Synthesis and characterization of multimeric salicylaldimine thiosemicarbazones and their Pd(II) and Pt(II) complexes

Article abstract of DOI:10.1016/j.poly.2011.10.005

A series of di- and trithiosemicarbazone ligands as well as their Pd(II) and Pt(II) 1,3,5-triaza-7-phosphaadamantane (PTA) complexes have been synthesised using templated reactions between various substituted salicylaldimine thiosemicarbazone ligands and

Full text of DOI:10.1016/j.poly.2011.10.005

Polyhedron 31 (2012) 486–493
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Polyhedron
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Synthesis and characterization of multimeric salicylaldimine
thiosemicarbazones and their Pd(II) and Pt(II) complexes
Tameryn Stringer a, Denver T. Hendricks b, Hajira Guzgay b, Gregory S. Smith a,
⇑
a Department of Chemistry, University of Cape Town, Private Bag, Rondebosch 7701, Cape Town, South Africa
b Division of Medical Biochemistry, University of Cape Town, Rondebosch 7701, Cape Town, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of di- and trithiosemicarbazone ligands as well as their Pd(II) and Pt(II) 1,3,5-triaza-7-phospha-
adamantane (PTA) complexes have been synthesised using templated reactions between various substi-
tuted salicylaldimine thiosemicarbazone ligands and metal precursors of the general formula cis-
[M(PTA)2Cl2], where M = Pd or Pt. Characterization of these complexes was achieved using various ana-
lytical and spectroscopic techniques: elemental analysis, ESI-MS, FT-IR, and NMR (1H, 13C{1H} and
31P{1H}) spectroscopy. The data revealed tridentate (O–N–S) coordination of the thiosemicarbazone moi-
eties via the imine nitrogen, thiolato sulfur and phenolic oxygen to each metal center. In vitro biological
evaluation of selected compounds was conducted against WHCO1 oesophageal cancer cells. Some of the
multimeric compounds display some promising biological activity.
Received 31 May 2011
Accepted 4 October 2011
Available online 13 October 2011
Keywords:
Salicylaldimine
Multimeric thiosemicarbazones
Palladium
Platinum
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
complexes in many solvents including water has hindered their bio-
logical evaluation [17]. This study is therefore an extension of the
Transitionmetal complexesof thiosemicarbazoneshave received
considerable attention mainly due to their broad spectrum of phar-
macological properties [1]. There are three main types of thiosemi-
carbazones that have been reported in literature namely mono-,
di- and bis(thiosemicarbazones). Monothiosemicarbazones as their
name suggests constitute one thiosemicarbazone moiety, while di-
and bis(thiosemicarbazones) each possess two thiosemicarbazone
moieties. Dithiosemicarbazones consist of the two moieties linked
via their amino nitrogen atoms to a hydrocarbon spacer, while
bis(thiosemicarbazones) have their moieties linked via their imine
nitrogen atoms to an organic spacer [2]. Thiosemicarbazones are
able to coordinate to metal ions in various ways due to their vast
number of donor atoms. Thiosemicarbazones usually bind to metal
ions by means of dissociation of the hydrazinic proton giving rise
to bidentate (N, S) coordination, forming a five-membered chelate
ring[3]. Intheeventthata thirddonorsiteis incorporated, tridentate
coordination is often observed. Thisis usuallyobservedfor thiosemi-
carbazones derived from salicylaldehydes [4–6]. Although the
chemistry of platinum and palladium complexes of many monothi-
osemicarbazones has been explored [4,6–10], there are very few re-
ports on the preparation of multimeric thiosemicarbazones and
their transition metal complexes [2,11–16]. Previously, we have re-
ported the preparation of dithiosemicarbazones and their palladium
triphenylphosphine complexes; however, the poor solubility of the
afore-mentioned work as well as a study conducted in our group
wherein similar monothiosemicarbazonederivatives were prepared
(Fig. 1) and evaluated for their activity against the T1 strain of Trich-
omonas vaginalis. These compounds displayed very promising activ-
ity [18]. Herein we report the synthesis and characterization of Pd(II)
and Pt(II) salicylaldimine dithiosemicarbazones as well as com-
plexes of a new type of thiosemicarbazone system which we have
coined ‘‘trithiosemicarbazones’’. The synthetic preparation, charac-
terization and some preliminary biological data of these compounds
are reported in this paper.
2. Experimental
2.1. Materials and methods
All reagents and solvents were purchased from commercial
sources (Sigma–Aldrich, Fluka, Merck, Kimix) and used as received.
Palladium dichloride and potassium tetrachloroplatinate was re-
ceived as a donation from Anglo Platinum. Ethane-1,2-dithiosemic-
arbazide [15], cis-[Pd(PTA)2Cl2] [19], cis-[Pt(PTA)2Cl2] [20],
dithiosemicarbazone ligands (1–3) [17] and complexes M1–M4
[18] (Fig. 1) were prepared following reported literature
procedures.
2.2. Instrumentation
⇑
Nuclear magnetic resonance (NMR) spectra were recorded
using a Varian Mercury 300 MHz spectrometer, a Varian Unity
Corresponding author. Tel.: +27 21 6505279; fax: +27 21 6505195.
E-mail address: gregory.smith@uct.ac.za (G.S. Smith).
0277-5387/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.poly.2011.10.005

T. Stringer et al. / Polyhedron 31 (2012) 486–493
487
the mixture refluxed for 8–16 h resulting in clear yellow solutions.
The volume of the yellow solution was reduced and water added to
precipitate the desired products for compounds 6, 7 and 9. The
products were collected using a Büchner funnel and washed with
water. Compound 8 was isolated as a yellow oil. The oil was dis-
solved in DCM and the extract washed with water. The product
was obtained after evaporation of the DCM.
N
NH2
N
O
Pd
P
S
R
Compound 6 was obtained from tris(2-aminoethyl) thiosemi-
carbazide (5) (0.146 g, 0.40 mmol) and salicylaldehyde (0.13 ml,
1.22 mmol). Compound 6 was isolated as a yellow powder. Yield
0.207 g (77%). M.p. 133–137 °C. Anal. Calc. for C30H36N10S3O3: C,
52.92; H, 5.33; N, 20.57; S, 14.12. Found: C, 52.86; H, 5.43; N,
N
N
N
19.72; S, 12.77%.
m
max/cmÀ1 803 (C@S); 1620 (C@N). 1H NMR
R = H (M1), 3-OMe (M2), 3-tBu (M3), 5-Cl (M4)
(300 MHz, DMSO-d6, 25 °C): d = 2.85 (6H, m, N–CH2), 3.72 (6H, m,
NH–CH2), 6.85 (6H, t, J = 8.82, Ar–H), 7.20 (3H, t, J = 8.82, Ar–H),
7.84 (3H, dd, J = 1.62, 7.79, Ar–H), 8.33 (3H, m, NH–CH2), 8.38
(3H, s, CH@N), 9.79 (3H, s, OH), 11.34 (3H, s, N–NH) ppm.
13C{1H} NMR (100 MHz, DMSO-d6, 25 °C): d = 42.60, 53.42,
116.83, 120.07, 121.09, 127.27, 131.77, 140.00, 157.15,
177.64 ppm. MS ESI: m/z 681 (100%, [M]+).
