Synthesis, characterization and cytotoxicity of platinum(II)/palladium(II) complexes with 1,3-diaminopropane and 4-toluensulfonyl-l-amino acid dianion

Article abstract of DOI:10.1016/j.ejmech.2012.09.052

Eight novel platinum(II)/palladium(II) complexes with 1,3-dap and 4-toluensulfonyl-l-amino acid dianion, [Pt(1,3-dap)(TsalaNO)]·0.5H ₂O (1a), [Pt(1,3-dap)(TsvalNO)] (1b), [Pt(1,3-dap)(TspheNO)] (1c), [Pt(1,3-dap)(TsserNO)] (1d), [Pd(1,3-dap)(Ts

Full text of DOI:10.1016/j.ejmech.2012.09.052

European Journal of Medicinal Chemistry 58 (2012) 281e286
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European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis, characterization and cytotoxicity of platinum(II)/palladium(II)
complexes with 1,3-diaminopropane and 4-toluensulfonyl- -amino acid dianion
L
,
b
,
a
,
,
,
,
,b,
Jinchao Zhang a , Lili Ma b, Huiru Lu a b, Yuechai Wang a b, Shenghui Li a b, Shuxiang Wang a
*
*
,
Guoqiang Zhou a
,
b
a College of Chemistry & Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Hebei University, Baoding 071002, China
b Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Eight novel platinum(II)/palladium(II) complexes with 1,3-dap and 4-toluensulfonyl-L-amino acid dia-
Received 28 July 2012
Received in revised form
22 September 2012
Accepted 24 September 2012
Available online 23 October 2012
nion, [Pt(1,3-dap)(TsalaNO)]$0.5H2O (1a), [Pt(1,3-dap)(TsvalNO)] (1b), [Pt(1,3-dap)(TspheNO)] (1c),
[Pt(1,3-dap)(TsserNO)] (1d), [Pd(1,3-dap)(TsalaNO)]$1.5H2O (2a), [Pd(1,3-dap)(TsvalNO)] (2b), [Pd(1,3-
dap)(TspheNO)] (2c) and [Pd(1,3-dap)(TsileNO)] (2d) have been synthesized and characterized by
elemental analysis, IR, UV, 1H NMR and mass spectrometry techniques. Crystal structure of the complex
1b has been determined by X-ray diffraction. The cytotoxicity was tested by MTT and SRB assays. The
complexes (1ae1d and 2ae2d) exert cytotoxicity against Bel-7402, HL-60, KB and BGC-823, but none of
them is more active than cisplatin. The results suggest that metal ions, amino acids and aliphatic N-
containing ligands have effect on cytotoxicity, while the IC50 values do not show definite correlation with
variation of them.
keywords:
Platinum(II)/palladium(II)
Synthesis
4-Toluenesulfonyl-L-amino acids
Ó 2012 Elsevier Masson SAS. All rights reserved.
1,3-Diaminopropane
Cytotoxicity
1. Introduction
anticancer drugs [10,11]. Aromatic N-containing ligands, including
pyridine, quinoline, phenanthroline and their derivatives, were
Nowadays, cisplatin is still one of the most successful antineo-
plastic drugs, which is used both alone and in combination with
other drugs for the clinical treatment of numerous types of cancers
including bladder, ovarian, head and neck, testicular and lung
cancers [1]. Cisplatin administration is often limited by severe toxic
side-effects, as well as the intrinsic and acquired resistance
possessed by various cancers [2e4]. To overcome the shortages of
cisplatin, numerous platinum-based compounds have been devel-
oped. Nevertheless, only carboplatin and oxaliplatin have received
worldwide approval, nedaplatin, lobaplatin and heptaplatin have
gained regionally limited approval and a few platinum drugs
continue to be evaluated in clinical trials [5,6]. These drawbacks
have spurred the chemists to find alternative chemotherapeutic
strategies [7e9].
introduced into metal-based anticancer drugs because of their
ability to participate as DNA intercalators [12e14]. Owing to higher
lability of palladium versus platinum analogs, amino acid ligands,
which do not dissociate easily in aqueous solution, have been used
to synthesize palladium anticancer complexes [15]. A series of
platinum(II)/palladium(II) complexes with aromatic N-containing
ligands and amino acids have shown significant cytotoxic activities.
Jin et al. synthesized and characterized nine complexes of plati-
num(II) with phen and amino acids (where amino acids are Gly, His,
Cys, Ile, Ala, Pro, Ser, Asp and Glu). The results indicated that the
IC50 value of [Pt(phen)(Pro)]Cl2$H2O was similar to cisplatin,
though most complexes were less cytotoxic than cisplatin [16]. In
addition, the cytotoxicity of some platinum(II) complexes with
phen and amino acids (where amino acids are Gly, Ala, Leu, and Tyr)
were reported by Mital et al. These complexes exhibit growth
inhibition of P388 lymphocytic leukemic cells, but the IC50 values
for the platinum(II) complexes are higher than those of cisplatin
[17]. Puthraya et al. reported the synthesis and cytotoxicity of
palladium(II) complexes of the formula [Pd(bipy)(AA)]nþ (where
AA is an anion of Cys, Asp, Glu, Met, His, Arg, Phe, Tyr, or Try and
n ¼ 0 or 1). Among the effective [Pd(bipy)(AA)]nþ complexes, side
chain of the amino acids may influence the inhibitory activity. This
inhibitory activity was found to be in decreasing order as follows:
Based on the structural and thermodynamic similarity between
platinum(II) and palladium(II) complexes, there is an increased
interest in the study of palladium(II) derivatives as potential
* Corresponding authors. College of Chemistry & Environmental Science, Chem-
ical Biology Key Laboratory of Hebei Province, Hebei University, Baoding 071002,
China. Tel./fax: þ86 0312 5079005.
