Synthesis and in vitro cytotoxicity of platinum(II) complexes with chiral N-monosubstituted 1,2-cyclohexyldiamine derivatives as the carrier groups

Article abstract of DOI:10.1080/00958972.2013.775430

Eight platinum(II) complexes with the new chiral ligands, (1R,2R)-N ¹-(pyridine-2-ylmethyl) cyclohexane-1,2-diamine(R) or (1S,2S)-N ¹-(pyridine-2-ylmethyl) cyclohexane-1,2-diamine(S) as the carrier groups were designed, synthesized,

Full text of DOI:10.1080/00958972.2013.775430

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Synthesis and in vitro cytotoxicity
of platinum(II) complexes with
chiral N-monosubstituted 1,2-
cyclohexyldiamine derivatives as the
carrier groups
Chuanzhu Gao a , Fan Fei a , Tianshuai Wang a , Bo Yang a
Shaohua Gou b , Jian Yang a & Liali Liao a
,
a Faculty of Life Science and Technology, Kunming University of
Science and Technology, Kunming, China
b Jiangsu Province Hi-Tech Key Laboratory for Bio-Medical
Research, Southeast University, Nanjing, China
Accepted author version posted online: 14 Feb 2013.Version of
record first published: 20 Mar 2013.
To cite this article: Chuanzhu Gao , Fan Fei , Tianshuai Wang , Bo Yang , Shaohua Gou , Jian Yang
& Liali Liao (2013): Synthesis and in vitro cytotoxicity of platinum(II) complexes with chiral N-
monosubstituted 1,2-cyclohexyldiamine derivatives as the carrier groups, Journal of Coordination
Chemistry, 66:6, 1068-1076
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Journal of Coordination Chemistry
Vol. 66, No. 6, 20 March 2013, 1068–1076
Synthesis and in vitro cytotoxicity of platinum(II) complexes
with chiral N-monosubstituted 1,2-cyclohexyldiamine
derivatives as the carrier groups
CHUANZHU GAO†, FAN FEI†, TIANSHUAI WANG†, BO YANG*†,
SHAOHUA GOU*‡, JIAN YANG† and LIALI LIAO†
†Faculty of Life Science and Technology, Kunming University of Science and Technology,
Kunming, China
‡Jiangsu Province Hi-Tech Key Laboratory for Bio-Medical Research, Southeast
University, Nanjing, China
(Received 15 October 2012; in final form 10 December 2012)
Eight platinum(II) complexes with the new chiral ligands, (1R,2R)-N1-(pyridine-2-ylmethyl) cyclo-
hexane-1,2-diamine(R) or (1S,2S)-N1-(pyridine-2-ylmethyl) cyclohexane-1,2-diamine(S) as the car-
rier groups were designed, synthesized, and spectrally characterized. All platinum(II) complexes
showed much better aqueous solubility than cisplatin and oxaliplatin. In vitro cytotoxicity of the
compounds against human HepG-2, MCF-7, A549, and HCT-116 cell lines was evaluated. Results
indicate that all compounds with R as the carrier group showed cytotoxicity against HCT-116,
A549, and MCF-7 cell lines; however, all compounds with S as carrier group exhibited disappoint-
ing cytotoxicity against tested cell lines. Compound R2, bearing ClCH2COO- as leaving group,
exhibited better cytotoxicity than that of carboplatin against A549 and MCF-7 cell lines and also
showed close activity to oxaliplatin against HCT-116 cell line.
Keywords: Chiral 1R,2R-diaminocyclohexane derivatives; Platinum(II) complexes; In vitro
cytotoxicity
1. Introduction
Cisplatin is one of the most successful and frequently used anticancer drugs in chemother-
apy, especially for testicular cancer, for which the overall cure rate exceeds 90%, and is
nearly 100% for early-stage disease [1, 2]. Nevertheless, clinical application is limited by
two factors: intolerable side effects and intrinsic/acquired resistance [3, 4]. Tremendous
efforts have been devoted to developing cisplatin analogs with improved pharmacological
properties and broader range of antitumor activities [5–11], resulting in successful develop-
ments of new anticancer platinum drugs, such as world-wide use of carboplatin and oxa-
liplatin [12, 13].
