Synthesis and characterisation of mixed-ligand platinum(II)-sulfoxide complexes, [PtCl(DMSO)(L)], for potential use as chemotherapeutic agents (HL = N,N-dialkyl-N'-(3-R-benzoyl)thiourea)

Article abstract of DOI:10.1016/S0277-5387(00)00419-8

A novel series of mixed-ligand platinum(II) complexes of the type [PtCl(DMSO)(L)], where HL = N,N-diethyl-N'-(3-R-benzoyl)thiourea, N,N-di(2-hydroxyethyl)-N'-(3-R-benzoyl)thiourea or N-morpholino-N'-(3-R-benzoyl)thiourea (R = H, Cl, NO₂, CH₃O, CH₃), have been synthesised and characterised by elemental analysis, IR spectroscopy and ¹H and ¹⁹⁵Pt NMR spectroscopy. The spectroscopic data are consistent with the complexes containing an O, S chelated ligand and an S-bonded sulfoxide ligand which is in a cis arrangement to that of the sulfur donor atom of the chelated ligand. Trends in the NMR spectra can be correlated with the electronic effects of the substituents on the phenyl ring of the acylthiourea ligands. (C) 2000 Elsevier Science S.A.

Full text of DOI:10.1016/S0277-5387(00)00419-8

www.elsevier.nl/locate/poly
Polyhedron 19 (2000) 1347–1354
Synthesis and characterisation of mixed-ligand
platinum(II)–sulfoxide complexes, [PtCl(DMSO)(L)], for potential
use as chemotherapeutic agents
(HL=N,N-dialkyl-N%-(3-R-benzoyl)thiourea)
C. Sacht *, M.S. Datt
Department of Chemistry, Rhodes Uni6ersity, PO Box 94, Grahamstown 6140, South Africa
Received 7 February 2000; accepted 26 April 2000
Abstract
A novel series of mixed-ligand platinum(II) complexes of the type [PtCl(DMSO)(L)], where HL=N,N-diethyl-N%-(3-R-ben-
zoyl)thiourea, N,N-di(2-hydroxyethyl)-N%-(3-R-benzoyl)thiourea or N-morpholino-N%-(3-R-benzoyl)thiourea (R=H, Cl, NO2,
CH3O, CH3), have been synthesised and characterised by elemental analysis, IR spectroscopy and 1H and 195Pt NMR
spectroscopy. The spectroscopic data are consistent with the complexes containing an O, S chelated ligand and an S-bonded
sulfoxide ligand which is in a cis arrangement to that of the sulfur donor atom of the chelated ligand. Trends in the NMR spectra
can be correlated with the electronic effects of the substituents on the phenyl ring of the acylthiourea ligands. © 2000 Elsevier
Science S.A. All rights reserved.
Keywords: Platinum(II); Sulfoxide; N,N-Dialkyl-N%-(3-R-benzoyl)thiourea; Acylthiourea; NMR; Chemotherapeutic agents
1. Introduction
in the literature have revealed that the latter approach
has yielded some exciting and successful results and two
of these complexes are currently undergoing Phase I
clinical trials, such as ZD0473 (cis-amminedichloro(2-
methylpyridine)platinum(II)) and BBR3464, a trinu-
clear 4+ charged platinum(II) complex, introduced by
Farrell et al., the structure of which is best described as
two trans-[PtCl(NH3)2]+ units bridged by a non-cova-
lent tetra-amine trans-[Pt(NH3)2{NH2(CH2)6NH2}2]2+
unit [1,2]. These results are encouraging and thus this
approach continues to be a promising strategy in the
design of metal-based drugs. This can be achieved by
the variation of either the firmly bound non-leaving
ligands or the labile leaving groups or both. The non-
leaving ligands could influence both the target selection
and reactivity of the metal ion. For instance, the lig-
ands may determine whether the compound may enter
a hydrophobic environment like membranes, approach
charged biomolecules like DNA or fit into the ligand
binding pocket of a particular protein. The leaving
groups will be exchanged for more nucleophilic
biomolecules and thereby infer a biological lesion. Or
The successful use of inorganic complexes as
chemotherapeutic agents is best exemplified by cisplatin
and its analogue carboplatin, which have been used
clinically since 1971 and 1981, respectively [1]. Because
of the beneficial clinical efficacy of cisplatin, the past 30
years have witnessed tremendous effort and progress in
trying to understand the mechanism of action of this
metal-based anticancer drug [1]. Moreover, the clinical
success of cisplatin has sparked considerable interest
and research in the search for improved metal-based
drugs for the use as chemotherapeutic agents [1,2].
