Preparation and in vitro cytotoxicity of oxaliplatin derivatives with chiral amino acid as the carrier group

Article abstract of DOI:10.1080/00958972.2014.945922

Novel platinum(II) compounds with a new chiral ligand were designed, prepared and biologically evaluated. Results indicated that compounds P3 and P4 showed better antitumor activity than carboplatin against two selected human cell lines. Eight oxaliplatin derivatives with chiral amino acid, 2-{[(1R,2R)-2-aminocyclohexyl]amino}propanoic acid, as the carrier group, were designed, synthesized, and spectrally characterized by IR,¹H NMR, MS spectra, and microanalyses. In vitro cytotoxicities against human HepG-2, MCF-7, A549, and HCT-116 cell lines were evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazo-liumbromide assay. Results indicated that all compounds exhibited sensitivity to HepG-2 cell line, and among them, compounds P3 and P4 which have CH₃(CH₂)₆COO^-and CH₃(CH₂)₈COO^-as the leaving groups, respectively, gave better antitumor activity than carboplatin against HepG-2 and A549 cell lines.

Full text of DOI:10.1080/00958972.2014.945922

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Preparation and in vitro cytotoxicity
of oxaliplatin derivatives with chiral
amino acid as the carrier group
Chuanzhu Gaoa, Tianshuai Wanga, Ji Chena, Yan Zhanga, Bo Yanga
& Shaohua Goub
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: 17 Jul 2014.Published
online: 11 Aug 2014.
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To cite this article: Chuanzhu Gao, Tianshuai Wang, Ji Chen, Yan Zhang, Bo Yang & Shaohua
Gou (2014) Preparation and in vitro cytotoxicity of oxaliplatin derivatives with chiral
amino acid as the carrier group, Journal of Coordination Chemistry, 67:13, 2195-2203, DOI:
10.1080/00958972.2014.945922
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Journal of Coordination Chemistry, 2014
Vol. 67, No. 13, 2195–2203, http://dx.doi.org/10.1080/00958972.2014.945922
Preparation and in vitro cytotoxicity of oxaliplatin derivatives
with chiral amino acid as the carrier group
CHUANZHU GAO†, TIANSHUAI WANG†, JI CHEN†, YAN ZHANG†, BO YANG*†
and SHAOHUA GOU*‡
†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 5 November 2013; accepted 4 June 2014)
Novel platinum(II) compounds with a new chiral ligand were designed, prepared and biologically
evaluated. Results indicated that compounds P3 and P4 showed better antitumor activity than carbo-
platin against two selected human cell lines.
Eight oxaliplatin derivatives with chiral amino acid, 2-{[(1R,2R)-2-aminocyclohexyl]amino}propa-
noic acid, as the carrier group, were designed, synthesized, and spectrally characterized by IR, 1H
NMR, MS spectra, and microanalyses. In vitro cytotoxicities against human HepG-2, MCF-7, A549,
and HCT-116 cell lines were evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazo-liumbro-
mide assay. Results indicated that all compounds exhibited sensitivity to HepG-2 cell line, and
among them, compounds P3 and P4 which have CH3(CH2)6COO– and CH3(CH2)8COO– as the
leaving groups, respectively, gave better antitumor activity than carboplatin against HepG-2 and
A549 cell lines.
Keywords: Chiral amino acid; Platinum(II) complexes; In vitro cytotoxicity
*Corresponding authors. Email: yangbo6910@sina.com.cn (B. Yang); sgou@seu.edu.cn (S. Gou)
© 2014 Taylor & Francis