Oxaliplatin is the first platinum-based drug with chiral 1R,2R-diaminocyclohexane as a
carrier ligand (abbreviated as DACH) and has become the first choice in treating advanced
colorectal carcinoma (ACRC) and supplanted cisplatin as the largest selling platinum
*Corresponding authors. Emails: yangbo6910@sina.com.cn (B. Yang); sgou@seu.edu.cn (S. Gou).
Journal of Coordination Chemistry
ISSN 0095-8972 print/ISSN 1029-0389 online Ó 2013 Taylor & Francis
http://dx.doi.org/10.1080/00958972.2013.775430

Platinum(II) with chiral cyclohexyldiamine
1069
therapeutic. But, the dose-limiting toxicity of oxaliplatin in clinical practice is still insuffer-
able. It has been reported that approximately 90% of patients treated with oxaliplatin
suffered from acute neurotoxicity, while 10–15% of patients suffered from cumulative sen-
sory [14]. Like other clinically available platinum anticancer drugs, such as carboplatin
and lobaplatin, oxaliplatin cannot offer any substantial clinical advantages over cisplatin,
either [15, 16].
Violating the set of classical structure–activity relationships (SAR) summarized by
Cleare and Hoeschele [17], recently much effort has been focused on design of non-
classical platinum complexes, such as orally active platinum(IV) complexes, sterically
hindered platinum(II) complexes, trans-platinum complexes, multinuclear platinum(II)
complexes, etc. [18–22]. Among non-classical anticancer platinum complexes, sterically
hindered platinum(II) complexes have attracted much attention. For instance, ZD0473
(formerly JM-473 and AMD-473), shown in figure 1, is a sterically hindered platinum(II)
complex owning a bulky methylpyridine ligand to connect metal ions, which is responsible
for its ability to overcome platinum resistance, under development as a potential treatment
for cisplatin-resistant cancer and is in phase (III) clinical trial at present [23, 24].
Inspired by the favorable steric effect of methylpyridine in ZD0473 and in order to
overcome the drawbacks of oxaliplatin, pyridine-2-ylmethyl has been introduced into
DACH to obtain a new tridentatꢀe chiral ligand, (1R,2R)-N1-ꢀ(pyridine-2-ylmethyl) cyclohex-
ane-1,2-diamine(R), and with I , CH3COOꢀ, ClCH2COO , CF3SO3ꢀ as leaving groups,
respectively [25–31], we have prepared platinum(II) complexes ([PtRI], R1–R3). Some
research exhibiting platinum complexes with (1S,2S)-cyclohexane-1,2-diamine also showed
a certain cytotoxicity [32]. So, to compare the effect of two different stereoisomers, we
also prepared (1S,2S)-N1-(pyridine-2-ylmethyl) cyclohexane-1,2-diamine(S) and its
corresponding platinum complexes [PtSI], S1–S3.
Herein reported are the platinum complexes and their in vitro cytotoxicity against four
human cancer cell lines.
2. Experimental
2.1. Materials
K2PtCl4 was purchased from a local chemical company, mono-Boc protecting DACH
(hereinafter 1), used as starting material and prepared according to the procedure reported
[33]. All reagents were of high purity and used without further purification. RPMI-1640
medium, trypsin, and fetal bovine serum were purchased from Gibco. 3-(4,5-Dimethylthia-
zol-2-yl)2,5-diphenyltetrazoliumbromide (MTT), benzylpenicillin, and streptomycin were
H3N
Cl
Cl
Cl
N
CH3
Figure 1. Structure of ZD0473.

