In vitro assessment of cytotoxicity, anti-inflammatory, antifungal properties and crystal structures of metallacyclic palladium(II) complexes

Article abstract of DOI:10.1016/j.jorganchem.2009.10.048

Metallacyclic palladium(II) complexes [Pd(L)(R₃P)Cl], L = TIQDTC (1,2,3,4-tetrahydroisoquinolinedithiocarbamate), 4MpipDTC (4-methylpipradinedithiocarbamate), MPizDTC (N-methylpiperazinedithiocarbamate), R₃P = Ph₃P, (o-tolyl)₃P, Ph₂ClP, were synthesized in a 1:1 molar metal-ligand ratio. These complexes were characterized by elemental analyses, FT-IR, multinuclear (¹H, ¹³C and ³¹P) NMR. The X-ray crystal structures of [Pd(TIQDTC)(Ph₃P)Cl] and [Pd(TIQDTC)((o-tolyl)₃P)Cl] show a slightly distorted square planar environment around the Pd(II) ion with S-Pd-S and P-Pd-Cl average bond angles of 74.51 and 92.41, respectively. These complexes were screened for cytotoxic, antifungal, anti-inflammatory and antibacterial activity. Some complexes exhibit a significant activity against fungi.

Full text of DOI:10.1016/j.jorganchem.2009.10.048

Journal of Organometallic Chemistry 695 (2010) 315–322
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
In vitro assessment of cytotoxicity, anti-inflammatory, antifungal properties
and crystal structures of metallacyclic palladium(II) complexes
a
b,
c
d
Farkhanda Shaheen a, , Amin Badshah , Marcel Gielen , Gianluca Croce , Ulrich Florke ,
*
*
Dick de Vos e, Saqib Ali a
a Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan
b Vrije Universiteit Brussel, Faculty of Engineering, HNMR Unit, B-1050 Brussels, Belgium
c DISTA, Universita del Piemonte Orientale, Alessandria I- 15100, Italy
d Department Chemie, Universität Paderborn, Warburgerstasse 100, D-33098 Paderborn, Germany
e Pharmachemie BV, P.O. Box 552, 2003 RN Haarlem, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 August 2009
Received in revised form 29 October 2009
Accepted 30 October 2009
Available online 18 November 2009
Metallacyclic palladium(II) complexes [Pd(L)(R3P)Cl], L = TIQDTC (1,2,3,4-tetrahydroisoquinolinedithio-
carbamate), 4MpipDTC (4-methylpipradinedithiocarbamate), MPizDTC (N-methylpiperazinedithio-
carbamate), R3P = Ph3P, (o-tolyl)3P, Ph2ClP, were synthesized in a 1:1 molar metal–ligand ratio. These
complexes were characterized by elemental analyses, FT-IR, multinuclear (1H, 13C and 31P) NMR. The
X-ray crystal structures of [Pd(TIQDTC)(Ph3P)Cl] and [Pd(TIQDTC)((o-tolyl)3P)Cl] show a slightly distorted
square planar environment around the Pd(II) ion with S–Pd–S and P–Pd–Cl average bond angles of 74.51
and 92.41, respectively. These complexes were screened for cytotoxic, antifungal, anti-inflammatory and
antibacterial activity. Some complexes exhibit a significant activity against fungi.
Keywords:
Palladium(II)
Dithiocarbamate
Organophosphine
Anti-inflammatory
Ó 2009 Elsevier B.V. All rights reserved.
1. Introduction
limited by its severe side effects such as nephrotoxicity (kidney
damage), neurotoxicity (nervous system damage), ototoxicity
Metal-containing compounds offer certain advantages over
purely organic compounds in drug therapy and broad applications
in the field of material sciences. Metal-based sulfur-containing
molecules like dithiocarbamates are currently under study as
adsorbents for the preparation of gold nanoparticles, stimulated
by the numerous nanotechnological possibilities for the develop-
ments of nanoscale optoelectronic devices, sensors and biosensors,
corrosion resistant materials and new catalysts. The interest in the
synthesis of functionalised monolayer protected metal nanoparti-
cles is expanding with an exponential rate [1–3], also used as
chemoprotectants in platinum-based chemotherapy [4]. Cisplatin
is one of the most effective drugs used not only in the treatment
of head and neck cancer, lung carcinoma, stomach carcinoma, tes-
ticular, ovarian, bladder, oesophageal, small and non-small cell
lung [5], breast, cervical and prostate cancers but also to treat
Hodgkin’s and non-Hodgkin’s lymphomas, neuroblastomas, sarco-
mas, multiple myelomas, melanomas and mesotheliomas [6,7].
However, the clinical usefulness of cisplatin has been frequently
(hearing loss) and myelotoxicity (bone marrow suppression)
[8,9], and by the development of acquired resistance against breast
and colon cancer [10]. Continuous efforts are still being made to re-
duce the toxicity of platinum anticancer complexes towards nor-
mal cells, circumventing acquired resistance to cisplatin and
decreasing its side effects. The interest in the chemical and bio-
chemical properties of platinum and palladium complexes with
thiocarbonyl and thiol donors has been increased because sulfur-
containing ligands are used as detoxicant agents against metal-
containing drugs [11]. Dithiocarbamates have been used for their
efficacy as inhibitors of cisplatin-induced side effects [12]. In par-
ticular, dithiocarbamates selectively remove platinum from the en-
zyme–thiol complexes by nucleophilic attack of the chelating
sulfur atoms to the platinum moiety [13]. Moreover the selectivity
protects normal tissues without inhibiting the antitumour effect
[14]. Their biological as well as catalytic activities are enhanced
by complexation with Pd(II) [15]. The dithiocarbamate moiety
can bind (chelate) palladium by a (–S:S0–) coordination mode
[11]. Several Pd dithiocarbamates complexes [Pd(ESTD)(2-pic)CL],
[Pd(MSDTM)Br]n and [Pd(ESTD)CL]n are known to exhibit cytotoxic
activities against HeLa, HL60, lung, ovarian melanoma, colon, renal,
prostate and breast cancer cell lines [17–21,50].
* Corresponding authors. Tel.: +32 (2) 629 32 79; fax: +32 (2) 629 32 81
(M. Gielen).
E-mail addresses: fshaheenpk@yahoo.com (F. Shaheen), mgielen@vub.ac.be
(M. Gielen).