Compound 7 was obtained from tris(2-aminoethyl) thiosemi-
carbazide (5) (0.060g, 0.16 mmol) and 3-methoxy salicylaldehyde
(0.076 g, 0.50 mmol). The product was isolated as a yellow amor-
phous solid. Yield 0.078 g (62%). M.p. 154–157 °C. Anal. Calc. for
Fig. 1. Monothiosemicarbazone complexes showing promising antiparasitic activ-
ity [18].
400 MHz spectrometer or a Bruker 400 MHz FT spectrometer.
Infrared (IR) spectra were determined using a Perkin Elmer Spec-
trum One FT-IR spectrometer and was carried out in the solid state
using KBr pellets unless stated otherwise. Elemental analyses of
these compounds were performed using a Thermo Flash 1112 Ser-
ies CHNS-O Analyser. ESI mass spectrometry determinations were
carried out using a Waters API Quattro instrument in either the po-
sitive or negative mode. Melting points are corrected and were
determined on a Reichert Thermovar hot stage microscope.
C
33H42N10S3O6: C, 51.41; H, 5.49; N, 18.17; S, 12.47. Found: C,
50.33; H, 5.61; N, 20.93; S, 13.42%.
m
max/cmÀ1 883 (C@S); 1605
(C@N). 1H NMR (400 MHz, DMSO-d6, 25 °C): d = 2.71 (6H, m, N–
CH2), 3.63 (6H, m, NH–CH2), 3.71 (9H, s, OCH3), 6.70 (3H, t,
J = 8.04, Ar–H), 6.86 (3H, d, J = 7.88, Ar–H), 7.40 (3H, d, J = 7.82,
Ar–H), 8.26 (3H, s, NH–CH2), 8.32 (3H, s, CH@N), 9.04 (3H, s, OH),
11.33 (3H, s, N–NH) ppm. 13C{1H} NMR (75 MHz, DMSO-d6,
25 °C): d = 41.57, 52.50, 55.82, 112.85, 117.86, 118.89, 120.73,
139.16, 145.87, 147.85, 176.88 ppm. MS ESI: m/z 771 (100%, [M]+).
Compound 8 was obtained from tris(2-aminoethyl) thiosemicar-
bazide (5) (0.269g, 0.73 mmol) and 3-tert-butyl salicylaldehyde
(0.36 ml, 2.10 mmol). The product was obtained as a yellow oil.
2.3. Synthesis of 5-chlorosalicylaldimine dithiosemicarbazone (4),
tris(2-aminoethyl) thiosemicarbazide (5) and the salicylaldimine
trithiosemicarbazone ligands (6–9)
5-Chlorosalicylaldimine dithiosemicarbazone (4) was prepared
using ethane-1,2-dithiosemicarbazide (0.218 g, 1.04 mmol) and
5-chlorosalicylaldehyde (0.330 g, 2.11 mmol). The reactants were
stirred in DMF (20 ml) at 120 °C for 5 h. The product was obtained
by precipitation with water. The precipitate was filtered on a Büch-
ner funnel, washed with water and dried at 110 °C. The product
was isolated as a yellow powder. Yield 0.507 g (90%). M.p. 237–
243 °C. Anal. Calc. for C18H18N6S2O2Cl2: C, 44.54; H, 3.74; N,
17.32; S, 13.21. Found: C, 44.31; H, 3.73; N, 16.97; S, 13.58%.
.
Yield 0.521 g (84%). Anal. Calc. for C42H60N10O3S3 CH2Cl2: C, 55.29;
H, 6.27; N, 15.00; S, 10.30. Found: C, 55.92; H, 6.30; N, 17.68; S,
11.84%.
m
max/cmÀ1 854 (C@S); 1646 (C@N). 1H NMR (400 MHz,
t
DMSO-d6, 25 °C): d = 1.36 (27H, m, Bu), 2.86 (6H, m, N–CH2), 3.72
(6H, m, NH–CH2), 6.84 (3H, t, JH–H = 7.65, Ar–H), 7.24 (6H, m, Ar–
3
m
max/cmÀ1 826 (C@S); 1616 (C@N). 1H NMR (400 MHz, DMSO-d6,
25 °C): d = 3.88 (4H, s, NH-CH2), 6.89 (2H, d, J = 8.76, Ar–H), 7.23
(2H, dd, J = 2.65, J = 8.75, Ar–H), 8.05 (2H, s, Ar–H), 8.36 (2H, s,
CH@N), 8.74 (2H, s, NH–CH2), 10.27 (2H, s, OH), 11.56 (2H, s, N–
NH) ppm. 13C{1H} NMR (100 MHz, DMSO-d6, 25 °C): d = 44.28,
118.39, 122.96, 124.08, 126.02, 131.08, 138.34, 155.85,
178.11 ppm. MS ESI: m/z 485 (100%, [M]+).
H), 8.25 (3H, s, NH–CH2), 8.27 (3H, s, CH@N), 10.14 (3H, s, OH),
11.39 (3H, s, N–NH) ppm. 13C{1H} NMR (75 MHz, DMSO-d6):
d = 25.46, 34.91, 42.52, 52.83, 119.16, 119.83, 128.90, 129.72,
137.24, 147.19, 155.86, 177.28 ppm. MS ESI: m/z 849 (100%, [M]+).
Compound 9 was obtained from tris(2-aminoethyl) thiosemi-
carbazide (5) (0.122 g, 0.33 mmol) and 5-chlorosalicylaldehyde
(0.155 g, 0.99 mmol). The product was obtained as a yellow pow-
der. Yield 0.226 g (87%). M.p. 141–145 °C. Anal. Calc. for
Tris(2-aminoethyl) thiosemicarbazide (5) was prepared from
tris(2-aminoethyl)amine (1.87 ml). This was added to a solution
of NaOH (1.502 g, 0.037 mol) in water (25 ml). To this solution,
CS2 (2.27 ml) was added and the mixture stirred for 4 h giving rise
to an orange solution. Sodium chloroacetate (4.375 g, 0.037 mol)
was added to the solution and stirred for 16 h. The solution was
then acidified with 2 M HCl (12 ml) to form a yellow precipitate.
C
30H33N10S3O3Cl3: C, 45.95; H, 4.24; N, 17.86; S, 12.26. Found: C,
45.28; H, 4.42; N, 17.29; S, 12.27%.
m
max/cmÀ1 821 (C@S); 1618
(C@N). 1H NMR (400 MHz, DMSO-d6, 25 °C): d = 2.87 (6H, m, N–
CH2), 3.75 (6H, m, NH–CH2), 6.91 (3H, d, J = 8.72, Ar–H), 7.24 (3H,
dd, J = 2.66, 8.73; Ar–H), 7.98 (3H, d, J = 2.62, Ar–H), 8.35 (3H, s,
CH@N), 8.57 (3H, m, NH–CH2), 10.22 (3H, s, OH), 11.50 (3H, s, N–
NH) ppm. 13C{1H} NMR (75 MHz, DMSO-d6, 25 °C): d = 41.58,
52.56, 117.63, 122.20, 123.26, 124.98, 130.11, 137.28, 154.98,
177.02 ppm. MS ESI: m/z 785 (100%, [M+H]+).
.
To this mixture, NH2NH2 H2O (10 ml) was added and the solution
stirred at 90 °C for 2 h. The solution was then removed from the
heat and stirred overnight yielding an oily off-white substance.