1070
C. Gao et al.
from Sigma. Four different human carcinomacelllines, HepG-2 (human hepatocellular
carcinoma cell), MCF-7 (human breast cancer cell), A549 (human lung cancer cell), and
HCT-116 (human colorectal cancer cell), were obtained from American Type Culture
Collection.
2.2. Instrumentation and measurement
Elemental analyses for C, H, and N were performed with a Perkin-Elmer 1400C
instrument, while Pt was determined according to the method in EP5. ESI-MS spectra
were carried out in a Finnigan MAT SSQ 710 (120–1000 amu) apparatus and IR spectra
were scanned by a Nicolet IR200 spectrophotometer from 4000 to 400 cmꢀ1 in KBr
pellets. 1H NMR spectra were recorded on a Bruker DRX-500 Avance spectrometer at
500 MHz in D2O using TMS as an internal reference. Specific rotations were tested on a
Shenguang WZZ-2B instrument.
2.3. Synthesis of compounds
2.3.1. Ligand R: (1R,2R)-N1-(pyridine-2-ylmethyl) cyclohexane-1,2-diamine. Mono-
Boc protecting DACH (1) (21.4 g, 100 mmol), and 2-pyridinecarboxaldehyde (12.8 g,
120 mmol) were dissolved in 300 mL of toluene and refluxed for 4 h. After concentrating
the solution, white solids of mono-Schiff base 2 were obtained. Compound 2 was
dissolved in 600 mL of methanol and 7.0 g (184 mmol) NaBH4 was added in portions. The
mixture was mixed for 5 h and EtO2 was used to extract the product into the organic phase
which was washed with water three times. The organic solution was mixed with excess
HCl/EtO2 (5 mol/L), leading to formation of HR hydrochloride 3, which was finally
neutralized by aqueous NaHCO3 solution (2 mol/L) to give free R 6.8 g (33.2 mmol).
Yield, 33.2%. Anal. Calcd for C12H19N3 (%): C, 70.24; H, 9.27; N, 20.49. Found (%): C,
70.08; H, 9.36; N, 20.39. IR(KBr, cmꢀ1): 3401–3285 (m, νN–H), 2928, 2856 (s, νC–H),
1
1593 (m, νPy), 760 (m, γPyH). ESI-MS m/z: [M+H]+ = 206(100%). H NMR (DMSO, ppm)
δ: 1.12–2.85(m, 10H, 4CH2 and 2CH of DACH), 4.47–4.50 (d, 2H, NH-CH2), 5.56–5.73
(m, 3H, NH and NH2), 7.31–8.46 (m, 4H, C5H4N).
2.3.2. Ligand S: (1S,2S)-N1-(pyridine-2-ylmethyl) cyclohexane-1,2-diamine. The
procedures for preparing ligand S were similar to R. Yield, 28.1%. Anal. Calcd for
C12H19N3 (%): C, 70.24; H, 9.27; N, 20.49. Found (%): C, 70.11; H, 9.33; N, 20.41. IR
(KBr, cmꢀ1): 3389–3270 (m, νN–H), 2926, 2860 (s, νC-H), 1590 (m, νPy), 758 (m, γPyH).
1
ESI-MS m/z: [M+H]+ = 206 (100%). H NMR (DMSO, ppm) δ: 1.09–2.83(m, 10H, 4CH2
and 2CH of DACH), 4.43–4.49 (d, 2H, NH-CH2), 5.51–5.78(m, 3H, NH and NH2),
7.329–8.44(m, 4H, C5H4N).
2.3.3. [PtRI]. To a stirring aqueous solution of KI (160 mmol), K2PtCl4 (24 mmol) in
water (80 mL) was added. The solution was stirred at 25 °C for 30 min under nitrogen to
get a black solution of K2PtI4. Then, an aqueous solution (40 mL) of R (24 mmol) was
added dropwise under stirring in the dark at 25 °C. After 24 h, the yellow precipitate was

Platinum(II) with chiral cyclohexyldiamine
1071
filtered, washed sequentially with water, ethanol, and ether, and then dried in vacuum.