During the last few years, we have been studying palladium(II)
complexes with dithiocarbamates [20] and some mixed ligands
0022-328X/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2009.10.048

316
F. Shaheen et al. / Journal of Organometallic Chemistry 695 (2010) 315–322
dithicarbamate and organophosphines, such as [Pd(L)(PR3)Cl]
[L = DCHDTC (N,N0-dicyclohexyldithiocarbamate), MCyHDTC (N-
methyl-N-cyclohexyldithiocarbamate); PR3 = PPh3, P(o-tolyl)3,
PPh2Cl] [16]. The new series of palladium metallacyclic complexes
with mixed tertiary phosphines/dithiocarbamate ligands described
in this paper is the continuation of our previous work: we have se-
lected the three ligands 1,2,3,4-tetrahydroisoquinolinedithiocarba-
mate (TIQDTC), 4-methylpiperidinedithiocarbamate (4MpipDTC)
and N-methylpiperazinedithiocarbamate (MPizDTC) to synthesize
were dried before use over sodium benzophenone by the standard
method [22].
3. Syntheses and characterizations
3.1. Synthesis of PdCl2(PR3)2 and of the dithiocarbamate ligands
The complexes [PdCl2(PR3)2] (R3P = Ph3P, (o-tolyl)3P, ClPh2P)
were prepared by a literature method [23a]. The dithiocarbamates
[RDTC] (R = 1,2,3,4-tetrahydroisoquinoline (TIQH), 4-methylpiperi-
dine (4MpipH), methylpiperazine (MPizH)) were prepared by the
reactions of secondary amines with carbon disulfide at 0 °C [23b].
a
series of complexes, [Pd(L)(PR3)Cl] (L = TIQDTC, 4MpipDTC,
MPizDTC; R3P = Ph3P, (o-tolyl)3P, ClPh2P). We characterized these
by elemental analyses, FT-IR, multinuclear (1H, 13C and 31P) NMR
and single X-ray crystallography, and screened them for cytotoxic,
antifungal, anti-inflammatory and antibacterial activity.
3.2. General synthetic procedure of Pd(II) complexes with mixed
ligands
2. Materials and instrumentation
Pd(II) complexes of mixed ligands were synthesized by sus-
pending [PdCl2(PR3)2] (1.14 mmol) in 15 cm3 of CH2Cl2 and adding
to it a solution of substituted dithiocarbamate ligand (1.14 mmol)
in 15 cm3 CH2Cl2 in a two neck flask fitted with a reflux condenser
at 40 °C. The reaction mixture was refluxed for 1 h to obtain a clear
solution and then cooled down to room temperature. The solvent
was removed under reduced pressure. The resultant solid was
recrystallized from CH2Cl2/n-hexane (3:1) (see Scheme 1).
Elemental analyses were carried out on a Fisons EA1108 CHNS-
O microanalyser. Melting points were determined with a Mitamura
Riken Kogyo (Japan) instrument. The FT-IR spectra of the synthe-
sized complexes were recorded on two instruments: a Nicolet
5SXC FT-IR spectrometer, using KBr discs from 4000 to 400 cmꢀ1
and a Perkin–Elmer FT-IR Nexus spectrometer by using CsI discs
from 500 to 200 cmꢀ1
.
The 1H and 13C NMR spectra were recorded on a Bruker
300 MHz spectrometer with CDCl3 as a solvent and TMS as refer-
ence, operating at 300 and 75.5 MHz, respectively. 31P NMR spectra
were recorded on Bruker WM-300 and AM-400 spectrometers
operating at 121.51 and 162.40 MHz, respectively. Spectra were
run in CDCl3 solution at ambient temperature and referenced to
external 85% phosphoric acid with downfield shifts defined as
positive.
Secondary amines such as 1,2,3,4-tetrahydroisoquinoline, 4-
methylpiperidine and methylpiperazine were purchased from Al-
drich (USA) and distilled before use. All reagents were of analytical
grade and used without further purification. The organic solvents
3.2.1. [Pd(TIQDTC)(PPh3)Cl] (1)
[Pd(TIQDTC)(PPh3)Cl] was synthesized by the method as de-
scribed above and recrystallized from a mixture of dichlorometh-
ane (20 cm3) and n-hexane (5 cm3). Orange crystals were
obtained after 15 days by slow evaporation at room temperature.
Data (85% yield). M.P.: 301–303 °C. Anal. Calc. for C28H26ClNPPdS2:
C, 54.82; H, 4.27; N, 2.28; P, 5.05 S, 10.45; Cl, 5.78. Found: C, 54.80;
H, 4.25; N, 2.30; P, 5.08; S, 10.43; Cl, 5.77%. 1H NMR (CDCl3): 4.28
(d, 2JHH = 7.6 Hz, 1H, HAC(1)–N), 4.21 (d, JHH = 7.6 Hz, 1H, HBC(1)–
2
N), 3.94–4.01 (m, 4H, HC4 and HC5); 7.47–7.67 (m, 15H, Ph); 13C
NMR (CDCl3): 208.6 (CSS–), 42.9 (C1–N), 41.9 (C5–N), 35.0 (C4–
Cl
SH
S
Pd
1
9
6
PR
3
2
3
8
7
N
S
Pd(PR ) Cl / CH Cl
2
3 2
2
2
(i)
S
N
Cl
5
1 hr. reflux
4
S
Pd PR
HS
N
3
Compounds 1, 2, 3
S
S
Pd(PR3)2Cl2 / CH2Cl2
1 hr. reflux
N
1
2
Cl
(ii)
1'
2'
3
S
Pd PR3
H C
3
Compounds 4, 5, 6
HS
H3C
S
S
N
N
Pd(PR3)2Cl2 / CH2Cl2
2
1
Compounds 7, 8, 9
(iii)
1 hr. reflux
1'
2'
N
N
H3C
o
H3C
m
p
i
identification of the (PR3)
phenyl carbon atoms
R3 = Ph3 (1, 4, 7), (o-tolyl)3 (2, 5, 8), ClPh2 (3, 6, 9),
o
m
Scheme 1. General synthetic pathway of the palladium(II) complexes.

F. Shaheen et al. / Journal of Organometallic Chemistry 695 (2010) 315–322
317
N), 142.5 (C2), 140.9 (C3), 132.8 (C6), 128.2 (C7), 129.1(C8), 138.1
(CDCl3): 207.2 (CSS–), 50.6 (C1–N), 29.7 (C2–N), 35.2 (C3–N),
1
2
(C9), 130.5 (iC, 1JCP = 109 Hz), 134.5 (oC, 2JCP = 11.5 Hz), 133.2 (mC,
129.6 (iC, JCP = 121.0 Hz), 132.0 (oC, JCP = 19.5 Hz), 130.5 (mC,
4
4
3JCP = 14.9 Hz), 129.2 (pC, JCP = 4.5 Hz); 31P NMR (CDCl3): 34.1 (s).