E-mail addresses: jczhang6970@yahoo.com.cn (J. Zhang), wsx@hbu.cn
(S. Wang).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2012.09.052

282
J. Zhang et al. / European Journal of Medicinal Chemistry 58 (2012) 281e286
nonpolar hydrophobic > polar uncharged > charged side groups
[12]. Mital et al. reported the synthesis and cytotoxicity of palla-
dium(II) complexes of type [Pd(phen)(AA)]þ (where AA is an anion
of Gly, Ala, Leu, Phe, Tyr, Try, Val, Pro, or Ser), but the IC50 values do
not show definite correlation with variation of the amino acid side
chains [18]. The cytotoxic study of [Pd(AMBI)(AA)]nþ (where AA is
an anion of Gly, Ala, Cys, Met, or Ser) was reported by A.A. El-Sherif.
The result indicated that [Pd(AMBI)(Met)]Cl$H2O showed signifi-
2. Result and discussion
2.1. Synthesis and characterization
The platinum(II)/palladium(II) complexes [Pt(1,3-dap)(TsalaNO)]$
0.5H2O (1a), [Pt(1,3-dap)(TsvalNO)] (1b), [Pt(1,3-dap)(TspheNO)]
(1c), [Pt(1,3-dap)(TsserNO)] (1d), [Pd(1,3-dap)(TsalaNO)]$1.5H2O
(2a), [Pd(1,3-dap)(TsvalNO)] (2b), [Pd(1,3-dap)(TspheNO)] (2c) and
[Pd(1,3-dap)(TsileNO)] (2d) have been prepared by the reaction of
[Pt(1,3-dap)Cl2] or [Pd(1,3-dap)Cl2] with 4-toluenesulfonyl-L-amino
acids: TsalaH2, TsvalH2, TspheH2, TsserH2 or TsileH2 in a mixture of
CH3OH/H2O (see Scheme 1).
cant activity against HCT116 cells with IC50 value of 0.74
while [Pd(AMBI)(Cys)] showed cytotoxicity against HEP2 with IC50
value of 0.60
g mLꢀ1. Their cytotoxicity against HCT116 and HEP2
m ,
g mLꢀ1
m
decreased in the sequences: Met > Ser > Ala > Gly > Cys, and
Cys > Ser > Ala > Met > Gly, respectively [19]. We previously re-
ported the synthesis and cytotoxicity of [Pd(bipy)(TsAANO)]$nH2O
and [Pd(phen)(TsAANO)]$nH2O (where AA is Ala, Val, Leu, or Phe
and n ¼ 0, 1, 1.5, 2, or 2.5). The results indicated that the complexes
had cytotoxicity against BGC-823, Bel-7402, KB and HL-60, more-
over, the complex [Pd(phen)(TsleuNO)]$H2O showed higher cyto-
toxicity than cisplatin against BGC-823, Bel-7402 and KB [20].
Considering that all the clinically used platinum-based anti-
cancer drugs have aliphatic N-containing ligands as carrier groups,
the structureeactivity relationships of the five-, six- and seven-
membered ring structure (which are abbreviated as 5-R, 6-R and
7-R, respectively) alky-1,4-butanediamine Pt(II) complexes with
two different leaving groups (either dichloride or cyclobutane-1,1-
dicarboxylate) toward L1210 cells were summarized. Among these
complexes, 7-R had the highest cytotoxic activity [21]. We previ-
ously reported the synthesis and cytotoxicity of five palladium(II)
complexes [Pd(en)(TsAANO)]$nH2O (where AA is Ser, Gly, Ala, Leu,
or Phe and n ¼ 0,1,1.5, or 2). The results indicated that the complexes
demonstrated the best cytotoxicity against HL-60, BGC-823, Bel-
7402, and KB when amino acid was Phe [22]. In order to further
explore the structureeactivity relationships of platinum(II)/palla-
The complex 2c was observed in the ESI-MS as singly charged
[M þ Na]þ ion of m/z 520.0. The experimental isotope pattern for
this ion matches theoretical prediction (see Fig. S1). ESI-MS of the
other seven complexes is similar to that of the complex 2c. These
results provide evidence for the formation of the complexes
(1ae1d and 2ae2d). What’s more, there is good agreement
between calculated and measured values for elemental analysis of
the complexes (1ae1d and 2ae2d).
4-Toluenesulfonyl-L-amino acids have shoulders at 267 and
273 nm in UVevis spectroscopy. After formation of the complexes,
the shoulders turn into a single peak at 266 nm for the complexes
(1ae1d) and at 268 nm for the complexes (2ae2d), respectively. In
addition, there is also a broad MLCT peak at 360e365 nm for the
complexes (1ae1d) and at 360e370 nm for the complexes (2ae2d),
respectively, which further confirms the coordination of the plati-
num(II)/palladium(II) and 1,3-dap.
The IR spectra of the complexes (1ae1d and 2ae2d) are similar.
The sulfonamide groups of TsalaH2, TsvalH2, TspheH2, TsserH2 and
TsileH2 have a strong and sharp yNH in 3260e3290 cmꢀ1 region.
These bands disappear for the complexes (1ae1d and 2ae2d),
showing that the sulfonamide group has been deprotonated. This
is further confirmed by the sulfonamide (I) shifting from
w1630 cmꢀ1 to w1550 cmꢀ1 and the disappearance of the
sulfonamide (II) from original region. New bands at about 550 cmꢀ1
dium(II) complexes with 4-toluenesulfonyl-L-amino acid dianion
and N-containing ligands, and find new metal-based anticancer
drugs, the synthesis, characterization and cytotoxicity of eight new
platinum(II)/palladium(II) complexes (1ae1d and 2ae2d) with 4-
are assigned to yPdeN
/yPteN. The carboxylate group of the complexes
toluenesulfonyl-L-amino acid dianion and 1,3-dap are reported in
(1ae1d and 2ae2d) shows two bands, an intense antisymmetric
this paper for the first time.
carboxylate stretching
y
and a symmetric carboxylate
Þ
ðas; cooꢀ
Scheme 1. Synthetic routines of the complexes (1ae1d and 2ae2d).

