Synthesis, characterization, and cytotoxicity of platinum(II)/palladium(II) complexes with 4-toluenesulfonyl-L-amino acid dianion and diimine/diamine

Article abstract of DOI:10.1080/00958972.2013.767447

Eight new platinum(II)/palladium(II) complexes with 4-toluenesulfonyl-L- amino acid dianion and diimine/diamine ligands, [Pd(en)(Tsile)]·H ₂O (1), [Pd(bipy)(Tsile)] (2), [Pd(bipy)(Tsthr)]·0.5H ₂O (3), [Pd(phen)(Tsile)]·0.5H₂O (4), [Pd(phen)(Tsthr)]·H₂O (5), [Pd(bqu)(Tsthr)]·1.5H ₂O (6), [Pt(en)(Tsser)] (7), and [Pt(en)(Tsphe)]·H ₂O (8), have been synthesized and characterized by elemental analyses, ¹H NMR and mass spectrometry. The crystal structure of 7 has been determined by X-ray diffraction. Cytotoxicities were tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and sulforhodamine B assays. The complexes exert cytotoxicity against HL-60, Bel-7402, BGC-823, and KB cell lines with 4 having the best cytotoxicity against HL-60, Bel-7402, and BGC-823 cell lines; the compounds are less cytotoxic than cisplatin.

Full text of DOI:10.1080/00958972.2013.767447

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Synthesis, characterization,
and cytotoxicity of platinum(II)/
palladium(II) complexes with 4-
toluenesulfonyl-L-amino acid dianion
and diimine/diamine
Luwei Li a b , Jinchao Zhang a b , Lili Ma a b , Zhilei Zhang a b
Shuxiang Wang a b , Shenghui Li a b & Guoqiang Zhou a b
,
a Department of Chemistry , Chemical Biology Key Laboratory of
Hebei Province, College of Chemistry & Environmental Science,
Hebei University , Baoding , P.R. China
b Key Laboratory of Medicinal Chemistry and Molecular Diagnosis
of the Ministry of Education , Hebei University , Baoding , P.R.
China
Accepted author version posted online: 17 Jan 2013.Published
online: 28 Feb 2013.
To cite this article: Luwei Li , Jinchao Zhang , Lili Ma , Zhilei Zhang , Shuxiang Wang , Shenghui Li
& Guoqiang Zhou (2013) Synthesis, characterization, and cytotoxicity of platinum(II)/palladium(II)
complexes with 4-toluenesulfonyl-L-amino acid dianion and diimine/diamine, Journal of
Coordination Chemistry, 66:4, 638-649, DOI: 10.1080/00958972.2013.767447
To link to this article: http://dx.doi.org/10.1080/00958972.2013.767447
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Journal of Coordination Chemistry
Vol. 66, No. 4, 20 February 2013, 638–649
Synthesis, characterization, and cytotoxicity of platinum(II)/
palladium(II) complexes with 4-toluenesulfonyl-L-amino acid
dianion and diimine/diamine
LUWEI LIyz, JINCHAO ZHANGyzꢀ, LILI MAyz, ZHILEI ZHANGyz, SHUXIANG
WANGyz, SHENGHUI LIyz and GUOQIANG ZHOUyz
†Department of Chemistry, Chemical Biology Key Laboratory of Hebei Province, College
of Chemistry & Environmental Science, Hebei University, Baoding, P.R. China
‡Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of
Education, Hebei University, Baoding, P.R. China
(Received 13 June 2012; in final form 5 November 2012)
Eight new platinum(II)/palladium(II) complexes with 4-toluenesulfonyl-L-amino acid dianion and
diimine/diamine ligands, [Pd(en)(Tsile)]·H2O (1), [Pd(bipy)(Tsile)] (2), [Pd(bipy)(Tsthr)]·0.5H2O
(3), [Pd(phen)(Tsile)]·0.5H2O (4), [Pd(phen)(Tsthr)]·H2O (5), [Pd(bqu)(Tsthr)]·1.5H2O (6), [Pt(en)
(Tsser)] (7), and [Pt(en)(Tsphe)]·H2O (8), have been synthesized and characterized by elemental
analyses, 1H NMR and mass spectrometry. The crystal structure of 7 has been determined by X-
ray diffraction. Cytotoxicities were tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide and sulforhodamine B assays. The complexes exert cytotoxicity against HL-60, Bel-7402,
BGC-823, and KB cell lines with 4 having the best cytotoxicity against HL-60, Bel-7402, and
BGC-823 cell lines; the compounds are less cytotoxic than cisplatin.
