Synthesis and X-ray structure of platinum(II), palladium(II) and copper(II) complexes with pyridine-pyrazole ligands: Influence of ligands' structure on cytotoxic activity

Article abstract of DOI:10.1016/j.poly.2008.12.013

The new pyrazole ligand 5-(2-hydroxyphenyl)-3-methyl-1-(2-pyridylo)-1H-pyrazole-4-phosphonic acid dimethyl ester (2a) has been used to obtain a series of platinum(II), palladium(II) and copper(II) complexes (3a-7a) as potential anticancer compounds. The m

Full text of DOI:10.1016/j.poly.2008.12.013

Polyhedron 28 (2009) 637–645
Contents lists available at ScienceDirect
Polyhedron
journal homepage: www.elsevier.com/locate/poly
Synthesis and X-ray structure of platinum(II), palladium(II) and copper(II)
complexes with pyridine–pyrazole ligands: Influence of ligands’ structure on
cytotoxic activity
a
b
b
c
Elzbieta Budzisz a, , Magdalena Miernicka , Ingo-Peter Lorenz , Peter Mayer , Urszula Krajewska ,
*
Marek Rozalski c
a Department of Cosmetic Raw Materials Chemistry, Faculty of Pharmacy, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland
b Department of Chemistry and Biochemistry, Ludwig Maximilians University, Butenandtstr. 5-13 (D), D-81377 Munich, Germany
c Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The new pyrazole ligand 5-(2-hydroxyphenyl)-3-methyl-1-(2-pyridylo)-1H-pyrazole-4-phosphonic acid
dimethyl ester (2a) has been used to obtain a series of platinum(II), palladium(II) and copper(II) com-
plexes (3a–7a) as potential anticancer compounds. The molecular structures of the platinum(II) and cop-
per(II) complexes 3a and 6a have been determined by X-ray crystallography. The cytotoxicity of the
phosphonic ligand 2a and its carboxylic analog 2b as well as their complexes has been evaluated on leu-
kemia and melanoma cell lines. Copper(II) complexes were found to be more efficient in the induction of
melanoma cell death than the platinum(II) or palladium(II) complexes. Cytotoxic effectiveness of com-
pound 7b against melanoma WM-115 cells was two times better than that of cisplatin. The reaction of
compound 5b with 9-methylguanine has been studied.
Received 14 August 2008
Accepted 5 December 2008
Available online 8 January 2009
Keywords:
Synthesis
X-ray structure
Cytotoxic effect
Pyrazole ligands
Platinum(II), Palladium(II), Copper(II)
complexes
Ó 2008 Elsevier Ltd. All rights reserved.
9-Methylguanine
1. Introduction
DNA intrastrand cross-links between adjacent purines. Trans com-
plexes can cross-link two bases on the same strand only if they are
New, efficient therapy for cancer is the challenge for medicine
of the XXI century. The clinical success of cisplatin and carboplatin
as antitumor agents constitutes the most impressive contribution
to the use of metals in medicine [1]. The severe problems associ-
ated with these anticancer metal-based drugs include serious tox-
icity and side-effects, and major difficulties concerning tumor cells
resistance. New potent and selective antitumor drugs are urgently
needed.
A new series of antitumor cis- and trans-platinum(II) complexes
that have nonplanar heterocyclic amine ligands such as piperidine,
piperazine and 4-picoline have been described [2,3]. Some of these
complexes, especially the trans analogs, could overcome multifac-
torial cisplatin resistance in human ovarian cell lines. The possibil-
ity to overcome cisplatin resistance could be related to the ability
of these compounds to form DNA lesions that are different from
those formed by cisplatin. While cisplatin interacts with double-
helical DNA forming preferentially 1,2-GG or AG intrastrand
cross-links, the trans complexes cannot form in double-helical
separated by at least one intervening base, forming mostly 1,3-
GNG cross-links, where N is adenine, cytosine or thymine. Impor-
tantly, these cross-links are stable in single-stranded DNA, while
in double-stranded DNA some of these cross-links readily isomer-
ize to the interstrand cross-links [4–7].
Novel metal-based complexes containing metal such as palla-
dium, copper, ruthenium, gold and rhodium have been reported
with promising chemotherapeutic potential and different mecha-
nisms of action in comparison with the platinum based drugs [8–
10].
Synthesis and structures of palladium(II) complexes containing
pyrazole and thiocyanate ligands have been documented in the lit-
erature [11]. Thiocyanate complexes of palladium(II) have been ap-
plied in analytical determinations [12] and in chemotherapy [13].
Copper(II) plays an important biological role in all living sys-
tems as an essential trace element [14]. The copper(II) complexes
with organic ligands have been used as analgesic, antipyretic,
antiinflammatory and platelet antiaggregating agents. Recently,
several reports have appeared in the literature describing the
anticancer activity of copper(II) derivatives of many classes of
nitrogen donors including thiosemicarbazone and imidazole [15].
There are also examples of copper complexes of ligands containing
* Corresponding author. Tel.: +48 42 677 91 25; fax: +48 42 678 83 98.
E-mail address: elora@ich.pharm.am.lodz.pl (E. Budzisz).