J. Zhang et al. / European Journal of Medicinal Chemistry 58 (2012) 281e286
283
Table 1
stretching
y
ꢀ
, at about 1620 and 1360 cmꢀ1, respectively. The
values of Dyðs; cooÞðÞ
y
Þ ꢀ
y
ÞÞ of the complexes (1ae1d and
ðs; cooꢀ
ꢁ
ꢀ
Selected bond lengths (A) and angles ( ) for the complex 1b.
ðcooꢀ
ðas; cooꢀ
2ae2d) are in the range 217e328 cmꢀ1, which is greater than
1b
Dy
of the corresponding sodium carboxylates, so the carbox-
ðcooꢀ
Þ
Pt(1)eN(1)
Pt(1)eN(2)
Pt(1)eN(3)
Pt(1)eO(1)
2.014(4)
2.026(4)
2.048(5)
2.023(4)
ylate group may be monodentate coordinated through oxygen
atoms [23]. This is further confirmed by the appearance of the
bands of yPdeO and yPteO. These results are in good agreement with
the results revealed by X-ray crystal analysis.
N(1)ePt(1)eN(2)
N(2)ePt(1)eN(3)
N(3)ePt(1)eO(1)
O(1)ePt(1)eN(1)
O(1)ePt(1)eN(2)
N(1)ePt(1)eN(3)
95.25(19)
87.39(19)
95.10(17)
82.24(16)
176.80(19)
177.26(19)
The overall pattern of the 1H NMR spectra of the complexes (1ae
1d and 2ae2d) resembles very closely to that of the free ligands.
TsvalH2 shows a doublet at
proton of the sulfonamide group, but these peaks disappear for the
d
¼ 5.35, which is associated with the
complex 1b, which showing that the sulfonamide group has been
deprotonated. The a-hydrogen of TsvalH2 appears as a dd quartet,
but this proton appears as a doublet in the complex 1b, which also
shows the deprotonation of sulfonamide group (see Fig. S2 and S3).
1H NMR spectra of the complexes (1a, 1c, 1d and 2ae2d) are similar
to that of the complex 1b. These facts further confirm that the
sulfonamide group coordinates to platinum(II)/palladium(II)
through deprotonated sulfonamide nitrogen atom.
2.3. Cytotoxic studies
In our present work, as listed in Table 2, most complexes exert
cytotoxic effects against tested carcinoma cell lines; in addition,
they have selectivity against tested carcinoma cell lines. But none of
them shows higher cytotoxicity than cisplatin. The structuree
activity relationships are summarized as follows:
2.2. Structural studies
(1) The metal ions have important effect on cytotoxicity. The pal-
ladium(II) complexes 2a and 2c show better activities than
corresponding platinum(II) complexes 1a and 1c against HL-
60, Bel-7402, BGC-823 and KB. In addition, the palladium(II)
complex 2b is more active than corresponding platinum(II)
complex 1b against Bel-7402, while it is less active than 1b
against HL-60.
(2) The amino acids also exert effects on the cytotoxicity. For the
platinum(II) complexes 1ae1d with the same 1,3-dap and
different amino acids, the cytotoxicity against HL-60
and Bel-7402 decreases in the same sequences:
Ser > Val > Phe > Ala. The sequences of their cytotoxicity
toward BGC-823 and KB are: Phe > Val > Ser > Ala, and
Val > Phe > Ser > Ala, respectively. For the palladium(II)
complexes 2ae2d with the same 1,3-dap and different amino
acids, the cytotoxicity against HL-60 and Bel-7402 decreases in
the same sequences: Ile > Ala > Phe > Val.
(3) The N-containing ligands have important effect on cytotoxicity.
For platinum(II) complexes with same amino acid and different
N-containing ligands, [Pt(1,3-dap)(TspheNO)] (1c) is less active
than [Pt(bipy)(TspheNO)] against HL-60, BGC-823, Bel-7402,
and KB. [Pt(1,3-dap)(TsvalNO)] (1b) has better cytotoxicity
than corresponding complex [Pt(bipy)(TsvalNO)] against HL-
60, BGC-823, and Bel-7402. [Pt(1,3-dap)(TsserNO)] (1d) has
lower IC50 values than [Pt(bipy)(TsserNO)] against HL-60 and
Bel-7402, but [Pt(bipy)(TsserNO)] shows higher cytotoxicity
than [Pt(1,3-dap)(TsserNO)] (1d) against BGC-823 and KB [26].
A view of the molecular structure of [Pt(1,3-dap)(TsvalNO)] (1b)
is exhibited in Fig. 1. The selected bond lengths and angles of the
complex are given in Table 1. The platinum atom shows square-
planar coordination given by two nitrogen atoms of 1,3-dap, one
deprotonated sulfonamide nitrogen atom and one carboxylic
oxygen atom in each molecule. The angle between planar N(2)e
Pt(1)eN(3) and planar O(1)ePt(1)eN(1) is 2.064(165)ꢁ which
indicates that the Pt(1)eO(1)eN(1)eN(2)eN(3) plane is slightly
distorted. The PteN (deprotonated sulfonamide) bond length
ꢀ
(2.014(4) A) is similar to the PteN (1,3-dap) bond lengths (2.026(4)
ꢀ
and 2.048(5) A), while it is shorter than PteO (carboxylic oxygen)
ꢀ
bond length (2.023(4) A). Sigel et al. reported that the coordinating
qualities of the deprotonated amide nitrogen atoms were “O-like”
as the deprotonated amide group is isoelectronic with the
carboxylate group, and this has been confirmed by stability
constants of some complexes [24]. Gong et al. also reported that the
deprotonated amide nitrogen atom was exactly different from the
ordinary amino nitrogen atom and its coordinating property might
be “O-like” [25]. So we deduce that the coordinating property of the
deprotonated sulfonamide nitrogen atom may be also “O-like” (see
Fig. 1).