Keywords: Platinum(II)/palladium(II); Synthesis; 4-Toluenesulfonyl-L-amino acids; Diimine/dia-
mine; Cytotoxicity
1. Introduction
The landmark discovery of cisplatin by Rosenberg in 1965 heralded a new era of metal-based
anticancer drugs [1]; cisplatin is one of the most effective drugs in treatment of testicular,
ovarian, small cell lung, bladder, cervical, head and neck carcinomas [2–6]. Carboplatin and
oxaliplatin have received worldwide approval, while nedaplatin, lobaplatin, and heptaplatin
have gained regionally limited approval [7–9]. Regardless of the achievements of current
platinum drugs, there are major drawbacks including effectiveness against a limited range of
cancers, drug-resistance, and severe side effects [10, 11]. These problems provide incentive
to discover new metal-based anticancer drugs.
Due to the structural and thermodynamic analogy between platinum(II) and palladium
(II) complexes, there is also interest in palladium(II) derivatives as potential anticancer
drugs [12–16]. Jin and Ranford have synthesized and characterized nine platinum(II)
complexes with phen and amino acids (where amino acids are Gly, His, Cys, Ile, Ala, Pro,
*Corresponding authors. Email: zjc@hbu.edu.cn (J. Zhang); wsx@hbu.edu.cn (S. Wang)
Journal of Coordination Chemistry
ISSN 0095-8972 print/ISSN 1029-0389 online Ó 2013 Taylor & Francis
http://dx.doi.org/10.1080/00958972.2013.767447

Platinum(II) and palladium(II) complexes
639
Ser, Asp, and Glu) as well as two palladium(II) complexes with phen and amino acids
(where amino acids are Asp and Glu) [17]. These complexes were less cytotoxic than cis-
platin. The IC50 values of [Pt(phen)(Pro)]Cl·2H2O and [Pd(phen)(Asp)]Cl·1.5H2O were
similar to cisplatin [17]. Mital et al. reported synthesis and cytotoxicity of palladium(II)
complexes, [Pd(phen)(AA)]+ (where AA is an anion of Gly, Ala, Leu, Phe, Tyr, Trp, Val,
Pro, or Ser) [18], with IC50 values of the palladium(II) complexes with Gly and Val com-
parable to that of cisplatin; the other palladium(II) complexes showed higher IC50 values.
The IC50 values do not show definite correlation with variation of the amino acid side
chains [17, 18]. Puthraya et al. reported synthesis and cytotoxicity of palladium(II) com-
plexes, [Pd(bipy)(AA)]n+ (where AA is an anion of Cys, Asp, Glu, Met, His, Arg, Phe,
Tyr, or Trp, and n = 0 or 1) [19]. In the L1210 system, complexes with Asp, Glu, Met, and
Arg have shown lower IC50 values than or comparable to cisplatin [19]. In the P388 sys-
tem, complexes with Asp and Glu showed lower IC50 values than cisplatin [19]. In the
Ehrlich ascites tumor system, complexes with Asp and Arg have lower IC50 values than
cisplatin [19]. Recently, we reported synthesis and cytotoxicity of a series of platinum(II)/
palladium(II) complexes with 4-toluenesulfonyl-L-amino acid dianion and diimine/diamine
[20–23]. These complexes displayed cytotoxic effects against HL-60, Bel-7402, BGC-823,
and KB cell lines with some complexes having better cytotoxicity than cisplatin. For
example, cytotoxicity of [Pd(phen)(Tsleu)]·H2O is better than that of cisplatin against
BGC-823, Bel-7402, and KB cell lines. The cytotoxicity of [Pt(bipy)(Tsphe)] is compara-
ble to that of cisplatin against BGC-823 and Bel-7402 cell lines. In order to further
explore the structure–activity relationships and discover new metal-based anticancer drugs,
in the present work, we present the synthesis, characterization, and cytotoxicity of eight
new platinum(II)/palladium(II) complexes with 4-toluenesulfonyl-L-amino acid dianion and
diimine/diamine (bpy, phen, and bqu/en) for the first time.