0277-5387/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.poly.2008.12.013

638
E. Budzisz et al. / Polyhedron 28 (2009) 637–645
a
-diimino (N@C–C@N) moiety such as phenanthroline that can in-
IR spectra were recorded on a Pye-Unicam 200G Spectrophotome-
ter in KBr and CsI. The 1H NMR spectra were registered at 300 MHz
on a Varian Mercury spectrometer. The MS data were obtained on a
LKB 2091 mass spectrometer (70 eV ionisation energy). The MS-
FAB data were determined on Finnigan Matt 95 mass spectrometer
(NBA, Cs+ gun operating at 13 keV). For the new compounds satis-
factory elemental analyses were obtained using a Perkin–Elmer PE
2400 CHNS analyser.
Dimethyl 2-methyl-4-oxo-4H-chromen-3-yl-phosphonate (1a)
[41], 2-methyl-4-oxo-4H-chromene-3-carboxylic acid methyl ester
(1b) [42], 5-(2-hydroxyphenyl)-3-methyl-1-(2-pyridylo)-1H-pyra-
zole-4-carboxylic acid methyl ester (2b) [39] and its platinum(II)
(3b), palladium(II) (4b) [40] and copper(II) (5b and 6b) [39,40]
complexes were prepared as described elsewhere.
duce apoptosis [16] and 2-(40-thiazolyl)benzimidazole that have
antimicrobial activity [17]. Various anticancer copper(II) com-
plexes occurred to alter the cell cycle and decrease the telomerase
activity [18–21]. A wide variety of biological activities of copper(II)
complexes can also be exemplified by recent finding of their anti-
amoebic activity against Entamoeba histolytica [22].
The interest in dinuclear copper(II) complexes with nitrogen-
containing ligands is caused by their resemblance to the active
sites of several copper-containing proteins. Besides that, the inves-
tigation of the magnetic properties of such complexes provides
more insight into the relationship between their structural features
and the strength of magnetic exchange interactions between the
metal ions [23–29].
The introduction of the aromatic N-containing ligands as pyra-
zole, pyridine, imidazole and 1,10-phenanthroline and their deriv-
atives whose donor properties are similar to the purine and
pyrimidine bases to antitumor agents is drawing attention [30].
Complexes of pyrazole-type ligands have been used in catalysis
[31,32], chemotherapy [33,34], electrochemical reduction of car-
bon dioxide [35], as metallomesogens [36,37] and as models of ac-
tive sites in metalloenzymes [38].
In our previous papers we described the synthesis of
5-(2-hydroxybenzoyl)-3-methyl-1-(2-pyridinyl)pyrazol-4-carboxylic
acid methyl ester 2b and its complexes with platinum(II) (3b), pal-
ladium(II) (4b) and copper(II) (5b and 6b) [39,40]. The cytotoxicity
assay of the ligand 2b and its complexes 3b–5b were performed on
L1210 and K562 leukemia cell lines. The complexes showed lower
cytotoxicity than cisplatin and the platinum(II) (3b) and copper(II)
(5b) complexes were found to be more efficient in the induction of
leukemia cell death than the palladium(II) complex 4b. Our inves-
tigation indicated that the antiproliferating activity of the plati-
num(II) (3b) and copper(II) (5b) complexes was partly due to the
modulation of cellular differentiation. However, all these com-
plexes 3b–5b were not strong cellular differentiation inducers in
comparison to cisplatin [40].
2.2. Synthesis of the ligand
2.2.1. 5-(2-Hydroxybenzoyl)-3-methyl-1-(2-pyridinyl)-1H-pyrazol-4-
phosphonic acid dimethyl ester (2a)
2-Hydrazinopyridin (109.1 mg, 1 mmol) in EtOH (5 ml) was
added at room temperature to a solution of dimethyl 2-methyl-
4-oxo-4H-chromen-3-yl-phosphonate 1a (268.0 mg, 1 mmol) in
EtOH (5 ml). The mixture was stirred for 24 h in room temperature.
EtOH was evaporated under reduced pressure. Ethyl acetate was
added to the oil product and it was left in 4 °C for 24 h. The solid
white product was filtered off and dried. Yield: 179.0 mg
(49.72%), mp: 101–105 °C. IR:
(C–CH3); 1607 (C@C, phenyl); 1228 (P@O); 1031 (O–CH3); 807
(P–O) cmꢀ1 1H NMR (CDCl3): d = 6.88–7.53 (m, 8H, aromat.);
m
max/cmꢀ1 3170 (OH); 2940
.
2.56 (s, 3H, CH3); 3.52–3.63 (dd, 6H, O–CH3). 13C NMR (CDCl3):
d = 14 (C–CH3); 52.5 (O–CH3); 107.3 (C–P); 154 (C–CH3); 146
(C@C, pyrazole); 147.5 (C@N, pyridin); 151 (C–N); 155.5 (C–OH).
31P NMR (CDCl3): d = 17.0. MS m/z: 358.0. Anal. Calc. for
C17H18N3O4P (359.322): C, 56.82; H, 5.05; N, 11.69. Found: C,
56.59; H, 4.95; N, 11.32%.
Here, we present the synthesis of new chelating ligand 5-(2-
hydroxybenzoyl)-3-methyl-1-(2-pyridinyl)pyrazol-4-phosphonic
acid dimethyl ester 2a and its solid complexes with platinum(II),
palladium (II) and copper(II) (3a–7a), the new copper(II) complex
7b with carboxylic ligand 2b as well as X-ray structures of the
phosphonic platinum(II) and copper(II) complexes 3a and 6a, cyto-
toxic studies of both ligands 2a and 2b and their complexes per-
formed on leukemia and melanoma cell lines and the reaction of
copper(II) complex 5b with 9-methylguanine (9MeG).