For the palladium(II) complexes with 4-toluenesulfonyl-L-
Table 2
The cytotoxicity of complexes in vitro (n ¼ 5).
Complexes
IC50
(
m
M)
HL-60
BGC-823
Bel-7402
KB
1a
1b
1c
1d
2a
2b
2c
2d
119.78 ꢂ 9.27
13.86 ꢂ 1.02
31.85 ꢂ 2.58
10.64 ꢂ 0.78
16.47 ꢂ 1.38
28.14 ꢂ 1.48
25.19 ꢂ 1.79
15.46 ꢂ 1.35
2.89 ꢂ 0.34
57.88 ꢂ 4.41
26.19 ꢂ 1.67
23.38 ꢂ 2.04
27.93 ꢂ 2.37
20.42 ꢂ 1.58
e
85.70 ꢂ 2.79
21.38 ꢂ 1.42
24.14 ꢂ 1.03
17.59 ꢂ 0.93
15.40 ꢂ 0.69
18.46 ꢂ 1.58
16.81 ꢂ 1.45
12.55 ꢂ 1.15
8.12 ꢂ 0.97
466.98 ꢂ 9.37
24.22 ꢂ 1.76
28.49 ꢂ 2.37
31.07 ꢂ 3.01
19.71 ꢂ 0.93
e
e
e
16.36 ꢂ 1.64
6.48 ꢂ 0.81
11.32 ꢂ 0.78
2.65 ꢂ 0.33
Cisplatin
Fig. 1. Molecular structure and atom-labeling scheme for the complex 1b.

284
J. Zhang et al. / European Journal of Medicinal Chemistry 58 (2012) 281e286
(1 mol Lꢀ1). 4-Toluenesulfonyl chloride (500 mg, 2.6 mmol) was
added to the solution, after 2.6 mL NaOH (1 mol Lꢀ1) was added
dropwise over 0.5 h. After further 8 h, the solution was cooled by ice
and acidified to pH ¼ 3e4 with HCl. The resulting white precipitate
was filtered. The collected solid was washed with cold H2O (50 mL)
and dried to give TsalaH2. TsalaH2: 1H NMR (600 MHz, DMSO-d6)
d(ppm) 8.04 (d, J ¼ 8.3 Hz, 1H, NH), 7.67 (d, J ¼ 7.9 Hz, 2H, ArH), 7.37
(d, J ¼ 8.1 Hz, 2H, ArH), 3.67e3.85 (m, 1H, CH), 2.37 (s, 1H, CH3), 1.14
(d, J ¼ 7.2 Hz, 3H, CH3). Melting point: 133.2e135.4 ꢁC.
amino acid dianion and N-containing ligands, when amino
acids are Ala, Val, Phe, and Ile, aliphatic N-containing ligand is
1,3-dap, they exert higher cytotoxicity than corresponding
complexes with 1,4-dab against Bel-7402. But [Pd(1,3-
dap)(TsalaNO)]$1.5H2O and [Pd(1,3-dap)(TsvalNO)] are less
active than corresponding complexes [Pd(1,4-dab)(TsalaNO)]
and [Pd(1,4-dab)(TsvalNO)] against HL-60. While [Pd(1,3-
dap)(TspheNO)] and [Pd(1,3-dap)(TsileNO)] have higher cyto-
toxicity
than
corresponding
complexes
[Pd(1,4-
dab)(TspheNO)]$0.5H2O and [Pd(1,4-dab)(TsileNO)] against
HL-60 [27,28].
TsvalH2, TspheH2, TsileH2 and TsserH2 were carried out in an
identical manner. TsvalH2: 1H NMR (600 MHz, CDCl3) d(ppm) 7.72 (d,
J ¼ 8.3 Hz, 2H, ArH), 7.27 (d, J ¼ 8.0 Hz, 2H, ArH), 5.35 (d, J ¼ 9.8 Hz,
1H, NH), 3.78 (dd, J ¼ 9.8, 4.7 Hz, 1H, CH), 2.16e2.03 (m, 1H, CH),
2.40 (s, 3H, CH3), 0.94 (d, J ¼ 6.8 Hz, 3H, CH3), 0.87 (d, J ¼ 8.2 Hz, 3H,
CH3). Melting point: 146.4e147.7 ꢁC. TspheH2: 1H NMR (600 MHz,
DMSO-d6) 8.18 (d, J ¼ 5.0 Hz, 1H, NH), 7.15e7.05 (m, 2H, ArH), 7.36e
7.16 (m, 5H, ArH), 7.12 (s, 2H, ArH), 3.82e3.92 (m, 1H, CH), 3.00e
2.87 (m, 1H, CH2), 2.83e2.66 (m, 1H, CH2), 2.34 (s, 3H, CH3).