2. Experimental
2.1. Materials
4-Toluenesulfonyl chloride, K2[PdCl4], and K2[PtCl4] were of chemical grade; en, bipy,
phen, and bqu were of analytical grade. Commercially pure Ile, Thr, Ser, and Phe were
purchased from Sigma. RPMI-1640 medium, trypsin, and fetal bovine serum were pur-
chased from Gibco. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT),
sulforhodamine B (SRB), benzylpenicillin, and streptomycin were from Sigma. Four differ-
ent human carcinoma cell lines: HL-60 (immature granulocyte leukemia), Bel-7402 (liver
carcinoma), BGC-823 (gastrocarcinoma), and KB (nasopharyngeal carcinoma) were
obtained from American type culture collection.
2.2. Instrumentation and measurement
1
Elemental analyses were determined on a Elementar Vario EL III elemental analyzer. H
NMR spectra were recorded on a Bruker AVIII 600 NMR spectrometer. Mass spectra were
measured by LC-MS apparatus Agilent 1200–6310. X-ray single crystal structure was

640
L. Li et al.
performed on a Bruker SMART APEX II CCD diffractometer. The OD was measured on a
microplate spectrophotometer (Bio-Rad Model 680, USA).
2.3. Synthesis of compounds
The palladium(II)/platinum(II) complexes [Pd(en)(Tsile)]·H2O (1), [Pd(bipy)(Tsile)] (2),
[Pd(bipy)(Tsthr)]·0.5H2O (3), [Pd(phen)(Tsile)]·0.5H2O (4), [Pd(phen)(Tsthr)]·H2O (5), [Pd
(bqu)(Tsthr)]·1.5H2O (6), [Pt(en)(Tsser)] (7), and [Pt(en)(Tsphe)]·H2O (8) were prepared
by reaction of [Pd(NN)Cl2] (NN = en, bipy, phen or bqu) or [Pt(en)Cl2] with 4-toluenesul-
fonyl-L-amino acids: TsileH2, TsthrH2, TsserH2, or TspheH2 in a mixture of CH3OH/H2O
(see figure 1) [24].
2.3.1. 4-Toluenesulfonyl-L-amino acids. To a rapidly stirred solution of Ile (262 mg,
2.0 mM) in 5.0 mL H2O was added 2.0 mL NaOH (1 M Lꢁ1). 4-Toluenesulfonyl chloride
(378 mg, 2.0 mM) was added to the solution. After that, 2.0 mL NaOH (1 M Lꢁ1) was
added dropwise over 0.5 h. After further 8 h, the solution was cooled by placing the flask
on ice and acidified to pH = 3–4 with HCl monitored by universal pH test strips. The
resulting white precipitate was filtered. The collected solid was washed with cold H2O
Figure 1. Synthetic schemes of 1–8.

Platinum(II) and palladium(II) complexes
641
1
(50 mL) and dried to give TsileH2. TsileH2: H NMR (600 MHz, CDCl3) δ 8.95 (s, 1H,
COOH), 7.72 (d, J = 8.1 Hz, 2H, ArH), 7.27 (d, J = 8.3 Hz, 2H, ArH), 5.32 (d, J = 9.7 Hz,
1H, NH), 3.82 (dd, J = 9.7, 4.9 Hz, 1H, NCH), 1.18 (m, 1H, CH), 1.39 (m, 1H, CH2), 1.14
(m, 1H, CH2), 0.90 (d, J = 6.8 Hz, 3H, CH3), 0.86 (t, J = 7.4 Hz, 3H, CH3).
1
TsthrH2, TsserH2, and TspheH2 were carried out in a similar manner. TsthrH2: H NMR
(600 MHz, DMSO-d6) δ 12.53 (s, 1H, COOH), 7.68 (d, J = 8.3 Hz, 2H, ArH), 7.53 (d,
J = 9.2 Hz, 1H, NH), 7.34 (d, J = 8.4 Hz, 2H, ArH), 3.96 (qd, J = 6.3, 3.8 HZ, 1H, CH),
1
3.64 (m, 1H, CH), 2.37 (s, 3H, CH3), 1.01 (d, J = 6.4 Hz, 3H, CH3). TsserH2: H NMR
(600 MHz, DMSO-d6) δ 7.89 (d, J = 8.6 Hz, 1H, NH), 7.68 (d, J = 7.9 Hz, 2H, ArH), 7.35
(d, J = 7.9 Hz, 2H, ArH), 3.73 (m, 1H, CH), 3.49 (m, 2H, CH2), 2.37 (s, 3H, CH3).