Synthesis of dimethyl 2-methyl-4-oxo-4H-chromen-3-yl-phos-
phonate (1a) [41], 2-methyl-4-oxo-4H-chromene-3-carboxylic
acid methyl ester (1b) [42], 5-(2-hydroxyphenyl)-3-methyl-1-(2-
pyridylo)-1H-pyrazole-4-carboxylic acid methyl ester (2b) [39]
and its platinum(II) (3b), palladium(II) (4b) [40] and copper(II)
(5b and 6b) [39,40] complexes were described elsewhere.
2.3. Synthesis of the complexes
2.3.1. Pt complex 3a
The aqueous solution of K2[PtCl4] (41.5 mg, 0.1 mmol, in 1 ml)
was slowly added drop-wise to the methanolic solution of the li-
gand 2a (36 mg, 0.1 mmol, in 5 ml). The mixture was stirred at
room temperature for 1 h. The yellow solid that precipitated after
24 h was filtered off, washed with water and diethyl ether and
dried to yield complex 3a. Yield: 24.0 mg (38.4%), td: 120 °C. IR:
m
max/cmꢀ1 3401 (OH); 2955 (C–CH3); 1612 (C@C, phenyl); 1226
(P@O); 808 (P–O); 1028 (O–CH3); 493 (Pt–N) cmꢀ1 1H NMR
.
(DMSO–d6): d = 6.67–7.53 (m, 8H, aromat.); 2.56 (s, 3H, CH3);
3.38–3.50 (dd, 6H, O–CH3). ESI MS(ꢀ): 624.1. Anal. Calc. for
C17H18N3O4PPtCl2 (625.306): C, 32.65; H, 2.90; N, 6.72. Found: C,
32.01; H, 2.43; N, 6.48%.
2. Experimental
2.3.2. Pd complex 4a
2.1. Materials
An aqueous solution of K2[PdCl4] (33.0 mg, 0.1 mmol, in 1 ml)
was slowly added drop-wise to a methanolic solution of ligand
2a (36.0 mg, 0.1 mmol, in 5 ml). The mixture was left with stir-
ring at room temperature for 1 h. After 24 h the resulting yellow
crystals were filtered off, washed with water, diethyl ether and
All substances were used without further purification. Potas-
sium tetrachloridoplatinate(II), potassium tetrachloridopalla-
date(II), copper(II) chloride dihydrate and copper(II) perchlorate
hexahydrate were purchased from Aldrich. Chloroform-d and
DMSO–d6 solvents for NMR spectroscopy were obtained from Dr.
Glaser AG, Basel. Solvents for synthesis (acetone, diethyl ether,
dimethylformamide, ethanol, ethyl acetate and methanol) were re-
agent grade or better and were dried according to standard proto-
cols [43]. The melting points were determined using an
Electrothermal 1A9100 apparatus and they are uncorrected. The
dried. Yield: 41.0 mg (77.6%), td: 345 °C. IR:
(OH); 2955 (C–CH3); 1611 (C@C, phenyl); 1226 (P@O); 1028
(O–CH3); 811 (P–O); 495 (Pd–N) cmꢀ1 1H NMR (DMSO–d6):
m
max/cmꢀ1 3399
.
d = 6.60–7.60 (m, 8H, aromat.); 2.82 (s, 3H, CH3); 3.44–3.53 (dd,
6H, O–CH3). ESI MS(ꢀ): 535.9. Anal. Calc. for C17H18N3O4PPdCl2
(536.648): C, 38.05; H, 3.38; N, 7.83. Found: C, 37.39; H, 3.57;
N, 7.56%.

E. Budzisz et al. / Polyhedron 28 (2009) 637–645
639
2.3.3. Cu complex 5a
supplemented with 10% fetal bovine serum and antibiotics
(100 g/ml streptomycin and 100 U/ml penicillin). For melanoma
WM-115 cells Dulbecco’s minimal essential medium (DMEM) in-
stead of RPMI 1640 was used. Cells were grown in 37 °C in a
humidified atmosphere of 5% CO2 in air.
A methanolic solution of CuCl2 ꢁ 2H2O (18.0 mg, 0.1 mmol, in
1 ml) was slowly added drop-wise to a solution of ligand 2a in
ethyl acetate (36.0 mg, 0.1 mmol, in 5 ml). The mixture was left
with stirring at room temperature for 0.5 h. After 24 h the resulting
green crystals were filtered off, washed with diethyl ether and
l
dried. Yield: 39.0 mg (79.6%), td: 163.8 °C. IR:
m
max/cmꢀ1 3482
2.4.2. Cytotoxicity assay by MTT
(OH); 2959 (C–CH3); 1605 (C@C, phenyl); 1546 (C@N); 1239
(P@O); 1038 (O–CH3); 799 (P–O); 508 (Cu–N) cmꢀ1. ESI MS(+):
457.0. Anal. Calc. for C17H18N3O4PCuCl2 (493.774): C, 37.14; H,
3.42; N, 7.50; Cl, 15.99. Found: C, 40.75; H, 3.59; N, 8.09; Cl, 14.36%.
Cytotoxicity of ligands 2a, b, their complexes 3a, b–7a, b, carbo-
platin and cisplatin was determined by the MTT [3-(4,5-dimethyl-
thiazol-2-yl)-2,5-diphenyltetrazolium bromide, Sigma, St. Louis,
MO] assay as described [44]. Briefly, after 46 h of incubation with
drugs, the cells were treated with the MTT reagent and incubation
was continued for 2 h. MTT-formazan crystals were dissolved in
20% SDS and 50% DMF at pH 4.7 and absorbance was read at 562
and 630 nm on an ELISA-plate reader (ELX 800, Bio-Tek, USA).