3JCP = 19.9 Hz), 128.3 (pC, JCP = 7.5 Hz); 31P NMR (CDCl3): 41.2(s).
3.2.2. [Pd(TIQDTC)(P(o-tolyl)3)Cl] (2)
3.2.7. [Pd(MPizDTC)(PPh3)Cl] (7)
A suspension of [PdCl2(P(o-tolyl)3)2] (1.14 mmol) in 20 cm3 of
CH2Cl2 and a solution of TIQDTC (1.14 mmol) in 15 cm3 CH2Cl2
were reacted according to the above mentioned method. Orange
crystals were obtained after recrystallization from a mixture of
dichloromethane and n-hexane. Data: (60% yield). M.P. 293–
295 °C. Anal. Calc. for C31H32ClNPPdS2: C, 56.80; H, 4.92; N, 2.14;
P, 4.72; S, 9.78; Cl, 5.41. Found: C, 56.79; H, 4.93; N, 2.13; P,
The complex [Pd(MCHDTC)(PPh3)Cl] was synthesized by the
method described above. Data: (85% yield). M.P. 341–343 °C. Anal.
Calc. for C24H26ClN2PPdS2: C, 49.75; H, 4.52; N, 4.83; P, 5.35; S,
11.07; Cl, 6.12. Found: C, 49.74; H, 4.52; N, 4.82; P, 5.33; S,
11.08; Cl, 6.11%. 1H NMR (CDCl3): 3.96–4.10 (m, 8H, H2C
(1,10,2,20)-N), 2.20, s (s, 3H, –CH3), 7.09–7.21 (m, 15H, Ph), 13C
NMR (CDCl3): 209.3 (CSS–), 58.9 (C1–N), 56.9 (C2–N), 32.2 (CH3),
2
1
2
4.72; S, 9.78; Cl, 5.40%. 1H NMR (CDCl3): 4.31 (d, JHH = 7.6 Hz,
125.5 (iC, JCP = 111.0 Hz), 129.3 (oC, JCP = 12.5 Hz), 127.5 (mC,
2
4
1H, HAC(1)–N), 4.27 (d, JHH = 7.6 Hz, 1H, HBC(5)–N), 2.30 (s, 9H,
3JCP = 15.6 Hz), 124.5 (pC, JCP = 5.5 Hz); 31P NMR (CDCl3): 28.8 (s).
–CH3), 7.28–7.48 (m, 12H, Ph); 13C NMR (CDCl3): 206.4 (CSS–),
47.3 (C1–N), 49.3 (C5–N), 38.5 (C4–N), 141.2 (C2), 139.9 (C3),
129.8 (C6), 125.1 (C7), 125.3 (C8), 134.4 (C9), 129.7 (iC,
3.2.8. [Pd(MPizDTC)(P(o-tolyl)3)Cl] (8)
The complex [Pd(MPizDTC)(P(o-tolyl)3)Cl] was synthesized by
adopting the above method. Data: (89% yield). M.P. 323–325 °C.
Anal. Calc. for C27H32ClN2PPdS2: C, 52.18; H, 5.19; N, 4.51; P,
4.98; S, 10.32; Cl, 5.70. Found: C, 52.17; H, 5.15; N, 4.53; P, 4.96;
S, 10.31; Cl, 5.69%. 1H NMR (CDCl3): 3.93–4.09 (m, 8H,
H2C((1,10,2,20)–N), 2.25 (s, 12H, –CH3), 7.08–7.16 (m, 12H, Ph),
13C NMR (CDCl3): 207.2 (CSS–), 63.0 (C1–N), 59.0 (C2–N), 29.8
2
1JCP = 112 Hz), 133.2 (oC, JCP = 10.5 Hz), 131.5 (mC, 3JCP = 12.9 Hz),
4
128.4 (pC, JCP = 5.5 Hz); 31P NMR (CDCl3): 32.3 (s).
3.2.3. [Pd(TIQDTC)(ClPh2P)Cl] (3)
A suspension of [PdCl2(P(Ph)2Cl)2] (1.14 mmol) in 20 cm3 of
methanol was reacted with a solution of TIQDTC (1.14 mmol) in
15 cm3 acetone. By adopting the method mentioned above, a yel-
low crystalline product was obtained at room temperature from
a mixture of CH2Cl2/OEt2 (1:1). Data: (73% yield). M.P. 241–
243 °C. Anal. Calc. for C22H21Cl2PPdNS2: C, 46.21; H, 3.70; N,
2.45; P, 5.42; S, 11.21; Cl, 12.39. Found: C, 46.21; H, 3.68; N,
2.45; P, 5.40; S, 11.20; Cl, 12.40%. 1H NMR (CDCl3): 4.33 (d,
1
2
(CH3), 124.2 (iC, JCP = 114.2 Hz), 129.2 (oC, JCP = 13.5 Hz), 127.3
(mC, JCP = 16.5 Hz), 123.3 (pC, JCP = 6.2 Hz); 31P NMR (CDCl3):
3
4
31.2 (s).
3.2.9. [Pd (MPizDTC)(ClPh2P)Cl] (9)
[Pd(MPizDTC)(PPh2Cl)Cl] was also prepared as described above.
Data: (85% yield). M.P. 265–267 °C. Anal. Calc. for
C18H21Cl2N2PPdS2: C, 40.20; H, 3.94; N, 5.21; P, 5.76; S, 11.92; Cl,
13.18. Found: C, 40.19; H, 3.92; N, 5.23; P, 5.75; S, 11.91; Cl,
2
2JHH = 7.8 Hz, 1H, HAC(1)–N), 4.27 (d, JHH = 7.6 Hz, 1H, HBC(5)–N),
7.52–7.61 (m, 10H, Ph); 13C NMR (CDCl3): 206.5 (CSS–), 59.3
((H2C)2–N); 208.6 (CSS–), 53.9 (C1–N), 59.9 (C5–N), 30.9 (C4–N),
136.2 (C2), 131.9 (C3), 129.8 (C6), 127.1 (C7), 128.3(C8), 130.0
1
13.16%. H NMR (CDCl3): 3.99–4.04 (m, 8H, H2C(1,10,2,20)–N),
1
2
(C9), 129.6 (iC, JCP = 120 Hz), 132.0 (oC, JCP = 16.5 Hz), 130.5
2.23 (s, 3H, –CH3), 7.31–7.39 (m, 10H, Ph), 13C NMR (CDCl3):
206.5 (CSS–), 58.6 (C1–N), 55.6 (C2–N), 31.5 (CH3), 129.5 (iC,
(mC, JCP = 18.5 Hz), 128.3 (pC, JCP = 6.5 Hz); 31P NMR (CDCl3):
3
4
33.7(s).
