Dinuclear and mononuclear platinum(II) and palladium(II) complexes with modified 2,2′-dipyridylamine ligands featuring a cisplatin analogous structure motif

Article abstract of DOI:10.1002/zaac.200500011

In modern cancer therapy the clinical application of platinum-based drugs is more and more limited by the occurrence of intrinsic or acquired resistances. In this context the potential use of dinuclear platinum complexes in chemotherapy is increasingly relevant. The novel complexes Pd(Bzdpa)Cl ₂, Pd₂(C₄H₈(dpa)₂)Cl ₄, and Pt₂(C₄H₈(dpa) ₂)Cl₄ allow a direct comparison of mono- and dinuclear palladium and platinum complexes respectively deriving from a 2,2′-dipyridylumine (Hdpa) ligand system. They were characterized by single crystal X-ray analysis as well as infrared spectroscopy and elemental analysis. The cisplatin analogous mononuclear palladium complex Pd(Bzdpa)Cl ₂ (1) (Bzdpa: (2,2′-dipyridylbenzyl)amine) belongs to a range of 2,2′-dipyridylamine-based compounds which were extensively studied in our laboratories. 1 crystallizes in the orthorhombic space group Pna2 ₁ with a = 13.722(3), b = 13.457(3), c = 9.483(2), V = 1751.1(6) A³, and Z = 4. The metal binding motif of 1 was expanded by a flexible butyl-linker to form the tetradentate C₄H ₈(dpa)₂ ligand. The resulting isotypic dinuclear complexes Pd₂(C₄H₈(dpa)₂)Cl ₄·2CH₃CN (2) and Pt₂(C₄H ₈(dpa)₂)Cl₄·2CH₃CN (3) crystallize in the triclinic space group P1 with a = 7.8427(2), b = 8.7940(2), c = 11.7645 (3), α = 79.219(2)°, β = 84.033(2)°, γ = 87.744(2)°, V = 792.58(3) A³ (2) and a = 7.831(5), b = 8.814(5), c = 11.817(5), α = 79.271(5)°, β = 83.571(5)°, γ= 88.063(5)°, V = 796.3(8) A³ (3), both with one centrosymmetrical molecule in the unit cell.