The values of IC50 (the concentration of test compound required
to reduce the cells survival fraction to 50% of the control) were
calculated from concentration–response curves and used as a mea-
sure of cellular sensitivity to a given treatment. Ligands, complexes,
carboplatin and cisplatin were tested for their cytotoxicity in a fi-
nal concentration 10ꢀ7–10ꢀ3 M. As a control, cultured cells were
grown in the absence of drugs. Data points represent means of at
least 12 repeats S.D.
2.3.4. Cu complex 6a
Recrystallization done by the diffusion of diethyl ether (5 ml)
into a DMF solution of 5a (20.0 mg, 0.04 mmol, in 1 ml) gave a
complex 6a. Yield: 21.0 mg (91.3%), mp: 185 °C. IR:
m
max/cmꢀ1
3410, 3061 (OH); 2953 (C–CH3); 1644 (C@O); 1600 (C@C, phenyl);
1233 (P@O); 1045 (O–CH3); 797 (P–O); 419 (Cu–N) cmꢀ1. Anal.
Calc. for C20H25N4O5PCuCl2 (566.869): C, 42.38; H, 4.95; N, 9.88.
Found: C, 41.59; H, 4.61; N, 9.74%.
2.3.5. Cu complex 7a
A
methanolic solution of Cu(ClO4)2 ꢁ 6H2O (26.5 mg, 0.07
mmol, in 2 ml) was slowly added drop-wise to a solution of ligand
2a in ethyl acetate (51.3 mg, 0.14 mmol, in 5 ml). The mixture was
refluxed 24 h. The resulting green crystals were filtered off, washed
with diethyl ether and dried. Yield: 59.4 mg (84.9%), td: 285.4 °C.
2.5. X-ray measurements
A crystal of 3a suitable for X-ray crystallography was selected
by means of a polarization microscope, mounted on the tip of a
glass fiber, and investigated on a Nonius KappaCCD diffractometer
IR:
1230 (P@O); 1102 (ClO4ꢀ); 1033 (O–CH3); 800 (P–O); 622 (ClO4
ꢀ); 569 (Cu–N) cmꢀ1
ESI MS(+): 781.2. Anal. Calc. for
m
max/cmꢀ1 3371 (OH); 2956 (C–CH3); 1614 (C@C, phenyl);
.
(Mo Ka radiation, k = 0.71073 Å). A multi-scan absorption correc-
C34H36N6O16P2CuCl2 (981.088): C, 41.62; H, 3.70; N, 8.57; P, 6.31;
Cl, 7.23. Found: C, 41.32; H, 3.48; N, 8.24; P, 6.19; Cl, 7.21%.
tion of the reflection intensities was performed with SADABS [45].
The structure was solved by direct methods with SHELXS-97 [46]
and refined by full-matrix least-squares calculations based on F2
2.3.6. Cu complex 7b
(SHELXL-97) [47]. All non-hydrogen atoms are refined anisotropi-
A
methanolic solution of Cu(ClO4)2 ꢁ 6H2O (30.9 mg, 0.08
cally. The C-bound hydrogen atoms are riding on their parent
atoms while the O-bound hydrogen atoms were located from the
electron density map.
A crystal of 6a suitable for X-ray crystallography was selected
by means of a polarization microscope, mounted on the tip of a
glass fiber, and investigated on a Nonius KappaCCD diffractometer
mmol, in 2 ml) was slowly added drop-wise to a solution of ligand
2a in ethyl acetate (51.5 mg, 0.16 mmol, in 5 ml). The mixture was
refluxed 24 h. The resulting green crystals were filtered off, washed
with diethyl ether and dried. Yield: 41.2 mg (56.1%), td: 268.8 °C.
IR:
m
max/cmꢀ1 3383 (OH); 2951 (C–CH3); 1723 (C@O); 1617
(C@C, phenyl); 1109 (ClO4ꢀ); 1048 (O–CH3); 622 (ClO4ꢀ); 569
(Cu–N) cmꢀ1. ESI MS(+): 681.2. Anal. Calc. for C34H30N6O14CuCl2
(881.094): C, 46.34; H, 3.43; N, 9.54; Cl, 8.05. Found: C, 46.01; H,
3.32; N, 8.88; Cl, 6.65%.
(Mo Ka radiation, k = 0.71073 Å). The structure was solved by di-
rect methods with SIR-97 [48] and refined by full-matrix least-
squares calculations based on F2 (SHELXL-97) [47]. All non-hydrogen
atoms are refined anisotropically. The hydrogen atoms are riding
on their parent atoms.
2.3.7. Cu complex 8b
A methanolic solution of 9-methylguanine (11.6 mg, 0.07 mmol,
in 10 ml) was added to a methanolic solution of 5b (31.0 mg,
0.07 mmol, in 5 ml). The mixture was refluxed 24 h. The resulting
green solid was filtered off, washed with diethyl ether and dried.
3. Results and discussion
3.1. Preparation of the ligands and their complexes
Yield: 19.9 mg (46.1%), mp: 202.9–203.4 °C. IR: m
max/cmꢀ1 3493
In the reaction of dimethyl 2-methyl-4-oxo-4H-chromen-3-yl-
phosphonate [41] with 2-hydrazinopyridine in methanolic solu-
tion we have obtained the new ligand 2a (Scheme 1).