1JCP = 119.5 Hz),
134.2
(oC,
2JCP = 15.5 Hz),
132.6
(mC,
4
3JCP = 18.5 Hz), 127.5 (pC, JCP = 7.2 Hz); 31P NMR (CDCl3): 29.4 (s).
3.2.4. [Pd(4MpipDTC)(PPh3)Cl] (4)
A complex prepared by above mentioned method. An orange
crystalline product was obtained at room temperature from a mix-
ture of CH2Cl2/n-hexane (3:1). Data: (81% yield). M.P. 238–240 °C
(decomposed). Anal. Calc. for C25H27NClPPdNS2: C, 50.68; H, 4.59;
N, 4.73; P, 5.23; S, 10.82; Cl, 5.98. Found: C, 50.67; H, 4.57; N,
4.72; P, 5.22; S, 10.83; Cl, 5.97%. 1H NMR (CDCl3): 3.93–4.36 (m,
4H, H2C(1,1’)–N); 0.92–2.35 (m, 5H, H2C(2,20,3), 7.52–7.54 (m,
15H, Ph), 13C NMR (CDCl3): 207.8 (CSS–), 49.9 (C1–N), 35.0 (C2–
N), 29.5 (C3–N), 130.6 (iC, 1JCP = 110.5 Hz), 133.4 (oC,
3.3. X-ray structure determination
3.3.1. X-ray structure determination of compound 1
An orange X-ray quality crystal of compound 1 was selected
with a dimension 0.30 ꢁ 0.20 ꢁ 0.05 mm and single crystal diffrac-
tion data was collected on an Oxford Xcalibur CCD area detector
diffractometer, using graphite monochromatic Mo Ka = 0.71069 Å
radiation. Reflection data was collected by using limits ꢀ15 6 h 6
17, ꢀ9 6 k 6 10, ꢀ18 6 l 6 11, out of 7866 reflections 3099 were
3
4
2JCP = 15.5 Hz),135.0 (mC, JCP = 18.7 Hz), 129.3 (pC, JCP = 6.3 Hz);
considered observed with I > 2r(I). Data reduction and absorption
31P NMR (CDCl3): 38.2 (s).
correction were performed using CrysAlisPro 171.29.9 (Oxford
Diffraction). The structure was solved by direct methods using
SIR2004 [24], refined by full-matrix least-squares using SHELX-97
and hydrogen atoms were generated in calculated position using
SHELX-97 [25].
3.2.5. [Pd(4MpipDTC))(P(o-tolyl)3)Cl] (5)
Data: (78% yield). M.P. 293–295 °C. Anal. Calc. for
C28H33ClPPdNS2: C, 54.20; H, 5.36; N, 2.26; P, 4.99; S, 10.33; Cl,
5.71. Found: C, 54.21; H, 5.35; N, 2.25; P, 4.98; S, 10.34; Cl,
1
5.71%. H NMR (CDCl3): 3.97–4.48 (m, 4H, H2C(1,10)–N), 0.98–
3.3.2. X-ray structure determination of compound 2
2.05 (m, 5H, H2C(2,20,3)–), 7.52–7.54 (m, 12H, Ph), 13C NMR
(CDCl3): 207.3 (CSS–), 51.2 (C1–N), 30.1 (C2–N), 34.5 (C3–N),
A
prism shaped orange single crystal of compound 2,
(0.45 ꢁ 0.30 ꢁ 0.30 mm) was mounted on a Philips PW 1000 dif-
fractometer, equipped with graphite monochromator and Mo K
1
2
129.5 (iC, JCP = 114.0 Hz), 134.0 (oC, JCP = 13.5 Hz), 132.5 (mC,
a
3JCP = 17.9 Hz), 127.7 (pC, JCP = 4.9 Hz); 31P NMR (CDCl3): 38.9 (s).
radiation. Unit cell dimensions were obtained by a least-square
refinement of the setting angles of 24 randomly distributed and
carefully centred reflections (6.00 < 2h < 18.00). Empirical absorp-
tion correction was applied using the local program based on
Walker and Stuart [26]. The structure was solved by direct method
by SIR97 [27] and refined by SHELXL-97, Full-matrix least-squares on
F2 method [23]. All the calculations were performed using the
WinGX System, Ver 1.61. [28]: molecular graphics: ORTEP-3 for
4
3.2.6. [Pd(4MpipDTC)(ClPh2P)Cl] (6)
Data: (80% yield). M.P. 281–284 °C (decomposed). Anal. Calc. for
C19H22Cl2PPdNS2: C, 42.51; H, 4.13; N, 2.61; P, 5.77; S, 11.94; Cl,
13.21. Found: C, 42.52; H, 4.12; N, 2.61; P, 5.76; S, 11.93; Cl,
1
13.20%. H NMR (CDCl3): 3.99–4.46 (m, 4H, H2C(1,10)–N), 0.90–
2.25 (m, 5H, H2C(2,20,3)–), 7.31–7.54 (m, 10H, Ph), 13C NMR

318
F. Shaheen et al. / Journal of Organometallic Chemistry 695 (2010) 315–322
Windows [29] The choice of space group P21/n involves a structural
disorder of the phenyl rings, the Pd(phen) moiety being located on
a symmetry mirror, cell refinement, data reduction calculations
were carried out by using local programs; Reflection data collected
by using index limits ꢀ12 6 h 6 12, ꢀ1 6 k 6 28, 0 6 l 6 17, refine-
ment of non-H atoms was done anisotropically.
38 °C), with food and water provided ad libitum. The animals were
divided into eleven groups (1 control, 1 standard and 9 test). Test
samples were suspended in 0.75% sodium carboxymethylcellulose
(CMC) and were given orally to the test animals. The animals of the
control group received the same experimental handling except
that the drug treatment was replaced with appropriate volumes
of the dosing vehicle. Nine groups of three animals each received
one compounds i.e. 25 mg/kg. The standard drug declofenac potas-
sium 10 mg/5 ml was used as reference drug.
