Platinum(II) complexes with 5,7-disubstituted-1,2,4-triazolo [1,5-a]pyrimidines: Spectroscopical characterization and cytotoxic activity in vitro

Article abstract of DOI:10.1016/j.saa.2012.01.050

Complexes of the types: cis-[PtI₂(dptp)₂] (1), cis-[PtI₂(NH₃)(dptp)] (2), trans-[PtI₂(dptp) (dmso)] (3) and trans-[PtI₂(dbtp)(dmso)] (4), where dptp = 5,7-diphenyl-1,2,4-triazolo[1,5-a]pyrimidine (dptp), dbtp = 5,7-ditertbutyl-1,2, 4-triazolo[1,5-a]pyrimidine have been synthesized and characterized by infrared and multinuclear magnetic resonance spectroscopic techniques (¹H, ¹³C, ¹⁵N, ¹⁹⁵Pt). In ¹⁹⁵Pt NMR, the cis-diiodo complexes were observed between -2601 ppm and -3261 ppm, while the trans coordination compounds were found at higher field (ca. -4389 ppm). In all cases significant ¹⁵N NMR shielding (92-95 ppm) were observed for N(3) atom indicating this nitrogen atom as a coordination site. The cis complexes have been assayed for antitumor activity in vitro against two human cell lines: A549 (non-small cell lung carcinoma) and T47D (breast cancer). The results indicate a moderate antiproliferative activity of (2) against human cancer lines.

Full text of DOI:10.1016/j.saa.2012.01.050

Spectrochimica Acta Part A 91 (2012) 126–129
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Spectrochimica Acta Part A: Molecular and
Biomolecular Spectroscopy
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Platinum(II) complexes with 5,7-disubstituted-1,2,4-triazolo [1,5-a]pyrimidines:
Spectroscopical characterization and cytotoxic activity in vitro
Iwona Łakomskaa,∗, Marzena Fandzlocha, Beata Popławskaa, Jerzy Sitkowskib
a Faculty of Chemistry, Nicolaus Copernicus University, Gagarina 7, 87-100 Torun´, Poland
b National Institute of Medicines, Chełmska 30/34, 00-725 Warszawa, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 November 2011
Accepted 19 January 2012
Complexes of the types: cis-[PtI2(dptp)2] (1), cis-[PtI2(NH3)(dptp)] (2), trans-[PtI2(dptp)(dmso)] (3)
and trans-[PtI2(dbtp)(dmso)] (4), where dptp = 5,7-diphenyl-1,2,4-triazolo[1,5-a]pyrimidine (dptp),
dbtp = 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine have been synthesized and characterized by
infrared and multinuclear magnetic resonance spectroscopic techniques (1H, 13C, 15N, 195Pt). In 195Pt NMR,
the cis-diiodo complexes were observed between –2601 ppm and –3261 ppm, while the trans coordina-
tion compounds were found at higher field (ca. −4389 ppm). In all cases significant 15N NMR shielding
(92–95 ppm) were observed for N(3) atom indicating this nitrogen atom as a coordination site. The
cis complexes have been assayed for antitumor activity in vitro against two human cell lines: A549 (non-
small cell lung carcinoma) and T47D (breast cancer). The results indicate a moderate antiproliferative
activity of (2) against human cancer lines.
Keywords:
Platinum complexes
Triazolopyrimidines
15N NMR
195Pt NMR
X-ray
Cytotoxic activity
© 2012 Elsevier B.V. All rights reserved.
1. Introduction
suggest that the presence of a bulky ligand (tert-butyl or a phenyl
group in the triazolopyrimidine ring) might be a major factor in the
Triazolopyrimidines are attractive objects of studies due to the
number and the arrangement of the nitrogen atoms in the aro-
matic cycle (Fig. 1). These ligands have several nitrogen atoms with
accessible lone pairs, hence they offer different varieties of coordi-
nation modes [1–3]. Triazolopyrimidines are able to bind in mono-
or bidentate (chelating or bridging) mode, hence one may expect
mono- or multinuclear complexes.