Several approaches have been taken over the past three
decades and some of these include the synthesis of
cisplatin analogues, variation of the metal ion as well as
the preparation of platinum complexes that are not
structurally analogous to cisplatin [1,2]. Recent reports
* Corresponding author. Tel.: +27-46-603-8260; fax: +27-46-622-
5109.
E-mail address: c.sacht@ru.ac.za (C. Sacht).
0277-5387/00/$ - see front matter © 2000 Elsevier Science S.A. All rights reserved.
PII: S0277-5387(00)00419-8

1348
C. Sacht, M.S. Datt / Polyhedron 19 (2000) 1347–1354
the metal complex may require an exchange of one or
more of the labile ligands by water in order to become
activated. These factors are also influenced by the non-
leaving ligand.
All samples were prepared using deuterated solvents
purchased from Aldrich Chemical Company, and 5 mm
NMR tubes were used throughout. Chemical shifts are
reported in parts per million (ppm) relative to the
central line of the solvent proton resonance of known
shifts relative to TMS, and coupling constants are
reported in hertz (Hz). 195Pt NMR spectra were
recorded at 86.02 MHz on a Bruker 400AMX spec-
trometer at 3091°C using 70–100 KHz spectral widths
and 13 ms pulses with 1 s pulse delay. Between 2048 and
16 000 transients, with a line broadening factor of 10
Hz, gave good spectra. All 195Pt shifts are quoted
relative to external H2PtCl6 (500 mg in 1 ml 30% (v/v)
D2O/1 M HCl). Melting points were determined on a
Reichert hot-stage microscope and are uncorrected.
Differential scanning calorimetry (DSC) was performed
on a Perkin–Elmer Delta series 7 instrument, under a
nitrogen atmosphere. The temperature range for the
DSC experiments was 50–250°C. Elemental analyses
were carried out at the microanalytical unit at the
University of Cape Town, South Africa. Thin-layer
chromatography (TLC) was performed on silica sheets
60F254 (Merck, Darmstadt). Reverse phase TLC was
performed on glass backed RP-C18F254S plates (Tech-
ware). Flash chromatography was performed on silica
gel 60 (Merck, Darmstadt).
In our laboratory we have focused on preparing a
series platinum(II) complexes of the type [Pt(acylth-
ioureato)Cl(RR%SO)], in which we have varied both the
non-leaving ligands and the labile leaving groups at-
tached to the platinum(II) centre [3]. We have used the
acylthiourea ligand system, R1C(O)NHC(S)NR2R2, as
the R1 and R2 groups can be readily varied to give a
wide range of ligand systems with different physical and
chemical properties, which could be used to fine-tune
the biological activity of the resultant complexes. We
have reported recently the synthesis and characterisa-
tion of the following [Pt(acylthioureato)Cl(RR%SO)]
complexes with the acylthiourea ligands: N,N-di(2-hy-
droxyethyl)-N%-benzoylthiourea, N,N-diethyl-N%-ben-
zoylthiourea and N,N-adipoylbis(N%,N%-diethylthiou-
rea) and the sulfoxides: dimethylsulfoxide (DMSO),
methylphenylsulfoxide (MPSO), R-methyl(p-tolyl)-
sulfoxide (R-MTSO) and S-methyl(p-tolyl)sulfoxide
(S-MTSO) [3]. We have since extended this series by
preparing [Pt(acylthioureato)Cl(DMSO)] complexes
using N,N-diethyl-N%-(3-R-benzoyl)thiourea, N,N-di-
(2-hydroxyethyl)-N%-(3-R-benzoyl)thiourea and N-
morpholino-N%-(3-R-benzoyl)thiourea ligands, where
R=H, Cl, NO2, OCH3 and CH3. Variation of the
amine attached to the thiocarbonyl functionality and
substitutents on the phenyl ring could influence the
lipophilicity/hydrophilicity and electronic properties of
the complexes and thus also affect the lability of the
leaving groups which could control the reactivity and
biological activity of the complexes. To this end, we
herein report the synthesis and full characterisation of
this novel series of platinum(II) complexes.