The product was dried at 115 °C and upon cooling a pale yellow so-
lid is obtained. Yield 1.059 g (23%). 1H NMR (400 MHz, DMSO-d6,
25 °C): d = 2.68 (6H, m, N–CH2), 3.56 (6H, m, NH–CH2), 4.43 (6H,
s, NH2), 7.87 (3H, s, NH–CH2), 8.60 (3H, s, NH2–NH) ppm. 13C{1H}
NMR (100 MHz, DMSO-d6, 25 °C): d = 41.73, 53.57, 181.76 ppm.
MS ESI: m/z 369 (100%, [M+H]+).
Synthesis of Pd(II) and Pt(II) thiosemicarbazone complexes
General procedure: A heated mixture of the ligand (di- or tri-) in
ethanol or methanol (30 ml) was stirred and to the mixture 2 equiv
(for the dithiosemicarbazones) or 3 equiv (for the trithiosemicar-
bazones) of triethylamine was added. Upon dissolution of the thi-
osemicarbazone, 2 or 3 equiv of [M(PTA)2Cl2] (M = Pd or Pt) was
General procedure for ligands 6–9: Tris(2-aminoethyl) thiosem-
icarbazide (5) (1 equiv) was added to hot ethanol (30 ml). To this
mixture, the appropriate salicylaldehyde (3 equiv) was added and
added accordingly, resulting in
a yellow or orange reaction

488
T. Stringer et al. / Polyhedron 31 (2012) 486–493
mixture. The reaction mixtures were refluxed for 8–48 h and then
cooled to room temperature. The resulting precipitate was filtered,
washed with the appropriate cold alcohol, diethyl ether and dried
in vacuo. The reactions were carried out at room temperature in the
case of compounds 3a, 3b, 8a and 8b.
NMR (300 MHz, DMSO-d6, 25 °C): d = 3.42 (4H, s, NH–CH2), 4.30
(12H, s, P–CH2 (PTA)), 4.42 (6H, d, J = 13.12, N–CHax–N (PTA)), 4.57
(6H, d, J = 12.93, N–CHeq–N (PTA)), 6.90 (2H, d, J = 9.04, Ar–H), 7.20
(4H, m, NH, Ar–H), 7.47 (2H, d, J = 2.83, Ar–H), 8.31 (2H, d,
J = 12.95, CH@N) ppm. 31P{1H} NMR (121 MHz, DMSO-d6, 25 °C):
d = À39.92 (2P, s, PTA) ppm. 13C{1H} NMR (75 MHz, DMSO-d6,
25 °C): d = 45.02, 49.90, 71.82, 117.10, 119.05, 122.38, 131.75,
132.00, 147.12, 160.36, 170.88 ppm. MS ESI: m/z 1009 (5%, [M+H]+).
2.4. Synthesis of binuclear Pd(II) (1a–4a) and Pt(II) (1b–4b)
thiosemicarbazone complexes
2.4.1. Compound 1a
2.4.5. Compound 1b
Compound 1a was obtained from compound
1
(0.039 g,
Compound 1b was obtained from compound 1 (0.070 g,
0.093 mmol), triethylamine (0.02 ml) and cis-[Pd(PTA)2Cl2]
(0.086 g, 0.17 mmol). The product obtained was a yellow powder.
Yield 0.067 g (82%). M.p. 250–254 °C. Anal. Calc. for
0.167 mmol), triethylamine (0.04 ml) and cis-[Pt(PTA)2Cl2]
(0.191 g, 0.329 mmol). The product obtained was a yellow powder.
Yield 0.141 g (83%). M.p. no melting < 300 °C. Anal. Calc. for
C
30H40N12S2P2O2Pd2Á2H2O: C, 36.93; H, 4.54; N, 17.23; S, 6.57.
C
30H40N12O2S2Pt2P2Á3H2O: C, 30.77; H, 3.96; N, 14.36; S, 5.47.
Found: C, 36.96; H, 4.63; N, 18.30; S, 6.03%.
m
max/cmÀ1 1598
Found: C, 30.50; H, 3.71; N, 14.93; S, 5.22%.
m
max/cmÀ1 1599
(C@N). 1H NMR (300 MHz, DMSO-d6, 25 °C): d = 3.40 (4H, s, NH–
CH2), 4.31 (12H, s, P–CH2 (PTA)), 4.42 (6H, d, J = 13.19, N–CHax–N
(PTA)), 4.57 (6H, d, J = 12.85, N–CHeq–N (PTA)), 6.56 (2H, t,
J = 7.88, Ar–H), 6.89 (2H, d, J = 8.15, Ar–H), 7.07 (2H, s, NH), 7.23
(2H, t, J = 8.55, Ar–H), 7.38 (2H, dd, J = 1.75, 7.98, Ar–H), 8.31 (2H,
d, J = 13.15, CH@N) ppm. 31P{1H} NMR (121 MHz, DMSO-d6,
25 °C): d = À40.55 (2P, s, PTA) ppm. 13C{1H} NMR (100 MHz,
DMSO-d6, 25 °C): d = 45.86, 50.65, 72.59, 115.12, 118.66, 121.42,
133.23, 134.92, 149.08, 162.44, 170.83 ppm. MS ESI: m/z 247
(30%, [M+2H+2Na]4+), 941 (50%, [M+H]+).
(C@N), 1635 (C@N). 1H NMR (400 MHz, DMSO-d6, 25 °C): d = 3.52
(4H, s, NH–CH2), 4.29 (12H, s, P–CH2 (PTA)), 4.48 (6H, d, J = 13.06,
N–CHax–N (PTA)), 4.57 (6H, d, J = 12.78, N–CHeq–N (PTA)), 6.69
(2H, t, J = 7.25, Ar–H), 7.04 (2H, d, J = 8.50, Ar–H), 7.29 (2H, s,
NH), 7.38 (2H, t, J = 7.62, Ar–H), 7.57 (2H, d, J = 7.85, Ar–H), 8.67
(2H, d, J = 11.19, CH@N) ppm. 31P{1H} NMR (161 MHz, DMSO-d6,
25 °C): d = À61.47 (2P, s, PTA) ppm, J = 3329.69. 13C{1H} NMR
(100.577 MHz, DMSO-d6, 25 °C): d = 45.97, 50.27, 72.84, 116.09,
119.01, 121.64, 133.15, 134.71, 147.46, 160.58, 172.45 ppm. MS
ESI: m/z 1117 (100%, [M]+).
2.4.2. Compound 2a
2.4.6. Compound 2b
Compound 2a was obtained from compound
2
(0.051 g,
Compound 2b was obtained from compound 2 (0.081 g,
0.11 mmol), triethylamine (0.02 ml) and cis-[Pd(PTA)2Cl2]
(0.103 g, 0.21 mmol). The precipitate was obtained as a yellow-or-
ange powder. Yield 0.083 g (79%). M.p. no melting < 300 °C. Anal.