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C. Gao et al.
1. Introduction
Cisplatin is one of the most frequently used chemotherapeutics in the treatment of malig-
nant tumors. However, clinical application of cisplatin is greatly limited by its side effects
including nephrotoxicity and neurotoxicity [1], narrow range of activity, intrinsic and/or
acquired resistance, and low aqueous solubility [2]. So far, tremendous efforts have been
devoted to developing new platinum compounds with improved pharmacological properties
and broader range of antitumor activity. This led to clinical development of cisplatin ana-
logs such as carboplatin and oxaliplatin which have been widely used for treating ovarian
cancers and colorectal tumors, respectively [3, 4].
Oxaliplatin, the first platinum-based drug owning a chiral moiety, 1R, 2R-diaminocyclo-
hexane (DACH), as the carrier group, has became the first line agent in treating advanced
colorectal cancer [5] and surpassed cisplatin as the biggest sale in this type of antitumor
drug. However, dose-limiting toxicity of oxaliplain is still serious. It has been reported that
90% of patients treated with oxaliplatin suffered from acute neurotoxicity, while 10–15% of
patients suffered from cumulative sensory [6]. Like other clinically available platinum anti-
cancer drugs, such as carboplatin and lobaplatin, oxaliplatin cannot offer any substantial
clinical advantages over the existing cisplatin [7].
Amino acids are the elementary units for composing all kinds of proteins. Introducing
amino acid into antitumor drugs could improve their target characteristics, relieve the toxici-
ties to normal cells, enhance the curative effect for tumors and take advantage of the O/N
groups as donors or acceptors for hydrogen bonds with DNA to further stabilize the DNA-
drug adducts [8]. Pt–amino acid complexes showed potential applications as antitumor
drugs such as DNA binding properties, HMG1 protein affinity for the platinated DNA and
cytotoxicity against HeLa cells [9]. More recently, synthetic amino acids showed better
qualities than natural amino acids in preparing Pt–amino acids with peptides incorporating
non-natural amino acids showing increased metabolic stability and, in some cases, also
enhanced biological activity [10, 11].
Our group have been studying new oxaliplatin derivatives that could improve their thera-
peutic effects and reduce their side effects [12–16]. Expecting interesting characteristics of
Pt complexes of an unnatural amino acid, and in order to overcome the drawbacks of oxa-
liplatin, we envisioned that introducing suitable carboxylic acids to DACH may offer some
new unnatural amino acids that could be taken as ligands to prepare Pt–amino acid
complexes. In this paper, an unnatural amino acid, 2-{[(1R,2R)-2-aminocyclohexyl]amino}
propanoic acid (HP) was prepared as the carrier group, and with CH3COO–, ClCH2COO–,
CH3(CH2)6COO–, CH3(CH2)8COO–, CH3(CH2)10COO–, CH3(CH2)12COO–,
, and
as the leaving group, eight platinum(II) complexes (P1–P8) were designed, synthe-
1
sized, and spectrally characterized by IR, H NMR, and MS spectra. Their in vitro cytotox-
icities against four human cancer cell lines were also reported.
2. Experimental
2.1. Materials
K2PtCl4 was purchased from a local chemical company. The optically pure (1R,2R)
trans-cyclohexanediamine, DACH, was purchased from a Chinese chemical company,