First we have investigated this reaction with the phosphonic
derivative 1a in an NMR tube. The progress of the conversion of
1a to 2a was monitored by 31P NMR spectroscopy and by thin layer
(C–NH2); 3125 (OH); 2924 (C–CH3); 2849 (N–CH3); 1713 (C@O);
1601 (C@C, phenyl); 1547 (C@N); 1011 (O–CH3); 695 (Cu–N)
cmꢀ1
. UV–Vis: kmax = 285.5 nm. MS-FAB (m/z): 686 (20%),
[LCu9MeGCl2+DMSO+H]+; 681 (100%), [LCu9MeGCl2+4H2O]; 644
(10%) [LCu9MeGCl2+2H2O]; 623 (5%), [LCu9MeGCl2+H2O]; 537
(10%), [LCu9MeG]2+; 443 (10%), [LCuCl2]; 408 (10%), [LCuCl]+; 372
(40%), [LCu]2+. Anal. Calc. for C23H22N8O4CuCl2 ꢁ H2O (626.93): C,
44.06; H, 3.53; N, 17.87. Found: C, 44.29; H, 3.84; N, 17.36%.
OH
H2N
NH
P(O)(OCH3)2
CH3
O
O
CH3
P(O)(OCH3)2
2.4. Cell and cytotoxicity assay
N
+
N
N
2.4.1. Cell cultures
N
Human skin melanoma WM-115 cells as well as human leuke-
mia promyelocytic HL-60 and lymphoblastic NALM-6 cell lines
were used. Leukemia cells were cultured in RPMI 1640 medium
1a
2a
Scheme 1. The synthesis of new highly substituted pyrazole ligand 2a.

640
E. Budzisz et al. / Polyhedron 28 (2009) 637–645
chromatography. In the 31P NMR spectrum (Fig. 1) obtained within
one hour after starting the reaction, the signal of one new product
at 17.20 ppm was observed, in addition to the signal of the sub-
strate 1a at 17.91 ppm. The intensity of this signal at 17.20 ppm
gradually increased until only traces of substrate were left and
we observed only one signal in the reaction mixture, what corre-
sponds to only one product formed during this reaction. According
to literature data hydrazinopyridine has only one dissociation con-
stant K1 = 7.24 for N2 and this nitrogen atom is responsible for
nucleophilic attack [49]. The N1 does not have nucleophilic activ-
ity. Therefore, the first step of reaction is nucleophilic attack of
hydrazinopyridine N2 atom at the chromone derivative 1a C2
OH
OH
N
P(O)(OCH3)2
CH3
COOCH3
CH3
N
N
N
N
N
2a
2b
Fig. 2. Structures of ligands 2a and 2b.
num(II), palladium(II) and copper(II) ions (M) (Scheme 3 and 4).
Complexes 3b, 4b and 5b were obtained to compare the influence
of the functional group on cytotoxic activity. The synthesis of the
carboxylic ligand 2b and its complexes 3b, 4b, 5b and 6b are de-
scribed elsewhere [39,40].
Complexes 3a and 4a were obtained by adding aqueous solu-
tion of K2PtCl4 or K2PdCl4, respectively, to the methanolic solution
of the ligand 2a (Scheme 3). The copper(II) complexes were ob-
tained in molar ratio L:Cu 1:1 (5a and 5b) by adding methanolic
solution of CuCl2 ꢁ 2H2O or 2:1 (7a and 7b) by adding methanolic
solution of Cu(ClO4)2 ꢁ 6H2O to the solution of ligands 2a or 2b in
atom. The second step of the reaction is the opening of the c-pyr-
one ring and cyclization to pyrazole derivative (Scheme 2). This
reaction proceeds according to the general mechanism described
for the reaction of chromones with nitrogen nucleophiles [50,51]
such as hydrazines [52–54]. A multimilligram reaction of 1a and
1b with one equivalent of 2-hydrazinopyridine gave the same
products as in the NMR tube.
The substituted pyrazoles 2a and 2b (Fig. 2) were used as the
ligands L in the formation of the MLCl2 complexes with plati-
Fig. 1. 31P NMR spectra of the reaction of transformation 1a to 2a.
N
H
N
( )
+
H2N
(
)
O
H
H2N
+
N
N
O
CH3
CH3
P(O)(OCH3)2
P(O)(OCH3)2
O
O
1a
OH
OH
OH
P(O)(OCH3)2
CH3
P(O)(OCH3)2
P(O)(OCH3)2
CH3
CH3
N
O
NH
HO
N
-H2O
N
N
HN
H
N
N
N
2a
Scheme 2. Mechanism of formation of the ligand 2a.

E. Budzisz et al. / Polyhedron 28 (2009) 637–645
641
OH
OH
OH
COOCH3
R
OH
COOCH3
R
O
+
K2MCl4
N
N
N
N
7
CH3
N
CH3
N
HN
CH3
Cl
Cl
6
N
+
N
1
CH3
N
N
N
N
Cu
M
N
H2N
N
Cl
9
N
O
Cu
Me
Cl
Cl
N
7
Cl
HN
6
1
2a-b
3a-b, 4a-b
3M = Pt
N
9MeG
H2N
N
5b
9
2a R = P(O)(OCH3)2
2b R = COOCH3
Me
8b
Scheme 5. Synthesis and proposed structure of complex 8b.
4 M = Pd
Scheme 3. Synthesis of the Pt(II) and Pd(II) complexes.
OH
OH
R
R
.
CuCl2
2H2O
N
N
1 : 1
CH3
N
CH3
N
N
N
Cu
2a-b
Cl
Cl
Cu(ClO4)2. 6H2O
2 : 1
5a-b
DMF/Et2O
2+
OH
R
OH
N
N
R
CH3
N
N
N
-
2ClO4
CH3
Cl
N
Cu
O
Cu
N
Fig. 3. The molecular structure of platinum(II) complex 3a.