Calc. for C32H44N12S2P2O4Pd2Á2H2O: C, 37.11; H, 4.67; N, 16.23; S,
0.171 mmol), triethylamine (0.05 ml) and cis-[Pt(PTA)2Cl2]
(0.196 g, 0.338 mmol). The product was obtained as a yellow pow-
der. Yield 0.175 g (95%). M.p. no melting < 300 °C. Anal. Calc. for
C
32H44N12O4Pt2P2S2: C, 32.65; H, 3.77; N, 14.28; S, 5.45. Found: C,
6.19. Found: C, 37.35; H, 4.72; N, 14.95; S, 5.59%.
m
max/cmÀ1 1598
31.44; H, 3.98; N, 13.13; S, 4.90%.
m
max/cmÀ1 1596 (C@N), 1619
(C@N). 1H NMR (300 MHz, DMSO-d6, 25 °C): d = 3.41 (4H, s, NH–
CH2), 3.77 (6H, s, OCH3), 4.33 (12H, s, P–CH2 (PTA)), 4.43 (6H, d,
J = 13.22, N–CHax–N (PTA)), 4.56 (6H, d, J = 12.85, N–CHeq–N
(PTA)), 6.49 (2H, t, J = 7.69, Ar–H), 6.89 (2H, dd, J = 1.60, 7.68, Ar–
H), 7.03 (4H, m, NH, Ar–H), 8.29 (2H, d, J = 13.17, CH@N) ppm.
31P{1H} NMR (121 MHz, DMSO-d6, 25 °C): d = À39.22 (2P, s,
PTA) ppm. 13C{1H} NMR (100 MHz, DMSO-d6, 25 °C): d = 45.15,
50.10, 56.28, 71.93, 113.42, 114.40, 117.77, 126.04, 148.07,
150.95, 153.12, 170.15 ppm. MS ESI: m/z 1001 (100%, [M+H]+).
(C@N). 1H NMR (400 MHz, DMSO-d6, 25 °C): d = 3.52 (4H, s, NH–
CH2), 3.84 (6H, s, OCH3), 4.31 (12H, s, P–CH2 (PTA)), 4.50 (6H, d,
J = 13.02, N–CHax–N (PTA)), 4.57 (6H, d, J = 12.72, N–CHeq–N
(PTA)), 6.62 (2H, t, J = 7.83, Ar–H), 7.02 (2H, d, J = 7.78, Ar–H),
7.19 (2H, d, J = 8.16, Ar–H), 7.29 (2H, s, NH), 8.65 (2H, d,
J = 11.18, CH@N) ppm. 31P{1H} NMR (161 MHz, DMSO-d6, 25 °C):
d = À60.18 (2P, s, PTA) ppm, J = 3321.44. 13C{1H} NMR (100 MHz,
DMSO-d6, 25 °C): d = 45.16, 49.40, 56.23, 72.07, 113.56, 114.37,
118.047, 125.58, 146.35, 150.93, 151.07, 171.63 ppm. MS ESI: m/z
1177 (100%, [M]+).
2.4.3. Compound 3a
Compound 3a was obtained from compound
3
(0.057 g,
2.4.7. Compound 3b
0.11 mmol), triethylamine (0.03 ml) and cis-[Pd(PTA)2Cl2]
(0.105 g, 0.21 mmol). The product obtained was a yellow-orange
powder. Yield 0.075 g (82%). M.p. no melting < 300 °C. Anal. Calc.
for C38H56N12S2P2O2Pd2: C, 43.39; H, 5.37; N, 15.98; S, 6.09. Found:
Compound 3b was obtained from compound 3 (0.090 g,
0.170 mmol), triethylamine (0.05 ml) and cis-[Pt(PTA)2Cl2]
(0.196 g, 0.338 mmol). The product obtained was a yellow amor-
phous solid. Yield 0.166 g (86%). M.p. no melting < 300 °C. Anal.
Calc. for C38H56N12S2P2O2Pt2: C, 37.13; H, 4.59; N, 13.68; S, 5.22.
C, 44.17; H, 5.46; N, 18.08; S, 5.98%. m
max/cmÀ1 1594 (C@N). 1H
NMR (300 MHz, DMSO-d6, 25 °C): d = 1.46 (18H, s, CH3 (tBu)),
3.52 (4H, s, NH–CH2), 4.37 (12H, s, P–CH2 (PTA)), 4.47 (6H, d,
J = 13.85, N–CHax–N (PTA)), 4.55 (6H, d, J = 12.70, N–CHeq–N
(PTA)), 6.54 (2H, t, J = 7.58, Ar–H), 7.09 (2H, s, NH), 7.30 (4H, m,
Ar–H), 8.33 (2H, d, J = 13.47, CH@N) ppm. 31P{1H} NMR
(121 MHz, DMSO-d6, 25 °C): d = À40.28 (2P, s, PTA) ppm. MS ESI:
m/z 365 (100%, [M+H+2Na]3+); 1052 (10%, [M]+).
Found: C, 38.04; H, 4.61; N, 13.76; S, 4.99%. m
max/cmÀ1 1594
cmÀ1 (C@N).
2.4.8. Compound 4b
Compound 4b was obtained from compound
4 (0.086 g,
0.177 mmol), triethylamine (0.05 ml) and cis-[Pt(PTA)2Cl2]
(0.206 g, 0.355 mmol). The product obtained was a yellow powder.
Yield 0.167 g (79%). M.p. no melting < 300 °C. Anal. Calc. for
2.4.4. Compound 4a
C
30H38N12O2S2Cl2Pt2P2Á6H2O: C, 27.85; H, 3.89; N, 12.99; S, 4.95.
Compound 4a was obtained from compound
4
(0.045 g,
Found: C, 27.47; H, 3.18; N, 13.14; S, 4.21%. m
max/cmÀ1 1595
0.09 mmol), triethylamine (0.02 ml) and cis-[Pd(PTA)2Cl2] (0.090 g,
0.18 mmol). The product obtained was a yellow powder. Yield
0.077 g (83%). M.p. no melting < 300 °C. Anal. Calc. for
(C@N), 1631 (C@N). 1H NMR (400 MHz, DMSO-d6, 25 °C): d = 3.55
(4H, s, NH–CH2), 4.31 (12H, s, P–CH2 (PTA)), 4.50 (6H, d, J = 13.82,
N–CHax–N (PTA)), 4.58 (6H, d, J = 12.69, N–CHeq–N (PTA)), 7.07
(2H, d, J = 9.09, Ar–H), 7.26 (2H, s, NH), 7.35 (2H, dd, J = 2.70,
8.91, Ar–H), 7.64 (2H, d, J = 2.84, Ar–H), 8.64 (2H, d, J = 10.99,
C30H38N12S2P2O2Cl2Pd2: C, 35.73; H, 3.79; N, 16.67; S, 6.36. Found:
C, 34.64; H, 4.01; N, 15.11; S, 6.01%.
m
max/cmÀ1 1595 (C@N). 1H

T. Stringer et al. / Polyhedron 31 (2012) 486–493
489
CH@N) ppm. 31P{1H} NMR (161 MHz, DMSO-d6, 25 °C): d = À61.60
(2P, s, PTA) ppm, J = 3343.30. MS ESI: m/z 1117 (100%, [MÀCl]+);
1187 (30%, [M+H]+).
(6H, m, N–CH2), 3.38 (6H, m, NH–CH2), 4.27 (18H, s, P–CH2
(PTA)), 4.41 (9H, d, J = 12.81, N–CHax–N (PTA)), 4.55 (9H, d,
J = 12.32, N–CHeq–N (PTA)), 6.89 (3H, d, J = 8.95, Ar–H), 7.20 (6H,
m, NH, Ar–H), 7.39 (3H, d, J = 2.74, Ar–H), 8.19 (3H, d, J = 12.92,
CH@N) ppm. 31P{1H} NMR (121 MHz, DMSO-d6, 25 °C):
d = À36.32 (3P, s, PTA) ppm. 13C{1H} NMR (100 MHz, DMSO-d6,
25 °C): d = 43.93, 49.90, 52.80, 71.82, 117.08, 119.02, 122.35,
131.73, 131.99, 147.16, 160.35, 170.69 ppm. MS ESI: m/z 1569
(10%, [M]+); 785 (90%, [M+2H]2+).