2.2. Preparation of ligands
The ligands were prepared according to the method
of Douglass and Dains [5]. The synthesis of N,N-di(2-
hydroxyethyl)-N%-benzoylthiourea (L3a) has been re-
ported recently [6,7]. The preparation of N,N-diethyl-
N%-(3-R-benzoyl)thioureas and N-morpholino-N%-(3-R-
benzoyl)thioureas (L1a–d; L2a–d), where R=H, Cl,
NO2 and OCH3, have also been described recently
[8–10]. The analytical data and selected IR data for the
new ligands are given below.
2. Experimental
N,N-Di(2-hydroxyethyl)-N%-(3-nitrobenzoyl)thiourea,
L3c: (70%), m.p. 138–141°C. Anal. required for
C12H15N3O5S: C, 46.00; H, 4.82; N, 13.41; S, 10.23.
Found: C, 46.23; H, 4.85; N, 13.48; S, 9.93%. IR (KBr
pellet, cm−1): w(NꢀH) 3175 (vs, br), w(CꢁO) 1697 (vs,
sh).
N,N - Di(2 - hydroxyethyl) - N% - (3 - methoxybenzoyl)-
thiourea, L3d: (77%), m.p. 103–106°C. Anal. required
for C13H18N2O4S: C, 52.33; H, 6.08; N, 9.39; S, 10.74.
Found: C, 53.11; H, 6.29; N, 9.42; S, 10.40%. IR (KBr
pellet, cm−1): w(NꢀH) 3232 (vs, br), w(CꢁO) 1688 (vs,
sh).
N,N-Di(2-hydroxyethyl)-N%-(3-chlorobenzoyl)-thio-
urea, L3b: (69%), m.p. 132–134°C. Anal. required for
C12H15ClN2O3S: C, 47.60; H, 4.99; N, 9.25; S, 10.59.
Found: C, 47.72; H, 5.09; N, 9.33; S, 10.58%. IR (KBr
pellet, cm−1): w(NꢀH) 3180 (s, br), w(CꢁO) 1693 (vs,
sh).
2.1. Materials and physical methods
The
potassium
tetrachloroplatinate
(Johnson
Matthey), DMSO (Merck), 3-substituted benzoyl chlor-
ides (Aldrich), benzoyl chloride (SaArchem) were used
as supplied. The diethyl amine, morpholine and acetone
were dried and distilled before use. All other sol-
vents were commercial grade and used as received. The
known complexes cis-[PtCl2(DMSO)2] [4], [PtCl-
(DMSO)(N,N-diethyl-N%-benzoylthioureato)] and [PtCl-
(DMSO)(N,N - di(2 - hydroxyethyl) - N% - benzoylthioure-
ato)] [3] were prepared by literature procedures. The IR
spectra were recorded as KBr disks on Perkin–Elmer
FT IR spectrum 2000, between 4000 and 250 cm−1. H
NMR (1D and 2D) spectra were recorded at 400.13
MHz on a Bruker 400AMX spectrometer at 3091°C.
1

C. Sacht, M.S. Datt / Polyhedron 19 (2000) 1347–1354
1349
N,N-Di(2-hydroxyethyl)-N%-(3-methylbenzoyl)-thio-
urea, L3e: (75%), m.p. 136–138°C. Anal. required for
C13H18N2O3S: C, 55.29; H, 6.42; N, 9.92; S, 11.35.