4. Biological assays
4.1. Antibacterial assays
4.3.2. Carrageenan-induced hind paw oedema test
The rat paw oedema was induced by subcutaneous injection of
0.1% carrageenan (50 ll) into the sub plantar region of each animal
The antibacterial activity of all the synthesized metal complexes
has been investigated against six strains of bacteria (Escherichia
coli, Bacillus subtilis, Shigella flexenari, Staphylococcus aureus, Samo-
nella typhi, Pseudomonas aeruginosa by the agar well diffusion
method [30,31]. Imipenum 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 containing
approximately 104–106 colony forming unit (CFU) per ml were
spread on the surface of Muller Hinton Agar (MHA) plates. Wells
were created in the medium with the help of a sterile metallic
borer and nutrients agar medium were prepared by suspending
nutrient agar (Merck) (20 g/l) of distilled water (pH 7.0), auto-
claved and cooled down to 45 °C. Then it was seeded with 10 ml
of prepared inocula to have 106 CFU/ml. Petri 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 inhi-
bition of 20 and 22 mm, respectively [32,33]. The results are shown
in Table 5.
left hind paw [35]. The measurement of paw volumes was carried
out by the plythesmographic method [36]. It was done by record-
ing the rat paw volume before the carrageenan injection at 0 h and
then at 1 h intervals for 4 h. Nine groups of three animals were gi-
ven compounds 1–9 (25 mg/kg), each group given one compound.
The standard drug declofenac potassium 10 mg/5 ml was used as a
positive control. The negative control group received 0.75% sodium
CMC, one hour before receiving carrageenan injection. The percent-
age oedema inhibition was calculated for each animal group in
comparison with its control treated group.
4.4. Cytotoxicity of compound 5 against seven human tumour cell lines
The cytotoxicity of compound 5 was tested in vitro by applying
seven well characterized human tumour cell lines [MCF-7 and
EVSA-T (breast cancers), WIDR (colon cancer), IGROV (ovarian can-
cer), M19 MEL (melanoma), A498 (renal cancer), H226 (non-small
cell lung cancer)] and the microculture sulforhodamine B (SRB) test
of which the protocol was described elsewhere [21a].
4.2. Antifungal assay
Cell lines WIDR, M19 MEL, A498, IGROV and H226 belong to the
currently used anticancer screening panel of the National Cancer
Institute, USA.
The agar tube dilution method [34a,34b] was used for the deter-
mination of the antifungal activity of compound with some modi-
fications. The compounds were solubilized in dimethylsulfoxide
and a dilution was performed in Sabouraud dextrose agar (SDA)
(Merck) medium. Media with acidic pH (pH 5.5–5.6) containing
relatively a high concentration of glucose (40%) were prepared by
mixing (SDA) 6.5 g/mL distilled water. The contents were dissolved
and dispensed as 4 mL volumes into screw-capped tubes and auto-
claved at 121 °C for 20 min. Tubes were allowed to cool down to
The cell line EVSA-T is (ER)-/(PgR)- and the MCF-7 cell line is
estrogen receptor (ER)+/ progesterone receptor (PgR)+.
The variability of the in vitro cytotoxicity test depends on i.a. 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 (coef-
ficient of variation) is 1–11% depending on the cell line and the in-
tra-experimental CV is 2–4%. These values may be higher with
other batches of cell lines and/or serum.
50 °C and the non-solidified SDA is loaded with 67
pipette out from the stock solution. This gave the final concentra-
tion of 200 g/mL of the compound in media. Tubes were allowed
lL of compound
l
5. Discussion
to solidify in slanting position at room temperature and prepared
in triplicate for each fungus species. Other media supplemented
with dimethylsulfoxide and reference antifungal drugs were used
as negative and positive control, respectively. Each tube was inoc-
ulated with 4 mm diameter piece of inoculums, removed from a
seven days old culture of fungus. The tubes were incubated at
28 °C for 7 days. Cultures were examined twice weekly during
the incubation. The growth in the media was determined by mea-
suring the linear growth (mm) and the growth inhibition was cal-
culated with reference to the negative control. A growth control of
the test strains and a susceptibility standard test using Terbinafine
5.1. Molecular structure determination
In the asymmetric unit of [Pd(TIQDTC)((PPh3)Cl], compound 1,
the central Pd atom is coordinated with chloride and two mole-
cules dithiocarbamate and triphenylphosphine. The dithiocarba-
mate acts as a bidentate chelate coordinating to Pd via both S
atoms, and is disordered in two positions related to the bond dis-
tances between sulfur and palladium, S1–Pd1 = 2.2865(10), S2–
Pd1 = 2.3462(9), the deviation of the Pd1 atom from the mean
plane through the ligand donor atoms is only 0.060(4) Å. The bond
distances in the S1–C28 = S2 chain indicate the greater delocaliza-
tion of electron, S1–C28 = 1.731(3) Å, C28–S2 = 1.710(4) Å. The
dithiocarbamate fragment S1–C28–S2 is essentially planar, the
maximum deviation being 0.401 Å for N1 and 0.021 Å for the sulfur
atoms. Because of these deviations the molecule exhibits a slightly
distorted square planar geometry shown in Fig. 1. The average tor-
sion angle deviations of the dithiocarbamate fragment and coordi-
nated phosphine with the phenyl group are ꢀ0.07° and ꢀ1.11°,
respectively. This is the result of steric hindrance of bulky
200 lg/ml as the reference system were performed applying the
same technique.
4.3. Anti-inflammatory activity
4.3.1. Test samples
Adult male Sprague–Dawley rats (180–230 g) were used in all
the experiments. The animals were housed under optimum condi-
tions of light and temperature (12 h light and dark cycle and 22–

F. Shaheen et al. / Journal of Organometallic Chemistry 695 (2010) 315–322
319
C21
N
S
S
Cl
Pd
P(o-tolyl)3
C25
Scheme 2. Dithiocarbamate disordered at a local plane of symmetry.
Fig. 1. ORTEP diagram of [Pd(TIQDTC)(PPh3)Cl].
Table 1
Crystal data and structure refinement for compounds 1 and 2.
dithiocarbamate and triphenylphosphine groups, which also effect
on the geometry of the compounds.
Selected bonds orders and angles of compound 1 between
Pd1–P1 = 2.2936(9) Å, Pd1–Cl2 = 2.2936(9) Å, Pd1–S1 = 2.2865(10)
Å, Pd1–S2 = 2.3462(9) Å, N1–C28 = 1.314(4) Å, bonds angle: S1–
Compound 1
Compound 2
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
Unit cell dimensions
a (Å)
C28H25ClNPPdS2
613.44
293(2)
0.71073
Monoclinic
P2(1)/c
C31H31ClNPPdS2
654.51
293(2)
0.71073
Monoclinic
P21/n
Pd1–P1 = 95.37(4)°,
S1–Pd1–Cl2 = 169.72(3)°,
P1–Pd1–Cl2 =
94.72(4)°, S1–Pd1–S2 =75.29(3)°, P1–Pd1–S2 = 170.08(3)°.