N
N
Cl
H
H3C
N
tions with DNA bases in particular have been investigated in detail
resulting in a growing body of structural data on metal-nucleobase
adducts [55]. Here, we have studied the reaction of complex 5b
with 9-methylguanine model DNA bases and we have obtained a
complex 8b. The compound 5b was chosen basing on the fact that
it was one of the most active among studied compounds. In this
reaction we have observed the change of colors from yellow (com-
plex 5b) to green (complex 8b), what can suggest occurring the
pentacoordinated compound. Scheme 5 shows a probable struc-
ture of complex 8b that has been proposed on the basis of complex
6a structure (Fig. 4). It is possible that 9-methylguanine could
coordinate to complex 5b similar to DMF molecule.
R
H3C
CH3
HO
6a-b
7a-b
a R = P(O)(OCH3)2
b R = COOCH3
Scheme 4. Synthesis of copper(II) complexes.
ethyl acetate (for complex 5a) or methanol (for complexes 5b, 7a
and 7b). In one of our earlier works [39] we postulated that the
interaction of ligand 2b with copper(II) ions in solution might be
related to interaction of the phenol 2-hydroxy group with metal
ion. The ionisation of this group introduces an additional negative
charge and enhances the donor properties of the potential nitrogen
functions. As a result copper(II) complexes in two different L:Cu
molar ratios, 1:1 or 2:1, could be formed (Scheme 4). Complexes
5a and 5b (L:Cu molar ratio: 1:1) occured to be neutral and com-
plexes 7a and 7b (L:Cu molar ratio: 2:1) occured to be ionic.
Recrystallization of compounds 5a and 5b by dissolving in DMF
and the diffusion of diethyl ether into the solution gave complexes
6a and 6b, respectively. All complexes were recrystallized but,
unfortunately only compound 3a, 6a and 6b yielded crystals suit-
able for X-ray diffraction. 6b structure was described in our recent
paper [40]. The structures 3a and 6a are presented here.
C12
C3
C11
C10
C2
C4
C5
C13
C1
O1
C14
C16
C19
N1
C9
O5
N2
C8
N4
C18
O3
O4
Cu
N3
C7
Cl1
C20
C6
C15
C17
Knowledge of the type of interactions and the structural envi-
ronment of metal complexes in relation to potential targets and
other biomolecules has helped to establish binding patterns and
can assist in the rational design of drugs. In this respect, interac-
Cl2
O2
Fig. 4. Molecular structure of Cu(II)–complex 6a.

642
E. Budzisz et al. / Polyhedron 28 (2009) 637–645
Table 1
IR data (m
, cmꢀ1) for ligand 2a, its complexes 3a–7a and complex 7b.
m
(cmꢀ1
)
C–OH
C@C, phenyl
P@O
C@O
P–O
O–CH3
C–CH3
M–N
2a
3a
4a
5a
6a
3170
3401
3399
3482
3410
3061 DMF
3371
1607
1612
1611
1605
1600
1228
1226
1226
1239
1233
807
808
811
799
797
1031
1028
1028
1038
1045
2940
2955
2955
2959
2953
493
495
508
419
1644
DMF
7a
7b
1614
1617
1230
800
1033
1048
2956
2951
569
569
3383
1723
3.2. Structural studies. Spectroscopic characterization of ligands 2a
and 2b and their complexes
we have observed the new bands characteristic for 9-methylgua-
nine. In UV–Vis spectrum we have observed the change of kmax
from 287 nm for complex 5b to 285.5 for complex 8b.
Spectroscopic characterization of ligand 2b and its complexes
with platinum(II) (3b), palladium(II) (4b) and copper(II) (5b and
6b) have been described in our previous papers [39,40].
The assignments of the most important bands in the IR spectra
for ligand 2a and the platinum(II), palladium(II) and copper(II)
complexes 3a–7a and 7b are listed in Table 1.
The FAB mass spectrum of 8b recorded in positive ion mode
contains a peak at m/z 686 due to [LCu9MeGCl2+DMSO+H]+ ion
and a strong peak at m/z 681(100%) attributed to [LCu9MeG-
Cl2+4H2O]. The peaks at m/z 537 and 443, have been assigned to
[LCu9MeG]2+ and [LCuCl2], correspondingly. The purity of complex
8b has been confirmed by elemental analysis.
The IR-band at 3170 cmꢀ1 of the free ligand is assigned to hy-
droxy group of the phenyl ring. Shift of this band to lower energy
may indicate the presence of hydrogen bond OHꢂꢂꢂO in the ligand’s
structure. This band shifts to higher energy for the complexes. The
IR spectra of ligand 2a and complexes show a large number of
absorptions in the 797–1723 cmꢀ1 range, which can be assigned
to the different vibration modes of phosphonic and carboxylate
function. The characteristic band at 2940 cmꢀ1 of the methyl group
of the free ligand which is assigned to the C–H vibration shifts to
higher energy for the complexes. The new bands at about 493–
569 cmꢀ1 in complexes may correspond to the metal–nitrogen
vibrations involving the N-atoms of the pyrazole ring [56]. The
new bands at 3061 and 1644 cmꢀ1 in 6a complex may correspond
to the C–OH and C@O vibration, respectively, involving the atoms
of DMF. The bands observed at 1102 and 622 cmꢀ1 in the spectrum
of 7a and 1109 and 622 cmꢀ1 in the spectrum of 7b are character-
istic for non-coordinated perchlorate ions [57].