Found: C, 56.12; H, 6.57; N, 9.48; S, 11.36%. IR (KBr
pellet, cm−1): w(NꢀH) 3192 (s, br), w(CꢁO) 1693 (vs,
sh).
straightforward, except for the assignments of the H4
and H6 protons which were confirmed by 2D [1H, 13C]
HMBC experiments. The chemical shift data are given
in Table 1. The data for the ligands that have been
reported already are included for comparison. The
numbering scheme for the thioamide protons are as
given in Tables 3–5.
N-Morpholino-N%-(3-methylbenzoyl)thiourea, L2e:
(72%), m.p. 141–142°C. Anal. required for C13H16-
N2O2S: C, 59.06; H, 6.10; N, 10.60; S, 12.13. Found: C,
59.12; H, 6.15; N, 10.58; S, 11.75%. IR (KBr pellet,
cm−1): w(NꢀH) 3150 (m), w(CꢁO) 1657 (vs, sh).
A notable feature of the 1H NMR spectra of the
ligands is the observation of separate resonances for the
methylene protons (Ha) attached to the nitrogen of the
respective thioamides. The magnetic inequivalence of
these methylene protons can be ascribed to the re-
stricted rotation around the CꢀN bond between the
thiocarbonyl and the amine nitrogen due to the partial
double bond character of this bond.
N,N-Diethyl-N%-(3-methylbenzoyl)thiourea,
L1e:
(55%), m.p. 96–97°C. Anal. required for C13H18N2OS:
C, 62.36; H, 7.25; N, 11.19; S, 12.81. Found: C, 62.37;
H, 7.28; N, 11.21; S, 12.20%. IR (KBr pellet, cm−1):
w(NꢀH) 3311 (s, sh), w(CꢁO) 1646 (s, sh).
1
The H NMR spectra of the N,N-di(2-hydroxyethyl)-
N%-(3-R-benzoyl)thiourea ligands in DMSO-d6 show in-
equivalent proton resonances for the hydroxyl protons.
The lower field signal is broad and unresolved, while
the higher field signal is a well-resolved triplet. This
inequivalence of the hydroxyl protons is due to the
presence of an intramolecular hydrogen bond between
one hydroxyl moiety and the amide NꢀH [6].
The proton resonances for the phenyl ring and NꢀH
protons are significantly affected by the presence of
electron-withdrawing and electron-releasing sub-
stituents on the benzoyl moiety. As shown in Table 1,
on increasing the electron withdrawing ability of the
R-group there is a downfield shift of the proton reso-
nances, the most pronounced shifts being observed for
the ligands L1c, L2c and L3c which contain the nitro
substituent.
2.3. Preparation of platinum(II) sulfoxide complexes
The complexes were prepared according to the fol-
lowing general procedure.
A solution of N,N-dialkyl-N%-(3-R-benzoyl)thiourea
(0.50 mmol) in 10 ml acetonitrile–7 ml ethanol was
added dropwise to
a
stirred solution of cis-
[PtCl2(DMSO)2] (0.50 mmol) in 1.5 ml acetonitrile–2.5
ml dimethylsulfoxide. Sodium acetate (0.063 g, 0.77
mmol) in 1.5 ml water was then added. The solution
was allowed to stir for 48 h. The yellow solution was
concentrated to ca. 10 ml and water (40 ml) was added
whereupon the solution became opaque. The opaque
solution was placed in the fridge (4°C) overnight. The
yellow precipitate was collected by filtration, washed
with water, a little ethanol and dried in vacuo over
silica gel. In some cases ,column chromatography is
required in order to obtain the pure product.
3.2. Synthesis of [PtCl(DMSO)(L)] complexes
The complexes were prepared according to the gen-
eral method described by Eqs. (1) and (2), where HL
represents an acylthiourea ligand. The structural for-
mulae for the complexes are given in Fig. 1.