Data for [PtRI]: 15.0 g, Yield: 95.8%, yellow solid. Anal. Calcd for C12H19I2N3Pt (%): C,
22.01; H, 2.91; N, 6.42; Pt, 29.81. Found (%): C, 22.16; H, 2.95; N, 6.44; Pt, 29.68. IR
(KBr, cmꢀ1): 3204–3103 (m, νN–H), 2930, 2856 (s, νC–H), 1590 (m, νPy), 760(m, γPyH).
ESI-MS m/z: [MꢀI]+ = 527(80%). 1H NMR (D2O, ppm) δ: 1.21–3.09 (10H, 4CH2 and
2CH of DACH), 4.40–4.51 (d, 2H, NHCH2), 7.41–8.60 (m, 4H, C5H4N).
2.3.4. [PtSI]. The procedure for preparing [PtSI] was similar to [PtRI]. Anal. Calcd for
C12H19I2N3Pt (%): C, 22.01; H, 2.91; N, 6.42; Pt, 29.81. Found (%): C, 22.11; H, 2.98;
N, 6.40; Pt, 29.71. IR(KBr, cmꢀ1): 3198–3131 (m, νN-H), 2928, 2858 (s, νC–H), 1596 (m,
1
νPy), 758 (m, γPyH). ESI-MS m/z: [MꢀI]+ = 527 (60%). H NMR (D2O, ppm) δ: 1.18–3.12
(10H, 4CH2 and 2CH of DACH), 4.36–4.48 (d, 2H, NHCH2), 7.36–8.56 (m, 4H, C5H4N).
2.3.5. R1. [PtRI] (4 mmol) was suspended in 250 mL pure water and a solution of 8 mmol
AgNO3 in 80 mL pure water was added. After stirring under nitrogen in the dark for 24 h at
40 °C, the precipitate was filtered off. Filtrate was blended with 12 mmol CH3COONa and
stirred at 55 °C for 24 h. The solution was concentrated to 5 mL and then cooled to 0 °C.
Pale yellow powder was collected, washed with a small amount of chilled water and ethanol,
and then dried at 60 °C in vacuum. Yield 43.6%. Anal. Calcd for C16H25N3O4Pt (%): C,
37.06; H, 4.83; N, 8.11; Pt, 37.64. Found (%): C, 37.11; H, 4.86; N, 8.10; Pt, 37.51. IR
(KBr, cmꢀ1): 3231–3109 (s, νN–H), 2932, 2858 (s, νC-H), 1592 (s, νC=O), 751 (m, γPyH). ESI-
1
MS m/z: [MꢀH]ꢀ = 517(100%). H NMR (D2O, ppm) δ: 1.01–2.98 (m, 10H of DACH and
6H of 2CH3COO), 4.33–4.44 (d, 2H, NHCH2), 7.38–8.58 (m, 4H, C5H4N). The procedures
for preparing R2, R3, S1, S2, and S3 were similar to R1.
2.3.6. R2. The leaving group of R2 is ClCH2COOꢀ, so the starting material is
ClCH2COONa. Yield 44.0%. Anal. Calcd for C16H23Cl2N3O4Pt (%): C, 32.71; H, 3.92;
N, 7.16; Pt, 33.22. Found (%): C, 32.68; H, 3.97; N, 7.09; Pt, 33.06. IR(KBr, cmꢀ1):
3208–3136 (s, νN–H), 2933, 2852 (s, νC–H), 1596 (s, νC=O), 750 (m, γPyH). ESI-MS m/z:
1
[MꢀH]ꢀ = 586 (80%). H NMR (D2O, ppm) δ: 1.06–3.13 (m, 10H of DACH and 4H of
2ClCH2COO), 4.36–4.50 (d, 2H, NHCH2), 7.38–8.56 (m, 4H, C5H4N).