3.2.1. X-ray structure of platinum(II) complex 3a
The molecular structure of complex 3a is shown in Fig. 3, and
selected bond lengths and angles are given in Table 1S. The mono-
meric complex 3a contains the bidentate pyridine–pyrazole ligand
and two chlorido ligands in cis-position. 3a exhibits a distorted
tetragonal planar configuration at the Pt(II) centre; the sum of
the angles around Pt1 is exactly 360.00°. While the two Pt–Cl
bonds are equal (Pt1–Cl1 2.2875(12), Pt1–Cl2 2.2871(13) Å), both
Pt–N bond lengths differ slightly (Pt1–N1 2.020(3), Pt1–N3
2.030(4) Å). The angle N1–Pt1–N3 (80.11(13)°) of the chelate
ligand is the smallest, then follows the angle Cl1–Pt1–Cl2
(86.38(5)°), whereas the two angles Cl1–Pt1–N3 = 94.00(9)° and
Cl2–Pt–N1 = 99.51(11)° are significantly larger than 90°, because
of the small angle of the N,N0-chelate system.
The five- and six-membered rings of pyridine–pyrazole lie in
the same plane together with the substituents (C9, C10 and P1)
at the pyrazole.
The phenolic substituent at atom C3 is bent out from this
molecular plane, because of steric hindrance and the OH group at
C11, which forms the hydrogen bridge O4–H4–O50 (2.603(6) Å
and 174°) with the O atom of a CH3OH molecule associated with
3a.
The selected chemical shifts assigned in the 1H NMR spectra of
the ligand 2a and its platinum(II) and palladium(II) complexes 3a
and 4a are shown in Table 2. The spectra are quite similar.
The ligand 2a and its complexes 3a and 4a show signals in the
range d 2.56–2.82 ppm for the methyl groups of pyrazole ring,
3.38–3.63 for O–CH3 of phosphonic groups and 6.60–7.60 for phe-
nyl groups. The 1H NMR spectra of copper(II) complexes could not
be measured due to their paramagnetism.
The phosphite substituent at C2 shows a distorted tetrahedral
configuration at the P(III) centre with two similar P–O distances
(P1–O2 1.571(4), P1–O3 1.557(4) Å) but a short P1–O1 distance
(1.459(4) Å) indicating the P@O double bond of the P(III) ester
function.
The main peaks in ESI MS spectra of copper(II) complexes were
observed for cations without chlorido or perchlorido ligands.
Occurring of the complex 8b has been confirmed by IR, UV–Vis,
FAB-MS and elemental analysis. Some characteristic IR vibrations
for the complex 8b are given in experimental section. Significant
differences in the IR spectra of complex 8b have been observed
in comparison with that of complex 5b. The latter shows a strong
3.2.2. X-ray structure of copper(II) complex 6a
The molecular structure of complex 6a is shown in Fig. 4, and
selected bond lengths and angles are given in Table 2S. The mono-
meric Cu(II) complex 6a with the coordination number 5 for the
central Cu(II) contains the bidentate pyrazole ligand, two chlorido
ligands and an O-coordinated DMF solvent molecule. 6a exhibits a
distorted trigonal bipyramidal configuration at the Cu centre,
whereby the two chlorido ligands Cl1 and Cl2 as well as the N1
atom of the chelate system form the equatorial plane, whereas
the second N atom N3 together with the O5 atom of the DMF
molecule lie in the axial positions. The Cu–Cl bonds differ more
(Cu–Cl1 2.3677(9), Cu–Cl2 2.2982(9) Å) than in a similar complex
published earlier by us [40], and the equatorial Cu–N bond
(Cu–N1 2.101(2) Å) is surprisingly longer than the axial Cu–N3
bond (2.006(2) Å).
band at 1717 cmꢀ1 due to (C@O). This band is shifted by 4 cmꢀ1
m
to lower frequencies in the spectra of complex 8b [57]. Beside this
Table 2
1H NMR spectra of ligand 2a and the corresponding complexes with platinum(II) (3a)
and palladium(II) (4a) metal ions (chemical shifts are given in ppm).
C–CH3
O–CH3
Aromaticity
2a
3a
4a
2.56
2.56
2.82
3.52–3.63
3.38–3.50
3.44–3.53
6.88–7.53
6.67–7.53
6.60–7.60

E. Budzisz et al. / Polyhedron 28 (2009) 637–645
643
Table 3
The Cu–O5 bond length (1.962(2) Å) is the shortest observed in
Crystallographic data of Pt(II) complex 3a and Cu(II) complex 6a.
6a around Cu, but is similar with those found in related Cu(II) com-
plexes. The distortion of the trigonal bipyramide results from the
three different angles within the trigonal plane (Cl1–Cu–Cl2
113.98(3), Cl1–Cu–N1 114.15(7), Cl2–Cu–N1 131.87(7)° and from
the non-linear angle N3–Cu–O5 164.91(9)°).
The angle N1–Cu–N3 of 77.85(8)° is the smallest one observed
in the trigonal bipyramide, and the other are larger than 90°C
(Cl1–Cu–N3 96.83(7), Cl2–Cu–N3 96.02(6), Cl1–Cu–O5 92.38(7),
Cl2–Cu–O5 91.09(6)°) with the only exception of N1–Cu–O5 angle
(87.49(9)°).
The phosphite substituent at C7 shows a distorted tetrahedral
configuration at the P(III) centre with two similar P–O distances
(P–O3 1.551(3), P–O4 1.545(4) Å) but a short P–O2 distance
(1.464(3) Å) indicating the P@O double bond of the P(III) ester
function.
The bidentate heterocycle together with the connected atoms
C9 and P of the substituents is nearly planar, with a maximum
deviation from planarity of 1° (at C4).
