Spectroscopic, kinetic and cytotoxic in vitro study of hexafluoroglutarate platinum(II) complex with 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine

Article abstract of DOI:10.1016/j.ica.2012.01.034

Reaction of cis-[PtI₂(dmtp)₂] (where dmtp - 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine) with silver hexafluoroglutarate [Ag₂(C₅F₆O₄)] yielded new complex [Pt(C₅F₆O₄)(dmtp)₂]·2H ₂O. The platinum(II) complex has been characterized by ¹H, ¹⁹F NMR and IR. In additional, kinetics of its hydrolysis and antiproliferative activity in vitro against three cell lines (A549 human non small cell lung carcinoma; A375.S2 human melanoma and mouse B16 melanoma tumors) has been studied.

Full text of DOI:10.1016/j.ica.2012.01.034

Inorganica Chimica Acta 387 (2012) 455–459
Contents lists available at SciVerse ScienceDirect
Inorganica Chimica Acta
journal homepage: www.elsevier.com/locate/ica
Note
Spectroscopic, kinetic and cytotoxic in vitro study of hexafluoroglutarate
platinum(II) complex with 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine
a,
⇑
a
a
b
b
Iwona Łakomska , Kamil Hoffmann , Adrian Topolski , Tomasz Kloskowski , Tomasz Drewa
a
Faculty of Chemistry, Nicolaus Copernicus University, Gagarina 7, 87-100 Toru n´ , Poland
Chair of Medical Biology, Nicolaus Copernicus University, Karłowicza 24, 85-092 Bydgoszcz, Poland
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 August 2011
Received in revised form 10 January 2012
Accepted 18 January 2012
Available online 28 January 2012
Reaction of cis-[PtI (dmtp) ] (where dmtp – 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine) with silver
2
2
hexafluoroglutarate [Ag
2
(C
5 6
F O
4
)] yielded new complex [Pt(C
5 6
F O
4
)(dmtp)
2 2
]ꢀ2H O. The platinum(II)
1
19
complex has been characterized by H, F NMR and IR. In additional, kinetics of its hydrolysis and anti-
proliferative activity in vitro against three cell lines (A549 human non small cell lung carcinoma; A375.S2
human melanoma and mouse B16 melanoma tumors) has been studied.
Ó 2012 Elsevier B.V. All rights reserved.
Keywords:
Platinum(II) complex
Dicarboxylate
Triazolopyrimidine
Hydrolysis
Cytotoxicity in vitro
1
. Introduction
On the other hand, after short-time incubation (1 h)
[
Pt(A9pyp)(dmso)(1,1-CBDCA)] demonstrated higher activity
against human ovarian cancer both sensitive (EC50 = 6.8 M) and
cisplatin-resistance cell lines (EC50 = 12.9 M) than cisplatin
(EC50 = 20 M and over 100 M, respectively).
Cisplatin is one of the most effective antitumor agents that are
l
currently used to treat various types of human cancer [1–3]. How-
ever, the application of this drug has been greatly hampered by
poor solubility in aqueous solution, drug resistance and several
side effects. Those clinical inconveniences in the cisplatin chemo-
therapy prompted to design new platinum compounds to afford
novel drugs with improved pharmacological properties and higher
antitumor activity [4–7]. Consequently, new platinum drugs have
been developed by modification of the labile chloride and stable
amine ligands with other groups. In this way, a new generation
of platinum drugs were designed [8]. Several examples within
the second generation like: carboplatin, oxaliplatin, JM216, malo-
natoplatin were obtained [9–11]. Nowadays, some of them are
increasingly used in cancer treatment [12].
Carboxylate platinum(II) compounds represent a class of new
promising anticancer prodrugs. Many platinum(II) complexes on
general formula: [Pt(A)(X)], where A = 2-hydroxy-1,3-propanedi-
amine or A9pyp = E-1-(9-anthryl)-3-(2-pyridyl)-2-propenone and
X = 1,1-cyclobutandicarboxylate or malonate, oxalate have been
described [13,14]. Some of platinum(II) complexes with 2-hydro-
xy-1,3-propanediamine exhibit high antitumor activity against se-
lected tumor cell lines (SGC-7901, LNcap, A549 and A549/ATCC).
l
l
l
Other promising antitumor platinum(II) prodrugs contain
hydroxydicarboxylate and different N-ligands (ethylenediamine,
1-ethylimidazol, 1-propylimidazol) [8]. Those complexes exhibit
low susceptibility to hydrolysis and low reactivity against glutathi-
one. In addition, their cytotoxic effects mainly depend on the kind
of amine ligand. The authors noted that the complexes with the
primary amine (ethylenediamine) were more effective than com-
pounds containing tertiary amine (1-alkylimidazole). On the other
hand, two of the 1-alkylimidazole complexes: bis(1-ethylimida-
zole)(L-malato)platinum(II) and bis(1-propylimidazole)(L-mala-
to)platinum(II), with very low toxicity in a short-term test
in vitro, show a considerable ability to arrest cells in G2 phase [15].