Oxaliplatin derivatives
2197
Aladdin reagent. Mono-Boc protecting DACH (
, hereinafter 1) was used as start-
ing material and prepared according to the procedure reported [17].
All reagents and solvents were of analytical grade and used without purification. RPMI-
1640 medium, trypsin, and fetal bovine serum were purchased from Gibco. 3-(4,5-Dimeth-
ylthiazol-2-yl)-2,5-diphenyltetrazo-liumbromide (MTT), benzyl penicillin, and streptomycin
were from Sigma. Four different human carcinoma cell lines, HepG-2 (human hepatocellu-
lar 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 carried out with a Perkin-Elmer 1400C instru-
ment. ESI-MS spectra were performed on a Finnigan MAT SSQ 710 (120–1000 am) appa-
ratus and IR spectra were scanned with a Nicolet IR200 spectrophotometer from 4000 to
1
400 cm−1 in KBr pellets. H 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. 2-{[(1R,2R)-2-aminocy-clohexyl]amino}propanoic acid (HP). 25.7 g mono-boc
protected DACH (1) was dissolved in 500 mL acetonitrile, then 18.7 g K2CO3 and 21.7 g
ethyl 2-bromopropanoate were added and refluxed for 6 h. Column chromatography (devel-
oper: petroleum ether/acetic ester/methanol = 5/1/1) gave intermediate 2. Dissolving 2 in
200 mL methanol with stirring, excessive HCl/Methanol was added and then a white solid
3 precipitated. Intermediate 3 was hydrolyzed in aqueous NaOH solution and intermediate
4 was obtained, which was then neutralized by HCl/Methanol to obtain a faint yellow solid
of HP; the yield was 38% (scheme 1). Anal. Calcd for C9H20Cl2N2O2: C, 41.71; H, 7.78;
N, 10.81. Found (%): C, 41.58; H, 7.80; N, 10.74. IR (KBr): 3343s(br), 2969s, 2928s,
2855s, 1583(sh)vs 1444vs, 1337m, 1302m, 1144m, 1074w, 976w, 916m, 880m, 867m,
1
768m, 598m, 436m. H NMR (D2O/TMS): δ 0.86 (d, 3H, CH3, J = 7.0) 1.04–1.08 (m, 4H,
2CH2 of DACH), 1.54–1.87 (m, 4H, 2CH2 of DACH), 2.00–2.26 (d, 2H, 2CH of DACH),
3.19–3.21 (m, 1H, NHCH(CH3)COO). ESI-MS m/z: [M − H − 2HCl]– = 185.6 (100%).
2.3.2. Compound [PtRI]. To a stirred aqueous solution of KI (160 mM), K2PtCl4
(24 mM) in water (80 mL) was added. The solution was stirred at 25 °C for 30 min under a
nitrogen atmosphere to get a black solution of K2PtI4. Then an aqueous solution (40 mL) of
HP (24 mM) and NaOH (24 mM) were added dropwise under stirring in the dark at 25 °C.
After 24 h, yellow precipitate was filtered, washed sequentially with water, ethanol, and
ether, and then dried in vacuum as a yellow solid. Yield: 58%. Data for [PtRI]: Anal. Calcd
for C9H17IN2O2Pt (%): C, 21.31; H, 3.38; N, 5.52. Found (%): C, 21.22; H, 3.30; N, 5.54.
IR (KBr, cm−1): 3467m, 3171s, 3113s, 2929m, 2856m, 1648vs, 1447m, 1376m, 1337m,
1
1260m, 1195w, 1140w, 1103w, 1021w, 872w, 617w, 459w. H NMR (D2O/TMS, ppm):

2198
C. Gao et al.
Scheme 1. Synthetic scheme for HP.
δ 0.84 (s, 3H, CH3), 1.08–1.91 (m, 8H, 4CH2 of DACH), 2.27–2.93 (d, 2H, 2CH of
DACH), 4.24 (s, 1H, NHCH(CH3)COO). ESI-MS m/z: [M + Na]+ = 530.0 (75%), [M + K]+
= 546 (100%).
2.3.3. Compound P1. Four millimole [PtRI] was suspended in 250 mL pure water and a
solution of 4 mM AgNO3 in 80 mL pure water was added. After stirring under a nitrogen
atmosphere in the dark for 24 h at 50 °C, the precipitate was filtered off. Filtrate was blended
with 4 mM CH3COONa and stirred at 55 °C for 24 h. The solution was concentrated to 3 mL
and then cooled to 0 °C. A pale yellow powder was collected, washed with a small amount
of chilled water and ethanol, and then dried at 60 °C in vacuum. Yield 23.6%. Anal. Calcd
for C11H20N2O4Pt (%): C, 30.07; H, 4.59; N, 6.38. Found (%): C, 30.10; H, 4.66; N, 6.56.
IR (KBr, cm−1): 3408m, 3100m, 2938m, 2862m, 1598s, 756m. 1H NMR (D2O, ppm):
δ 0.98–3.03 (m, 16H, 10H of DACH and 3H of CH3COO and 3H of NHCH(CH3)COO),
4.26 (s, 1H, NHCH(CH3)COO). ESI-MS m/z: [M − H]– = 438 (100%).
The procedures for preparing P2–P8 were similar to P1.
2.3.4. Compound P2. The leaving group of compound P2 is ClCH2COO–, so the starting
material was ClCH2COONa. Yield 26.0%. Anal. Calcd for C11H19ClN2O4Pt (%): C, 27.88;
H, 4.04; N, 5.91. Found (%): C, 27.96; H, 4.07; N, 5.96. IR (KBr, cm−1): 3411m, 3103m,
1
2936m, 2866m, 1596s, 751m. H NMR (D2O, ppm): δ 1.01–3.06 (m, 15H, 10H of DACH
and 2H of ClCH2COO and 3H of NHCH(CH3)COO), 4.28 (s, 1H, NHCH(CH3)COO).
ESI-MS m/z: [M − H]– = 472 (80%).
2.3.5. Compound P3. The leaving group of compound P3 is CH3(CH2)6COO–, so the
starting material was CH3(CH2)6COONa. Yield 49.1%. Anal. Calcd for C17H32N2O4Pt (%):
C, 39.00; H, 6.16; N, 5.35. Found (%): C, 39.02; H, 6.22; N, 5.36. IR (KBr): 3479m,

