Triphenyl phosphine adducts of platinum(IV) and palladium(II) dithiocarbamates complexes: A spectral and in vitro study

Article abstract of DOI:10.1016/j.saa.2004.01.031

Triphenyl phosphine adducts of dithiocarbamate complexes of platinum(IV) and palladium(II) of the type [Pt(L)₂PPh₃Cl₂] and [Pd(L)₂PPh₃] [L: morpholine dithiocarbamate (L ¹), aniline dithioc

Full text of DOI:10.1016/j.saa.2004.01.031

Spectrochimica Acta Part A 60 (2004) 3087–3092
Triphenyl phosphine adducts of platinum(IV) and palladium(II)
dithiocarbamates complexes: a spectral and in vitro study
N. Manav, A.K. Mishra, N.K. Kaushik∗
Department of Chemistry, University of Delhi, Delhi 110007, India
Received 15 December 2003; accepted 27 January 2004
Abstract
Triphenyl phosphine adducts of dithiocarbamate complexes of platinum(IV) and palladium(II) of the type [Pt(L)2PPh3Cl2] and [Pd(L)2PPh3]
[L: morpholine dithiocarbamate (L1), aniline dithiocarbamate (L2) and N-(methyl, cyclohexyl) dithiocarbamate (L3)] were prepared and
characterized by elemental analysis, electronic, IR, 1H NMR and 13C NMR spectral studies. Thermal studies of the complexes were carried
out. In vitro antitumor activity has been screened towards human adenocarcinoma cell lines and showed significant inhibition even at very
low concentration.
© 2004 Elsevier B.V. All rights reserved.
Keywords: Dithiocarbamate complexes; Spectral, thermal and in vitro study; Triphenyl phosphine
−
[M = Pd or Pt; (S–S)− = R2NCS2−, ROCS2−, (RO)2PS2
1. Introduction
and R2PS2−] easily form adducts with various tertiary phos-
Platinum(IV) and palladium(II) complexes with tertiary
phines [12–16].
phosphines have been poorly characterized [1–3]. The re-
−
action of all M(S–S) compounds (M = Pt, Pd; (S–S)−
=
S2CNR2 (R = Me, Et), −S2COR (R = Et · PhCH2),
−S2P(OEt)2 and −S2PR2 (R = Me, Et, Ph)] with tertiary
phosphines occurs by stepwise cleavage of metal–sulphur
bonds to generate four-coordinate compounds of for-
2. Experimental
2.1. Dithiocarbamates L (L: L1, L2, L3 and L4)
The dithiocarbamates were prepared by the method de-
scribed by Gilman and Blatt [17] with some modifications.
0.4 mol of corresponding amine was dissolved in
methanol and chilled. To this a chilled solution of 2.24 g
(0.04 mol) potassium hydroxide in aqueous methanol was
mixed with constant stirring. The mixed solution was
treated with an ice cold solution of 2.5 cm3 (0.04 mol) car-
bon disulphide (density 1.27) in 4 cm3 methanol keeping
the temperature of the reaction mixture below 10 ◦C. Dur-
ing the process, desired crystalline precipitates separated.
It was filtered and washed with ice cold aqueous methanol
and recrystallized.
ꢀ
ꢀ
mulae [M(S–S)2PR3 ] and [M(S–S)(PR3 )2] (S–S) with
unidentate/bidentate and ionic/bidentate coordination re-
spectively [4–7]. All the ionic compounds readily revert to
ꢀ
the [M(S–S)2PR3 ] complexes in the presence of non-polar
solvents via nucleophilic attack by (S–S)− on the metal.
The investigation of platinum and palladium complexes
is important for the treatment of human cancer [8–10]. Even
at very low concentration these have been found to be active
as revealed by in vitro studies. The general consensus is that
they derived their activity through different adducts that they
formed with DNA [11].
The synthesis of triphenyl phosphine adducts was planned
after considering that square planar [M(S–S)2] complexes
2.2. Mixed ligand complexes
2.2.1. [Pt(L)2(PPh3)Cl2], [Pd(L)2 (PPh3)]
(where L = L1, L2 and L3)
∗
Corresponding author. Tel.: +91-11-27667725x1391;
fax: +91-11-7256605.
The complexes were prepared by taking [Pt(L)2Cl2] and
[Pd(L)2] as starting materials. [Pt(L)2Cl2] and [Pd(L)2] was
E-mail addresses: navneet92@rediffmail.com (N. Manav),
ajaykmishra1@yahoo.com (A.K. Mishra).
1386-1425/$ – see front matter © 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.saa.2004.01.031