The chemistry of platinum group metals with 1,2,4-triazolo
[1,5-a]pyrimidine ligands have been dominated by Pt(II) [4–7],
Pd(II) [8–10] and Ru(III) [11,12] compounds. Reported X-ray struc-
tures confirmed the presence of monodentate triazolopyrimidines
in many coordination compounds. As reported, in each case the
heterocyclic ligand binds via N(3), in mononuclear Pt(II) [4–7],
Pd(II) [8–10] and Ru(III) [11,12] coordination compounds.
However, the crystal structures of binuclear complexes, both
homonuclear [7,13,14] and heteronuclear [15,16] with bridging
triazolopyrimidines were also found. In all cases, triazolopyrimi-
dine acts as a two coordination center ion via N(3) and N(4) atoms.
On the other hand, 1,2,4-triazolo[1,5-a]pyrimidines and
their transition metal complexes revealed biological activity
[4,12,17,18]. Our previous studies on dichloro platinum(II) com-
pounds with 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidines
antitumor activity of the platinum(II) compounds.
As continuation of these studies we now report new
diiodo platinum(II) complexes with bulky 5,7-disubstituted-
a
1,2,4-triazolo[1,5-a]pyrimidine (5,7-diphenyl-1,2,4-triazolo[1,5-a]
pyrimidine
(dptp)
and
5,7-ditertbutyl-1,2,4-triazolo
[1,5-a]pyrimidine (dbtp)).
2. Experimental
2.1. Chemistry
2.1.1. Materials
3-Amino-1,2,4-triazole (98%), 1,3-diphenyl-1,3-propanedione
(99%) and 2,2,6,6-tetramethyl-3,5-heptanedione (98%), were pur-
chased from Aldrich, whereas the inorganic salts and solvents of
analytical grade from POCh Gliwice (Poland).
K2PtCl4 was prepared from metallic Pt by known pro-
cedures [19]. 5,7-disubstituted derivatives of 1,2,4-triazolo
[1,5-a]pyrimidines were prepared according to Bülow and Haas
method [20] by the reaction of 3-amino-1,2,4-triazole with
1,3-diphenyl-1,3-propanedione for dptp and 2,2,6,6-tetramethyl-
3,5-heptanedione for dbtp [21].
2.1.2. Instrumentation
IR spectra were measured with a PerkinElmer Spectrum 2000
FTIR spectrometer, using KBr (400–4000 cm−1) and polyethylene
discs (100–400 cm−1). NMR spectra were recorded at 298 K in
∗
Corresponding author.
E-mail addresses: dziubek@cc.uni.torun.pl, dziubek@umk.pl (I. Łakomska).
1386-1425/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.saa.2012.01.050

I. Łakomska et al. / Spectrochimica Acta Part A 91 (2012) 126–129
127
2.1.3.3. trans-[PtI2(dptp)(dmso)]
(3). A
suspension
of
R
cis-[PtI2(dmso)2] (0.045 g; 0.07 mmol) in 5 mL of dmso was treated
with the stoichiometric amount of dptp (0.020 g; 0.07 mmol) in
the 25 mL of methanol. The reaction mixture was stirred at room
temperature in the dark for 7 days. The light orange precipitate
was filtered, washed with water, methanol, diethyl ether and dried
in vacuum. Yield 0.045 g (75%). Anal. Found: C, 28.7; H, 2.4; N, 7.1%.
Calc. for C19H18I2N4SOPt: C, 28.6; H, 2.3; N, 7.0%.
8
N
7
1
N
6
5
2
3
4
3a
N
R
N
2.1.3.4. trans-[PtI2(dbtp)(dmso)]
(4). A
suspension
of
Fig. 1. IUPAC numbering of 1,2,4-triazolo[1,5-a]pyrimidine derivative; R = C6H5 for
cis-[PtI2(dmso)2] (0.092 g; 0.15 mmol) in 5 mL of dmf was treated
with the stoichiometric amount of dbtp (0.035 g; 0.15 mmol) in
10 mL of ethanol. The reaction mixture was stirred at room tem-
perature in the dark for 48 h. Slow evaporation of the solvent gave
orange precipitate which was dried in vacuum. Yield 0.061 g (53%).