3. Results and discussion
3.1. Ligand synthesis and characterisation
K2PtCl4+3DMSO“cis-[PtCl2(DMSO)2]
cis-[PtCl2(DMSO)2]+HLB“ase[PtCl(DMSO)(L)]
+cis-[Pt(L)2]
(1)
The ligands were prepared according to the method
of Douglass and Dains [5] and were obtained in yields
ranging from 55–77%. The synthesis involves the reac-
tion of a 3-substituted benzoyl chloride with potassium
thiocyanate in acetone followed by condensation of the
3-R-benzoylisothiocyanate with the appropriate sec-
ondary amine. The ligands were purified by recrystalli-
sation from ethanol and characterised by elemental
(2)
As indicated by Eq. (2), it was found, for ligands
L1a–e and L2a–e, that in addition to the formation of
the desired complex, [PtCl(DMSO)(L)], the correspond-
ing neutral cis-[Pt(L)2] complex was also formed as a
minor product. This was evident from both the TLC
1
1
analysis, H NMR and IR spectroscopy. The analytical
and the H NMR spectra. Integration of the proton
and spectroscopic data are consistent with the proposed
structures given in Fig. 1.
resonances indicated that the cis-[Pt(L)2] was present as
the minor product (ca. 5–15%). The cis-[Pt(L)2] com-
plexes have a higher mobility on silica gel (Rf ca. 0.8)
compared to the [PtCl(DMSO)(L)] complexes (Rf 0.5–
0.6) and consequently the complexes were readily sepa-
rated using flash column chromatography. The
The assignments of the 1H NMR spectra of the
N,N-diethyl-N%-(3-R-benzoyl)thiourea,
N,N-di(2-hy-
droxyethyl)-N%-benzoylthiourea and N-morpholino-N%-
(3-R-benzoyl)-thiourea ligands were in general

1350
C. Sacht, M.S. Datt / Polyhedron 19 (2000) 1347–1354
platinum complexes containing the N,N-di(2-hydroxy-
ethyl)-N%-(3-R-benzoyl)thiourea ligands were isolated
by filtration free of the cis-[Pt(L)2] complex. This is
most likely due to the cis-[Pt(L)2] complex being more
hydrophilic than the [PtCl(DMSO)(L)] complex.
ance of the NꢀH stretching vibrations and shifts of the
w(CꢁO) peaks to higher frequencies upon complexation
of the acylthiourea ligands. A shift to a higher fre-
quency would also be expected for the CꢁS stretch
vibration, but this vibration could not be assigned
unambiguously. The strong IR band in the region of
1130–1150 cm−1 is assigned to the w(SO) stretching
frequency. The w(SO) peak is shifted to a higher fre-
quency upon complexation, relative to the uncoordi-
nated dimethylsulfoxide, which is indicative of a
sulfoxide bonded through the sulfur atom [4,11].
The analytical data, 195Pt NMR chemical shifts and
relevant IR data for the [PtCl(DMSO)(L)] complexes
1
are given in Table 2. The H NMR data for all the
platinum complexes are given in Tables 3–5.
3.3. Characterisation of [PtCl(DMSO)(L)] complexes
3.3.1. Infrared spectra
3.3.2. NMR spectra
The IR spectra of the platinum(II) sulfoxide com-
plexes are very similar. Notable features of the infrared
spectra of the platinum complexes are the disappear-
In accordance with the IR spectra, the NꢀH signal,
observed for the ligands in the 8–11 ppm region,
disappears upon complexation. A downfield shift is
Fig. 1. The structural formulae of the ligands and their corresponding platinum(II) sulfoxide complexes.

