N
bond [48], which makes the nitrogen substituents magneti-
cally non-equivalent [49]. Similarly, for the 4-meth-
ylpiperidinedithiocarbamate complex 2, peaks due to
methyl and methylene protons were observed in the region
0.90–2.51 ppm, the methyl protons appearing as a doublet
Fig. 1. ORTEP view of the palladium complex 3.
non-equivalent and appear as two doublets at 4.75 (Dd =
2
0.0230 ppm, JHH = 6.9 Hz) and at 5.21 ppm (Dd =
2
0.0233 ppm, JHH = 7 Hz). One signal is present for the
N-CH3 proton at 3.17 ppm. A similar behavior for
N-CH2 is observed in the N,N0-dibenzyldithiocarbamate
complex 4. The proton spectrum of the N,N-dic-
yclohexyldithiocarbamate complex 5 is very simple:the
CH protons bound to nitrogen show a complex pattern
between 5.31 and 5.17 ppm and the signals of chain meth-
ylene protons were observed in the ranges 0.90–2.19. In
the case of the N-cyclohexyl-N-methyldithiocarbamate
complex 6, a single resonance of methyl protons was
observed as a singlet at 3.26 ppm and N-cyclohexyl protons
3
at 0.98 ppm (Dd = 0.029 ppm, JHH = 8.7 Hz) and the N-
(CH2)2 methylene protons being detected at 3.93 ppm
and 4.64 ppm. In complex 3, the N-CH2 protons are

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F. Shaheen et al. / Journal of Organometallic Chemistry 692 (2007) 3019–3026
Table 5
Table 6
˚
˚
Bond lengths (A) and angles (ꢀ) for compound 3
Selected bond distances (A) and bond angles (ꢀ) for compound 4
˚
˚
Bond lengths (A)
Bond angles (ꢀ)
Bond lengths (A)
Bond angles (ꢀ)
C(1)–S(1)
N(1)–C(1)
C(1)–S(2)
S(1)–Pd
S(2)–Pd
Pd–S(1)#1
Pd–S(2)#1
1.816(11)
1.425(13)
2.007(12)
2.299(3)
2.312(3)
2.299(3)
2.312(3)
N(1)–C(1)–S(1)
N(1)–C(1)–S(2)
S(1)–C(1)–S(2)
C(1)–S(1)–Pd
C(1)–S(2)–Pd
S(1)–Pd–S(1)#1
S(1)–Pd–S(2)
S(1)#1–Pd–S(2)
S(1)–Pd–S(2)#1
S(1)#1–Pd–S(2)#1
S(2)–Pd–S(2)#1
124.5(7)
126.4(7)
109.1(6)
84.8(4)
80.4(3)
180.0
85.02(10)
94.98(10)
94.98(10)
85.02(10)
180.00(17)
S(1)–Pd
S(2)–Pd
Pd–S(1)#1
Pd–S(2)#1
2.299(3)
2.312(3)
2.299(3)
2.312(3)
N(1)–C(1)–S(1)
N(1)–C(1)–S(2)
S(1)–C(1)–S(2)
C(1)–S(1)–Pd
C(1)–S(2)–Pd
S(1)–Pd–S(1)#1
S(1)–Pd–S(2)
S(1)#1–Pd–S(2)
S(1)–Pd–S(2)#1
S(1)#1–Pd–S(2)#1
S(2)–Pd–S(2)#1
124.5(7)
126.4(7)
109.1(6)
84.8(4)
80.4(3)
180.0
85.02(10)
94.98(10)
94.98(10)
85.02(10)
180.00(17)
Symmetry transformations used to generate equivalent atoms: #1 ꢀx, ꢀy,
ꢀz.
Symmetry transformations used to generate equivalent atoms: #1 ꢀx, ꢀy,
ꢀz.
Table 7
13C NMR chemical shifts, d (ppm) for the PdII complexes 1–6
Compounds
C1
C2
C3
C4
C5
CH3
[PdII(pipDTC)2] (1)
[PdII(MpipDTC)2] (2)
[PdII(MBzDTC)2] (3)
[PdII(DBzDTC)2] (4)
[PdII(DCyDTC)2] (5)
[PdII(CyMDTC)2] (6)
208.6
206.4
206.5
209.3
203.3
206.5
47.9
47.3
59.9
58.9
63.0
58.6
25.7
24.7
–
–
31.3
142.7
141.0
32.7
27.4
132.0
129.8
26.2
23.4
29.7
–
–
30.7
129.7
127.7
25.7
29.0
29.7
25.2
3.4. Biological assays
3.4.1. Antibacterial inhibition studies
Metal–dithiocarbamates are capable of inhibiting bacte-
rial growth and activity by interfering with the metabolic
processes in the bacteria. In the present work, we have syn-
thesized dithiocarbamate Pd(II) complexes. The antibacte-
rial activity of the Pd(II) complexes have been determined
against six strains of bacteria (E. coli, B. subtilis, Shigella
flexenari, Staphylococcus aureus, Samonella typhi, and P.
aeruginosa). The results are given in Table 8. Significant
anti-bacterial activities were observed as compared to a
standard drug except for complexes (4) and (5). The metal
complexes containing piperidine (1), 4-methylpiperridine
(2), N-methylbenzylamine (3) exhibit a good activity against
E. coli. The metal complexes of dicyclohexyldithiocarba-
mate (5) and N-cyclohexyl-N-methyldithiocarbamate (6)
exhibit a low activity against all reported bacteria, except
‘‘Shigella flexenari’’.