Oxaliplatin derivatives
2199
3250m, 3097m, 2922s, 2855m, 1577vs(sh), 1468m, 1388m, 1303m, 1153w, 1106m,
1
1039w, 873w, 623w, 459w. H NMR (DMSO/TMS): δ 1.13–2.66 (m, 28H, 3H of NHCH
(CH3)COO and 10H of DACH and 15H of COO(CH2)6CH3), 3.49–3.55 (m, 1H, NHCH
(CH3)COO), 5.30–6.19 (3H, NH and NH2). ESI-MS m/z: [M + H]+ = 524.0 (100%).
2.3.6. Compound P4. The leaving group of compound P4 is CH3(CH2)8COO–, so the
starting material was CH3(CH2)8COONa. Yield 44.0%. Anal. Calcd for C19H36N2O4Pt (%):
C, 41.37; H, 6.58; N, 5.08. Found (%): C, 41.29; H, 6.62; N, 5.11. IR (KBr): 3478m,
3240m, 3097m, 2954s, 2850m, 1654s, 1559vs, 1447m, 1384m, 1107w, 835w, 722w, 696w.
1H NMR (DMSO/TMS): δ 0.84–2.63 (m, 32H, 3H of NHCH(CH3)COO and 10H of
DACH and 19H of COO(CH2)8CH3), 3.28–3.51 (m, 1H, NHCH(CH3)COO), 5.32–6.17
(3H, NH and NH2); ESI-MS m/z: [M + H]+ = 552.0 (100%).
2.3.7. Compound P5. The leaving group of compound P5 is CH3(CH2)10COO–, so the
starting material was CH3(CH2)10COONa. Yield 51.8%. Anal. Calcd for C21H40N2O4Pt (%):
C, 43.51; H, 6.96; N, 4.83. Found (%): C, 43.56; H, 7.02; N, 4.91. IR (KBr): 3481m,
3249m, 3097m, 2924s, 2850s, 1600s(sh), 1467m, 1390m, 1339m, 1303m, 1276w, 1107w,
1
1039w, 837w, 7221w, 690, 459w. H NMR (DMSO/TMS): δ 1.25–2.87 (m, 36H, 3H of
NHCH(CH3)COO and 10H of DACH and 23H of COO(CH2)10CH3), 3.50–3.53 (m, 1H,
NHCH(CH3)COO), 5.31–6.50 (3H, NH and NH2); ESI-MS m/z: [M − H]– = 578.2 (100%).
2.3.8. Compound P6. The leaving group of compound P6 is CH3(CH2)12COO–, so the
starting material was CH3(CH2)12COONa. Yield 49.6%. Anal. Calcd for C23H44N2O4Pt (%):
C, 45.46; H, 7.30; N, 4.61. Found (%): C, 45.49; H, 7.36; N, 4.51. IR (KBr): 3478m,
1
3243m, 3096m, 2920s, 2849m, 1559s(sh), 1446m(sh), 1421m, 722w. H NMR (DMSO/
TMS): δ 1.11–2.52 (m, 40H, 3H of NHCH(CH3)COO and 10H of DACH and 27H of COO
(CH2)12CH3), 3.34–3.39 (m, 1H, NHCH(CH3)COO), 5.31–6.73 (3H, NH and NH2); ESI-MS
m/z: [M − H]– = 606.2 (100%).
2.3.9. Compound P7. The leaving group of compound P7 is
, so the starting mate-
rial was . Yield 44.9%. Anal. Calcd for C15H26N2O4Pt (%): C, 36.51; H, 5.31; N,
5.68. Found (%): C, 36.56; H, 5.38; N, 5.66. IR (KBr): 3385s(sh), 3240m, 2945s, 2865s,
1
1662s, 1557s, 1447m, 1407s, 1325m, 1111w, 775m, 577m, 460w. H NMR (D2O/TMS): δ
1.18–3.02 (m, 22H, 3H of NHCH(CH3)COO and 10H of DACH and 9H of (CH2)4CH
(COO)), 3.75–3.97 (m, 1H, NHCH(CH3)COO); ESI-MS m/z: [M + H]+ = 494.0 (20%),
[M + H2O + H]+ = 512.9 (100%).
2.3.10. Compound P8. The leaving group of compound P8 is
, so the starting
material was . Yield 51.2%. Anal. Calcd for C16H28N2O4Pt (%): C, 37.87; H, 5.56;
N, 5.52. Found (%): C, 37.96; H, 5.58; N, 5.56. IR (KBr): 3420m, 3203m, 2929s, 2852m,
1
1654s, 1567vs, 1416vs(sh), 1278m, 1222w, 1110w, 1036w, 893w, 774m, 645m, 504m. H