Net formula
C18H22Cl2N3O5PPt
657.342
C20H25Cl2CuN4O5P
566.862
Mr (g molꢀ1
Crystal size (mm)
T (K)
)
0.20 ꢁ 0.12 ꢁ 0.02
0.13 ꢁ 0.10 ꢁ 0.08
200(2)
200(2)
Crystal system
Space group
a (Å)
b (Å)
c (Å)
Triclinic
P1
Triclinic
ꢀ
ꢀ
P1
8.5306(3)
9.1983(3)
15.4352(5)
73.1170(19)
82.9815(19)
69.927(2)
1088.21(6)
2
9.6019(3)
10.3758(3)
12.8774(3)
74.7244(17)
77.1466(16)
87.7010(17)
1206.37(6)
2
1.56056(8)
1.232
–
10477
0.0316
0.0539
3.36–27.48
4144
0.0584, 0.7208
5518
303
a
(°)
b (°)
c
(°)
V (Å3)
Z
Calculated density (g cmꢀ3
)
2.00615(11)
6.802
l
(mmꢀ1
)
Transmission factor range
Reflections measured
Rint
0.448–0.873
20466
0.0441
Mean
r
(I)/I
0.0371
h range
3.16–27.20
4348
0.0346, 1.4247
4792
The only exception is the phenyl substituent which shows the
distortion angle N2–C8–C9–C10 of 70.2(4)°.
Observed reflections
x, y (weighting scheme)
Reflections in refinement
Parameters
A view to the crystal packing of 3a shows that the associated
MeOH molecule forms two short and almost linear O–H–O bridges
(O4–H4–O50 2.603(6) Å/173(7)°; O5–H5–O10 2.689(6) Å/174(6)°
resulting in a polymeric chain shown in Fig. 5. Compound 6a, how-
ever, forms a dimmer because of the hydrogen bonds (O1–H1–O20
3.009(2) Å/137.5(2)°) which are longer and significantly bent
(Table 3).
283
Restraints
2
0
R(Fobs
)
0.0293
0.0700
0.0446
0.1240
1.051
0.001
Rw(F2)
S
1.069
Shift/errormax
0.001
Minimum/maximum electron
density (e Åꢀ3
CCDC
ꢀ1.056, 2.142
ꢀ0.767, 1.112
)
679540
679541
3.3. Biological activity
In our recent publication [40] we presented the cytotoxicity as-
says of the ligand 2b and its complexes 3b–5b performed on L1210
and K562 leukemia cell lines. Here we present biological studies of
these compounds as well as newly synthesized ligand 2a and its
complexes on human acute leukemia HL-60 and NALM-6 and mel-
anoma WM-115 cell lines in order to compare the influence of the
functional group on cytotoxic activity (Table 4). Compounds 6a and
6b were not tested for biological activity, as they were obtained
only to establish X-ray structures. It can be supposed that their
cytotoxicity would be strictly related to the presence of DMF mol-
ecule in their structure and DMF is highly cytotoxic by itself. That
is why the test of biological activity of the clear complexes 5a and
5b without DMF molecule was only provided. Cisplatin and carbo-
platin were used as the reference compounds. Ligands 2a and 2b
have very low cytotoxic activity. Most phosphonic compounds
exhibited lower cytotoxicity than carboxylic analogs. The cytotoxic
effect of platinum(II) and palladium(II) complexes are rather low.
All copper(II) complexes exhibited relatively high cytotoxic activity
with the IC50 values in micromolar range against leukemia cell
Table 4
IC50 values (in lM) of the ligands 2a and 2b and their complexes.
Compound
HL-60
NALM-6
IC50
WM-115
a
2a
2b
3a
3b
4a
4b
5a
5b
716.5 28.9
649.4 74.4
613.1 22.2
58.1 2.2
610.2 40.8
133.9 28.8
56.96 4.97
48.9 1.7
43.9 3.6
6.5
0.8 0.1
4.3 1.3
875.1 119.9
>1000
766 40.4
55.1 3.8
804.2 57.2
413.7 40.4
49.88 2.23
54.1 2.4
>1000
>1000
549.0 68.5
76.7 13.4
591.3 51.9
483.6 22.3
90.5 11.69
93.4 5.0
81.7 3.2
8.0 0.3
7a
7b
47.6
4.6
0.3
40.7 5.5
0.7 0.3
0.7 0.2
Cisplatin
Carboplatin
18.2 4.3
422.2 50.2
a
IC50 – concentration of a tested compound required to reduce the fraction of
surviving cells to 50% of that observed in the control, non-treated cells. Mean values
of IC50 (in lM) S.D. from four experiments are presented.
Fig. 5. Part of the crystal packing of 3a with the intermolecular hydrogen bridges with MeOH.

644
E. Budzisz et al. / Polyhedron 28 (2009) 637–645
lines although their cytotoxic effectiveness was lower in compari-
son to cisplatin and carboplatin. The copper(II) complex 7b exhib-
ited the highest cytotoxic activity with IC50 values in the range of
charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html, or
from the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or e-mail: de-
posit@ccdc.cam.ac.uk. Supplementary data associated with this
article can be found, in the online version, at doi:10.1016/
j.poly.2008.12.013.
6.5 lM for HL-60 and 8.0 lM for WM-115 cell lines. So, cytotoxic
effectiveness of compound 7b against melanoma WM-115 cells
was two times better than that of cisplatin. The result strongly sup-
port the view that the observed cytotoxicity can be confidently
attributed to the presence of the metal centres.
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