Anal. Found: C, 24.1; H, 3.6; N, 7.9%. Calc. for C15H26I2N4SOPt: C,
23.7; H, 3.5; N, 7.4%.
dptp and C(CH3)3 for dbtp.
dmf-d7 solutions on a Varian INOVA 500 spectrometer, operated
at 499.8, 125.7, 50.6, 107.4 MHz for 1H, 13C, 15N and 195Pt, respec-
tively. The 15N NMR spectra were recorded in the inverse gated
decoupling mode by using a 30◦ flip angle, a spectral range of
18 kHz, an acquisition time of 0.2 s, a relaxation delay of 5 s and col-
lecting 60k data points. The 1H–{15N}correlation spectra (g-HMQC)
were optimized for a coupling constant of 8 or 1 Hz with the follow-
ing experimental conditions: an acquisition time of 0.3 s, spectral
windows of 5000 (F2) and 15,000 Hz (F1), 4096 data points, 512
time increments (zero filled to 2048), a 1.4 s relaxation delay and
64 transients per increment. C, H, N were determined by elemental
semimicroanalysis.
2.2. Cytotoxic activity
The antiproliferative activity in vitro against two human tumor
cell lines: A549 (non-small cell lung carcinoma) and T47D (breast
cancer) were performed.
Cells were platted in 96-well sterile plates (Sarstedt, Costar) at
the density of 104 cells per well (in 100 ␮L of culture medium) and
incubated for 24 h. The tested compound was added to the final
concentrations from 0.1 to100 ␮g/mL and the incubation conti-
nued for additional 72 h. The results of cytotoxic activity in vitro
were expressed as an IC50 – the dose of compound (in ␮M) that
inhibits proliferation rate of the tumors cells by 50%, as compared
to the control untreated cells. The details of this technique were
described by Skehan [24]. The test of the antiproliferative activity
in vitro against both cell lines was performed by using the SRB test
[25].
2.1.3. Preparation of platinum(II) complexes
The compound K[PtCl3(NH3)] was prepared from K2[PtCl4]
by the known method [22]. cis-[PtI2(dmso)2] used as a sub-
strate for syntheses of complexes (3) and (4) was prepared from
cis-[PtCl2(dmso)2] [23]. The details of synthesis are as follows:
2.1.3.1. cis-[PtI2(dptp)2] (1). A solution of K2PtCl4 (0.100 g;
0.24 mmol) in 10 mL of water was treated with the stoichiometric
amount of KI (0.201 g; 1.21 mmol) in 20 mL of the same solution
and the reaction mixture was stirred in the dark at room tem-
perature for 1 h. Two equivalents of dptp (0.132 g; 0.48 mmol)
in 15 mL of methanol were added to the resulting K2PtI4. The
reaction mixture was further stirred under the same conditions for
few days. The yellow precipitate was filtered, washed with water,
methanol, diethyl ether and dried in vacuum. Yield 0.196 g (82%).
Anal. Found: C, 40.3; H, 2.7; N, 10.6%. Calc. for C34H24I2N8Pt: C,
40.1; H, 2.4; N, 10.3%.
3. Results and discussion
3.1. NMR spectroscopy
In order to determine composition of coordination spheres and
structures of the novel mixed platinum(II) complexes with tria-
zolopyrimidine derivatives we have measured 1H, 13C, 15N and
195Pt NMR spectra. The 1H and 13C NMR chemical shifts of the stu-
died complexes are listed in Table 1. The 1H NMR spectra exhibit
singlets of H(2) and H(6) in range 7.53–9.52 ppm. Both characteris-
tic ligand signals have been shifted in lower field after platination
(ꢀıcoord. = 0.26 − 1.03 ppm). The coordination shifts for the novel
diiodo platinum(II) complexes (1–4) are close to those found for
their dichloro anologues (ꢀıcoord. = 0.27 − 0.87 ppm) [6,25,26].