15.903
22.233(2)
13.836(2)
90.00
108.07(2)
90.00
2649.4 (8)
4
1.538
9.810(3)
22.336(8)
13.867(5)
90
103.49(2)
90
2954.7(18)
4
1.471
5.2. Molecular structure of compound 2
b (Å)
c (Å)
a
(°)
The molecular structure of [Pd(TIQDTC)((o-tolyl)3P)Cl]
compound 2, is shown in Fig. 2. The geometry around the Pd(II)
centre is a slightly distorted square planar geometry, with the
metal coordinated by the S,S-chelating bidentate dithiocarbamate,
a chloride and a tris(o-tolyl)phosphine. The dithiocarbamate is
disordered in two positions related by a local plane of symmetry
with site occupancy factor of 0.66 and 0.44, respectively, see
Scheme 2.
Selected bond orders and angles of compound 2 between S11–
Pd = 2.3636(11) Å, S21–Pd = 2.2933(11) Å, Pd–P1 = 2.3085(10) Å,
Pd–Cl = 2.3282(11) Å, N15–C25 = 1.491(17), C11–N11 = 1.315(13)
Å, bonds angles: P1–Pd–S21 = 97.46, P1–Pd–S11 = 171.55(3),
S21–Pd–S11 = 74.71, P1–Pd–Cl = 92.43(4), S21–Pd–P1 = 97.46(4),
S21–Pd–Cl = 169.16 (3), S11–Pd–Cl = 95.15 (4) (see Table 1).
b (°)
c
(°)
V (Å3)
Z
Density (calculated) (Mg/m3)
Absorption coefficient (mmꢀ1
F(0 0 0)
)
1.037
1244
0.935
1336
Crystal size (mm3)
0.30 ꢁ 0.20 ꢁ 0.05 0.45 ꢁ 0.30 ꢁ 0.30
Theta range for data collection (°)
Index ranges
0.814–23.26
ꢀ15 6 h 6 17,
ꢀ9 6 k 6 10,
ꢀ18 6 l 6 11,
3099
3.02–27.00
ꢀ12 6 h 6 12,
ꢀ1 6 k 6 28,
0 6 l 6 17
Reflections collected
Independent reflections [R(int)
]
3099 [0.0220]
6998/6433
[0.0319]
Reflections [I > 2 (I)]
r
2568
99.9%
Empirical
1.000 and 0.945
Completeness to theta = 23.26°
Absorption correction
Maximum and minimum
transmission
99.7%
Empirical
1.000 and 0.945
5.3. Infrared study
FT-IR spectroscopy has been used mainly to understand the
geometry of the molecule by hunting out the band that belongs
to the different types of metal–ligand coordinations. The most sig-
nificant bands of all the synthesized complexes are listed in Table 2.
The dithiocarbamate compounds exhibit a characteristic band in
Refinement method
Full-matrix least- Full-matrix least-
squares on F2
3099/0/407
1.029
squares on F2
6433/5/404
1.013
Data/restraints/parameters
Goodness-of-fit (GOF) on F2
Final R indices [I > 2
r
(I)]
R1 = 0.0238,
wR2 = 0.0493
R1 = 0.0353,
wR2 = 0.0539
R1 = 0.0379,
wR2 = 0.0889
R1 = 0.0632,
wR2 = 0.0982
the range (1580–1425) cmꢀ1 assignable to the
m(C–N) [37]. The ab-
R indices (all data)
sence of m(S–H) vibrations, (which were observed in the parent
Largest difference in peak
and hole (e Åꢀ3
0.395 and ꢀ0.252 0.512 and ꢀ1.040
dithiocarbamates in the range of 2734–2664 cmꢀ1) in the synthe-
)
Table 2
Principal FT-IR Spectral data (cmꢀ1) of [(*L) Pd (PR3)Cl] complexes by using KBr
pellets.
Complexes
IR (
(C–N)
m )
, cmꢀ1
m
m
(CSS)sy
m
(Pd–Cl)
m(Pd–S)
Compound 1
Compound 2
Compound 3
Compound 4
Compound 5
Compound 6
Compound 7
Compound 8
Compound 9
1436 s
1475 s
1470 s
1498 s
1483 s
1431 s
1461 s
1467 s
1486 s
1026 m
1034 m
1055 w
1092 m
1075 br
1066 br
1020 w
1037 m
1021 m
303 m
298 m
330 w
311 s
316 m
312 s
299 w
315 m
323 m
358 m
382 m
392 w
372 m
377 m
374 m
379 w
349 m
368 m
s = sharp, m = medium, w = weak, br = broad; R3P = Ph3P, (o-tolyl)3P, ClPh2P.
*L = 1,2,3,4-tetrahydroisoquinolinedithiocarbamate, 4-methylpiperidinedithiocar-
bamate, methylpiperazinedithiocarbamate.
Fig. 2. ORTEP diagram of [Pd(TIQDTC)((o-tolyl)3P)Cl] molecule.

320
F. Shaheen et al. / Journal of Organometallic Chemistry 695 (2010) 315–322
sized complexes indicate that the S–H proton is replaced by a me-
tal ion. The C–N and C–S stretching frequencies can be used to dif-
ferentiate between mono- and bidentate modes of binding of
H2C(1,10)–N methylene protons. For the complexes 7–9, the reso-
nances of the methylene protons N–(CH2)2 near to the thiocarbonyl
will show a slight downfield shift in the range of d = 3.61–4.07 ppm
rather than (CH2)2N methylene proton. The signal of methyl proton
(singlet) CH3–N appears at 2.20–2.25 ppm in the complexes 7–9.
The proton resonances of the phenyl group of the tertiary phos-
phine of all compounds appear as complex patterns in the range
7.05–7.67 ppm.
dithiocarbamate ligands [38]. The position of the m(C–N) absorp-
tion is at 1446–1435 cmꢀ1 in the free ligands and complexes. In
the complexes showing an S–S chelate to metal coordination, the
m
(C–N) stretching frequencies are shifted to higher frequency
by about ꢂ40 cmꢀ1 on coordination with palladium. The
m(C–N)
stretching vibration appears in the region 1475–1486 cmꢀ1 for
both ligands and its complexes, which indicates the non-involve-
ment of C–N bond in the formation of the metal complexes due
to hindrance of sulfur atoms and owing to the increased double
bond character in the CS group, caused by electron delocalization
towards the metal centre [39,40]. In the case of a single coordina-
tion with the thiocarbonyl sulfur, the shift is approximately 10–
20 cmꢀ1 [41]. This suggests that the C–N bonds in the complexes
have some partial double bond character. Partial double bond char-
acter for the C–N bond would result in some partial double bond
character for the C–S bonds [41,42]. Further evidence of dithiocar-
bamate-metal coordination can be deduced from the presence of
only one band in the region 1053–900 cmꢀ1 that is assumed to
indicate a completely symmetrically bonding of the dithiocarba-
mate ligand, acting in a bidentate fashion, while a split band is
indicative of an unsymmetrically bound bidentate ligand [39,43].