2.5. Synthesis of trinuclear Pd(II) (6a–9a) and Pt(II) (6b–9b)
thiosemicarbazone complexes
2.5.1. Compound 6a
Compound 6a was obtained from compound
6 (0.044 g,
0.06 mmol), triethylamine (0.03 ml) and cis-[Pd(PTA)2Cl2]
(0.0951 g, 0.19 mmol). The product was obtained as a yellow pow-
der. Yield 0.083 g (87%). M.p. 245–247 °C (with decomposition).
Anal. Calc. for C48H66N19S3O3Pd3P3Á8H2O: C, 35.81; H, 5.13; N,
2.5.5. Compound 6b
Compound 6b was obtained from compound
6 (0.074 g,
16.54; S, 5.97. Found: C, 35.58; H, 4.77; N, 16.67; S, 4.70%. mmax
/
0.109 mmol), triethylamine (0.05 ml) and cis-[Pt(PTA)2Cl2]
(0.185 g, 0.319 mmol). The product was obtained as a yellow-or-
ange amorphous solid. Yield 0.078 g (41%). M.p. 231–233 °C. Anal.
Calc. for C48H66N19S3O3Pt3P3: C, 33.29; H, 3.84; N, 15.37; S, 5.55.
cmÀ1 1598 (C@N). 1H NMR (400 MHz, DMSO-d6, 25 °C): d = 2.72
(6H, m, N–CH2), 3.33 (6H, m, NH–CH2), 4.28 (18H, s, P–CH2
(PTA)), 4.41 (9H, d, J = 13.27, N–CHax–N (PTA)), 4.55 (9H, d,
J = 12.69, N–CHeq–N (PTA)), 6.55 (3H, t, J = 6.84, Ar–H), 6.92 (3H,
d, J = 8.27, Ar–H), 7.04 (3H, s, NH), 7.26 (3H, t, J = 7.94, Ar–H),
7.39 (3H, d, J = 7.91, Ar–H), 8.31 (3H, d, J = 12.99, CH@N) ppm.
31P{1H} NMR (161 MHz, DMSO-d6, 25 °C): d = À40.55 (3P, s,
PTA) ppm. 13C{1H} NMR (100 MHz, DMSO-d6, 25 °C): d = 44.48,
50.67, 54.08, 72.66, 115.17, 118.80, 121.51, 133.30, 135.05,
149.09, 162.52, 171.15 ppm. MS ESI: m/z 1466 (25%, [M+H]+).
Found: C, 33.07; H, 4.07; N, 15.35; S, 4.69%.
m
max/cmÀ1 1599
(C@N). 1H NMR (400 MHz, DMSO-d6, 25 °C): d = 2.70 (6H, m, N–
CH2), 3.33 (6H, m, NH–CH2), 4.15 (18H, s, P–CH2 (PTA)), 4.36 (9H,
d, J = 13.11, N–CHax–N (PTA)), 4.44 (9H, d, J = 12.78, N–CHeq–N
(PTA)), 6.60 (3H, t, J = 7.25, Ar–H), 6.98 (3H, d, J = 8.49, Ar–H),
7.10 (3H, s, NH), 7.32 (3H, t, J = 7.22, Ar–H), 7.46 (3H, d,
J = 8.31, Ar–H), 8.57 (3H, d, J = 11.20, CH@N) ppm. 31P{1H}
NMR (161 MHz, DMSO-d6, 25 °C): d = À61.49 (3P, s, PTA) ppm,
J = 3348.80. 13C{1H} NMR (100 MHz, DMSO-d6, 25 °C): d = 44.80,
50.19, 53.92, 72.79, 115.66, 118.77, 121.29, 132.68, 134.29,
147.06, 160.58, 172.32 ppm. MS ESI: m/z 1731 (50%, [M]+).
2.5.2. Compound 7a
Compound 7a was obtained from compound
7 (0.041 g,
0.05 mmol), triethylamine (0.03 ml) and cis-[Pd(PTA)2Cl2]
(0.0782 g, 0.16 mmol). The product was obtained as an orange
powder. Yield 0.046 g (57%). M.p. 234–239 °C (with decomposi-
tion). Anal. Calc. for C51H72N19S3O6Pd3P3Á4H2O: C, 37.63; H, 4.95;
N, 16.35; S, 5.90. Found: C, 37.31; H, 4.80; N, 16.15; S, 6.53%.
2.5.6. Compound 7b
Compound 7b was obtained from compound
7 (0.164 g,
m
max/cmÀ1 1595 (C@N), 1621 (C@N). 1H NMR (300 MHz, DMSO-
0.213 mmol), triethylamine (0.10 ml) and cis-[Pt(PTA)2Cl2]
(0.368 g, 0.633 mmol). The product obtained was a yellow powder.
Yield 0.054 g (14%). M.p. 237–241 °C (with decomposition). Anal.
Calc. for C51H72N19O6S3Pt3P3: C, 33.63; H, 3.98; N, 14.61; S, 5.28.
d6, 25 °C): d = 2.72 (6H, m, N–CH2), 3.36 (6H, m, NH–CH2), 3.78
(9H, s, OCH3), 4.31 (18H, s, P–CH2 (PTA)), 4.44 (9H, d, J = 13.15,
N–CHax–N (PTA)), 4.55 (9H, d, J = 12.65, N–CHeq–N (PTA)), 6.46
(3H, m, Ar–H), 6.95 (9H, m, NH, Ar–H), 8.33 (3H, d, J = 13.18,
CH@N) ppm. 31P{1H} NMR (121 MHz, DMSO-d6, 25 °C):
d = À36.00 (3P, s, PTA) ppm. 13C{1H} NMR (100 MHz, DMSO-d6,
25 °C): d = 44.91, 50.83, 53.74, 56.98, 72.72, 114.18, 114.87,
118.57, 126.85, 148.79 151.69, 153.73, 170.82 ppm. MS ESI: m/z
1556 (100%, [M]+); 778 (20%, [M+2H]2+).
Found: C, 32.03; H, 4.05; N, 13.79; S, 4.65%.
m
max/cmÀ1 1592
(C@N), 1631 (C@N). 1H NMR (300 MHz, DMSO-d6, 25 °C): d = 2.72
(6H, t, J = 6.37, N–CH2), 3.42 (6H, m, NH–CH2), 3.80 (9H, s, OCH3),
4.24 (18H, s, P–CH2 (PTA)), 4.48 (18H, s, N–CH2 (PTA)), 6.50 (3H,
t, J = 7.79, Ar–H), 6.86 (3H, s, NH), 6.95 (3H, dd, J = 1.50, 7.65, Ar–
H), 7.07 (3H, dd, J = 1.55, 8.24, Ar–H), 8.51 (3H, d, J = 11.22,
CH@N) ppm. 31P{1H} NMR (121 MHz, DMSO-d6, 25 °C):
d = À56.90 (3P, s, PTA) ppm, J = 3333.81. 13C{1H} NMR (75 MHz,
DMSO-d6, 25 °C): d = 44.09, 49.52, 53.13, 56.23, 72.01, 113.67,
114.14, 118.04, 125.55, 146.09, 150.98, 154.49, 171.51 ppm. MS
ESI: m/z 1821 (44%, [M]+); 912 (10%, [M+2H]2+).
