Synthesis, characterization, and antitumor activity of platinum(II) complexes of mixed ammine/amine with bidentate carboxylates

Article abstract of DOI:10.1081/SIM-120013145

Complexes of the type Pt(II)(CH₃NH₂)(NH₃)[(OC)₂ (CH₂)_n]·0.5H₂O [(1)-(3)] (n = 0, 1 and 2) have been synthesized for the first time. At the same time, we also have synthesized thr

Full text of DOI:10.1081/SIM-120013145

This article was downloaded by: [Selcuk Universitesi]
On: 09 January 2015, At: 21:03
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthesis and Reactivity in Inorganic and Metal-
Organic Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsrt19
SYNTHESIS, CHARACTERIZATION, AND ANTITUMOR
ACTIVITY OF PLATINUM(II) COMPLEXES OF MIXED
AMMINE/AMINE WITH BIDENTATE CARBOXYLATES
Jinchao Zhang a , Yuqin Gong b & Xiaoming Zheng a
a Department of Chemistry , Zhejiang University Xixi Campus , Hangzhou, 310028, P. R.
China
b Department of Chemistry , Zhejiang University Xixi Campus , Hangzhou, 310028, P. R.
China
Published online: 15 Feb 2007.
To cite this article: Jinchao Zhang , Yuqin Gong & Xiaoming Zheng (2002) SYNTHESIS, CHARACTERIZATION, AND
ANTITUMOR ACTIVITY OF PLATINUM(II) COMPLEXES OF MIXED AMMINE/AMINE WITH BIDENTATE CARBOXYLATES, Synthesis
and Reactivity in Inorganic and Metal-Organic Chemistry, 32:1, 49-57, DOI: 10.1081/SIM-120013145
To link to this article: http://dx.doi.org/10.1081/SIM-120013145
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of
the Content. Any opinions and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied
upon and should be independently verified with primary sources of information. Taylor and Francis shall
not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other
liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

SYNTH. REACT. INORG. MET.-ORG. CHEM., 32(1), 49–57 (2002)
SYNTHESIS, CHARACTERIZATION, AND
ANTITUMOR ACTIVITY OF
PLATINUM(II) COMPLEXES OF MIXED
AMMINE=AMINE WITH BIDENTATE
CARBOXYLATES
JinchaoZhang, Yuqin Gong, * and Xiaoming Zheng
Department of Chemistry, Zhejiang University Xixi
Campus, Hangzhou, 310028, P. R. China
ABSTRACT
O
k
Complexes of the type Pt(II)(CH3NH2)(NH3)[(OC)2-
(CH2)n]Á0:5H2O [(1)7(3)] (n ¼ 0, 1 and 2) have been syn-
thesized for the first time. At the same time, we also have
synthesized three precursor complexes. They were character-
ized by elemental analyses, molar conductance, differential
1
thermal analyses and spectral (IR, UV, H NMR) studies.
In vitro antitumor activity results indicate that these com-
plexes have significant activity against HL-60 and U937, but
show poor activity against K562, (HL-60, U937 and K562 are
human leukemic tumor cell lines).
*Corresponding author. E-mail: cdfei@mail.hz.zj.cn
49
Copyright # 2002 by Marcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
50
ZHANG, GONG, AND ZHENG
INTRODUCTION
Cisplatin and carboplatin are the presently used antitumor platinum
drugs, but they have the disadvantages of exhibiting cross-resistance, re-
quiring intravenous administration and producing severe acute and chronic
toxicity. The requirement to circumvent acute nephrotoxicity and emesis
frequently necessitates hospitalisation.
At the early stage of drug development, cisplatin analogs with either
bis(alkylamine) or diamine as their non-leaving ligands and various
anionic groups as their leaving groups were the main choice in this de-
velopment effort. Recently some mixed ammine=amine platinum com-
plexes have appeared in the literature. Preliminary results indicated that
these new drugs were less toxic than the parent cisplatin172. Carboxylate
(especially bidentate) platinum(II) complexes seem to be quite promising
because they were less toxic and more soluble than the corresponding
chloro analogs3. But few carboxylate platinum(II) complexes are
reported.
Therefore, we synthesized three new mixed ammine=amine
platinum complexes Pt(CH3NH2)(NH3)[(OCO)2(CH2)n]Á0.5H2O (n ¼ 0, 1
and 2). Also discussed are the properties and structures of these complexes.
EXPERIMENTAL
Materials
All chemicals used in this work were of analytical grade and purchased
from the Shanghai Chem. Co. or Zhejiang Chem. Co.
Physical Measurements
C, H and N were analyzed using a Carlo Erba 1106 elemental ana-
lyzer. IR spectra were recorded in the region 40007200 cmÀ1 (in KBr pellets)
on a model-683 Perkin-Elmer infrared spectrophotometer. Electronic
spectra were taken on an UV-3400 Toshniwal spectrophotometer. 1H NMR
spectra were obtained on a JEOL FX-90Q spectrometer at 90 MHz.
Molar conductances were measured with a DDS-11A conductivity meter
at 25 ꢀC. TG-DTA were recorded on a RIGAKU 8150 thermal analyses
meter.