This single band observed in the 1053–900 cmꢀ1 region which is
characteristic of CS2 group vibrations due to sulfur chelation attrib-
uted the band of tasym CSS and tsym CSS at 1023 cmꢀ1 and
973 cmꢀ1 [44]. A characteristic band of the PPh3 ligand was ob-
served around 1448 cmꢀ1 and assigned to the symmetric and
asymmetric stretching and bending of P–Ph bonds [45].
The 13C{1H} NMR spectra of all the complexes were recorded for
CDCl3 solutions. The resonance of the –CSS carbon was observed
around 206.4–209.3 ppm, the number of signals found corresponds
with the presence of magnetically non-equivalent carbon atoms,
that were assigned by comparison with literature values [51].
The resonance of the C@S carbon at d(189.6–195.3 ppm) in the free
dithiocarbamic acids. The significant downfield shift in the thiocar-
bonyl carbon can be due to a strong deshielding effect after com-
plexation. Moreover, a significant downfield shift was observed
for the C–N carbons. The downfield shift is consistent with an in-
crease in the double bond character of the C–N bond. The other res-
onances were only slightly shifted.
The 31P NMR spectra of the complexes 1–9 were run in CDCl3
solutions at ambient temperature and are referenced to external
standard 85% phosphoric acid with downfield shifts defined as po-
sitive. According to the 31P NMR spectra, the tertiary phosphines
are symmetrically bounded to the central palladium atom and ex-
hibit a low-field resonance due to the trans-influence of S-bonded
to dithiocarbamate ligand and interaction with palladium(II), while
a high-field resonance is generally observed for the free phospho-
In the complexes reported in this paper, the presence of only
Table 3
one band in the region of 1053–940 cmꢀ1, the
m(CSS) mode, sug-
Antifungal activity of palladium(II) complexes. Terbinafine, used as control, inhibited
all fungi at 200
gests a symmetrical behaviour of the bidentate dithiocarbamate
lg/ml.
moiety. According to the literature [42,46,47], for complexes, the
Compounds
Growth effect% inhibition (fungi)
Dm values m(CSS)asym–m
(CSS)sym are 125–139 cmꢀ1, indicating that
F. moniliformes F. solani Mucor sp. A. niger A. fumigatus
the sulfur atoms of the dithiocarbamate group are linked to the
central metal atom in a bidentate fashion. A new Pd–S band ap-
peared in the region of 400–300 cmꢀ1 after complexation [48].
Compound 1
Compound 2
Compound 3
Compound 4
Compound 5
Compound 6
Compound 7
Compound 8
Compound 9
Linear length
69
77
66
30
31
27
63
78
59
45
48
29
33
78
69
62
45
50
59
25
20
19
9
41
39
49
11
23
20
100
53
40
59
10
09
05
68
42
61
90
33
45
39
43
59
43
54
52
49
39
5.4. 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 ob-
served, which indicates that the ligands are coordinated to palla-
dium through sulfur atoms [49]. The mode of coordination has
also been confirmed by single crystal X-ray diffraction. In the 1H
NMR spectra of the synthesized [Pd(TIQDTC)(R3P)Cl] complexes
1–3 recorded in CDCl3, the broad signal of the methylene protons
of (CH2)2N at C4/C5 moiety appeared at 3.94–4.01 ppm exhibit
downfield shifts. These signals for the N–CH2 methylene protons
of (CH2)2N originated from the different position (syn or anti) with
respect to the thiocarbonyl group in the square planar molecule,
the separation being larger than in the free dithiocarbamic acids
due to coordination and barrier of rotation about the C–N bond
[50], which makes the nitrogen substituents magnetically non-
in ꢀve control
ꢀve Control group with 0.75% CMC (carboxymethylcellulose) sodium.
Table 4
Anti-inflammatory activity of palladium(II) compounds of [PdII(*L)(R3P)Cl] on carra-
geenan induced rat paw oedema.
Sample name
% Oedema inhibition at time (h)
First hour
Second hour Third hour
Fourth hour
Standard drug
Compound 1
Compound 2
Compound 3
Compound 4
Compound 5
Compound 6
Compound 7
Compound 8
Compound 9
2.32 4.52
28.71 2.34
18.45 3.78
29.84 3.51
18.51 2.51
15.84 2.23
27.73 3.23
25.51 1.51
23.84 3.23
25.73 4.23
3.49 4.32
35.91 4.06
38.15 3.65
46.28 6.13
49.7 6.23
25.99 6.32
55.38 4.32
39.7 6.13
35.99 5.32
45.38 5.32
68.70 3.05
55.19 20.78
72.65 2.99
79.57 2.84
65.33 2.12
58.66 1.72
89.47 1.52
55.33 3.12
78.66 2.72
79.47 2.52
74.14 2.72
70.41 6.35
88.68 1.08
93.87 2.35
87.46 3.53
97.46 2.25
92.48 1.25
89.46 3.53
95.46 2.25
94.48 2.25
equivalent [50]. The N–CH2 protons at C1 are non-equivalent and
2
appear as two doublets at 4.28 (
D
d = 0.03 ppm, JHH = 7.6 Hz) and
2
at 4.21 ppm (Dd = 0.03 ppm, JHH = 7.6 Hz). A similar behaviour
for N–CH2 is observed in the complexes 2 and 3. One signal is pres-
ent in the spectrum of complex 2 for the methyl proton of (o-to-
lyl)P at 1.97 ppm. The proton resonances of the phenyl group of
the tertiary phosphines of all compounds appear as complex pat-
terns in the range d = 7.28–7.67 ppm. In the complexes 4–6, the
methylene protons (H, 2, 20, 3) belonging to the –CH2/CH moiety
exhibit downfield shifts in the range of d = 0.92–2.35 ppm and
two signals appeared around d = 3.93–4.36 ppm for the
Values
are
mean SEM;
n = 3
in
each
group.
*L = 1,2,3,4-tetra-
hydroisoquinolinedithiocarbamate, methylpiperazinedithiocarbamate; R3P = Ph3P,
(o-tolyl)3P, ClPh2P.

F. Shaheen et al. / Journal of Organometallic Chemistry 695 (2010) 315–322
321
Table 5
Antibacterial activity of the [PdII(L)(R3P)Cl]complexes: zones of inhibition (in%).