Melting point: 150.4e152.9 ꢁC. TsileH2: 1H NMR (600 MHz, CDCl3)
d(ppm) 7.72 (d, J ¼ 8.1 Hz, 2H, ArH), 7.27 (d, J ¼ 8.3 Hz, 2H, ArH), 5.32
(d, J ¼ 9.7 Hz, 1H, NH), 3.82 (dd, J ¼ 9.7, 4.9 Hz, 1H, CH), 1.86e1.77
(m, 1H, CH), 1.44e1.34 (m, 1H, CH2), 1.20e1.10 (m, 1H, CH2), 0.90
(d, J ¼ 6.8 Hz, 3H, CH3), 0.86 (t, J ¼ 7.4 Hz, 3H, CH3). Melting point:
134.1e134.5 ꢁC. TsserH2: 1H NMR (600 MHz, DMSO-d6) d(ppm) 7.89
(d, J ¼ 8.6 Hz,1H, NH), 7.68 (d, J ¼ 7.9 Hz, 2H, ArH), 7.35 (d, J ¼ 7.9 Hz,
2H, ArH), 3.80e3.69 (m, 1H, CH), 3.53e3.45 (m, 2H, CH2), 2.37 (s,
3H, CH3). Melting point: 223.9e224.9 ꢁC.
In summary, for platinum(II)/palladium(II) complexes with 4-
toluenesulfonyl-L-amino acid dianion and aliphatic N-containing
ligands, all amino acids, aliphatic N-containing ligands and centre
metal ions have significant effects on cytotoxicity. For the plati-
num(II) complexes (1ae1d), when amino acid is Ala, the complex
has the least cytotoxicity. For the palladium(II) complexes (2ae2d),
when amino acid is Ile, the complex has the best cytotoxicity. But
the IC50 values do not show definite correlation with variation of
them. In addition, the effect on cytotoxicity is also related to tumor
cell type.
3. Conclusions
We have synthesized and characterized eight new palladium(II)/
platinum(II) complexes with 4-toluenesulfonyl-L-amino acid dia-
nions and 1,3-dap. Most complexes exert cytotoxic effects against
tested carcinoma cell lines, but none of them shows higher cyto-
toxicity than cisplatin. The cytotoxic experiment indicates that
metal ions, amino acids and aliphatic N-containing ligands have
effect on cytotoxicity, but the cytotoxicity do not show definite
correlation with variation of them. These results will be helpful for
the design of new metal-based antitumor agents.
Precursor complexes [Pt(1,3-dap)Cl2] (i), [Pd(1,3-dap)Cl2] (ii)
were synthesized according to a published procedure [29]. Yield: i:
Kelly solid, Yield: 45.4%, Anal. Calcd. for C3H10Cl2N2Pt (%): C, 10.59;
H, 2.96; N, 8.24. Found (%): C, 10.93; H, 2.70; N, 7.84; ii: Kelly solid,
Yield: 65.4%, Anal. Calcd. for C3H10Cl2N2Pd (%): C, 14.33; H, 4.01; N,
11.14. Found (%): C, 14.60; H, 3.68; N, 11.10.
4.3.1. [Pt(1,3-dap)(TsvalNO)] (1b)
4. Experimental section
[Pt(1,3-dap)Cl2] (20.0 mg, 0.059 mmol) was added to a 6 mL
CH3OH/H2O (volume 2:1) solution of TsvalH2 (23.9 mg,
0.088 mmol) when the solution temperature was heated to 50 ꢁC,
the mixture was adjusted to pH ¼ 9 by NaOH solution, then stirred
for 3e4 h. The solution was concentrated to about 80% of the
original volume by reduced pressure distillation. By evaporating
the concentrated solution at room temperature, the colorless
crystals suitable for X-ray diffraction were obtained after a few
weeks and separated from the solution. IR (KBr, cmꢀ1): 1605, 1379,
548, 418. 1H NMR (600 MHz, DMSO-d6) d(ppm) 8.02 (d, J ¼ 8.2 Hz, 2H,
ArH), 7.29 (d, J ¼ 8.1 Hz, 2H, ArH), 5.44e5.30 (m, 1H, NH2), 5.30e
5.15 (m, 1H, NH2), 5.13e4.99 (m, 1H, NH2), 4.92e4.85 (m, 1H,
NH2), 3.37 (d, J ¼ 4.6 Hz, 1H, CH), 2.53e2.51 (m, 4H, CH2), 2.36 (s,
3H, CH3), 2.00e1.90 (m, 1H, CH), 1.73e1.65 (m, 1H, CH2), 1.56e1.47
(m, 1H, CH2), 1.08 (d, J ¼ 6.9 Hz, 3H, CH3), 1.05 (d, J ¼ 6.9 Hz, 3H,
CH3). ESI-MS: 561.5 [M þ Na]þ. Anal. Calcd. for C15H25N3O4PtS (%):
C, 33.45; H, 4.68; N, 7.80. Found: C, 33.64; H, 4.55; N, 7.91.
4.1. Materials
4-Toluenesulfonyl chloride, K2[PdCl4] and K2[PtCl4] were of
chemical grade, 1,3-dap were of analytical grade. Commercially
pure Ala, Val, Phe, Ile and Ser were purchased from Sigma. RPMI-
1640 medium, trypsin and fetal bovine serum were purchased
from Gibco. MTT, SRB, benzylpenicillin and streptomycin were from
Sigma. Four different human carcinoma cell lines: HL-60 (immature
granulocyte leukemia), Bel-7402 (liver carcinoma), BGC-823 (gas-
trocarcinoma) and KB (nasopharyngeal carcinoma) were obtained
from American Type Culture Collection.
4.2. Instrumentation and measurement
Elemental analysis was determined on an Elementar Vario EL III
elemental analyzer. The IR spectra were recorded on a Perkine
Elmer Model-683 spectrophotometer using KBr pellets. The 1H
NMR spectra were recorded on a Bruker AVIII 600 NMR spec-
trometer. The mass spectra were measured by LCeMS apparatus
Agilent 1200-6310. X-ray single crystal structure was performed on
a Bruker SMART APEX II CCD diffractometer. The OD was measured
on a microplate spectrophotometer (Bio-Rad Model 680, USA).