1
TspheH2: H NMR (600 MHz, DMSO-d6) δ 12.67 (s, 1H, COOH), 8.18 (d, J = 5.0 Hz, 1H,
NH), 7.09 (m, 2H, ArH), 7.19 (m, 5H, ArH), 7.12 (s, 2H, ArH), 3.86 (m, 1H, CH), 2.93
(m, 1H, CH2), 2.72 (m, 1H, CH2), 2.34 (s, 3H, CH3).
2.3.2. Precursor complexes [M(NN)Cl2]. Precursor complexes [Pd(en)Cl2] (i), [Pd
(bipy)Cl2] (ii), [Pd(phen)Cl2] (iii), [Pd(bqu)Cl2] (iv), and [Pt(en)Cl2] (v) were synthesized
according to a published procedure [25].
2.3.3. [Pd(en)(Tsile)]·H2O (1). A 3 mL CH3OH/H2O (volume 1:1) solution of TsileH2
(34 mg, 0.12 mM) was heated to 48 °C, and then [Pd(en)Cl2] (14 mg, 0.06 mM) was added
to the solution. The mixture was adjusted to pH = 9 by NaOH solution monitored by uni-
versal pH test strips and stirred for 2 h. Then, the solution was transferred into a 10 mL
test tube and the test tube was capped by polypropylene film with a few pierced holes. By
evaporating the solution at room temperature, a yellow solid was obtained after a few
1
weeks. Complex 1 was separated from the solution. H NMR (600 MHz, DMSO-d6) δ 8.01
(d, J = 8.1 Hz, 2H, ArH), 7.31 (d, J = 8.0 Hz, 2H, ArH), 4.99 (m, 1H, NH2), 4.87 (m, 1H,
NH2), 4.77 (d, J = 4.8 Hz, 1H, NH2), 4.26 (m, 1H, NH2), 3.27 (d, J = 3.7 Hz, 1H, CH),
2.45 (m, 2H, CH2), 2.36 (m, 2H, CH2), 2.37 (s, 3H, CH3), 1.65 (m, 2H, CH2), 1.42 (m,
1H, CH), 1.11 (d, J = 6.6 Hz, 3H, CH3), 0.85 (t, J = 7.2 Hz, 3H, CH3). ESI-MS: 472.5[M
+ Na]+. Anal. Calcd for C15H27N3O5PdS (%): C, 38.51; H, 5.82; N, 8.98. Found (%): C,
38.20; H, 5.74; N, 9.15.
2.3.4. [Pd(bipy)(Tsile)] (2). The synthesis of 2 was carried out in a similar manner to 1
starting from [Pd(bipy)Cl2] (20 mg, 0.06 mM) and TsileH2 (34 mg, 0.12 mM). Yellow solid.
1H NMR (600 MHz, CDCl3) δ 9.34 (d, J = 5.6 Hz, 1H, ArH), 8.59 (d, J = 5.4 Hz, 1H,
ArH), 8.28 (t, J = 6.4 Hz, 1H, ArH), 8.26 (t, J = 7.5 HZ, 1H, ArH), 8.12 (d, J = 8.2 Hz, 2H,
ArH), 8.07 (m, 2H, ArH), 7.64 (ddd, J = 7.2, 5.6, 1.3 Hz, 1H, ArH), 7.57 (ddd, J = 7.2,
5.5, 1.6 Hz, 1H, ArH), 7.26 (d, J = 7.9 Hz, 2H, ArH), 3.73 (d, J = 5.3 Hz, 1H, CH), 2.39 (s,
3H, CH3), 2.08 (m, 2H, CH2), 1.66 (m, 1H, CH), 1.15 (d, J = 6.7 Hz, 3H, CH3), 0.92 (t,
J = 7.3 Hz, 3H, CH3). ESI-MS: 568.1[M + Na]+. Anal. Calcd for C23H25N3O4PdS (%): C,
50.60; H, 4.62; N, 7.70. Found (%): C, 50.68; H, 4.46; N, 7.79.
2.3.5. [Pd(bipy)(Tsthr)]·0.5H2O (3). The synthesis of 3 was carried out in a similar
manner to 1 starting from [Pd(bipy)Cl2] (20 mg, 0.06 mM) and TsthrH2 (33 mg, 0.12 mM).