ORDER
REPRINTS
PLATINUM(II) COMPLEXES
Antitumor Evaluation
51
Human leukemic tumor cells were maintained in a plastic culture flask
containing RPMI 1640 culture medium (RPMI 1640 is a powder with
Lglutamine without sodium bicarbonate) supplemented with PSN anti-
biotics (PSN is penicillin and streptomycin) mixture and 10% fetal bovine
serum.
The cytotoxic activity of complexes was measured by an MTT assay
(MTT is thiazoyl blue tetrazolium bromide). Briefly, a 96-well culture plate
was dispensed in triplicate with 200 mL of culture medium containing the
platinum complexes at several concentrations. The complexes were dis-
solved in normal saline solution as appropriate for maximal stability, and
sterilized through 0.22 mm filter discs. Aliquots (0.1 mL) of a cell suspension
(16105 cells=mL) were thenÀa2dded, and after incubating for sixtyeight hours
at 37 ꢀC in 5% CO2, 1610 mL of a MTT solution (5Â10À3 g=mL) was
added to each well. After four hours of incubation, the medium was care-
fully removed, and replaced by 0.25 mL of 100% dimethyl sulfoxide to
dissolve MTT formazan crystals. The plates were then agitated on a shaker
for 5 min and absorbances were measured at 570 nm in a multiwell scanning
spectrophotometer (model DG 3022A). The cytotoxicity was determined by
expressing the mean optical densities for drug-treated cells at each con-
centration as a percentage of that of untreated cells, and IC50 values were
calculated according to median effect analysis.
Preparation of Platinum Complexes
The precursor complexes cis-Pt(CH3NH2)2I2, [Pt(CH3NH2)I2]2 and
cis-Pt(CH3NH2)(NH3)I2 were synthesized according to the literature3.
Pt(CH3NH2)(NH3)[(OCO)2(CH2)n]Á0.5H2O (1)
Solid Ag2CO3 (1 mmol, 0.275 g) was added to an aqueous solution
40 mL of oxalic acid (1 mmol, 0.900 g) and 5 mL of methanol, followed by
an equimolar amount of cis-Pt(CH3NH2)(NH3)I2. The mixture was stirred
in the dark for 40 h, filtered twice through Celite, and the solution eva-
porated to dryness in vacuo and washed with diethyl ether and acetone.
The pale yellow compound was dried under vacuum over P4O10. The syn-
thetic procedures for Pt(CH3NH2)(NH3)[(OCO)2(CH2)n]Á0.5H2O (2) and
Pt(NH3)(CH3NH2)[(OCO)2(CH2)n]Á0.5H2O (3) were similar.