Additionally, the 1H NMR spectrum of (2) exhibited a broad
signal for the NH3 protons (ı = 4.54 ppm), which confirms binding
ammonia molecule to the metal.
2.1.3.2. cis-[PtI2(NH3)(dptp)] (2). A solution of K[PtCl3(NH3)]
(0.056 g; 0.16 mmol) in 10 mL of water was treated with the sto-
ichiometric amount of KI (0.104 g; 0.63 mmol) in 10 mL of the same
solution and the reaction mixture was stirred in the dark at room
temperature for 1 h. Equivalent of dptp (0.043 g; 0.16 mmol) in
15 mL of methanol was added to the resulting K[PtI3(NH3)]. The
reaction mixture was further stirred under the same conditions for
few days. The yellow precipitate was filtered, washed with water,
methanol, diethyl ether and dried in vacuum. Yield 0.083 g (72%).
Anal. Found: H, 2.4; N, 10.7%. Calc. for C17H15I2N5Pt: H, 2.1; N,
10.5%.
However, 1H NMR data are insufficient to determine which
of the heterocyclic nitrogen atoms participate in formation of
platinum-triazolopyrimidine bond. Therefore 15N–1H HETCOR
NMR spectra were measured. The 15N NMR data for (1–4) are
Table 1
1H and 13C NMR spectroscopical data for platinum complexes (coordination shifts in parentheses).
Compound
1H
13C
H(2)
H(6)
C(2)
C(3a)
C(5)
C(6)
C(7)
(1) cis-[PtI2(dptp)2]
9.52 (+1.03)
9.08 (+0.59)
9.17 (+0.68)
9.11 (+0.47)
8.21 (+0.60)
8.50 (+0.89)
8.52 (+0.91)
7.53 (+0.26)
156.6 (−0.2)
154.2 (−2.6)
155.3 (−1.5)
154.0 (−1.3)
153.3 (−3.8)
154.1 (−3.0)
153.0 (−4.1)
152.5 (−4.0)
163.4 (+1.7)
164.0 (+2.3)
164.1 (+2.4)
179.4 (+3.5)
109.4 (+1.9)
109.7 (+2.2)
110.4 (+2.9)
107.9 (+3.3)
149.8 (+1.2)
150.2 (+1.6)
150.1 (+1.5)
159.3 (+1.4)
(2) cis-[PtI2(NH3)(dptp)]
(3) trans-[PtI2(dptp)(dmso)]
(4) trans-[PtI2(dbtp)(dmso)]

128
I. Łakomska et al. / Spectrochimica Acta Part A 91 (2012) 126–129
Table 2
15N and 195Pt NMR spectroscopical data for platinum complexes (coordination shifts in parentheses).
Compound
15N
Pta
N(1)
N(3)
N(4)
N(8)
(1) cis-[PtI2(dptp)2]
−111.8 (−1.3)
−112.3 (−1.8)
−109.4 (−1.1)
−107.0 (+0.6)
−231.5 (−80.8)
−228.3 (−77.6)
−244.4 (−93.7)
−245.9 (−92.8)
−128.1 (−7.7)
−130.9 (−10.4)
−123.7 (−3.3)
−116.1 (−0.3)
−163.0 (−3.7)
−161.9 (−2.6)
−162.1 (−2.8)
−161.3 (−2.6)
−3261 (−1637)
−2601 (−977)
−4393 (−2769)
−4389 (−2765)
(2) cis-[PtI2(NH3)(dptp)]
(3) trans-[PtI2(dptp)(dmso)]
(4) trans-[PtI2(dbtp)(dmso)]
a
For 195Pt value in parentheses is the shift related to K2PtCl4 (ı = −1624 ppm).