642
L. Li et al.
1
Yellow solid. H NMR (600 MHz, DMSO-d6) δ 9.08 (dd, J = 5.6, 1.2 Hz, 1H, ArH), 8.60
(d, J = 8.1 Hz, 1H, ArH), 8.54 (d, J = 8.0 Hz, 1H, ArH), 8.36 (m, 2H, ArH), 8.29 (d,
J = 5.4 Hz, 1H, ArH), 7.94 (d, J = 8.2 Hz, 2H, ArH), 7.86 (ddd, J = 7.2, 5.7, 1.1 Hz, 1H,
ArH), 7.79 (ddd, J = 6.9, 3.3, 1.0 Hz, 1H ArH), 7.27 (d, J = 8.0 Hz, 2H, ArH), 4.79 (d,
J = 5.5 Hz, 1H, OH), 3.99 (m, 1H, CH), 2.35 (s, 3H, CH3), 1.11 (d, J = 6.3 Hz, 3H, CH3).
ESI-MS: 556.0[M + Na]+. Anal. Calcd for C21H22N3O5.5PdS (%): C, 46.46; H, 4.08; N,
7.74. Found (%): C, 46.80; H, 3.81; N, 7.51.
2.3.6. [Pd(phen)(Tsile)]·0.5H2O (4). The synthesis of 4 was carried out in a similar
manner to 1 starting from [Pd(phen)Cl2] (21 mg, 0.06 mM) and TsileH2 (34 mg, 0.12 mM).
Yellow solid. 1H NMR (600 MHz, CDCl3) δ 9.71 (d, J = 5.1 Hz, 1H, ArH), 8.93 (d,
J = 4.9 Hz, 1H, ArH), 8.63 (dd, J = 15.0, 8.2 Hz, 2H, ArH), 8.17 (d, J = 7.9 Hz, 2H, ArH),
8.06 (m, 2H, ArH), 7.98 (dd, J = 8.0, 5.4 Hz, 1H, ArH), 7.88 (dd, J = 8.1, 5.1 Hz, 1H,
ArH), 7.23 (d, J = 7.9 Hz, 2H, ArH), 3.87 (d, J = 5.1 Hz, 1H, CH), 2.36 (s, 3H, CH3), 2.15
(m, 2H, CH2), 1.77 (m, 1H, CH), 1.25 (d, J = 6.5 Hz, 3H, CH3), 0.95 (t, J = 7.2 Hz, 3H,
CH3). ESI-MS: 592.1[M + Na]+. Anal. Calcd for C25H26N3O4.5PdS (%): C, 51.86; H, 4.53;
N, 7.26. Found (%): C, 51.67; H, 4.41; N, 7.36.
2.3.7. [Pd(phen)(Tsthr)]·H2O (5). The synthesis of 5 was carried out in a similar man-
ner to 1 starting from [Pd(phen)Cl2] (21 mg, 0.06 mM) and TsthrH2 (33 mg, 0.12 mM).
1
Yellow solid. H NMR (600 MHz, DMSO-d6) δ 9.40 (m, 1H, ArH), 8.95 (m, 2H, ArH),
8.62 (m, 1H, ArH), 8.23 (m, 3H, ArH), 8.08 (m, 1H, ArH), 8.00 (d, J = 8.1 Hz, 2H, ArH),
7.28 (d, J = 8.1 Hz, 2H, ArH), 4.83 (s, 1H, OH), 4.00 (m, 1H, CH), 3.45 (d, J = 3.5 Hz,
1H, CH), 2.35 (s, 3H, CH3), 1.18 (d, J = 6.3 Hz, 3H, CH3). ESI-MS: 582.2[M + Na]+. Anal.
Calcd for C23H23N3O6PdS (%): C, 47.97; H, 4.03; N, 7.30. Found (%): C, 47.86; H, 3.83;
N, 6.89.
2.3.8. [Pd(bqu)(Tsthr)]·1.5H2O (6). The synthesis of 6 was carried out in a similar
manner to 1 starting from [Pd(bqu)Cl2] (26 mg, 0.06 mM) and TsthrH2 (33 mg, 0.12 mM).