2200
C. Gao et al.
NMR (D2O/TMS): δ 1.23–2.94 (m, 24H, 3H of NHCH(CH3)COO and 10H of DACH and
11H of cyclohexyl), 3.87–4.05 (m, 1H, NHCH(CH3)COO); ESI-MS m/z: [M + H]+ = 508.1
(100%).
2.4. Cell culture
HepG-2, MCF-7, A549, and HCT-116 cell lines were cultured in an RPMI-1640 medium
supplemented with 10% fetal bovine serum, 100 unit mL−1 of penicillin, and 100 μg mL−1
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 a concentration of 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 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 et al. [18]. Tumor cells were plated onto 96-well ster-
ile plates in 100 mL of medium at a density of 4 × 103 – 8 × 103 cells per well and incu-
bated 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. Removing the liquid, DMSO (100 mL) was added to dissolve the
MTT formazan. The OD for each well was measured on a microplate reader at a wave-
length of 490 nm. All cytotoxicity tests were carried out three times in parallel; IC50 values
were obtained from curves constructed by plotting cell survival (%) versus compound
concentration (in μM).
3. Results and discussion
3.1. Preparation for chiral ligands and targeted platinum complexes
Mono-Boc protected DACH was used as starting material to prepare HP as before, since it
is difficult to directly get the mono-substituted derivatives due to the equivalent reactivity
of the two amino groups in DACH, and the ligand was obtained via four steps (scheme 1).
Before preparing the targeted platinum complexes, important intermediates [PtRI] were
prepared by adopting a similar method as described in the literature [19]. Then AgNO3 was
used to remove iodide of [PtRI] to form [PtR(H2O)]NO3, which was in situ used to react
with the sodium salts of the corresponding acids, respectively, to afford compounds P1–P8
(scheme 2). Coupling of the propanoic acid to the amine nitrogen to form the tridentate HP
ligand produces a chiral center at carbon 2 of the propanoic acid, and another chiral center
is produced once the nitrogen to which C-2 is bound becomes coordinated to platinum [14].

Oxaliplatin derivatives
3.2. Characterization of the complexes
2201
1
Intermediates [PtRI] and platinum complexes were characterized by IR, H NMR, ESI-MS
spectra, and microanalysis. Found values for each compound in the elemental analyses were
in agreement with calculated values. The IR spectra of these complexes are similar. Pt–N
coordinations were confirmed by examination of νNH2/νNH shifting to lower frequencies
compared with their free amino groups. Carboxylate anions binding with Pt(II) were con-
firmed by examination of the C=O absorptions shifting from free carboxylic acids near
1
1700 cm−1 to bands near 1590 cm−1 in each case. The H NMR spectra of the complexes
are consistent with their corresponding protons both in the chemical shifts and the number
of hydrogens. All prepared complexes showed a peak of [M + H]+ or [M − H]– in their ESI
mass spectra, which are consistent with expected molecular formula weights. Typical iso-
topes of Pt elements: 194Pt (33%), 195Pt (34%), and 196Pt (25%), were found with three pro-
tonated ion isotopic peaks.
3.3. Aqueous solubility
Poor aqueous solubility is a severe problem for some platinum anticancer drugs in clinic
use, such as cisplatin. Hence, the aqueous solubility of targeted platinum compounds was
tested at 25 °C, ranging from 2.3 to 53.2 mg/mL.
3.4. Cytotoxic studies
In vitro cytotoxicity of targeted platinum compounds was tested by MTT colorimetric assay
against HepG-2 human hepatocellular carcinoma cell, MCF-7 human breast cancer cell,
Scheme 2. Synthetic scheme for targeted platinum(II) compounds.