collected in Table 2. Analysis of the magnitude of the 15N NMR
coordination shifts revealed the strongest shielding effect on N(3)
atom. Such a great diamagnetic shifts on N(3) (ꢀıcoord. = −77.6
to −93.7 ppm) unambiguously indicate that complexation occurs
via this nitrogen atom. Dichloro analogues of studied complexes
exhibit very similar shielding shifts on N(3) (ꢀıcoord. = −77.1 to
−94.6 ppm) also indicating this atom as a Pt(II)-ligand coordination
site [6,25,26]. The absolute values of the coordination shifts on N(3)
are lower for cis complexes (1) (−80.8 ppm) and (2) (−77.6 ppm)
than for trans compounds containing S-bonded dmso (−93.7 ppm
(3) and −92.8 ppm (4)). Such a phenomenon was already reported
for dichloro counterparts of (1–4) [6,25]. The increased shielding of
the Pt(II) coordinated nitrogen nucleus is, most likely, caused by the
diiodo complexes. The C terms in the Ramsey equation represent
the metallic coefficients of the platinum d orbitals. A more covalent
bond will result in a decrease in the C terms and hence a shielding
of the 195Pt NMR signals [29].
3.2. Infrared studies
Characteristic bands of the whole pyrimidine ring skele-
tal vibrations appeared at 1548 (1), 1549, (2) 1552 (3) and
1539 cm−1 (4), whereas those of the triazolopyrimidine ring at
1612 (1), 1610 (2), 1614 (3), 1615 cm−1 (4). In the spectra of free
ligands the former band was found at 1539 (dptp), 1530 cm−1
(dbtp) and the latter one at 1611 (dptp), 1615 cm−1 (dbtp) [30].
The two most characteristic bands, assigned previously by us
as triazolopyrimidine ring skeletal vibration and pyrimidine ring
skeletal vibration are shifted not more than 13 cm−1. Similar
effect has already been observed for different complexes with
1,2,4-triazolo[1,5-a]pyrimidine ligands, where the N(3) coordina-
tion occurred [6,9,25]. The strong absorption bands at ranges:
1020–1129 cm−1 (3), 1061–1129 (4) indicate S-bonded dmso, as
expected for this typical soft coordination center [31–34]. In
addition, the IR spectrum of cis-[PtI2(NH3)(dptp)] (2) show absorp-
tion bands: ꢁa(NH3) (3290 cm−1), ꢁs(NH3) (3055 cm−1) indicating
the coordination of ammonia molecule. The deformation bands
ıa(HNH) and ıs(HNH) were also observed at lower frequencies,
namely 1495 cm−1 and 1377 cm−1, respectively. Additionally coor-
dination of ammonia molecule to platinum center was confirmed
decrease of the absolute value of the paramagnetic term in its 15
N
NMR shielding constant [6,25]. The monodentate coordination of
heterocyclic ligands to Pt(II) in solution is very important for in vitro
test and their application as antitumor prodrugs [26].
The analysis of 13C NMR spectra revealed shielding effect of
carbons adjacent to N(3) coordination site, i.e., C(2) and C(3a)
(0.2–4.1 ppm) and deshielding effect of the others carbon atoms:
C(5), C(6) and C(7) (1.2–3.5 ppm) (Table 1). These results con-
firm monodentate coordination Pt(II)-heterocyclic ligand via N(3)
atom. Similar results have already been observed for analogous
complexes with two chloride anions in the coordination sphere.
Shielding shifts were noted for C(2) and C(3a) of (1–4) dichloro
counterparts (0.9–3.6 ppm), whereas the others carbons: C(5), C(6)
and C(7) were deshielded (1.7–3.6 ppm) [25,30]. Moreover, the
shielding of the carbon atoms which are in direct neighborhood
to coordination site N(3), as well as the deshielding of the other
carbons and the protons inside the heterocyclic ring was already
described for some Pd(II) chloride complexes with tp and its deriva-
tives [27].
by evident absorption band ꢁ(Pt-NNH3) at 483 cm−1
The far-IR spectra of new obtained complexes show ligand
vibration as well as new bands originating from Pt I and Pt
.