1
Yellow solid. H NMR (600 MHz, DMSO-d6) δ 9.66 (d, J = 8.4 Hz, 1H, ArH), 9.05 (d,
J = 8.7 Hz, 1H, ArH), 8.99 (d, J = 8.6 Hz, 1H, ArH), 8.90 (d, J = 8.7 Hz, 1H, ArH), 8.82 (d,
J = 8.6 Hz, 1H, ArH), 8.65 (d, J = 8.8 Hz, 1H, ArH), 8.19 (dd, J = 15.0, 8.0 Hz, 2H, ArH),
7.86 (m, 4H, ArH), 7.38 (d, J = 8.1 Hz, 2H, ArH), 7.06 (d, J = 8.1 Hz, 2H, ArH), 5.71 (d,
J = 3.0 Hz, 1H, OH), 4.25 (m, 1H, CH), 3.31 (d, J = 1.5 Hz, 1H, CH), 2.21 (s, 3H, CH3),
1.22 (d, J = 6.3 Hz, 3H, CH3). ESI-MS: 632.1[M + Na]+. Anal. Calcd for C29H28N3O6.5PdS
(%): C, 52.69; H, 4.27; N, 6.36. Found (%): C, 52.59; H, 3.96; N, 6.38.
2.3.9. [Pt(en)(Tsser)] (7). The synthesis of 7 was carried out in a similar manner to 1
starting from [Pt(en)Cl2] (19 mg, 0.06 mM) and TsserH2 (31 mg, 0.12 mM). White solid.
1H NMR (600 MHz, DMSO-d6) δ 8.04 (d, J = 8.2 Hz, 2H, ArH), 7.31 (d, J = 7.9 Hz, 2H,
ArH), 5.58 (m, 2H, NH2), 5.43 (m, 1H, NH2), 4.98 (m, 1H, NH2), 4.11 (m, 1H, OH), 3.66
(m, 1H, CH2), 3.57 (m, 1H, CH2), 3.42 (m, 1H, CH), 2.36 (m, 2H, CH2), 2.37 (s, 3H,
CH3), 2.29 (m, 2H, CH2). ESI-MS: 511.5[M + Na]+. Anal. Calcd for C12H19N3O5PtS (%):
C, 28.13; H, 3.74; N, 8.20. Found (%): C, 28.32; H, 3.65; N, 8.11.

Platinum(II) and palladium(II) complexes
643
2.3.10. [Pt(en)(Tsphe)]·H2O (8). The synthesis of 8 was carried out in a similar manner
to 1 starting from [Pt(en)Cl2] (19 mg, 0.06 mM) and TspheH2 (38 mg, 0.12 mM). White
1
solid. H NMR (600 MHz, DMSO-d6) δ 8.01 (d, J = 8.2 Hz, 2H, ArH), 7.26 (m, 6H, ArH),
7.17 (m, 1H, ArH), 5.51 (m, 2H, NH2), 5.26 (m, 1H, NH2), 4.94 (m, 1H, NH2), 3.62 (dd,
J = 6.4, 5.1 Hz, 1H, CH), 2.99 (qd, J = 13.2, 5.8 Hz, 2H, CH2), 2.36 (s, 3H, CH3), 2.30 (m,
2H, CH2), 2.22 (m, 2H, CH2). ESI-MS: 572.5[M + Na]+. Anal. Calcd for C18H25N3O5PtS
(%): C, 36.61; H, 4.27; N, 7.12. Found (%): C, 36.90; H, 4.44; N, 7.09.
2.4. Data collection and structural refinement of 7
Data collection for 7 was performed on a Bruker SMART APEX II CCD diffractometer
equipped with graphite monochromated Mo Kα radiation (λ = 0.71073 Å) at 296(2) K.
Multi-scan absorption corrections were applied using SADABS. The structure was solved
by the direct method using SHELX-97. Full-matrix least-squares refinement on F2 was
performed using SHELXL-97 with anisotropic thermal parameters for all nonhydrogen
atoms. Table 1 lists the crystallographic details. Crystallographic data for structural analysis
of 7 have been deposited with the Cambridge Crystallographic Data Center, CCDC –
838,825. Copies of this information may be obtained free of charge from The Director,
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax:+44 1223 336033; E-mail: depos-
it@ccdc.cam.ac.uk or http://www.ccdc.cam.ac.uk).
2.5. Cell culture
Four different human carcinoma cell lines: HL-60, Bel-7402, BGC-823, and KB were cul-
tured in RPMI-1640 medium supplemented with 10% fetal bovine serum, 100 units/mL of
Table 1. Crystallographic data for 7.
Formula
Fw
C
12H19N3O5PtS
512.45
T(K)
296(2)
Cryst. syst.