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N. Manav et al. / Spectrochimica Acta Part A 60 (2004) 3087–3092
prepared by adding aqueous solution of the corresponding
metal chloride (K2PtCl6 or PdCl2) to the aqueous solution
of desired dithiocarbamate L (where L = L1, L2 and L3) in
1:2 ratio.
and subsequent serial dilutions were made in RPMI 1640
medium. The cells were treated with various concentrations
of the compounds (10 ␮M–10 pM) and allowed to incubate
at 37 ◦C in a CO2 incubator. A second dose of the com-
pounds was added to the cells after 24 h and, thereafter, the
cells were incubated for a further 24 h. Appropriate controls
for assessing cytotoxicity due to DMSO were included in
the assay.
Cytotoxicity was assessed using 3-[4,5-dimethylthiazol-
2-yl]-2,5-diphenyltetrazolium bromide (MTT). Briefly,
MTT dissolved in 50 cm3 phosphate buffered saline (PBS)
(pH 7.4) was added to the cells at a final concentration of
0.5 mg cm−3. The cells were incubated at 37 ◦C for 3 h.
Thereafter, the medium was aspirated and the cells were an-
alyzed with 150 ␮l DMSO added to each well. Absorbance
was measured at 570 nm and percentage cytotoxicity was
calculated:
A suspension of corresponding dithiocarbamate complex
X (X = [Pt(L1)2Cl2] (0.167 g, 0.25 mmol), [Pt(L2)2Cl2]
(0.170 g, 0.25 mmol), [Pt(L3)2Cl2] (0.127 g, 0.25 mmol),
[Pd(L1)2] (0.095 g, 0.25 mmol), [Pd(L2)2] (0.096 g,
0.25 mmol), [Pd(L3)2] (0.097 g, 0.25 mmol)), in CS2 was
treated with triphenyl phosphine (0.065 g, 0.25 mmol) dis-
solved in toluene, the mixture was left under continuous
magnetic stirring for 1 h. The resulting yellow coloured so-
lution was filtered and after few hours yellow precipitate was
formed and the precipitation was completed by addition of
light petroleum ether. The yellow precipitates were filtered
off, washed with diethyl ether and dried under vacuum.
2.3. Physical measurements
optical density in sample well
cytotoxicity (%) = 1−
× 100
optical density in control well
All the reagents used were of AR grade. IR and far IR
spectra were recorded on a Perkin-Elmer Spectrum 2000
FTIR spectrometer. Electronic spectra were recorded on
Beckman DU-64 UV-Vis spectrophotometer. Conductance
measurements were carried out on a Elico conductivity
Bridge Model CM-102, India. 1H NMR and 13C NMR were
recorded on Bruker a spectrospin advance 300 spectrome-
ter and BAS-CV 50 W voltammetric analyser was used to
record the voltammograms of complexes. TG/DTA curves
were simultaneously recorded on a Perkin-Elmer, Model
TGA-7, USA in static air, DTA. curves were recorded on a
Rigaku, model 8150 thermoanalyser in static air at a heating
3. Results and discussion
Satisfactory results of elemental analysis (Table 1) and
spectral studies reveal that the complexes are of good purity.
The complexes obtained are microcrystalline or powder like
and yellow to brown in color. Conductance measurements
for these complexes are <10 ꢀ−1 mol−1 cm2 indicating that
these compounds are non electrolytes. These complexes are
soluble in DMSO and insoluble in most of the organic sol-
vents, so all the attempts to recrystallize platinum(IV) and
palladium(II) complexes were unsuccessful.
rate of 10 ◦C min−1
.
2.4. Antitumor screening
3.1. Electronic spectra
In vitro growth inhibitory assay; human color adenocar-
cinoma cell line was cultured in RPMI 1640 medium sup-
plemented with 10% fetal calf serum (FCS), 100 ␮g cm−3
streptomycin. 100 ␮g cm−3 penicillin and 50 ␮g cm−3 gen-
tamycine. For the assay, 10,000 cells were plated per well
of a 96-well tissue culture plate and allowed to adhere
overnight at 37 ◦C in a 5% CO2 incubator. The following
day, the medium was changed to RPMI 1640 containing 5%
FCS. The compounds to be tested were dissolved in DMSO
In the present studies, all the complexes are found to
be diamagnetic. The platinum(IV) complexes are octa-
hedral and palladium(II) complexes are square planar in
structure. The geometries are supported by their electronic
spectra. Ground state of platinum(IV) which belong to d6
1
system is A1g. Four bands can be expected correspond-
1
3
1
3
ing to A1g → T1g (23,900–24,200 cm−1), A1g → T2g
(17,200–18,250 cm−1) 1A1g → T1g (38,300–28,000 cm−1
)
1
Table 1
Elemental analysis of mixed ligand complexes
Complexes
Found (calculated) (%)
C
H
N
S
Cl
Metal
[Pt(L1)2(PPh3)Cl2]
[Pd(L1)2(PPh3)]
[Pt(L2)2(PPh3)Cl2]
[Pd(L2)2(PPh3)]
[Pt(L3)2(PPh3)Cl2]
[Pd(L3)2(PPh3)]
40.3 (39.4)
40.0 (40.5)
43.8 (44.4)
55.0 (54.5)
45.0 (45.1)
55.2 (54.8)
3.9 (3.6)
4.4 (4.5)
3.7 (3.1)
4.0 (3.8)
4.1 (4.8)
6.2 (5.8)
4.1 (3.3)
3.9 (4.0)
4.0 (3.2)
3.2 (3.4)
3.9 (3.1)
3.1 (3.8)
15.1 (15.0)
18.3 (18.5)
14.0 (14.8)
19.0 (18.2)
14.8 (14.1)
17.3 (17.2)
8.0 (8.3)
–
8.6 (8.2)
–
8.3 (7.8)
–
22.9 (23.0)
15.3 (15.3)
23.2 (22.7)
15.3 (15.0)
21.1 (21.7)
14.3 (14.3)