ORDER
REPRINTS
52
ZHANG, GONG, AND ZHENG
RESULTS AND DISCUSSION
All data of the precursor complexes are collected in Table I.
The formation of the complexes may be represented by the following
equations:
KI
K2PtCl4
cis-PtðCH3NH2Þ2I2
!
CH3NH2
HClO4
!
PtðCH3NH2Þ2I2
½PtðCH3NH2Þ I2ꢁ
2
2
NH3ÁH2O
½PtðCH3NH2Þ2I2ꢁ2
cis-PtðCH3NH2ÞðNH3ÞI2
!
Ag2CO3
PtðCH3NH2ÞðNH3ÞI2
!
dicarboxylic acid
PtðCH3NH2ÞðNH3Þ½ðOCOÞ2ðCH2ÞnꢁÁ0:5H2Oꢁ
n ¼ 0 ð1Þ; n ¼ 1 ð2Þ; n ¼ 2 ð3Þ
The physical and analytical data of the complexes (1)7(3) are pre-
sented in Table II. The new complexes are sparingly soluble in water, but
insoluble in ethanol, ether and methanol. The molar conductivity of the
complexes (1)7(3) in nitrobenzene indicated that they are non-electro-
lytes4.They are quite stable in air and the thermal behaviour is similiar (see
Table II).
Table I. Analyses and Other Data of the Precursor Complexes
Found (Calcd.) (%)
Complex=Emprical
Formula
Colour
Decomp.
Yield
(%)
(Formula Wt.) Temp.(ꢀC)
C
N
H
cis-Pt(CH3NH2)2I2
(C2H10N2I2Pt)
[Pt(CH3NH2)I2]2
(C2H10N2I4Pt)
cis-Pt(CH3NH2)(NH3)I2
(CH8N2I2Pt)
Yellow
(511.0)
Red brown
(960.0)
Yellow
140
150
125
4.61
5.47
1.9870
(4.70) (5.48) (1.97)
2.482.94 1.09 90
(2.50) (2.91) (1.05)
2.56 5.72 1.6870
(2.42) (5.64) (1.62)
(497.0)

ORDER
REPRINTS
PLATINUM(II) COMPLEXES
53

ORDER
REPRINTS
54
ZHANG, GONG, AND ZHENG
IR Spectra
The important IR frequencies are listed in Table III. The u(N-H)
stretching frequencies of the precursor and new complexes show two med-
ium strong bands at ꢂ 3240 and ꢂ 3270 cmÀ1. A new band appearing at
4607480 cmÀ1 is assigned to Pt-N stretching, confirming the presence of
coordinated amines. The u(Pt-I) stretching vibrations absorb below
200 cmÀ1 and were not observed as expected.
The carboxylate groups of the new complexes (1)7(3) show two bands,
and intense antisymmetric carboxylate stretching uas(OCOÀ) and symmetric
stretching uas(OCOÀ), at about 1650 and 1400 cmÀ1, respectively.
Trends in the positions and the separation between these bands are the
most useful tools in assigning structures from infrared spectra. The data of
Table III show that the values of Du ¼ uasðOCOÀÞ À usðOCOÀÞ of the
complexes (1)7(3) are in the range 2407280 cmÀ1, which is greater than Dv
of the corresponding sodium oxalate, malonate or succinate. According to
the literature, we may suggest that the carboxylate groups act as mono-
denate ligands in the complexes (1)7(3)5. At the same time, a new band
appeared at about 580 cmÀ1 and is assigned to Pt-O stretching. This in-
dicates that the carboxylate group takes part in coordination. Morever, the
u(O-H) band of the compexes (1)7(3) occurs as broad shoulder centered at
3500 cmÀ1. Therefore, we suggest that the complexes (1)7(3) include water,
and this is also confirmed by TG-DTA.
UV Spectra
The UV spectra of malonic acid and succinic acid in water show no
absorption, while oxalic acid shows one absorption maximum at 212 nm.
The complexes (1) and (3) did not show any absorption. Complex (2) had a
new peak at about 193.18nm.
1H NMR Spectra
1
1
The important H NMR spectral data are listed in Table IV. The H
NMR spectra (in D2O as solvent) of the complexes (1)7(3) show doublets at
about 2.30 and 4.70 ppm. They are assigned to the hydrogen atoms of the
methyl group of the methylamine and the exchanging water (HOD). The
shift of the methylene group of the complexes (1)7(3) is greater than that of
1
free malonic acid and succinic acid. The H NMR spectra also confirm the
coordination of the ligands to platinum.