Name of
bacteria
% Zone of inhibition of samples (mm)
% Zone of
inhibition
of std drug (mm)
Compound 1 Compound 2 Compound 3 Compound 4 Compound 5 Compound 6 Compound 7 Compound 8 Compound 9
Escherichia coli 30
Bacillus subtilis 19
25
20
11
26
18
07
30
10
14
31
14
09
27
21
14
29
19
15
28
14
05
24
22
13
33
30
35
Shigella
flexenari
S. aureusa
09
24
27
21
18
23
18
29
10
17
09
18
09
09
10
16
13
29
39
26
28
20
22
20
33
31
43
25
40
Samonella typhi 23
P. aeruginosab
30
Concentration of the standard drug (‘‘Imipenum”) = 10
lg/disc. Concentration of sample = 3 mg/mL, (–) no activity.
a
S = Staphylococcus.
b
P = Pseudomonas.
rus ligand [52]. The 31P NMR spectra of all complexes displayed a
Table 6
Inhibition doses ID50 in vitro cytotoxicities of compound 5 and of six reference
compounds doxorubicin (DOX), cisplatin (CPT), 5-fluorouracil (5-FU), methotrexate
(MTX), etoposide (ETO) and taxol (TAX) using SRB as cell viability test. The
concentrations were 83 ꢁ 103, 27 ꢁ 103, 9 ꢁ 103, 3 ꢁ 103, 1 ꢁ 103, 330, 100, 33, 10,
3 ng/ml.
singlet at d 29.4–31.8 ppm.
5.5. Biological assays
5.5.1. Antifungal activity
Cpd.
A498
EVSA-T
H226
IGROV
M19MEL MCF-7
WIDR
The results of antifungal assay given in Table 3 show that the
compounds 1–9 possess antifungal activity against the following
five fungi Fusarium moniliformes, Fusarium saolani, Mucor sp., Asper-
5
22,074 7474
22,089
199
3269
340
2287
3934
<3
8371
60
169
297
7
10,628
16
558
442
23
11,782
10
699
750
18
14,245
11
967
225
<3
DOX
CPT
5FU
MTX
ETO
TAX
90
8
2253
143
37
422
475
5
gillus niger, Aspergillus fumigatus. At the concentration of 200 lg/ml
compounds 1–9 inhibited the growth of F. moniliformes from 78%
to 60%, respectively. The compounds show minimum activity
against the Mucor sp. i.e. 09–23%. The inhibition growth of all com-
pounds against F. moniliformes is maximum, while, against Mucor
sp., the activity of all compounds is not significant; the compounds
showed a moderate activity against A. niger, A. fumigatus. The rank-
order of growth effect of % inhibition of fungi is F. moniliformes > F.
saolani > A. fumigatus ꢃ A. niger > Mucor sp. which clearly indicates
that palladium(II) complexes are significantly active against these
fungi.
1314
<3
317
<3
580
<3
505
<3
2594
<3
150
<3
um”. The metal complexes 1–3 containing TIQDTC, 4–6
containing 4MpipDTC and 7–9 containing MPizDTC with tertiary
phosphines exhibit a low activity against ‘‘S. flexenari” and a signif-
icant activity against ‘‘E. coli”. The complexes 1–9 exhibit a moder-
ate activity against B. subtilis, S. aureus, S. typhi, P. aeruginosa
bacteria.
5.5.2. Anti-inflammatory activity
The in vitro pharmacological assessment of compounds 1–9 (see
table 4) exhibit a significant inhibition of cyclooxygenase (COX-1
and COX-2) enzyme relative to other NSAIDs, the injection of car-
rageenan induces the liberation of bradykinin, which later induces
the biosynthesis of prostaglandin and other autacoids, which are
responsible for the formation of the inflammatory exudates [53].
The constitutive isoform of COX, COX-1 has clear physciological
functions and inducible isoform COX-2 was discovered few years
ago, and induced in a number of cells by pro-inflammatory stimuli.
The carrageenan-induced oedema tests involving both COX-1 and
COX-2 activities [54], it is not as clear whether the complexes of
palladium(II) with dithiocarbamate/tertiary phosphine acts by
inhibiting COX-1 alone or by inhibiting both COX-1 and COX-2.
Therefore, it is suggested that the mechanism of action of
synthesized compounds may be related to the anti-inflammatory
mechanism of declofenac potassium in the inhibition of the inflam-
matory process by carrageenan [55].
5.5.4. Cytotoxicity of compound 5 against seven human tumour cell
lines
The cytotoxicity of compound 5 was tested in vitro by applying
seven well characterized human tumour cell lines (MCF-7, EVSA-T,
WIDR, IGROV, M19 MEL, A498, H226). Table 6 shows the experi-
mental results.
Compound 5 showed mostly moderate to low cytotoxicity
against the seven human tumour cell lines (ID50 2500–20,000 ng/
ml).
6. Conclusions
The spectroscopic (IR, NMR) and single crystal X-ray diffraction
techniques suggest that the coordination in all the [Pd(L)(R3P)Cl]
complexes is square planar through the sulfur donating atoms,
the NCSS group coordinating the metal centre acting as a bidentate
symmetrical mode. This study provides useful information about
the bonding nature and potential of Pd(II) complexes as cross-link-
ing agents. These synthesized Pd(II) complexes form adducts with
DNA bases (guanine or adenine) at N-7 and N-4 positions, respec-
tively. The in vitro bioassays of the synthesized complexes have
been studied by testing them in various strains of bacteria and fun-
gi. Against bacteria, the complexes exhibit a low inhibitory effect
as compared to their antifungal and anti-inflammatory effect. It
is important to observe that this antibacterial effect is not accom-
panied by cytotoxicity. This indicates a certain degree of specificity
of the compounds studied.
5.5.3. Antibacterial activity
Metal dithiocarbamates are capable of inhibiting bacterial
growth and activity by interfering with the metabolic processes
in the bacteria. In the present work, we have synthesized Pd(II)
complexes with mixed ligands dithiocarbamate/organophosphine.
The antibacterial activity of the Pd(II) complexes have been deter-
mined against six strains of bacteria:E. coli, B. subtilis, S. flexenari, S.
aureus, S. typhi, P. aeruginosa.
The results are given in Table 5. Significant antibacterial activi-
ties were observed when compared to a standard drug ‘‘Imipen-

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Acknowledgements
The authors are thankful to Higher Education Commission,
Islamabad, Pakistan for financial support through Project No. 20-
623/R& D/06/258 and Prof. Viterbo for crystallographic support.
Ms P.F. van Cuijk in the Laboratory of Translational Pharmacology,
Department of Medical Oncology, Erasmus Medical Center, Rotter-
dam, the Netherlands, carried out the in vitro cytotoxicity experi-
ments, under the supervision of Dr. E.A.C. Wiemer and Prof. Dr.
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