2202
C. Gao et al.
Table 1. Cytotoxicity of the targeted compounds against four tumor cell lines.
IC50 (μM L−1
)
Compd.
HepG-2
MCF-7
A549
HCT-116
P1
P2
P3
P4
P5
P6
P7
P8
56.3
41.6
8.6
>100
>100
>100
>100
>100
>100
>100
>100
9.2
>100
>100
10.1
9.6
36.1
38.6
>100
>100
13.1
>100
>100
36.1
>100
>100
>100
>100
>100
>100
>100
4.3
7.1
38.6
36.9
73.1
88.6
11.0
>100
Carboplatin
Oxaliplatin
>100
A549 human lung cancer cell, and HCT-116 human colorectal cancer cell, with carboplatin
and oxaliplatin as positive controls.
The cytotoxicities of oxaliplatin against HepG-2, MCF-7, and A549 human lung cancer
cells were tested and results showed that oxaliplatin was insensitive to them (table 1). All
platinum compounds showed a certain activity against the HepG-2 cell line, but showed
very low activity (<100 μM L−1) against MCF-7 cell line. To cell lines A549 and HCT-116,
a portion of the targeted complexes showed cytotoxicity and no significant regularity was
found.
Among all platinum compounds, P3 and P4 gave lower IC50 values than carboplatin
against HepG-2 and A549 cell lines. From P1–P6, it could be seen that all of them have
taken carboxylates as the leaving group, and the length of carbon chains increases, P1 =
P2 < P3 < P4 < P5 < P6. Aqueous solubility of the new platinum complexes was also tested
and showed a reverse order to the length of carbon chains, P2 > P1 > P3 > P4 > P5 > P6.
Compounds P3 and P4 of intermediate carbon chain length showed favorable activity against
tested tumors. Speculating the reasons, if the carbon chains for the leaving group are much
shorter, the solubility of platinum compounds (P1–P2, 43.5–53.2 mg/mL) may be too good
to break down before forming the adducts with the tumor DNA base pairs, but when the
carbon chains are much longer, the platinum compounds showed poor water solubility
(P5–P6, 3.1–2.3 mg/mL), which is a common reason for platinum complexes having poor
antitumor activity. P3 and P4, which took CH3(CH2)6COO– and CH3(CH2)8COO– as leaving
groups, respectively, showed medium aqueous solubility (P3–P4, 16.8–14.4 mg/mL) for
medium length carbon chains, exhibiting better cytotoxicities than other platinum complexes
in this study.
Compounds P7 and P8 showed unsatisfactory in vitro cytotoxicity to all tested cell lines.
The reason may be that the cycloalkanes in the leaving group have steric hindrance for
bonding between the platinum complexes and DNA base-pairs.
4. Conclusion
A new chiral DACH derivative, HP, was designed, synthesized, and characterized to pre-
pare eight Pt(II) complexes. In vitro cytotoxicity tests showed that all compounds exhibited
sensitivity to the HepG-2 cell line with P3 and P4, bearing CH3(CH2)6COO– and

Oxaliplatin derivatives
2203
CH3(CH2)8COO– as the leaving groups, respectively, which gave better antitumor activity
than carboplatin against HepG-2 and A549 cell lines. Li et al. [20] and Zhang et al. [21]
reported some new platinum(II) complexes with amino acid dianion ligands and some
showed selective cytotoxicities against tested tumor cell lines and are similar to the
platinum compounds reported in this manuscript. Consequently, the prepared platinum
compounds, especially P3 and P4, may serve for further investigation.
Funding
This work is supported by the National Natural Science Foundation of China Project [grant number 21361014],
[grant number 21302074] to C.Z. Gao; the National Natural Science Foundation of China Project [grant number
21362016] to B. Yang; the National Natural Science Foundation of China Project [grant number 21272041] to
S.H. Gou; Doctoral Program of the Ministry of Education of PR China [grant number 20125314120007] to
C.Z. Gao.
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