2.3.7. R3. The leaving group of R3 is CF3SOꢀ3 , so the starting material is CF3SO3Na.
Yield 46.1%. Anal. Calcd for C14H19F6N3O6S2Pt (%): C, 26.21; H, 2.96; N, 6.55; Pt,
30.42. Found (%): C, 26.12; H, 2.99; N, 6.46; Pt, 30.18. IR(KBr, cmꢀ1): 3298–3106 (s,
ν
N–H), 2938, 2856 (s, νC–H), 1590 (s, νC=O), 750 (m, γ
PyH). ESI-MS- m/z:
[MꢀCF3SO3]+ = 492 (100%). 1H NMR (D2O, ppm) δ: 1.16–3.08 (m, 10H of DACH),
4.31–4.49 (d, 2H, NHCH2), 7.36–8.52 (m, 4H, C5H4N).
2.3.8. S1. The leaving group of S1 is the same as for R1. Yield 36.8%. Anal. Calcd for
C16H25N3O4Pt (%): C, 37.06; H, 4.83; N, 8.11; Pt, 37.64. Found (%): C, 37.08; H, 4.81;
N, 8.16; Pt, 37.58. IR(KBr, cmꢀ1): 3233–3111 (s, νN–H), 2936, 2856 (s, νC–H), 1598
1
(s, νC=O), 750 (m, γPyH). ESI-MS m/z: [MꢀH]ꢀ = 517 (75%). H NMR (D2O, ppm) δ:

1072
C. Gao et al.
1.03–3.08 (m, 10H of DACH and 6H of 2CH3COO), 4.31–4.40 (d, 2H, NHCH2), 7.36–
8.51 (m, 4H, C5H4N).
2.3.9. S2. The leaving group of S2 is ClCH2COOꢀ, so the starting material is
ClCH2COONa. Yield 39.3%. Anal. Calcd for C16H23Cl2N3O4Pt (%): C, 32.71; H, 3.92;
N, 7.16; Pt, 33.22. Found (%): C, 32.59; H, 3.93; N, 7.11; Pt, 33.01. IR(KBr, cmꢀ1):
3303–3123 (s, νN–H), 2936, 2856 (s, νC–H), 1598 (s, νC=O), 756 (m, γPyH). ESI-MS m/z:
1
[MꢀH]ꢀ = 586 (100%). H NMR (D2O, ppm) δ: 1.06–3.13 (m, 10H of DACH and 4H of
2ClCH2COO), 4.36–4.50 (d, 2H, NHCH2), 7.38–8.56 (m, 4H, C5H4N).
2.3.10. S3. The leaving group of S3 is CF3SOꢀ3 , so the starting material is CF3SO3Na.
Yield 37.3%. Anal. Calcd for C14H19F6N3O6S2Pt (%): C, 26.21; H, 2.96; N, 6.55; Pt,
30.42. Found (%): C, 26.08; H, 3.02; N, 6.51; Pt, 30.20. IR(KBr, cmꢀ1): 3266–3116 (s,
ν
N–H), 2936, 2858 (s, νC–H), 1596 (s, νC=O), 760 (m, γ
PyH). ESI-MSꢀ m/z:
[MꢀCF3SO3]+ = 492 (70%). 1H NMR (D2O, ppm) δ: 1.10–3.06 (m, 10H of DACH),
4.30–4.44 (d, 2H, NHCH2), 7.38–8.56 (m, 4H, C5H4N).
2.4. Cell culture
Four different human carcinoma cell lines, HepG-2, MCF-7, A549, and HCT-116, were
cultured in an RPMI-1640 medium supplemented with 10% fetal bovine serum, 100 unit
mLꢀ1 of penicillin, and 100 μg mLꢀ1 of streptomycin. Cells were maintained at 37 °C in a
humidified atmosphere of 5% CO2 in air.