2.5.3. Compound 8a
Compound 8a was obtained from compound
8 (0.082 g,
0.965 mmol), triethylamine (0.04 ml) and cis-[Pd(PTA)2Cl2]
(0.142 g, 0.289 mmol). The product was obtained as a yellow pow-
der. Yield 0.099 g (63%). M.p. decomposes at 274 °C.
m
max/cmÀ1
1594 (C@N), 1624 (C@N). 1H NMR (300 MHz, DMSO-d6, 25 °C):
t
d = 1.43 (27H, s, Bu), 2.75 (6H, m, N–CH2), 3.41 (6H, m, NH–CH2),
2.5.7. Compound 8b
4.33–4.54 (36H, m, CH2 (PTA)), 6.46 (3H, t, J = 7.54, Ar–H), 7.21
(9H, m, NH, Ar–H), 8.26 (3H, d, J = 13.44, CH@N) ppm. 31P{1H}
NMR (121 MHz, DMSO-d6, 25 °C): d = À40.11 (3P, s, PTA) ppm.
13C{1H} NMR (100 MHz, DMSO-d6, 25 °C): d = 29.82, 35.66, 44.73,
51.48, 53.85, 72.31, 114.39, 118.60, 130.06, 133.76, 139.17,
149.95, 161.14, 169.41 ppm. MS ESI: m/z 1634 (30%, [M]+); 818
(70%, [M+2H]2+).
Compound 8b was obtained from compound 8 (0.085 g,
0.010 mmol), triethylamine (0.04 ml) and cis-[Pt(PTA)2Cl2]
(0.167 g, 0.289 mmol). The product was isolated as a yellow pow-
der. Yield 0.069 g (38%). M.p. 259–264 °C (with decomposition).
.
Anal. Calc. for C60H90N19O3S3Pt3P3 4CH2Cl2: C, 34.32; H, 4.41; N,
11.88; S, 4.29. Found: C, 34.28; H, 5.23; N, 16.25; S, 4.82%. mmax
/
cmÀ1 1594 (C@N), 1628 (C@N). 1H NMR (300 MHz, DMSO-d6,
t
25 °C): d = 1.45 (27H, s, Bu), 2.71 (6H, m, N–CH2), 3.40 (6H, m,
2.5.4. Compound 9a
NH–CH2), 4.27 (18H, s, P–CH2 (PTA)), 4.44 (18H, m, N–CH2
(PTA)), 6.53 (3H, t, J = 7.58, Ar–H), 7.07 (3H, s, NH), 7.30 (6H, d,
J = 7.75, Ar–H), 8.58 (3H, d, J = 11.35, CH@N) ppm. 31P{1H} NMR
(121 MHz, DMSO-d6, 25 °C): d = À60.76 (3P, s, PTA) ppm,
J = 3340.49. 13C{1H} NMR (100 MHz, DMSO-d6, 25 °C): d = 30.02,
35.95, 44.70, 51.27, 53.88, 72.64, 115.47, 119.13, 130.09, 133.74,
139.51, 148.21, 159.25, 171.31 ppm. MS ESI: m/z 1900 (60%,
[M]+); 951 (100%, [M+2H]2+).
Compound 9a was obtained from compound
9 (0.097 g,
0.124 mmol), sodium acetate (0.030 g, 0.362 mmol) and cis-
[Pd(PTA)2Cl2] (0.178 g, 0.362 mmol). The product obtained was a
yellow powder. Yield 0.164 g (84%). M.p. 241–246 °C (with decom-
position). Anal. Calc. for C48H63N6O3S3Pd3P3Cl3: C, 36.75; H, 4.05; N,
16.97; S, 6.13. Found: C, 35.12; H, 4.03; N, 16.00; S, 5.40%. mmax
/
cmÀ1 1597 (C@N). 1H NMR (300 MHz, DMSO-d6, 25 °C): d = 2.78

490
T. Stringer et al. / Polyhedron 31 (2012) 486–493
2.5.8. Compound 9b
aided in the assignment of the spectra. The proton NMR spectrum
Compound 9b was obtained from compound
9
(0.158 g,
of compound 4 revealed a twofold symmetry about the ethane
bridge. The imine signal appears at 8.36 ppm, while a singlet
attributed to the aliphatic protons of the ethylene bridge appear
at 3.88 ppm. A peak for the amino protons adjacent to the ethylene
spacer appear as a singlet at 8.74 ppm and the signal attributed to
the hydrazinic protons appear downfield at 11.56 ppm. These
shifts are consistent with those observed for the other members
of this series, thus confirming the integrity of this compound [17].
The proton NMR spectra of the trithiosemicarbazones (6–9)
bear great similarity to the spectra of their dithiosemicarbazone
counterparts. Signals for the imine protons are found between
8.35 and 8.57 ppm. Signals attributed to the hydrazinic protons ap-
pear in the range of 11.34–11.50 ppm. The methylene protons of
the alkyl bridges are found at approximately 2.85 and 3.75 ppm,
respectively. The carbon-13 NMR spectra of these compounds fur-
ther support their structures. Signals for the thione carbon atoms
of compounds 6–9 appear in the region of 176.88–177.64 ppm,
while the imine signals are found between 137.28 and
140.00 ppm. Absorption bands for the imine stretching frequencies
are observed in the region between 1605 and 1650 cmÀ1 in the IR
spectra of these ligands. This confirms formation of imine bonds as
a result of condensation of the thiosemicarbazides with the various
salicylaldehydes. Mass spectrometry data also supports the attain-
ment of these compounds. Compound 5 displayed a base peak at
m/z 369 corresponding to the [M+H]+ ion. Compounds 6, 7, 8 and
9 all displayed base peaks corresponding to their molecular ions
at m/z 681, 771, 849 and 785, respectively.
0.202 mmol), triethylamine (0.100 ml) and cis-[Pt(PTA)2Cl2]
(0.347 g, 0.598 mmol). The product obtained was a dark yellow
powder. Yield 0.196 g (54%). M.p. 250–254 °C. Anal. Calc. for
C
48H63N19O3S3Pt3P3Cl3: C, 31.42; H, 3.46; N, 14.51; S, 5.24. Found:
C, 30.19; H, 3.95; N, 13.65; S, 4.94%.
m
max/cmÀ1 1596 (C@N), 1628
(C@N). 1H NMR (300 MHz, DMSO-d6, 25 °C): d = 2.71 (6H, t,
J = 6.10, N–CH2), 3.39 (6H, m, NH–CH2), 4.23 (18H, s, P–CH2
(PTA)), 4.43 (9H, d, J = 13.48, N–CHax–N (PTA)), 4.51 (9H, d,
J = 12.75, N–CHeq–N (PTA)), 6.99 (3H, d, J = 9.07, Ar–H), 7.12 (3H,
m, NH), 7.27 (3H, dd, J = 2.80, 9.02, Ar–H), 7.52 (3H, d, J = 2.79,
Ar–H), 8.53 (3H, d, J = 11.04, CH@N) ppm. 31P{1H} NMR
(121 MHz, DMSO-d6, 25 °C): d = À58.19 (3P, s, PTA) ppm,
J = 3341.09. 13C{1H} NMR (75 MHz, DMSO-d6, 25°C): d = 43.95,
49.27, 53.06, 71.93, 118.07, 119.20, 122.50, 131.49, 131.62,
145.28, 158.27, 172.36 ppm. MS ESI: m/z 1835 (30%, [M]+); 918
(55%, [M+2H]2+).