Space group
a (Å)
Orthorhombic
P212121
7.900(3)
b (Å)
10.788(4)
c (Å)
17.561(7)
1496.6(1)
V (Å3)
Z
4
Dc (Mg mꢁ3
F(000)
)
2.275
984
Cryst. dimens. (mm)
h Range (°)
0.56 ꢂ 0.45 ꢂ 0.41
2.22–28.48
ꢁ10 < h < 9
ꢁ13 < k < 14
ꢁ23 < l < 22
3759/202
hkl Ranges
Data/parameters
Goodness-of-fit on F2
Final R indices [I > 2σ(I)]
1.121
R1 = 0.0319; wR2 = 0.0849

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L. Li et al.
penicillin, and 100 μg/mL of streptomycin. Cells were maintained at 37 °C in a humidified
atmosphere of 5% CO2 in air.
2.6. Solutions
The complexes were dissolved in DMSO at 5 mM and diluted in culture medium at 1.0,
10, 100, and 500 μM as working-solutions. To avoid DMSO toxicity, the concentration of
DMSO was less than 0.1% (v/v) in all experiments.
2.7. Cytotoxicity analysis
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 the final concentrations. Con-
trol 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 [26]. 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 forma-
zan. The OD of each well was measured on a microplate spectrophotometer at 570 nm.
The SRB assay was performed as previously described for Bel-7402, BGC-823, and KB
[27]. Upon completion of the incubation for 44 h, the cells were fixed in 10% aqueous tri-
chloroacetic acid (100 mL) for 30 min at 4 °C, washed five times with water and stained
with 0.1% aqueous SRB in 1% aqueous 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 of
unbuffered Tris base (100 mL) and OD was measured at 540 nm as above. The IC50 value
was determined from a plot of % viability against dose of compounds added.
3. Results and discussion
3.1. Synthesis and characterization
Elemental analysis data of 1–8 are in agreement with calculated values. Mass spectra of
1–8 have molecular ion peaks. These experimental results provide support for the sug-
gested composition and structures of the complexes.
1
Although the overall patterns of the H NMR spectra of 1–8 resemble the free ligands,
the signals shift upon coordination. TsileH2 shows a doublet at δ = 5.32, which is associated
with the proton of the sulfonamide group, but this peak disappears for 4, which shows that
1
the sulfonamide group has been deprotonated. The methylene H resonances (amino acid)
shift downfield as a result of deprotonated sulfonamide nitrogen coordinating to Pd(II). The
α-hydrogen of TsileH2 appears as a dd, but this proton appears as a doublet in 4, which also
1
shows deprotonation of sulfonamide (figures 2 and 3). H NMR spectra of 1, 2, 3, 5, 6, 7,
and 8 are similar to that of 4. These observations further confirm that the sulfonamide group
coordinates to platinum(II)/palladium(II) through deprotonated sulfonamide nitrogen.

Platinum(II) and palladium(II) complexes
645
Figure 2. 1H NMR spectrum of TsileH2 in CDCl3.
3.2. Structural studies
A view of the molecular structure of [Pt(en)(Tsser)] (7) is shown in figure 4. Selected bond
lengths and angles are given in table 2. The platinum shows square-planar coordination by
two nitrogens of en, one deprotonated sulfonamide nitrogen, and one carboxylic oxygen.
The angle between planar O(1)–Pt(1)–N(1) and planar N(2)–Pt(1)–N(3) is 3.0(2)°, which
indicates that the Pt(1)–O(1)–N(1)–N(2)–N(3) plane is slightly distorted. The Pt–N (depro-
tonated sulfonamide) bond length (2.027(6) Å) is similar to the Pt–N (en) bond lengths
(2.034(6) and 2.030(6) Å), while it is longer than Pt–O (carboxylic oxygen) bond length
(1.999(5) Å). Examination of the crystallographic packing diagram revealed several hydro-
gen bonds. To depict hydrogen bonds clearer, only a portion of the complex molecule is
shown in figure 5. Hydrogens bound to N3i hydrogen bond to noncoordinated oxygen
(O2ii) of a neighboring unit (ii = x + 1/2, ꢁy + 1/2, ꢁz) and to the hydroxyl oxygen (O2iii)
of a different neighboring unit (iii = ꢁx, y + 1/2, ꢁz + 1/2). Hydrogen bound to N2iv of the
neighboring unit (iv = x + 1/2, y, z) hydrogen bond to noncoordinated O2i. An intramolecu-
lar hydrogen bond with a length 2.2 Å was also observed between O4i and hydrogen from
amine N2i, and another intramolecular hydrogen bond is observed between O3i and the
hydrogen from hydroxyl O5i at 2.3 Å. No π–π stacking was observed between the phenyl
rings of the complex, which indicates that hydrogen bonds play an important role in crys-
tal formation.