2.5. Solutions
The platinum complexes were dissolved in DMSO at 5 mM as stock solution and diluted
in culture medium at concentrations of 0, 10, 20, 50, and 100 μM as working-solutions. To
avoid dimethylsulfoxide (DMSO) toxicity, the concentration of DMSO was less than 0.1%
(v/v) in all experiments.
2.6. Cytotoxicity analysis
MTT assay was carried out to evaluate the in vitro cytotoxicity of the resulting platinum
complexes as described by Mosmann [34]. Tumor cells were plated onto 96-well sterile
plates in 100 mL of medium at a density of 4 ꢁ 103 to 8 ꢁ 103 cells per well and incubated
for 24 h at 37 °C in a 5% CO2 containing incubator. The prepared compounds [PtRI],
[PtSI], R1–R3, and S1–S3 were added in final concentrations ranging from 0 to 100 μM.
After 48 h, 50 μl MTT in PBS (5 mg/mL) was added to each well and the plates were incu-
bated for 3 h at 37 °C. The liquid was removed and DMSO (100 mL) added to dissolve the
MTT formazan. The OD for each well was measured on a microplate reader at 490 nm.
All cytotoxicity tests were carried out three times parallelly; IC50 values were from curves
constructed by plotting cell survival (%) versus compound concentration (in μM).

Platinum(II) with chiral cyclohexyldiamine
3. Results and discussion
3.1. Preparation of chiral ligands and platinum complexes
1073
Mono-Boc protecting DACH was used as starting material to prepare the ligands R/S as
before, since it is difficult to directly get the monsubstituted derivatives due to equivalent
reactivity of the two amino groups in DACH, and the ligand was obtained via four steps
(figure 2).
Before preparing the targeted platinum complexes, important intermediates [PtRI]/[PtSI]
were first prepared by similar method described [35]. Then, AgNO3 was used to remove
the iodide of [PtRI]/[PtSI] to form in situ [PtR(H2O)]NO3, which was used to react with
sodium salts of the corresponding acetates, respectively, to afford R1/S1 to R3/S3
(figure 3).
3.2. Characterization of the complexes
1
Intermediates [PtRI]/[PtSI] and targeted platinum complexes were characterized by IR, H
NMR, ESI-MS spectra, and microananlysis. Elemental analyses for each compound were
in good agreement with calculated values. IR spectra of these complexes are similar, and
Pt-N coordinations were confirmed by νNH2/νNH shifting to lower frequencies compared
with free amino groups. Carboxylate binding with Pt(II) was confirmed by the C=O
absorptions shifting from free carboxylic acids near 1700 cmꢀ1 to bands near 1590 cmꢀ1
1
in R2/S2–R3/S3. The H NMR spectra of the complexes are consistent both in chemical
shifts and number of hydrogens. All prepared complexes showed a peak of [MꢀZ]+ or
[MꢀH]ꢀ in their ESI mass spectra, consistent with expected molecular formula weights.
Typical isotopes of Pt element: 194Pt (33%), 195Pt (34%), and 196Pt (25%), were found
with three protonated ion isotopic peaks.
3.3. Aqueous solubility and optical rotation of complexes
Poor aqueous solubility is a severe problem for some platinum anticancer drugs in clinical
use, such as cisplatin. Hence, the aqueous solubility of our Pt compounds was tested at
25 °C (table 1). Compared with cisplatin (1 mg/mL) and oxaliplatin (8 mg/mL), all
CHO
NH-Boc
NH-Boc
NH-Boc
N
N
NaBH4
N
*
*
*
*
*
*
NH
2
N
N
H
1
2
HCl/EtO2
NH
2
NH
2
N
N
NaHCO3
*
*
*3HCl
*
*
N
N
H
H
R/S
3
Figure 2. Synthetic scheme for ligands R/S.