The next strategy towards creating carboxylate platinum(II)
compounds was focused on substitution of acetate as leaving li-
0
gand. Several trans-[Pt(acetate)
2
(A)(A )], where A = quanoline, iso-
0
0
quanoline, pyridine, 3-picoline, 4-picoline, A = NH
[16,17] or A = isopropylamina, A = N-methylimidazol, N-methyl-
3
and A = A
0
3
pyrazole [18] have been reported. Complexes contain NH , quano-
line, isoquanoline and pyridine ligands indicated lower resistance
factor against ovarian cancer cell line than cisplatin or oxaliplatin
[
16]. In addition, complexes with 3-picoline and 4-picoline pre-
⇑
Corresponding author. Fax: +48 56 654 2477.
E-mail addresses: dziubek@umk.pl, dziubek@cc.uni.torun.pl (I. Łakomska).
sented significant cytotoxicity against sensitive Pam 212 and
insensitive Pam 212-ras which show a lack of cross-resistance
0
020-1693/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.ica.2012.01.034

4
56
I. Łakomska et al. / Inorganica Chimica Acta 387 (2012) 455–459
dmtp
dmtp
O
O
dmtp
dmtp
O
dmtp
dmtp
OH
OH
−
−
+
OH , k1
+ OH , k
2
Pt
Pt
Pt
O−
OH
k1 (solv)
fast
k2 (solv)
fast
+
H O
+ H O
2
2
dmtp
dmtp
O
dmtp
dmtp
OH2
OH
Pt
Pt
O−
OH2
−O
=
hexafluoroglutarate
O−
Scheme 1. Propose the reaction sequence products during basic hydrolysis.
the reaction of Ag
method [22].
2 3
CO with hexafluoroglutaric acid by published
3
2
2
1
1
0
0
.0
.5
.0
.5
.0
.5
.0
3
20 K
2
2
.2. Preparation of compounds
2 2
.2.1. cis-[PtI (dmtp) ]
To a solution of K
2 4
PtCl (0.100 g, 0.24 mmol) in 5 mL of water,
the aqueous solution of KI (0.201 g, 1.20 mmol) in 5 mL was added
and the reaction mixture was stirred for 0.5 h. Then two equiva-
lents of dmtp (0.071 g, 0.48 mmol) dissolved in 5 mL of water
was added quickly. The reaction mixture was further stirred for
k
310 K
4
8 h in darkness. The dark yellow precipitate cis-[PtI
was filtered, washed with water, ethanol, diethyl ether and dried
in vacuum over P 10. Yield 0.156 g (87%). Anal. Calc./exp for
14 20 2 8
C H I N Pt: C, 22.56/22.20; H, 2.16/2.16; N, 15.04/14.95. IR
2 2
(dmtp) ]
4
O
3
00 K
ꢁ
1
1
(
KBr, cm ): 1626 (s,
m
tp), 1551 (s,
m
py); H NMR (DMSO-d
6
):
d 9.11 (s, H2), d 7.27 (s, H6), d 2.35 (s, 5CH
3
), d 2.66 (s, 7CH ).
3
0
.00
0.02
0.04
0.06
0.08
0.10
0.12
2
.2.2. [Pt(C
cis-[PtI
of water. After 0.5 h of stirring the solution of [Ag
(0.058 g, 0.13 mmol) in 40 mL mixture of water and ethanol (v/v,
:1) was dropped. The reaction suspension was then continuously
5
F
6
O
4
)(dmtp)
(dmtp) ] (0.100 g, 0.13 mmol) was suspended in 20 mL
(C )]
2 2
]ꢀ2H O
−
[
OH ], M
2
2
ꢁ
2
5 6 4
F O
Fig. 1. Dependence of the kobs1 on [OH ] in 300 (ꢀ), 310 (j) and 320 K (N).
Pt ] = 1.6 ꢂ 10 M, I = 0.1 M (Na , ClO
II
ꢁ5
+
ꢁ
ꢁ
[
4
, OH ).
1
stirred in the dark for 48 h at room temperature. The AgI precipi-
tate was filtered off. The clear filtrate was evaporated to dryness.