C. Sacht, M.S. Datt / Polyhedron 19 (2000) 1347–1354
1351
Table 1
1H NMR data for the acylthiourea ligands
Ligand
L1a
L1b
L1c
R-group
H
lH2
lH3
lH4
lH5
lH6
lHa
lHb
lHg
lHR
lHNH
7.823
7.816
8.654
7.324
7.639
7.832
7.828
8.681
7.375
7.642
7.85
7.461
7.563
7.539
8.170
7.065
7.355
7.594
7.565
8.181
7.119
7.395
7.59
7.461
7.410
7.662
7.324
7.355
7.488
7.431
7.712
7.375
7.363
7.50
7.823
7.692
8.418
7.324
7.608
7.832
7.696
8.443
7.375
7.610
7.85
4.018
3.606
4.016
3.594
3.987
3.595
3.993
3.580
4.026
3.605
4.230
3.663
4.228
3.644
4.232
3.659
4.226
3.670
4.226
3.656
3.97
1.322
1.222
1.322
1.300
1.328
3.838
3.835
3.844
3.853
3.837
8.238
8.165
8.774
8.428
8.176
8.410
8.361
8.577
8.386
8.380
10.86
10.818
11.129
10.829
10.813
Cl
NO2
OCH3
CH3
H
L1d
L1e
3.815
2.403
L2a
L2b
L2c
7.488
Cl
NO2
OCH3
CH3
H b
L2d
L2e
3.853
2.413
a
L3a
7.50
3.75
3.69
3.726
5.60
4.85
3.73
L3b a
L3c a
L3d a
L3e a
Cl
7.882
8.659
7.438
7.685
7.671
8.279
7.162
7.413
7.540
7.792
7.438
7.382
7.811
8.435
7.438
7.650
3.990
3.726
4.007
3.735
3.985
3.742
3.981
3.742
5.516
4.843
5.538
4.857
5.624
4.840
5.621
4.840
NO2
OCH3
CH3
3.735
3.742
3.742
3.814
2.368
a Spectra were recorded in DMSO-d6.
b Ref. [6].
observed for the H2 and H6 aromatic protons and an
upfield shift for the H3, H4 and H5 proton resonances
relative to that of the free ligand, with the exception of
the H4 proton resonances for complexes 1c, 2c and
3a–d which undergo downfield shifts.
dialkyl-N%-benzoylthiourea
ligands,
which
were
confirmed by the crystal structure of the [PtCl(N,N-di-
ethyl-N%-benzoylthioureato)(MPSO)] complex [3]. The
methylphenyl sulfoxide (MPSO) is sulfur bonded to the
platinum and cis to the sulfur of the N,N-diethyl-N%-
benzoylthiourea ligand. Variation of the electronic
properties of the benzoyl moieties appears to have little
1
The H NMR chemical shift for the methyl protons
of the coordinated dimethylsulfoxide are shifted 1 ppm
downfield relative to free dimethylsulfoxide, which is
typical for sulfur bonded sulfoxides [3,4]. The assign-
ment of the mode of coordination of the dimethylsul-
foxide was further supported by the presence of
platinum satellites due to vicinal coupling of the methyl
protons of the dimethylsulfoxide with the platinum
centre, 195Pt (33.7%, I=1/2). The 3J(195Pt–1H) cou-
pling constants were approximately 23 Hz, which is the
same order of magnitude found for sulfur bonded
sulfoxides [4]. The data are consistent with that re-
ported for the [PtCl(L)(RR%SO)] complexes with N,N-
1
affect on the H NMR chemical shift position of the
methyl protons of the coordinated sulfoxide.