N
stretchings. Spectra of (3) and (4) have exhibited one new strong
broad absorption band at 196 cm−1 (3) and 150 cm−1 (4). For cis
complexes of (1), (3) two absorption band in region 179–200 cm−1
(1), 189–200 cm−1 (3) are reported. The frequencies of these
bands are similar to those found in the spectra of Pt(II) diiodo
complexes with adamantanamine derivatives and related ligands
(140–203 cm−1) [35,36] and was assigned to Pt I stretching vibra-
tion. This is in agreement with group theory, when idealized C2v
(2 bands) and D2h (1 band) symmetries are considered for the
cis and trans complexes, respectively [35]. The IR spectra contain
also the bands at 268–279 cm−1 (1–3), 226 cm−1 (4). Those can be
assigned to Pt N stretching modes [25,36,37].
The analysis of 1H, 13C and 15N NMR spectra shows similar shift-
ing pattern and comparable values of chemical shifts for the new
diiodo platinum(II) complexes and their dichloro counterparts.
195Pt NMR data of the complexes under discussion are listed in
Table 2. The observed presence of single resonance signals points
monodentate structures of the new coordination compounds. The
195Pt signals of the compounds (1–4) are shifted toward higher
fields in comparison with K2PtCl4 and they appear between −2601
and −4393 ppm. However signals for trans compounds are detected
at higher field than cis. Generally, studied complexes exhibit a
much higher shielding of the platinum signals than that observed
for their dichloro analogues (range from −2072 to −2955 ppm)
[6,25,26]. Similar results to (3) and (4) 195Pt NMR data (−4393 and
−4389 ppm respectively) were obtained by Rochon for the number
of diiodo Pt(II) complexes containing sulfoxides (R2SO) and pyri-
midine (pm). 195Pt singlet signals for trans-[PtI2(R2SO)(pm)] were
observed between −4387 and −4438 ppm, while the correspond-
ing dichloro analogues, trans-[PtCl2(R2SO)(pm)], were observed at
much lower fields (about −3060 ppm) [28]. 195Pt chemical shifts
of the diiodo complexes are observed at higher fields than their
dichloro analogues because the iodo ligands are more polarizable
than the chloro ligands. This results in a more covalent bond for the
3.3. Cytotoxic activity
The results of the in vitro cytotoxic assays of the cis-[PtI2(dptp)2]
(1), cis-[PtI2(NH3)(dptp)] (2) against two tumor cell lines: A549
(non-small cell lung carcinoma) and T47D (breast cancer) are
summarised in Fig. 2. Of the two diiodo complexes tested in
the cancer cell lines, cis-[PtI2(NH3)(dptp)] was observed to have
similar or higher cytotoxicity compared to cis-DDP (Fig. 2). In
contrast, the cytotoxicity displayed by cis-[PtI2(dptp)2] was lower
than that observed for the cis-[PtI2(NH3)(dptp)], suggesting that

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129
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carcinoma) and the T47D (breast cancer) cell lines.
replacement of the NH3 molecule with bulkier 5,7-diphenyl-1,2,4-
triazolo[1,5-a]pyrimidine significantly increased the IC50 values.
Different results were observed for the activity of the
dichloro platinum(II) complexes with 5,7-diphenyl-1,2,4-
triazolo[1,5-a]pyrimidine [26]. The cis-[PtCl2(dptp)2] and
cis-[PtCl2(NH3)(dptp)] had higher cytotoxicity than cisplatin.
In addition, cis-[PtCl2(dptp)2], was 9 times more active than
cisplatin and almost 30 times more active than cis-[PtI2(dptp)2]
against A549. It is clear from the in vitro testing discussed above
that the choice of leaving groups plays a major role in affect-
ing the cytotoxic activity of the platinum(II) complexes with
5,7-diphenyl-1,2,4-triazolo[1,5-a]pyrimidine.
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Four new diiodo square-planar platinum(II) complexes with
triazolopyrimidines (dbtp and dptp) were successfully synthesized
and characterized using the multinuclear magnetic resonance (1H,
13C, 15N, 195Pt NMR) and IR. The antiproliferative activity in vitro
of two cis-platinum(II) complexes against two human cancer cell
lines was also examined. From this study it was evident that the
dichloro analogues are more active than diiodo.