Yield 0.068 g (70%). Anal. Calc./exp for C19H20F N O Pt: C, 29.79/
[
17]. Moreover, platinum(II) compounds containing isopropylami-
na, N-methylimidazol, N-methylpyrazole exhibit activity against
cell of mouse leukemia.
6
8 6
29.39; H, 2.63/2.93; N, 14.64/14.60. Thermal decomposition pro-
ceeds in two steps. The first endothermic process is due to the loss
of one molecule of hydrated water in the temperature range 50–
175 °C (weight loss Calc./exp: 2.41/2.64). The second stage is much
more complicated and it is corresponding to the decomposition of
heterocycles ring, dicarboxylate and elimination of the second
water molecule. The total decomposition take places at 985 °C
and finally leads to metallic platinum.
Literature data and our previously studies [19,20] on the coor-
dination of platinum(II) with triazolopyrimidine derivatives have
shown a good antiproliferative activity against various types of tu-
mor cell, but their solubility in water were rather low. As part of
our continuing effort to develop new platinum antitumor agents,
in this paper we report the synthesis, spectroscopic studies, cyto-
toxic in vitro and kinetic properties of mononuclear platinum(II)
with bidentate hexafluoroglutarate and 5,7-dimethyl-1,2,4-
triazolo [1,5-a]pyrimidine.
ꢁ1
IR (KBr, cm ): 1635 (s, mtp), 1558 (s, mpy) 1681 (s, mas(COO)), 1371
1
(s, ms(COO)), 270 (w, mPt–N), 558 (m, mPt–O). H NMR (DMSO-d ): d 9.00
6
1
9
(
s, H2), d 7.39 (s, H6), F NMR (DMSO-d
6
): d ꢁ39.29 (s,
2
a-CF ),
d ꢁ47.33 (s, b-CF ).
2
2
. Experimental
.1. Materials
,7-Dimethyl-s-triazolo[1,5-a]pyrimidine (98%), hexafluoroglu-
2
2.3. Instrumentation
5
The C, H, N content was determined with an elemental analyzer
CHN, Vario Macro Elementary GMBH. IR spectra were measured
with a Perkin-Elmer Spectrum-2000 FT–IR spectrometer, using
taric acid (97%) were purchased from Aldrich. The inorganic salts
and solvents of analytical grade were obtained from POCh Gliwice
ꢁ
1
ꢁ1
(
Poland).
PtCl
21]. Disilver hexafluoroglutarate (Ag
KBr (400–4000 cm ) and polyethylene discs (100–400 cm ).
1
19
K
2
4
was prepared from metallic Pt by known procedures
) was prepared by
The H, F spectra were performed with a BRUKER AMX 300
NMR. The solvent was dmso-d , the concentrations of saturated
[
2
5
C F
6
O
4
6

I. Łakomska et al. / Inorganica Chimica Acta 387 (2012) 455–459
457
Table 1
Rate constants and activation parameters for the first step of [Pt{(C
5
6
F O
4
)(dmtp)
2
]ꢀ2H
2
O degradation processes and corresponding rate constants for oxaliplatin.
103
k
1
(s
ꢁ1
M
ꢁ1
)
103
k1(solv) (s
ꢁ1
)
Compound
Pt(C )(dmtp)
T (K)
[
5
F
6
O
4
2
]ꢀ2H
2
O (I = 0.1 M)
300
2.48 ± 0.17
8.66 ± 0.57
20.5 ± 2.3
0.92
0.148 ± 0.012
0.342 ± 0.038
0.56 ± 0.16
0.72
3
3
10
20
Oxaliplatina (I = 0.5 M)
Activation parameters of the first step
310
ꢁ
Reaction with OH (k
1
)
2
Reaction with H O (k1(solv))
–
ꢁ1
D
D
H
S
(kJ mol
(J mol
)
73 ± 7
ꢁ49 ± 21
46 ± 7
ꢁ165 ± 22
–
ꢁ1 ꢁ1
K
)
a
Literature data [23].
Fig. 2. Cell morphology: (A) A549 control, (B) A375.S2 control, (C) B16 control and (D) B16 50 lg/mL of platinum complex.
solutions being ca. 0.01–0.05 M at a temperature of 298 K. The ref-
erence standard was TMS for H and CF Cl for F. Thermal anal-
2 2
ysis was recorded using 2960 SIMULTANEOUS DSC-TGA (TA
Instruments). The conditions of measurement: temperature range
mented with 5
lg/mL amphotericin B, 100 lg/mL streptomycin
1
19
and 100 U/mL penicillin. All cell lines were grown in plastic tissue
culture T-flasks 25 cm (Nunc) at 36 °C and 5% CO
2
2
.