All the [Pt(acylthioureato)Cl(DMSO)] complexes
show 195Pt chemical shifts in the −3200 to −3300
ppm region. This chemical shift range is characteristic
of complexes with the coordination sphere [PtSOSCl]
[3]. The 3-substitution of the benzoyl moiety of these
complexes results in a small but significant difference in
the 195Pt chemical shifts for the [Pt(acylthioure-
ato)Cl(DMSO)] complexes, demonstrating the sensitiv-
ity of the 195Pt nucleus to subtle electronic changes on

1352
C. Sacht, M.S. Datt / Polyhedron 19 (2000) 1347–1354
Table 2
Analytical and selected spectroscopic data for the platinum(II) sulfoxide complexes
Compound
R-group
M.p. (°C) a
Yield (%)
Analytical data
w(SꢁO) (cm−1
)
195Pt NMR (ppm)
(% C/H/N/S) b
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
H
139–141
160–162
187–190
138–140
109–111
197–dec a
165–dec a
208–dec a
189–dec a
187–dec a
139–140
130–132
152–154
145–147
127–129
72
67
60
80
45
51
89
94
49
86
75
77
68
69
35
31.84; 3.93; 5.19; 11.69
(30.91; 3.89; 5.15; 11.79)
29.48; 3.51; 4.78; 11.07
(29.07; 3.48; 4.84; 11.08)
28.56; 3.34; 6.88; 10.68
(28.55; 3.42; 7.14; 10.89)
31.52; 4.06; 4.93; 11.13
(31.38; 4.04; 4.88; 11.17)
32.57; 4.20; 4.94; 11.18
(32.28; 4.15; 5.02; 11.49)
30.92; 3.54; 4.80; 10.82
(30.13; 3.43; 5.02; 11.49)
28.52; 3.04; 4.77; 11.13
(28.38; 3.06; 4.73; 10.82)
28.39; 3.12; 6.87; 10.65
(27.88; 3.01; 6.97; 10.63)
31.00; 3.58; 4.74; 10.92
(30.64; 3.60; 4.76; 10.90)
31.63; 3.65; 4.98; 11.28
(31.49; 3.70; 4.90; 11.21)
29.17; 3.66; 4.81; 11.05
(29.19; 3.67; 4.86; 11.13)
28.20; 3.34; 4.79; 10.41
(27.54; 3.30; 4.59; 10.50)
27.44; 3.26; 6.84; 10.19
(27.08; 3.25; 6.77; 10.32)
30.14; 4.00; 4.87; 10.40
(29.73; 3.82; 4.62; 10.58)
30.73; 3.86; 4.84; 10.79
(30.53; 3.93; 4.75; 10.87)
1139
1144
1153
1137
1137
1147
1148
1145
1150
1147
1146
1138
1146
1148
1149
−3256
−3229 c
−3250
Cl
NO2
OCH3
CH3
H
−3242
−3256
−3257
−3231 c
−3224 c
−3219 c
−3230 c
−3232 c
−3229 c
−3223 c
−3219 c
−3228 c
−3231 c
Cl
NO2
OCH3
CH3
H
Cl
NO2
OCH3
CH3
a Melting points were determined by DSC.
b Calculated values are given in parentheses.
c Spectra recorded in DMSO-d6.
Table 3
1H NMR data for N,N-diethyl-N%-(3-R-benzoyl)thiourea platinum(II) sulfoxide complexes a
R-group
lH2
lH3
lH4
lH5
lH6
lHh
lHi
lHSme
lHR
H
8.181
8.116
7.370
7.484
7.455
7.370
7.312
8.181
8.070
1.357
1.296
1.361
1.301
1.362
1.355
1.299
1.276
1.212
3.829
3.825
3.595
3.598
Cl
NO2
OCH3
8.968
7.739
8.336
7.038
7.580
7.279
8.522
7.789
3.843
3.822
3.608
3.594
3.833
2.313
CH3
7.911
7.238
7.192
7.911
3.749
3.596
a The spectra were recorded in CDCl3 at 303 K.

C. Sacht, M.S. Datt / Polyhedron 19 (2000) 1347–1354
1353
Table 4
1H NMR data for N-morpholino-N%-(3-R-benzoyl)thiourea platinum(II) sulfoxide complexes a
R-group
H
lH2
lH3
lH4
lH5
lH6
lHh
lHi
lHSme
3.602
3.604
3.614
3.600
3.601
lHR
8.164
8.089
8.917
7.705
7.959
7.376
7.503
7.472
8.352
7.054
7.313
7.376
7.318
7.587
7.285
7.254
8.164
8.056
8.507
7.765
7.959
4.205
4.093
4.183
4.096
4.228
4.118
4.197
4.090
4.200
4.092
3.799
3.809
3.833
3.789
3.803
Cl
NO2
OCH3
CH3
3.837
2.384
a The spectra were recorded in CDCl3 at 303 K.