4.3.2. [Pt(1,3-dap)(TsalaNO)]$0.5H2O (1a)
The synthesis of 1a was carried out in an identical manner to 1b
starting from [Pt(1,3-dap)Cl2] (20.0 mg, 0.059 mmol) and TsalaH2
(21.5 mg, 0.088 mmol). White solid. IR (KBr, cmꢀ1): 1656, 1328, 557,
450. 1H NMR (600 MHz, DMSO-d6) d(ppm) 8.01 (d, J ¼ 8.2 Hz, 2H,
ArH), 7.32 (d, J ¼ 8.0 Hz, 2H, ArH), 5.48e5.40 (m, 1H, NH2), 5.40e
5.25 (m, 1H, NH2), 5.20e5.50 (m, 1H, NH2), 5.05e4.90 (m, 1H,
NH2), 3.54 (q, J ¼ 7.0 Hz, 1H, CH), 2.70e2.58 (m, 2H, CH2), 2.58e2.52
(m, 2H, CH2), 2.37 (s, 3H, CH3),1.75e1.67 (m,1H, CH2),1.58e1.50 (m,
1H, CH2), 1.28 (d, J ¼ 7.0 Hz, 3H, CH3). ESI-MS: 549.9 [Me
0.5H2O þ K]þ. Anal. Calc. for C13H22N3O4.5PtS: C, 30.06; H, 4.27;
N, 8.09. Found: C, 29.97; H, 4.13; N, 8.49.
4.3. Synthesis of compounds
4-Toluenesulfonyl-L-amino acids were synthesized according to
the following procedure. To a rapidly stirred solution of Ala
(232 mg, 2.6 mmol) in 5.0 mL H2O was added 2.6 mL NaOH

J. Zhang et al. / European Journal of Medicinal Chemistry 58 (2012) 281e286
285
4.3.3. [Pt(1,3-dap)(TspheNO)] (1c)
NH2), 3.85e3.73 (m, 1H, CH), 3.36e3.31 (m, 2H, CH2), 3.04e2.94 (m,
1H, CH2), 2.93e2.84 (m, 1H, CH2), 2.34 (d, J ¼ 21.1 Hz, 5H, CH3, CH2),
1.60e1.40 (m, 2H, CH2). ESI-MS: 520.0 [M þ Na]þ. Anal. Calc. for
The synthesis of 1c was carried out in an identical manner to 1b
starting from [Pt(1,3-dap)Cl2] (20.0 mg, 0.059 mmol) and TspheH2
(28.1 mg, 0.088 mmol). White solid. IR (KBr, cmꢀ1): 1644,1349, 555,
429. 1H NMR (600 MHz, DMSO-d6) d(ppm) 7.98 (d, J ¼ 8.1 Hz, 2H,
ArH), 7.31e7.25 (m, ¼ 15.3, 6H, ArH), 7.25e7.20 (m, 1H, ArH), 5.10e
5.02 (m, 2H, NH2), 5.01e4.98 (m, 1H, NH2), 4.80e4.70 (m, 1H, NH2),
3.83 (t, J ¼ 5.2 Hz, 1H, CH), 3.02 (dd, J ¼ 12.9, 4.7 Hz, 1H, CH2), 2.91
(dd, J ¼ 12.9, 5.7 Hz, 1H, CH2), 2.63e2.55 (m, 1H, CH2), 2.45e2.37
(m, 2H, CH2), 2.37 (s, 3H, CH3), 2.27e2.21 (m, 1H, CH2), 1.57e1.50
(m, 2H, CH2). 13C NMR (150 MHz, DMSO-d6) d(ppm) 185.09 (1C,
COO), 141.84 (1C, Ar), 140.83 (1C, Ar), 138.09 (1C, Ar), 130.78 (2C,
Ar), 129.45 (2C, Ar), 127.99 (2C, Ar), 127.12 (2C, Ar), 126.23 (1C, Ar),
64.26 (1C, CH), 43.44 (1C, CH2), 43.40 (1C, CH2), 42.14 (1C, CH2),
28.00 (1C, CH2), 21.36 (1C, CH3). ESI-MS: 625.5 [M þ K]þ. Anal. Calc.
for C19H25N3O4PtS: C, 38.90; H, 4.30; N, 7.16. Found: C, 38.94; H,
4.36; N, 7.37.
C19H25N3O4PdS: C, 45.83; H, 5.06; N, 8.44. Found: C, 45.98; H, 4.59;
N, 8.34.