2.6. Cytotoxic assay
Selected thiosemicarbazones and their complexes were evalu-
ated for their in vitro anticancer activity against the WHCO1
oesophageal cancer cell line, derived from biopsies of primary
oesophageal squamous cell carcinomas [21] and kindly provided
by Professor Rob Veale (University of Witwatersrand, South Africa).
IC50 determinations were carried out using the MTT assay. Briefly,
3000 cells were seeded per well in 96-well plates. Cells were incu-
bated at 37 °C under 5% CO2 (24 h), after which aqueous DMSO
3.2. Synthesis and characterization of binuclear Pd(II) (1a–4a),
binuclear Pt(II) (1b–4b), trinuclear Pd(II) (6a–9a) and trinuclear Pt(II)
(6b–9b) thiosemicarbazone complexes
solutions of each compound (10
tration of DMSO = 0.2%) were plated at various concentrations.
After 48 h incubation, observations were made, and MTT
(10 L) solution added to each well. After 4 h incubation, solubili-
zation solution (100 L) was added to each well, and plates were
lL, with a constant final concen-
a
l
Reaction of the thiosemicarbazones has been carried out with
metal precursors containing a water soluble phosphine, namely
1,3,5-triaza-7-phosphaadamantane (PTA) to afford an interesting
series of multimeric thiosemicarbazone compounds with potential
biological properties. Polynuclear thiosemicarbazone palladium
and platinum complexes were then prepared from the afore-men-
tioned ligands using two PTA precursors namely; [Pd(PTA)2Cl2] and
[Pt(PTA)2Cl2] [19,20]. Binuclear complexes (1a–4a and 1b–4b)
were prepared by reaction of the dithiosemicarbazone ligands
and the respective platinum group metal precursor in the presence
of triethylamine in a 1:2:2 molar ratio, respectively. The trinuclear
complexes (6a–9a and 6b–9b) were obtained in a similar manner,
however, a 1:3:3 (ligand:metal precursor:base) molar ratio was
used. The method used to prepare these complexes is outlined in
Scheme 2. These complexes were obtained as yellow or orange
solids in various yields. The trinuclear complexes are sparingly sol-
uble in polar solvents whereas the dithiosemicarbazone complexes
have poor solubility even in DMSO. The complexes do not exhibit
good solubility in water despite incorporation of the water-soluble
phosphine ligand. The insoluble nature of complex 3b in most deu-
terated solvents (including DMSO-d6) did not allow for any NMR
spectroscopic data to be obtained for this complex. The 1H NMR
data obtained for the rest of the complexes revealed that complex-
ation of each thiosemicarbazone moiety occurs in a dianionic man-
ner through the thiolate sulfur and phenolic oxygen. This is
supported by the absence of signals accounting for the phenolic
and hydrazinic protons. Two types of methylene protons are pres-
ent in the PTA co-ligand. One type is assigned to the P–CH2–N pro-
tons, which occur as a singlet in the region of 4.40 ppm. Signals for
the protons of the N–CH2–N moiety possess an AB spin system and
appear as two doublets. One doublet corresponds to the three
N–CHaxial–N protons, while the other is observed for the three
N–CHequatorial–N protons. This is consistent with other PTA
l
incubated overnight. Plates were read at 595 nm on a BioTek
microplate reader.
3. Results and discussion
3.1. Synthesis and characterization of multimeric thiosemicarbazone
ligands (4–9)
A series of multimeric thiosemicarbazone ligands have been
prepared including a 5-chlorosalicylaldimine dithiosemicarbazone
(4) and four new trithiosemicarbazones (6–9). Ligand 4 was ob-
tained using the method previously reported by our group [17]
whereby ethane-1,2-dithiosemicarbazide was condensed with
5-chlorosalicylaldehyde in DMF, followed by precipitation of the
desired product with water. The trithiosemicarbazones (6–9) were
obtained by condensation of tris(2-aminoethyl) thiosemicarbazide
(5) and various salicylaldehydes. These trithiosemicarbazones pos-
sess three thiosemicarbazone moieties linked to a nitrogen core via
ethyl linkers. Compound 5 was obtained by slight variation of the
method previously described by Dilworth and co-workers [15]. A
solution of the tris(2-aminoethyl)amine in water was treated with
carbon disulfide, sodium chloroacetate and HCl, presumably
affording a triacid precursor in situ, which is further reacted with
hydrazine hydrate to deliver the desired product. Condensation
of 5 with salicylaldehyde, 2-hydroxy-3-methoxy benzaldehyde,
3-tert-butyl salicylaldehyde and 5-chlorosalicylaldehyde gave rise
to ligands 6, 7 and 9 as pale yellow amorphous solids, while 8
was obtained as a yellow oil (Scheme 1). The structures of these
ligands were confirmed using 1H and 13C NMR spectroscopy, IR
spectroscopy, elemental analysis as well as ESI mass spectrometry.
Two-dimensional NMR experiments such as COSY and HSQC also

T. Stringer et al. / Polyhedron 31 (2012) 486–493
491
S
HO
NH
S
O
H2N
S
N
NH2
1) 3 eq NaOH/H2O
2) 3 eq CS2
3) 3 eq ClCH2CO2Na
4) HCl
NH
N
N
H
HO
S
S
S
O
O
NH2
OH
NH2NH2. H2O
R
R
H2N
HN
OH
OH
NH2
HN
O
S
3 eq
N
S
N
HN
H
S
HN
HN
HN
S
NH
OH
R
N
NH
N
6 - 9
5
S
NH
S
N
NH
NH
NH
H2N
OH
R
R = H (6), 3-OMe (7), 3-tBu (8), 5-Cl (9)
Scheme 1. Preparation of trithiosemicarbazone ligands.
transition metal complexes [22–24]. In both the Pd and Pt com-
plexes, the signal for the imine proton is observed as a doublet.
Coupling constants of approximately 13 Hz are observed for the
Pd complexes and 11 Hz for the Pt derivatives. This is expected
as the metal center coordinates to the azomethine nitrogen as well,
supporting coordination in a tridentate manner. The appearance of
the imine proton signal as a doublet is documented in literature for
similar triphenylphosphine complexes [4–6,17]. 31P{1H} NMR
spectroscopy was used to further confirm complexation of the li-
corresponding to the [M]+ fragment are observed in the case of
compounds 1b, 2b, 3a, 6b, 7a, and 7b. Peaks of the form [M+2H]+
are seen for complexes 8a, 8b, 9a and 9b. For complex 4b, a base
peak corresponding to the [MÀCl]+ fragment is also observed.
3.3. Preliminary biological data
Investigation of the biological activity of larger TSC molecules is
limited in literature. This therefore prompted our investigation
into the design and synthesis of larger thiosemicarbazone systems
for biological evaluation. The preparation of trithiosemicarbazone
compounds as potential anticancer agents stemmed from the phe-
nomenon that macromolecules are able to accumulate more effi-
ciently in tumor cells in comparison to healthy cells [25]. This
phenomenon is referred to as the Enhanced Permeability and
Retention (EPR) effect. Tumor cells display increased vascular per-
meability due to an increased porosity of surrounding blood ves-
sels. This aids in diffusion of macromolecules into cancerous
cells. Once inside these cells, the molecules are retained due to
poor lymphatic drainage of the cell [25]. This supports the use of
larger compounds for selective targeting of abnormal cells.