Table 5
1H NMR data for N,N-di(2-hydroxyethyl)-N%-(3-R-benzoyl)thiourea platinum(II) sulfoxide complexes a
R-group
H
lH2
lH3
lH4
lH5
lH6
lHh
lHi
lHk
lHR
8.069
7.985
8.759
7.594
7.870
7.441
7.602
7.678
8.445
7.176
7.416
7.441
7.526
7.794
7.397
7.361
8.069
8.014
8.445
7.651
7.870
4.008
3.921
4.005
3.924
4.042
3.939
3.993
3.913
4.001
3.917
3.772
3.696
3.780
3.689
3.789
3.717
3.785
3.709
3.775
3.694
5.052
4.936
5.060
4.944
5.077
4.957
5.052
4.932
5.048
4.930
Cl
NO2
OCH3
CH3
3.792
2.366
a The spectra were recorded in DMSO-d6 at 303 K.
the benzoyl moiety [11]. The electron-withdrawing af-
fect of the nitro- and chloro- substituents results in
notable downfield shifts of the 195Pt signal: NO2 (Dl:
10–14 ppm)\Cl (Dl: 6–7 ppm)\OCH3:H:CH3,
which is consistent with the mesomeric/inductive effects
expected for a 3-substituted benzoyl group and parallels
the trend observed for the H NMR data. No signifi-
cant effect was observed with variation of the
thioamide moiety.
The sensitivity of the 195Pt NMR signal to changes in
the benzoyl substituent indicates that these groups infl-
uence the electron density at the platinum centre and
are therefore expected to have an influence on the
substitution reaction kinetics of these complexes. Since
the rate of substitution of the dimethylsulfoxide and
chloride ligands is of utmost importance in gaining
insight into the reactivity and mode of binding of these
complexes to DNA detailed studies are underway cur-
1

1354
C. Sacht, M.S. Datt / Polyhedron 19 (2000) 1347–1354
rently to evaluate the substitution kinetics of these
complexes. In the meanwhile, preliminary substitution
reaction kinetic studies of [PtCl(DMSO)(N,N-diethyl-
N%-(3-R-benzoyl)thioureato)] and the anionic nucle-
ophile azide have revealed that the rate of substitution
of the chloride leaving group is influenced by the elec-
tronic properties of the R group on the phenyl ring.
The rate of substitution decreases in the order of
NO2\Cl\OCH3:H:CH3. These results are in
agreement with the 195Pt NMR results, which provide
evidence that the electron-withdrawing substituents on
the phenyl ring results in a decrease in the electron
density at the Pt centre thereby making it more suscep-
tible to nucleophilic attack. The substitution of the
chloride-leaving group was established from the 1H
NMR spectrum of the complex. In the presence of the
azide anion a significant upfield shift was observed for
the protons of the coordinated DMSO and there was
no significant appearance of free DMSO at 2.5 ppm.
It is also noteworthy to mention that preliminary in
vitro cytotoxicity studies against a HeLa cell line have
shown that both the benzoyl substituent and the
thioamide moiety play an important role in determining
whether the complexes exhibit any anticancer activity.
The [PtCl(DMSO)(N,N-diethyl-N%-benzoylthioureato)],
and [PtCl(DMSO)(N,N-di(2-hydroxyethyl)-N%-benzoyl-
thioureato)] complexes did not exhibit any cytotoxic
behaviour, whereas a notable concentration-dependent
anti-proliferative effect was observed for the HeLa cell
line treated with the [Pt(acylthioureato)Cl(DMSO)]
complexes containing the N,N-diethyl-N%-(3-nitroben-
zoyl)thiourea, N-morpholino-N%-(3-nitrobenzoyl)thiou-
rea or N-morpholino-N%-(3-methoxybenzoyl)thiourea
ligands [12]. These preliminary results are most encour-
aging in that they support our hypothesis that the
acylthiourea ligand could play an important role in the
biological activity of this series of complexes and can
thus be used to fine-tune their anti-tumour behaviour.
Detailed studies are thus currently underway to investi-
gate the biological activity of this series of complexes
and to try and establish a structure–activity relation-
ship.
Acknowledgements
We wish to thank Rhodes University and the Na-
tional Research Foundation for financial support,
Johnson Matthey for the generous loan of K2PtCl4 and
Kerry Horne for the synthesis of ligands L1b and L1d.
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