N. Manav et al. / Spectrochimica Acta Part A 60 (2004) 3087–3092
3089
Table 2
Table 3
Electronic spectral data of mixed ligand complexes of Pt(IV) and Pd(II)
IR absorption frequencies (cm−1) of mixed ligand complexes of Pt(IV)
and Pd(II)
λmax (nm)
log(ε)
ν(C
ν(C
ν(M–S)
ν(M–Cl)
=
=
S)
N)
[Pt(L1)2(PPh3)Cl2]
[Pd(L1)2(PPh3)]
[Pt(L2)2(PPh3)Cl2]
[Pd(L2)2(PPh3)]
[Pt(L3)2(PPh3)Cl2]
[Pd(L3)2(PPh3)]
275
350
4.0
3.5
[Pt(L1)2(PPh3)Cl2]
[Pd(L1)2PPh3]
[Pt(L2)2(PPh3)Cl2]
[Pd(L2)2(PPh3)]
[Pt(L3)2(PPh3)Cl2]
[Pd(L3)2(PPh3)]
1510, 1490
1505, 1496
1512, 1492
1509, 1497
1520, 1498
1515, 1500
1008, 998
1003, 978
1012, 990
1000, 978
998, 975
400
390
398
392
399
389
295
–
291
–
301
–
270
380
3.9
3.2
295
340
3.9
3.6
1005, 982
285
355
3.6
3.1
Table 4
Percentage cytotoxicity (w.r.t. control) of the complexes
280
353
4.0
3.9
Concentration
[Pt(L1)2(PPh3)Cl2]
[Pt(L2)2 PPh3Cl2]
276
360
3.8
3.6
100 nM
10 nM
1 nM
100 pM
10 pM
1 pM
74.30
89.29
87.50
66.62
45.60
38.40
67.30
28.80
+6.40
+34.20
+35.00
+33.10
1
1
and A1g
→
T2g (27,500–25000 cm−1) transitions [17].
Symbol ‘+’ denotes proliferation.
Palladium(II) is d8 system and three spin allowed singlet–
singlet d–d transitions are predicted [18–20]. The ground
1
1
state is A1g and three predicted transitions are A1g
→
3.3. 1H and 13C NMR spectra
1A2g (16,800–12000 cm−1), A1g → B1g (17,500–23,100
1
cm−1) and A1g
→
Eg (21,000–26,500 cm−1). These
1
1
The 1H NMR spectra of complexes were recorded in
d6-DMSO taking TMS as internal standard.
transitions are from the lower lying d orbitals to the
empty dx2−y2 orbital. Strong charge transfer transitions
may interfere and prevent the observation of all the ex-
pected bands [18,21–24]. Strong bands between 26,000 and
28,000 cm−1 are assignable to a combination of M → LCT
(metal–ligand charge transfer) and d–d bands. The very
intense band at ca. 450 nm is assignable to combination of
sulphur → metal charge transfer (L␲ → MCT) and d–d
bands.
δ (ppm): 7.3−7.8 (m, 15H, –C6H5), 3.87 (m, 16H, –CH2).
δ (ppm): 7.3−7.7 (m, 15H, –C6H5), 3.82 (m, 8H, –CH2)
δ (ppm): 9.1 (s, br, 2H, –NH), 7.3−7.8 (m, 25H, –C6H5).
δ (ppm): 9.0 (s, br, 2H, –NH), 7.3−7.87 (m, 25H, –C6H5).
δ (ppm): 7.2–7.76 (m, 15H, –C6H5), 2.15 (s, 6H, –CH3),
1.10–1.92 (m, 22H, –C6H11).
δ (ppm): 7.3–7.78 (m, 15H, –C6H5), 2.12 (s, 6H, –CH3),
1.12–1.87 (m, 22H, –C6H11).
In electronic spectra of mixed ligand complexes, two
∗
bands are observed. Band I is due to ␲ → ␲ transition
and band II is due to metal → ligand charge transfer. Elec-
tronic spectral data of mixed ligand complexes is presented
in Table 2.
3.2. IR spectra
In the IR spectra of the complexes, the doublets in
the region 1000 cm−1 separated by ca. 20 cm−1 was ob-
served, as reported by Bonati and coworkers [25–27] it
indicates that one dithiocarbamate ligand is bidentate and
another is monodentate. Whereas in (Pt(L2)Cl2] and [PdL2]
complexes one singlet was observed ca. 1000 cm−1 indi-
cating that both dithiocarbamate ligands are bidentately
bound.
In far IR spectra contains the M–S stretching frequencies
[28] in the region 390–320 cm−1. The band at ∼390 cm−1
is assigned to ␯(Pt–Cl) vibrations. The IR and far IR bands of
mixed ligand complexes of platinum(IV) and palladium(II)
has been presented in Table 3.
Fig. 1. TG and DTG curves of [Pt(L1)2(PPh3)Cl3] complex.