ORDER
REPRINTS
PLATINUM(II) COMPLEXES
55

ORDER
REPRINTS
56
ZHANG, GONG, AND ZHENG
Table IV. 1H NMR Spectral Data of the Ligands and Complexes (1)7(3)
Compound
CH3NH2
7CH2
HOD
Malonic acid
Succinic acid
3.37 (s, 2H)
2.43 (s, 4H)
(1)
(2)
(3)
2.20 (s, 3H)
2.37 (s, 3H)
2.30 (s, 3H)
4.70
4.70
4.70
3.71 (s, 2H)
2.51 (s, 4H)
Based on the above physical data, we conclude that in the dicarboxylate
chelates with platinum(II) each carboxylate group coordinates to platinu-
m(II) as monodentate ligand. The complexes (1)7(3) may have the following
structure as shown in Fig. 1.
Antitumor Properties
Cytotoxicity data for the complexes (1)7(3) are presented in Table V.
These data indicate a dose-dependent activity. The activity increases at
higher doses. Complex (3) shows the highest activity against the three kinds
of tumors. Complex (2) has the poorest antitumor activity. Morever, we find
that according to the experimental results the complexes are sensitive to
U937 and HL-60, but insensitive to K562.
Figure 1. Suggested Structure of the Complexes. (n ¼ 0 (1); n ¼ 1 (2) and n ¼ 2 (3)).

ORDER
REPRINTS
PLATINUM(II) COMPLEXES
57
Table V. In Vitro Antitumor Activities to HL-60, U937, and K562 Tumour Cell
Lines
HL-60
U937
K562
Compound
IC50 (mg=mL)
%Inhibition of 160 mg=mL
(1)
(2)
(3)
19.05
24.32
16.21
17.57
21.87
14.45
14.615
1.79
22.30
This class of platinum complexes seems to be quite promising, ac-
cording to the experimental results and the literatures, since they have good
antitumor activites and solubility in water. Accordingly, rapid development
of this class of platinum complexes toward clinical trials is expected.
ACKNOWLEDGMENT
This project was supported by the Natural Science Foundation of
Zhejiang Province (No. 298068).
REFERENCES
1. Ernest, W.; Christen, M.G. Current Status of Platinum-Based Anti-
tumor Drugs. Chem. Rev. 1999, 99, 245172466.
2. Khokhar, A.R.; Deng, Y.J.; Salaam, A.B.; Motofumi, Y.; Zahid, H.S.
Synthesis and Antitumor Activity of Ammine=Amine Platimum(II) and
(IV) Compexes. J. Inorg. Biochem. 1993, 51, 6777687.
3. Rochon, F.D.; Kong, P.C. Iodo-Bridged Complexes of Platimun(II)
and Synthesis of Cis-Mixed-Amine Platinum(II) Compounds. Can. J.
Chem. 1986, 64, 189471896.
4. Geary, W.J. The Use of Conductivity Measurements in Organic Sol-
vents for the Characterization of Coordination Compounds. Coord.
Chem. Rev. 1971, 7, 8 17122.
5. Deacon, G.B.; Phillips, R.J. Relationships Between the Carbon-Oxygen
Stretching Frequencies of Carboxylato Complexes and the Type of
Carboxylate Coordination. Coord. Chem. Rev. 1980, 33, 2277250.
Received May 6, 1999
Accepted October 4, 2001
Referee I: K. M. Doxsee
Referee II: J. C. Fanning

Request Permission or Order Reprints Instantly!
Interested in copying and sharing this article? In most cases, U.S. Copyright
Law requires that you get permission from the article’s rightsholder before
using copyrighted content.
All information and materials found in this article, including but not limited
to text, trademarks, patents, logos, graphics and images (the "Materials"), are
the copyrighted works and other forms of intellectual property of Marcel
Dekker, Inc., or its licensors. All rights not expressly granted are reserved.
Get permission to lawfully reproduce and distribute the Materials or order
reprints quickly and painlessly. Simply click on the "Request
Permission/Reprints Here" link below and follow the instructions. Visit the
U.S. Copyright Office for information on Fair Use limitations of U.S.
copyright law. Please refer to The Association of American Publishers’
(AAP) website for guidelines on Fair Use in the Classroom.
The Materials are for your personal use only and cannot be reformatted,
reposted, resold or distributed by electronic means or otherwise without
permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the
limited right to display the Materials only on your personal computer or
personal wireless device, and to copy and download single copies of such
Materials provided that any copyright, trademark or other notice appearing
on such Materials is also retained by, displayed, copied or downloaded as
part of the Materials and is not removed or obscured, and provided you do
not edit, modify, alter or enhance the Materials. Please refer to our Website
User Agreement for more details.
Order now!
Reprints of this article can also be ordered at
http://www.dekker.com/servlet/product/DOI/101081SIM120013145