2
0–1000 °C, in atmosphere of nitrogen and heating rate 3.5 °C
2.6. Cytotoxic influence of drugs
per minute.
Viability was based on the presence of living cells. After trypsi-
nization and centrifugation of cells to 50 L of the cells solution
2.4. Kinetic measurements
l
was taken and mixed-up with the same volume of trypan blue.
Cells were counted in Neubauer chamber under the inverted
microscope at 100ꢂ magnification. Application of the dye has en-
abled distinguishes living cells from the dead cells. The number
of living cells was calculated using formula:
Hydrolysis of the [Pt(C
5
F
6
O
4
)(dmtp)
2
]ꢀ2H
2
O were monitored
spectrophotometrically on Shimadzu UV-1601PC equipped with
thermostat Julabo 25 at 340 nm. The pseudo-first-order
conditions were applied. Concentrations were as follow:
F
ꢁ
5
ꢁ
2ꢁ
[
0
Pt] = 1.6 ꢂ 10 M, [OH ] = 0.03–0.10 M. Ionic strength was equal
+
ꢁ
A
4
4
.1 M (Na , OH , ClO
4
) during all the kinetic measurements.
ꢂ 2 ꢂ 10 ꢂ B
Reactions were initiated by adding 0.050 mL of platinum(II)
complex solution (total volume of solution: 2 mL). Influence of
where A – number of cells counted in Neubauer chamber at 100ꢂ
magnification; B – mL of volume in which cells were suspended.
ꢁ
OH ions concentration and temperature (300–320 K) has been e
established. Data from all the kinetic runs (A = f(t)) were fitted
using two-exponential function. Each kinetic run was repeated
–3 times.
4
Cells were seeded on 24-well plates at a density of 5 ꢂ 10 cells
on well. Cells were allowed to adhere for 24 h and were then
exposed on platinum(II) complex. B16 cell line were first exposed
to wide range of platinum complex concentrations (0.01–
2
2.5. Cell lines
100 lg/mL after 24 h incubation), to determine appropriate drug
concentration. Next cytotoxicity tests for A549, A375.S2 and B16
A549, A375.S2 and B16 lines were cultured in DMEM/HAM’S
cells were exposed on narrow range of the platinum(II) complex
F-12 medium containing 10% fetal bovine serum (FBS), supple-
concentrations (10, 25, 50 and 100 lg/mL). Cells were exposed

4
58
I. Łakomska et al. / Inorganica Chimica Acta 387 (2012) 455–459
Fig. 3. Viability of B16, A375.S2 and A549 after platinum complex treatment. j – [Pt(C
5
F
6
O
4
)(dmtp)
2
]ꢀ2H
2
O;
– cisplatin.
on platinum(II) complex through 12, 24 and 48 h. After each time
of incubation, medium with cytotoxic drug was removed from
wells, each well was flushed with 0.5 mL PBS and then cells were
detached from wells using 0.5 mL 0.05% trypsin. After centrifuga-
tion at 300 g through 5 min cells were suspended in 1 mL of med-
ium. The cytotoxicity of drugs against cancer cell lines was
established on the basis of a comparison of viability of the cells
in the various concentrations of platinum(II) complex to lifetime
of cells derived from control. The results of cytotoxic activity
in vitro were expressed as IC50. The platinum(II) complex was
tested in triplicates in each experiment.
The adequate kinetic parameters for the second step of hydroly-
ꢁ4
ꢁ1
ꢁ1
sis have been roughly estimated only (k
2
ꢄ 5 ꢂ 10
s
M ,
ꢁ4 ꢁ1
k
2(solv) ꢄ 10
s
at 310 K), because of a poor reproducibility.