1074
C. Gao et al.
HN
KI
R/S
N
I
*
*
K2PtCl4
K2PtI4
Pt
NH
I
2
[PtRI]/[PtSI]
H2O AgNO3
HN
HN
N
*
NO
NaZ
N
*
*
3
Z
Pt
Pt
2
*
H
O
Z
2
NH
NH
2
R1-R3/S1-S3
O
S
F
F
O
O
-
O
Z
=
Cl
-
,
-
,
O
F
O
O
Figure 3. Synthetic scheme for targeted platinum(II) compounds.
prepared platinum compounds are greatly improved ranging from 22.3 to 46.8 mg/mL.
Optical rotations of all complexes were tested (table 1).
3.4. Cytotoxic studies
In vitro cytotoxicities of platinum compounds were tested by MTT colorimetric assay
against HepG-2 human hepatocellular carcinoma cell, MCF-7 human breast cancer cell,
A549 human lung cancer cell, and HCT-116 human colorectal cancer cell, with carboplatin
and oxaliplatin as positive controls. All platinum compounds with R as the carrier group
showed activity against MCF-7, HCT-116, and A549 cell lines (table 2). Among them, R2
gave lower IC50 values than carboplatin against MCF-7 and A549 cell lines and also
exhibited close activity to oxaliplatin against HCT-116 cell line. Compound R1 showed
better antitumor activity than carboplatin against HCT-116. However, compounds with S
as the carrier group showed very low or no cytotoxicity against the four tested cell lines.
Table 1. Aqueous solubility and optical rotation of complexes.
ꢂC
Complex
Aqueous solubility (mg/mL, 25 °C)
a1D5 (C = 1.0, H2O)
[PtRI]
R1
R2
R3
[PtSI]
S1
22.3
39.8
44.0
30.1
23.6
40.4
46.8
28.6
46.9°
35.1°
29.8°
31.3°
ꢀ43.2°
ꢀ33.6°
ꢀ31.1°
ꢀ29.0°
S2
S3

Platinum(II) with chiral cyclohexyldiamine
1075
Table 2. Cytotoxicity of the targeted compounds against four tumor cell lines.
IC50 (μmol·Lꢀ1
)
Compd.
HepG-2
MCF-7
A549
HCT-116
[PtRI]
R1
R2
>100
>100
>100
58.1
11.6
9.5
63.2
26.8
7.9
81.6
21.3
7.6
R3
[PtSI]
S1
S2
S3
>100
>100
>100
>100
>100
9.7
Not tested
22.6
30.1
>100
>100
>100
>100
11.2
48.3
>100
86.3
>100
>100
68.1
>100
15.3
58.5
>100
Not tested
4.3
Carboplatin
Oxaliplatin
Not tested
Not tested
Based on the above results, platinum complexes with values of specific rotations from
ꢂ
+29.8° to +46.9° ða1D5 C (C = 1, H2O)), similar to those of oxaliplatin (+76.1°), show
cytotoxicity, exhibiting similar SARS to oxaliplatin bearing the trans-(1R,2R)-cyclohexane-
1,2-diamine as the carrier group [36,37]. Results also indicated that when CH3COOꢀ or
ClCH2COOꢀ was leaving groups, R1 and R2 showed much better antitumor activity than
compounds bearing Iꢀ or CF3SOꢀ3 as the leaving groups.
4. Conclusions
N-monosubstituted chiral DACH derivatives, R and S, were synthesized and spectrally
characterized to prepare eight Pt(II) complexes. All compounds showed much better
aqueous solubility than cisplatin and oxaliplatin. In vitro cytotoxicity tests showed that
compounds bearing R as the carrier group had antitumor activity against MCF-7,
A549, and HCT-116 cell lines, with R2 showing better antitumor activity than carbo-
platin against MCF-7 and A549 cell lines and also showed close cytotoxicity to
oxaliplatin against HCT-116. Compound R1 also exhibited better activity than carbo-
platin against MCF-7. Consequently, the prepared platinum compounds, especially R2,
deserve further investigation.
Acknowledgment
This work is supported by the National Natural Science Foundation of China Project
20971022 to S.H. Gou and 21062009 to B.Yang.
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