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N. Manav et al. / Spectrochimica Acta Part A 60 (2004) 3087–3092
On the basis of these spectroscopic studies, the probable
structure of the complexes is:
Cl
N
S
Cl
Cl
N
S
N
S
Pt
Pd
Cl
3.4. Antitumor screening
Some complexes were tested for the in vitro antitumor
activity. The complexes were tested on primary adenocar-
cinoma (color). Appropriate controls for DMSO (solvent)
were included in the final values. The complexes showed
good activity at 100 and 10 nM solutions. But proliferation
started in complexes on further dilution. In [Pt(L1)PPh3Cl2]
Fig. 4. TG and DTG curves of [Pd(L3)2(PPh3)Cl3] complex.
Fig. 2. TG and DTG curves of [Pt(L3)2(PPh3)Cl3].
Fig. 5. DTA curves of [Pt(L1)2(PPh3)Cl3].
Fig. 3. TG and DTG curves of [Pd(L1)2(PPh3)Cl3] complex.
Fig. 6. DTA curves of [Pd(L1)2(PPh3)].

N. Manav et al. / Spectrochimica Acta Part A 60 (2004) 3087–3092
3091
Table 5
Thermal data (TG and DTG) for mixed ligand complexes
Complex
Step no. TG
Temperature range (K)
DTG
DTA
Thermal effect Tmax ꢁH (kJ g−1
)
n
Ea (kJ mol−1
)
Sꢁ= (J K−1 mol−1
)
Peak (K)
[Pt(L1)2(PPh3)Cl2]
I
II
III
354–678
678–813
813–1083
1
1
1
91.1
42.3
41.1
36.2
14.3
13.6
618
770
1070
Exotherm
621
55.0
[Pd(L1)2(PPh3)]
[Pt(L3)2(PPh3)Cl2]
[Pd(L3)2(PPh3)]
I
II
III
396–644
644–734
734–918
1
1
1
86.5
42.1
41.0
34.2
14.3
13.7
593
690
868
Exotherm
663
115.0
I
II
III
340–651
653–960
970–1070
1
1
1
134.6
15.2
70.1
55.4
2.3
26.2
603
750
1008
I
II
413–686
686–899
1
1
153.8
44.9
63.8
15.4
570, 650
813
complex, the activity found was significant enough at 1 pm
concentration. Antitumor activity of the complexes is given
in Table 4.
of metal sulphide and after the third and final step the weight
left corresponds to the metals as residue.
Ea values and S# values are found to be higher for first step
of decomposition than subsequent steps in all the complexes.
The complexes were further tested for any adverse effect
on the various organs like liver, kidneys, brain and blad-
der of rabbits. The study was carried out by taking the
rabbits weighing about 2–2.5 kg. Two sets of procedures
were planned, one control and the other experimental. In
the control rabbit 99mTc-labelled GHA was injected intra-
venously through the dorsal ear vein-whereas in the experi-
mental rabbit platinum complex was injected (iv) followed
by 99mTc-GHA injection (iv). Two hours after the first in-
jection imaging was performed starting from 5 min to 4 h
under the effect of selective using a planar gamma camera
fitted with a paralleled collimater. In both the rabbits brain,
kidneys and bladder were the organs which accumulated the
activity. Liver was visualized in the very initial images but
activity was cleared quickly from it. Administration of plat-
inum complex did not change the pattern of localization of
activity. It was concluded that the complex had no effect on
the bioroutine of 99mTc-GHA, it did not reflect any addi-
tional information depicting its presence in the system.
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