The performed kinetic measurements show that the studied
complex is stable in acidic and neutral medium and there is no
hydrolysis in such conditions. It can generate difficulties in its
anti-tumor activity, because it is commonly accepted that hydroly-
sis of a platinum(II) anticancer drug is the first step of their inter-
actions with biomolecules in cancer cells. Hydrolysis of
[Pt(C
5
F
6
O
4
)(dmtp)
2
]ꢀ2H
2
O can be observed only in strongly basic
ꢁ
environment ([OH ] > 0.01 M). Substitution of the first O-donor
atom of hexafluoroglutarate by OH group is around 10 times fas-
ꢁ
ter than the adequate process with water molecule as an incoming
ligand. Similar studies concerning oxaliplatin degradation [23] (Ta-
3
. Results and discussion
.1. Kinetic of hydrolysis
The [Pt(C )(dmtp)
1
ble 1) show that the k for both complexes differ much more than
3
k1(solv). Thus, in a solvent-dependent path of the first step of the
studied reactions, incoming water molecules possess similar reac-
F
5 6
O
4
2
]ꢀ2H
2
O is stable in acidic or neutral
ꢁ
tivity toward platinum(II) center. Unlike, OH group reacts dis-
aqueous solutions, however in basic solution its hydrolysis is ob-
served. Influence of basicity changes on the rate of reaction have
been determinated. The kinetic tests have been performed in solu-
tinctly faster with [Pt(C
differences, the OH ion still behaves as a poor nucleophile in
5
F
6
O
4
)(dmtp)
2
]ꢀ2H
2
O. Despite all this
ꢁ
ꢁ
the reaction with both: [Pt(C
5
F
6
O
4
)(dmtp)
2
]ꢀ2H
2
O and oxaliplatin
tions with different OH ion concentrations. In all experiments pH
[
23]. Activation parameters confirm that the first step of hexa-
was higher than 12. It means that the processes reversible to those
described here are negligible. Two-exponential character of A = f(t)
dependency can be easily explained taking into account structure
and a coordination mode of the leaving group, i.e. C
the platinum complex (Scheme 1).
ꢁ
fluoroglutarate substitution in [Pt(C
5
F
6
O
4
)(dmtp)
2
2
]ꢀ2H O by OH
as well as a solvent molecule undergoes via an associative mecha-
nism. This behavior is typical for the substitution reactions in
square planar complexes like presented here.
2ꢁ
5
F
6
O
4
, in
Fitting of the A = f(t) dataset with a two-exponential equation
gives two observed rate constants, kobs1 and kobs2. A linear depen-
dence of these rate constants on incoming ligand concentration can
be expressed as:
3.2. Morphological changes after incubation with cytotoxic drug
ꢁ
K
obsi ¼ k
i
½OH ꢃ þ kiðsolvÞ
ð1Þ
All cancer cell lines in the control lines have been presented re-
where i = 1 or 2; k
i
is a second-order rate constant of a first/second
gular shape and size. Lines A549, A375.S2 and B16 were elongated
and spindle-shaped, cells tightly covered bottle area with nume-
rous cytoplasmic lamellipodia (Fig. 2A–C). Cells lost regular shape
and size and cell–cell contact (Fig. 2D) are observed when the B16
2ꢁ
step of C
5
F
6
O
4
liberation process (Scheme 1) and ki(solv) characte-
rizes a corresponding solvent-assisted path of the reaction.
ꢁ
An influence of [OH ] on kobs1 in three different temperatures is
presented in Fig. 1.
tumor cells were treated with [Pt(C
5
F
6
O
4
)(dmtp)
2
]ꢀ2H
2
O. In addi-
Based on this linear fittings rate constants k
1
and k1(solv) as well
tion, many cells lost their attachment to surface of culture bottle,
majority of cells were rounded in appearance (Fig. 2D). In contrast,
incubation of cell lines (A549 and A375.S2) with the platinum
complex did not causes changes in the cell morphology.
as the appropriate activation parameters (Eyring equation) have
been calculated. Results related to the first step of reaction were
gathered in Table 1.

I. Łakomska et al. / Inorganica Chimica Acta 387 (2012) 455–459
459
3.3. Cytotoxicity in vitro
Appendix A. Supplementary material
The
Pt(C
antiproliferative
activity
in
vitro
of
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.ica.2012.01.034.
[
5
F
6
O
4
)(dmtp) O against two human cells (A549, B-
2
]ꢀ2H
2
A375.S2) and one mice cell lines B16 is summarized in Fig. 3. The
cytotoxicity of platinum(II) complex against both human mela-
noma cell lines is rather low (Fig. 3). In contrast to human cell lines,
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F
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4
. Conclusion
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[
[
[
[
[
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_
new hexafluoroglutarate platinum(II) coordination compound
with 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine as nonleaving
ligands. It should be noted that the cytotoxicity of hexaflurogluta-
rate platinum(II) compound is higher than cisplatin only against
mouse cell line. Additionally, only base hydrolysis of
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[
5
Pt(C F
6
O
4
2 2
)(dmtp) ]ꢀ2H O can be observed. These inconveniences
generate difficulties in use of [Pt(C
mor prodrug.
5
F
6
O
4
)(dmtp)
2
]ꢀ2H
2
O as antitu-
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2008) 2765.
(
[
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Acknowledgments
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[
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The authors are grateful to Professor Alina Grzanka for prepared
of cancer cell lines and MSc Natalia Gurtowska and MSc Joanna
Olkowska for help during some cytotoxic tests.
[
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10736.