Fig. 2. Diamond view of the palladium complex 4.
were observed between 0.90–2.9 and 4.00–5.00 ppm,
respectively.
The 13C{1H} NMR spectra of all the complexes were
recorded for CDCl3 solutions. The resonance of the –CSS
carbon was observed around 203 ppm, about 5–6 ppm
downfield shift compared to the free dithiocarbamic acids.
The downfield shift can be ascribed to the bidentate nature
of the dithiocarbamates. Moreover, a significant downfield
shift was observed for the C–N carbons. The downfield
shift is consistent with an increase in the double bond char-
acter of C–N bond. The other resonances were only slightly
shifted. 13C NMR data of the compounds are given in
Table 7.
3.4.2. Cytotoxicity screenings
The results of the in vitro cytoxicity tests of compounds
1–6 are given in Table 1 as the inhibition doses ID50
observed against a panel of seven human tumour cell lines,
MCF-7 and EVSA-T, two breast cancers, WiDr, a colon
cancer, IGROV, an ovarian cancer, M19 MEL, a mela-
noma, A248, a renal cancer, and H226, a non-small cell
lung cancer. The cytotoxicity results are compared with
those obtained for clinically used reference compounds like
doxorubicin DOX, cisplatin CPT, 5-fluorouracil 5FU,
methotrexate MTX, etoposide ETO, and taxol TAX.

F. Shaheen et al. / Journal of Organometallic Chemistry 692 (2007) 3019–3026
3025
Table 8
Antibacterial Activity of the [PdII(Am*DTC)2] complexes: zones of inhibition (in %)
Name of bacteria
% Zone of inhibition of samples (mm)
% Zone of inhibition of
standard drug (mm)
Cdp-1
Cdp-2
Cdp-3
Cdp-4
Cdp-5
Cdp-6
Escherichia coli
Bacillus subtilis
28
18
–
21
23
31
27
12
–
25
18
18
22
14
10
23
27
16
20
23
15
19
14
19
18
20
–
29
23
22
24
20
14
20
33
18
33
30
35
43
25
40
Shigella flexenari
Staphylococcus aureus
Samonella typhi
Pseudomonas aeruginosa
Concentration of the standard drug (‘‘Imipenum’’) = 10 lg/disc.
Concentration of sample = 3 mg/ml.
–, No activity.
Table 9
Inhibition doses ID50
Compound
A498
EVSA-T
H226
IGROV
M19MEL
MCF-7
WiDr
1
38688
37033
10084
90
2253
143
37
1314
<3
46807
37992
2112
8
422
475
5
37535
37957
14616
199
3269
340
2287
3934
<3
38616
59428
1032
60
169
297
7
51168
49184
8818
16
558
442
23
505
<3
38141
30168
10855
10
699
750
18
2594
<3
48690
43790
13780
11
967
225
<3
150
<3
2
3
DOX
CPT
5FU
MTX
ETO
TAX
317
<3
580
<3
It is evident from Table 9 that the studied compounds 1
and 2 exhibit very low cytotoxic activities whereas com-
pound 3 shows mostly a low activity.
Appendix A. Supplementary material
CCDC 296816 and 611518 contain the supplementary
crystallographic data for 3 and 4, respectively. These data
can be obtained free of charge via http://www.ccdc.cam.ac.
uk/conts/retrieving.html, or from the Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: (+44) 1223-336-033; or e-mail: depos-
it@ccdc.cam.ac.uk. Supplementary data associated with
this article can be found, in the online version, at
doi:10.1016/j.jorganchem.2007.03.019.
4. Conclusion
The complexes reported here have been obtained in the
crystalline state, and the structures of two of them are
reported. This study provides useful information about
the bonding nature in the Pd(II) complexes, and the spec-
troscopic techniques used support and suggest that the
coordination in all the PdII(DTC)2 complexes yield a
square planar geometry through the sulfur donating atoms,
the NCSS group coordinating the metal center in a biden-
tate symmetrical mode. The in vitro antibacterial activities
of the synthesized complexes have been studied by testing
them in various bacterial strains which shows their inhibi-
tory effect. It is important to observe that this antibacterial
effect is not accompanied by cytotoxicity. This indicates a
certain degree of specificity of the compounds studied.
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