Although the systems investigated in this study are not considered
to be macromolecules, it is worthwhile investigating the effect of
varying size and metal nuclearity on biological activity. Herein
gand. Each Pd complex displays
a singlet at approximately
À40.00 ppm for the phosphorus nuclei of the PTA ligands, while
each corresponding Pt derivative displays typical resonances at
approximately À60.00 ppm. Infrared spectroscopy confirms coor-
dination of ligands in the thiolate form as two absorption bands
corresponding to the C@N bonds are found in each spectrum of
most of the compounds. Bands of higher frequency are observed
between 1619 and 1635 cmÀ1, while bands of lower frequency
are observed between 1592 and 1599 cmÀ1. Upon complexation,
a new band is observed due to formation of a second C@N bond
upon deprotonation of the hydrazinic nitrogen. Mass spectrometry
data also supports the integrity of these complexes. Due to the
poor solubility of complex 3b in most solvents, mass spectrometry
could not be conducted. In the case of complexes 1a, 2a, 4a and 6a,
the spectra displayed peaks corresponding to the [M+H]+ ion. Peaks

492
T. Stringer et al. / Polyhedron 31 (2012) 486–493
R
HO
S
H
N
H
N
N
N
N
H
N
H
S
OH
R
1 - 4
1) 2 eq. Et3N
EtOH / MeOH
2) 2 eq. cis-[M(PTA)2Cl2]
PTA
R
S
M
O
H
N
N
N
N
N
H
N
O
M
S
R
N
PTA
1a-4a (Pd) and 1b-4b (Pt)
N
S
N
R
HN
HN
O
R
H
HN
M
N
N
HO
H
N
H
N
N
N
S
PTA
N
N
1) 3 eq. Et3N
O
M
S
NH
S
R
2) 3 eq. cis-[M(PTA)2Cl2]
OH
N
NH
R
PTA
N
S
NH
EtOH / MeOH
M
N
S
O
PTA
HO
R
6a-9a (Pd) and 6b-9b (Pt)
R
R = H; M = Pd (1a,6a),M = Pt (1b,6b)
R = 3-OMe; M = Pd (2a,7a),M = Pt (2b,7b)
t
R = 3-Bu; M = Pd (3a,8a), M = Pt (3b,8b)
R = 5-Cl; M = Pd (4a,9a),M = Pt (4b,9b)
Scheme 2. Preparation of multimeric thiosemicarbazone complexes.
we discuss some preliminary results obtained from the biological
evaluation of selected thiosemicarbazone ligands and complexes
against the oesophageal cancer WHCO1 cell-line. The IC50 values
are represented in Table 1. The synthesis of complexes M1–M3
(Fig. 1) has been reported by our group [18].
the PTA ligand. The dithiosemicarbazone complexes proved prob-
lematic during the biological evaluation due to the poor solubility
ofthesecompoundsintheaqueoustestingmediumdespitethepres-
ence of the water-soluble phosphine, therefore no reproducible data
could be obtained for these complexes. The low water-solubility is
mainly attributed to the thiosemicarbazone moiety, as the solubility
of these compounds did not improve substantially despite the use of
a water soluble co-ligand. There has also been a report of self-aggre-
gation of thiosemicarbazone systems, which may contribute to their
water-insoluble nature [26]. Complex 9b showed good activity
against this particular cell-line, but its activity is comparable to the
activity of the free ligand (9). Overall, some of the selected
compounds display promising anticancer activity, but further struc-
ture–activity studies are required in order to improve on the efficacy
of these types of compounds.
Trithiosemicarbazone ligand
(IC50 = 32.98 M), while the 5-chloro derivative (9) displays in-
creased activity with an IC50 value of 4.42 M. The activity of this li-
gand is very similar to that of the analogous dithiosemicarbazone
(IC50 = 4.43 M). In this case, increasing the number of thiosemicar-
7 displays moderate activity
l
l
l
bazone moieties does not lead to an appreciable increase in the
activity of the compound. The mononuclear palladium complexes
(M1–M3) display good activity in the low micromolar range. It ap-
pears as though the nature of the R-group does not play a significant
role on activity in this series. The biological evaluation of similar
mononuclear salicylaldimine triphenylphosphine complexes was
previously reported against the same cell-line [6]. Comparison of
the results revealed that the PTA derivatives display enhanced activ-
ity in comparison to their PPh3 counterparts. This may be attributed
to slightly enhanced aqueous solubility of these compounds due to
4. Conclusions
A series of multimeric salicylaldimine thiosemicarbazones (4,
6–9) and their corresponding palladium and platinum complexes

T. Stringer et al. / Polyhedron 31 (2012) 486–493
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Table 1
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IC50 values (lM) obtained for selected compounds in WHCO1 cells.
a,b
Compound
R
Type
M
IC50
(lM)
(h) D.X. West, A.E. Liberta, S.B. Padhye, R.C. Chikate, P.B. Sonawane, A.S.
Kumbhar, R.G. Yerande, Coord. Chem. Rev. 123 (1993) 49;
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(j) J.P. Scovill, D.L. Klayman, C.F. Franchino, J. Med. Chem. 25 (1982) 1261;
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(l) A. Papageorgiou, Z. Iakovidou, D. Mourelatos, E. Mioglou, L. Boutis, A. Kotsis,
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M1
M2
M3
4
6
7
7a
7b
9
H
mono
mono
mono
di
tri
tri
tri
tri
tri
tri
Pd
Pd
Pd
–
–
–
Pd
Pt
–
1.37
1.04
1.05
4.43
4.85
3-OMe
3-tBu
5-Cl
H
3-OMe
3-OMe
3-OMe
5-Cl
32.98
inactive
0.13
4.42
3.14
9b
5-Cl
Pt
a
Drug concentration required for 50% inhibition of cell viability.
b
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(2005) 1154.
Standard error
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aldimine dithiosemicarbazone and new trithiosemicarbazone
complexes have been prepared efficiently using templated proce-
dures. The salicylaldimine ligands were complexed using two me-
tal precursors of the general formula cis-[M(PTA)2Cl2], where
M = Pd and Pt. Spectroscopic and analytical data supports triden-
tate coordination of each thiosemicarbazone moiety to the imine
nitrogen, thiolate sulfur and phenolic oxygen atoms (O–N–S) giv-
ing rise to neutral complexes. The thiosemicarbazone complexes
display very low water-solubility despite incorporation of
a
water-soluble phosphine, this low aqueous solubility seems to be
elevated in the dithiosemicarbazone compounds. Despite this, se-
lected compounds were screened for anticancer activity in vitro
against WHCO1 oesophageal cancer cells and some of the com-
plexes, particularly the mononuclear derivatives, show promising
activity.
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We gratefully acknowledge the University of Cape Town, the
National Research Foundation (NRF) of South Africa, CANSA, and
the Carnegie Corporation for financial support. The Anglo Platinum
Corporation as well as the Johnson Matthey Research Centre is
acknowledged for a generous loan of palladium dichloride and
potassium tetrachloroplatinate.
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