4.3.8. [Pd(1,3-dap)(TsileNO)] (2d)
The synthesis of 2d was carried out in an identical manner to 1b
starting from [Pd(1,3-dap)Cl2] (20.0 mg, 0.080 mmol) and TsserH2
(30.9 mg, 0.119 mmol). Yellow solid. IR (KBr, cmꢀ1): 1643, 1331, 567,
442. 1H NMR (600 MHz, DMSO-d6) d(ppm) 7.99 (d, J ¼ 8.1 Hz, 2H,
ArH), 7.34 (d, J ¼ 8.0 Hz, 2H, ArH), 4.52e4.45 (m, 1H, NH2), 4.35e
4.26 (m, 1H, NH2), 4.25e4.20 (m, 1H, NH2), 4.10e4.02 (m, 1H,
NH2), 2.55e2.52 (m, 1H, CH), 2.48e2.40 (m, 2H, CH2), 2.38 (s, 3H,
CH3), 2.37e2.32 (m, 1H, CH), 1.77e1.69 (m, 2H, CH2), 1.70e1.63 (m,
2H, CH2), 1.52e1.41 (m, 2H, CH2), 1.10 (d, J ¼ 6.8 Hz, 3H, CH3), 0.88 (t,
J ¼ 7.3 Hz, 3H, CH3). 13C NMR (150 MHz, DMSO-d6) d(ppm) 182.84
(1C, COO), 142.77 (1C, Ar), 140.70 (1C, Ar), 129.59 (2C, Ar), 126.98
(2C, Ar), 68.47 (1C, CH), 41.72 (1C, CH2), 41.39 (1C, CH2), 40.76 (1C,
CH2), 28.56 (1C, CH), 25.74 (1C, CH2), 21.37 (1C, CH3), 16.41 (1C,
CH3), 12.45 (1C, CH3). ESI-MS: 501.1 [M þ K]þ. Anal. Calc. for
4.3.4. [Pt(1,3-dap)(TsserNO)] (1d)
The synthesis of 1d was carried out in an identical manner to 1b
starting from [Pt(1,3-dap)Cl2] (20.0 mg, 0.059 mmol) and TsileH2
(22.8 mg, 0.088 mmol). White solid. IR (KBr, cmꢀ1): 1611, 1391, 551,
423. 1H NMR (600 MHz, DMSO-d6) d(ppm) 8.04 (d, J ¼ 8.2 Hz, 2H,
ArH), 7.68 (d, J ¼ 8.3 Hz, 2H, ArH), 5.50e5.40 (m, 1H, NH2), 5.30e
5.25 (m, 1H, NH2), 5.10e5.00 (m, 1H, NH2), 5.00e4.90 (m, 1H,
NH2), 4.30e4.25 (dd, J ¼ 6.9, 5.1 Hz, 1H, CH), 3.64e3.60 (m, 1H,
CH2), 3.59e3.54 (m, 1H, CH2), 3.48e3.44 (m, 1H, OH), 2.68e2.63 (m,
1H, CH2), 2.62e2.61 (m,1H, CH2), 2.61e2.57 (m,1H, CH2), 2.57e2.54
(m, 1H, CH2), 2.37 (s, 3H, CH3), 1.73e1.67 (m, 1H, CH2), 1.59e1.51 (m,
1H, CH2). ESI-MS: 565.95 [M þ K]þ. Anal. Calc. for C13H21N3O5PtS: C,
29.66; H, 4.02; N, 7.98. Found: C, 31.09; H, 4.17; N, 7.84.
C16H27N3O4PdS: C, 41.43; H, 5.87; N, 9.06. Found: C, 41.14; H, 5.88;
N, 8.96.
4.4. Data collection and structural refinement of the complex (1b)
The data collection of the complex 1b was performed on
a Bruker SMART APEX II CCD diffractometer equipped with
ꢀ
a graphite monochromatized Mo K
a
radiation (
l
¼ 0.71073 A) at
296(2) K. Multi-scan absorption corrections were applied using the
SADABS program. The structure was solved by the direct method
using the SHELXS-97 program. Refinements on F2 were performed
using SHELXL-97 by the full-matrix least-squares method with
anisotropic thermal parameters for all non-hydrogen atoms. Table 3
lists crystallographic details. Crystallographic data for the structural
analysis of the complex 1b have been deposited with the Cam-
bridge Crystallographic Data Centre, CCDC e 831020. Copies of this
information may be obtained free of charge from The Director,
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax: þ44 1223
336033; E-mail: deposit@ccdc.cam.ac.uk or http://www.ccdc.cam.
ac.uk).
4.3.5. [Pd(1,3-dap)(TsalaNO)]$1.5H2O (2a)
The synthesis of 2a was carried out in an identical manner to 1b
starting from [Pd(1,3-dap)Cl2] (20.0 mg, 0.080 mmol) and TsalaH2
(29.0 mg, 0.119 mmol). Yellow solid. IR (KBr, cmꢀ1): 1596, 1379, 549,
400. 1H NMR (600 MHz, DMSO-d6) d(ppm) 7.97 (d, J ¼ 8.1 Hz, 2H,
ArH), 7.35 (d, J ¼ 7.9 Hz, 2H, ArH), 4.63e4.57 (m, 1H, NH2), 4.45e
4.39 (m, 1H, NH2), 4.35e4.28 (m, 1H, NH2), 4.20e4.12 (m, 1H,
NH2), 3.40 (q, J ¼ 7.0 Hz, 1H, CH), 2.54e2.52 (m, 2H, CH2), 2.48e2.41
(m, 2H, CH2), 2.38 (s, 3H, CH3),1.72e1.64 (m,1H, CH2),1.52e1.44 (m,
1H, CH2), 1.29 (d, J ¼ 7.0 Hz, 3H, CH3). ESI-MS: 444.4 [Me
H2O þ Na]þ. Anal. Calc. for C13H23N3O5PdS: C, 35.50; H, 5.27; N,
9.55. Found: C, 34.96; H, 4.98; N, 10.33.
Table 3
Crystallographic data for the complex 1b.