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L. Li et al.
Figure 3. 1H NMR spectrum of 4 in CDCl3.
Figure 4. Molecular structure and partial atom-labeling scheme for 7.
3.3. Cytotoxic studies
Complexes 1–8 exert cytotoxicity against HL-60, Bel-7402, BGC-823, and KB cell lines
(table 3) with 4 having the best cytotoxicity against HL-60, Bel-7402, and BGC-823 cell

Platinum(II) and palladium(II) complexes
Table 2. Selected bond lengths (Å) and angles (°) for 7.
647
Bond length (Å)
Angles (°)
Pt(1)–N(1)
Pt(1)–N(2)
Pt(1)–N(3)
Pt(1)–O(1)
N(1)–Pt(1)–N(2)
N(2)–Pt(1)–N(3)
N(3)–Pt(1)–O(1)
O(1)–Pt(1)–N(1)
O(1)–Pt(1)–N(2)
N(1)–Pt(1)–N(3)
2.027(6)
2.034(6)
2.030(6)
1.999(5)
102.3(2)
82.2(2)
92.3(2)
83.3(2)
174.2(2)
174.9(2)
Figure 5. Inter and intra molecular hydrogen bonds in 7.
Table 3. The cytotoxicities of the complexes in vitro (n = 5).
IC50 SD (μM)
Complexes
HL-60
BGC-823
Bel-7402
KB
[Pd(en)(Tsile)]·H2O (1)
[Pd(bipy)(Tsile)] (2)
15.89 1.21
18.66 1.07
16.76 1.08
9.20 0.97
12.46 1.05
16.54 1.21
13.43 0.97
12.43 1.09
2.89 0.34
30.12 2.08
23.74 1.23
25.78 1.11
21.70 2.08
23.45 1.32
30.89 1.34
38.76 2.43
35.67 1.43
6.48 0.81
29.76 1.65
44.52 1.43
40.76 1.45
18.01 1.32
38.98 2.08
30.76 2.07
31.56 1.56
30.21 1.02
8.12 0.97
10.78 1.06
9.28 1.07
6.54 0.97
6.08 0.87
5.98 0.65
22.54 1.23
10.43 1.34
8.98 0.96
2.65 0.33
[Pd(bipy)(Tsthr)]·0.5H2O (3)
[Pd(phen)(Tsile)]·0.5H2O (4)
[Pd(phen)(Tsthr)]·H2O (5)
[Pd(bqu)(Tsthr)]·1.5H2O (6)
[Pt(en)(Tsser)] (7)
[Pt(en)(Tsphe)]·H2O (8)
Cisplatina
aThe IC50 (μM) values of Cisplatin were cited from our previous work [21].

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L. Li et al.
lines, but the compounds are less cytotoxic than cisplatin. Recently, we reported cytotoxic-
ities of a series of platinum(II)/palladium(II) complexes with 4-toluenesulfonyl-L-amino
acid dianion and diimine/diamine [20–23]. These various studies indicate that amino acid
side chain, the chelating diimine/diamine, and the central metal ion affect cytotoxicity, but
the IC50 values do not show a definite correlation with variation of these parameters. In
the present work, although we might expect to see cytotoxic dependencies on the nature of
the amino acid side chain, the chelating diimine/diamine, and the central metal ion, no
obvious trends are observed.
4. Conclusions
We have synthesized and characterized eight new palladium(II)/platinum(II) complexes
with 4-toluenesulfonyl-L-amino acid dianions and diimine/diamine. Of these complexes, 4
have the best cytotoxicity against HL-60, Bel-7402, and BGC-823 cell lines, but none of
the eight complexes are more cytotoxic than cisplatin. While one might expect to see cyto-
toxic dependencies on the nature of the amino acid side chain, the chelating diimine/dia-
mine, and the central metal ion, no obvious trends are observed.
Acknowledgements
This work was supported by Hebei Province Nature Science Fund for Distinguished
Young Scholars (Grant No. B2011201164), the Nature Science Fund of Hebei Province
(Grant No. B2011201135), the Key Basic Research Special Foundation of Science
Technology Ministry of Hebei Province (Grant No. 11966412D and 12966418D), the
Pharmaceutical Joint Research Foundation of the Natural Science Foundation of Hebei
Province, and China Shiyao Pharmaceutical Group Co. LTD (B2011201174).
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