4.3.6. [Pd(1,3-dap)(TsvalNO)] (2b)
1b
The synthesis of 2b was carried out in an identical manner to 1b
starting from [Pd(1,3-dap)Cl2] (20.0 mg, 0.080 mmol) and TsvalH2
(32.3 mg, 0.119 mmol). Yellow solid. IR (KBr, cmꢀ1): 1605,1325, 558,
433. 1H NMR (600 MHz, DMSO-d6) d(ppm) 8.00 (d, J ¼ 8.1 Hz, 2H,
ArH), 7.33 (d, J ¼ 8.0 Hz, 2H, ArH), 4.48e4.42 (m, 1H, NH2), 4.33e
4.21 (m, 2H, NH2), 4.11e4.04 (m, 1H, NH2), 3.27 (d, J ¼ 4.3 Hz, 1H,
CH), 2.54e2.52 (m, 1H, CH2), 2.47e2.40 (m, 2H, CH2), 2.38 (s, 3H,
CH3), 2.37e2.34 (m, 1H, CH2), 1.98e1.90 (m, 1H, CH), 1.70e1.63 (m,
1H, CH2), 1.50e1.41 (m, 1H, CH2), 1.17 (d, J ¼ 6.8 Hz, 3H, CH3), 1.06 (d,
J ¼ 6.8 Hz, 3H, CH3). ESI-MS: 487.6 [M þ K]þ. Anal. Calc. for
Formula
Fw
T (K)
C15H25N3O4PtS
538.53
296(2)
Tetragonal
P43212
9.9122(4)
9.9122(4)
39.4933(15)
3880.3(3)
8
Cryst syst
Space group
ꢀ
a (A)
ꢀ
b (A)
ꢀ
c (A)
V (nm3)
Z
Dc (Mg mꢀ3
F(000)
)
1.844
2096
C
15H25N3O4PdS: C, 40.05; H, 5.60; N, 9.34. Found: C, 39.67; H, 5.26;
Cryst dimens (mm)
0.41 ꢃ 0.21 ꢃ 0.02
2.06e28.32
ꢀ13 < h < 13
ꢀ13 < k < 13
ꢀ52 < l < 34
4839/221
1.327
N, 9.23.
q
range (ꢁ)
hkl ranges
4.3.7. [Pd(1,3-dap)(TspheNO)] (2c)
The synthesis of 2c was carried out in an identical manner to 1b
starting from [Pd(1,3-dap)Cl2] (20.0 mg, 0.080 mmol) and TspheH2
(38.0 mg, 0.119 mmol). Yellow solid. IR (KBr, cmꢀ1): 1628, 1346, 551,
420. 1H NMR (600 MHz, DMSO-d6) d(ppm) 8.01e7.83 (m, 2H, ArH),
7.32e7.10 (m, 7H, ArH), 5.11e4.96 (m, 3H, NH2), 4.80e4.70 (m, 1H,
Data/parameters
Goodness-of-fit on F2
Final R indices [I > 2s(I)]
R1 ¼ 0.0303
wR2 ¼ 0.0619

286
J. Zhang et al. / European Journal of Medicinal Chemistry 58 (2012) 281e286
4.5. Cell culture
Met
Cys
L
-methionine
-cysteine,
L
Four different human carcinoma cell lines: HL-60, Bel-7402,
BGC-823 and KB were cultured in RPMI-1640 medium supple-
mented with 10% fetal bovine serum, 100 units/mL of penicillin and
TsalaH2 4-toluenesulfonyl-
TsvalH2 4-toluenesulfonyl-
TsileH2 4-toluenesulfonyl-
TsserH2 4-toluenesulfonyl-
TspheH2 4-toluenesulfonyl-
L
L
L
L
L
-alanine
-valine
-isoleucine
-serine
-phenylalanine
100
m
g/mL of streptomycin. Cells were maintained at 37 ꢁC in
a humidified atmosphere of 5% CO2 in air.
MLCT
DMF
metal-to-ligand charge transfer
dimethyl formamide
4.6. Solutions
DMSO dimethyl sulfoxide
The complexes were dissolved in DMSO at a concentration of
5 mM as stock solution, and diluted in culture medium at
SRB
MTT
sulforhodamine B
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
concentrations of 1.0, 10, 100, and 500
mM as working-solution. To
bromide
avoid DMSO toxicity, the concentration of DMSO was less than 0.1%
(v/v) in all experiments.
OD
SD
optical density
standard deviation
4.7. Cytotoxicity analysis
Appendix A. Supplementary data
The cells harvested from exponential phase were seeded
equivalently into a 96-well plate, and then the complexes were
added to the wells to achieve final concentrations. Control wells
were prepared by addition of culture medium. Wells containing
culture medium without cells were used as blanks. All experiments
were performed in quintuplicate. The MTT assay was performed as
described by Mosmann for HL-60 [30]. Upon completion of the
incubation for 44 h, stock MTT dye solution (20 mL, 5 mg/mL) was
added to each well. After 4 h incubation, 2-propanol (100 mL) was
added to solubilize the MTT formazan. The OD of each well was
measured on a microplate spectrophotometer at a wavelength of
570 nm. The SRB assay was performed as previously described for
Bel-7402, BGC-823, and KB [31]. Upon completion of the incubation
for 44 h, the cells were fixed in 10% trichloroacetic acid (100 mL) for
30 min at 4 ꢁC, washed five times and stained with 0.1% SRB in 1%
acetic acid (100 mL) for 15 min. The cells were washed four times in
1% acetic acid and air-dried. The stain was solubilized in 10 mM
unbuffered Tris base (100 mL) and OD was measured at 540 nm as
above. The IC50 value was determined from plot of % viability
against dose of compounds added.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2012.09.052.
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This work was supported by the Nature Science Fund for
Distinguished Young Scholars of Hebei Province (Grant No.
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No. B2011201135), the Key Basic Research Special Foundation of
Science Technology Ministry of Hebei Province (Grant No.
11966412D, 12966418D), the Pharmaceutical Joint Research Fun-
dation of the Natural Science Foundation of Hebei Province and
China Shiyao Pharmaceutical Group Co., LTD (B2011201174).
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AMBI
Ala
Val
Ile
2-aminomethyl benzimidazole
L
L
L
L
L
L
L
L
L
-alanine
-valine
-isoleucine
-serine
Ser
Phe
Leu
Tyr
Pro
Gly
-phenylalanine
-leucine
-tyrosine
-proline
-glycine