Full text of DOI:10.1002/zaac.200500011

Dinuclear and Mononuclear Platinum(II) and Palladium(II) Complexes with
Modified 2,2Ј-Dipyridylamine Ligands Featuring a Cisplatin Analogous
Structure Motif
Sarah Fakih, Wing Chau Tung, Dirk Eierhoff, Christian Mock, and Bernt Krebs*
Münster, Institut für Anorganische und Analytische Chemie der Westfälischen Wilhelms-Universität
Received January 11th, 2005.
Dedicated to Professor Gerd Becker on the Occasion of his 65th Birthday
Abstract. In modern cancer therapy the clinical application of plati-
num-based drugs is more and more limited by the occurrence of
intrinsic or acquired resistances. In this context the potential use
of dinuclear platinum complexes in chemotherapy is increasingly
relevant. The novel complexes Pd(Bzdpa)Cl2, Pd2(C4H8(dpa)2)Cl4,
and Pt2(C4H8(dpa)2)Cl4 allow a direct comparison of mono- and
dinuclear palladium and platinum complexes respectively deriving
from a 2,2Ј-dipyridylamine (Hdpa) ligand system. They were
characterized by single crystal X-ray analysis as well as infrared
spectroscopy and elemental analysis. The cisplatin analogous
mononuclear palladium complex Pd(Bzdpa)Cl2 (1) (Bzdpa: (2,2Ј-
dipyridylbenzyl)amine) belongs to a range of 2,2Ј-dipyridylamine-
based compounds which were extensively studied in our laborato-
ries. 1 crystallizes in the orthorhombic space group Pna21 with a ϭ
3
˚
13.722(3), b ϭ 13.457(3), c ϭ 9.483(2), V ϭ 1751.1(6) A , and Z ϭ
4. The metal binding motif of 1 was expanded by a flexible butyl-
linker to form the tetradentate C4H8(dpa)2 ligand. The resulting
isotypic dinuclear complexes Pd2(C4H8(dpa)2)Cl4·2CH3CN (2) and
Pt2(C4H8(dpa)2)Cl4·2CH3CN (3) crystallize in the triclinic space
¯
group P1 with a ϭ 7.8427(2), b ϭ 8.7940(2), c ϭ 11.7645 (3), Ͱ ϭ
3
˚
79.219(2)°, β ϭ 84.033(2)°, γ ϭ 87.744(2)°, V ϭ 792.58(3) A (2)
and a ϭ 7.831(5), b ϭ 8.814(5), c ϭ 11.817(5), Ͱ ϭ 79.271(5)°,
β ϭ 83.571(5)°, γ ϭ 88.063(5)°, V ϭ 796.3(8) A (3), both with one
3
˚
centrosymmetrical molecule in the unit cell.
Keywords: Platinum; Palladium; 2,2Ј-Dipyridylamine ligands
Introduction
teristically induced by cisplatin and its mononuclear ana-
logues cannot be observed [16]. Thus a fundamentally dif-
ferent mode of action of multinuclear platinum complexes
is postulated on the basis of a different nuclear processing
of the DNA adducts. For BBR 3464 and other dinuclear
complexes Brabec et. al could show that as a result of the
lacking DNA bending the bifunctional DNA adducts do
not attract HMG domain proteins which strongly mediate
the shielding of cisplatin-induced DNA lesions [18, 19]. The
nature of the bridging group is thus of crucial importance
for the extent, geometry and intracellular processing of the
DNA distortion.
Highly flexible compounds have been realized by using
alkyl linkers of various lengths or different alkyldiamine lin-
kers [20Ϫ22]. In these complexes the coordinating platinum
unit is implemented into the whole molecule as cis- or
transplatin in which one ligand is exchanged by the corre-
sponding linker. Here we report the first dinuclear platinum
complex deriving from an aromatic 2,2Ј-dipyridylamine
(Hdpa) metal binding unit. Mononuclear complexes with a
2,2Ј-dipyridylamine ligand system, their reactions with
model nucleobases and cytotoxicity have been extensively
studied in our group [23Ϫ25]. The systematic research on
this type of compounds included the substitution of plati-
num by its homologue palladium for structural investi-
gation purposes. Because of the lanthanoid contraction
their ionic radii are nearly the same. Although their kinetic
behavior is quite different, they show a similar coordi-
native behavior.
Chemotherapy with the clinically available platinum-based
anticancer drugs is restricted by several drawbacks. Next to
the occurrence of severe side effects such as ototoxicity [1],
neurotoxicity [2, 3], and nephrotoxicity [4Ϫ6] intrinsic or
acquired resistances of the tumor cells strongly limit the
application of cytostatic platinum compounds. The intro-
duction of so called third generation platinum complexes
aims at improved compounds with new structural features
leading to altered and possibly advanced functional proper-
ties. In this context multinuclear platinum complexes be-
came increasingly relevant in order to circumvent cellular
resistance [7Ϫ9]. With the compound BBR 3464 the first
trinuclear platinum complex entered human clinical trials
and is presently undergoing phase II studies [10]. BBR 3464
has superior cytostatic activity in tumor cell lines and xeno-
grafts poorly responsive to cisplatin [11, 12].
The bifunctional DNA binding of multinuclear platinum
complexes is characterized by the formation of long range
intrastrand and interstrand cross-links [13Ϫ17]. Due to the
flexibility of the bridging groups within most of the multi-
nuclear complexes a large number of different DNA ad-
ducts can be formed. Significantly, the DNA kink charac-
* Prof. Dr. Bernt Krebs
Inst. f. Anorg. u. Analyt. Chemie der Universität
Corrensstr. 36
D-48149 Münster
Fax: ϩ49 (0)251/8338366
e-mail: krebs@uni-muenster.de
Our functional investigations which were exclusively
carried out on the platinum complexes proved that the steri-
Z. Anorg. Allg. Chem. 2005, 631, 1397Ϫ1402
DOI: 10.1002/zaac.200500011
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim
1397

S. Fakih, W. C. Tung, D. Eierhoff, C. Mock, B. Krebs
1H-NMR (300 MHz, CDCl3): δ ϭ 1.76 (m, 4H, CH2), 4.20 (m, 4H,
CH2-N), 6.79 (dd, 4H, CHPy), 7.03 (dt, 4H, CHPy), 7.45 (ddd, 4H, CHPy),
cally not demanding 2,2Ј-dipyridylamine unit provides a
favorable structural feature for an unhindered DNA-com-
plex interaction [26] leading to significant cytostatic activity
in the range of cisplatin in several tumor cell lines [27, 28].
The platinum homologue of the presented palladium com-
plex Pd(Bzdpa)Cl2 (1) has accordingly been functionally in-
vestigated using the cisplatin resistant malignant human gli-
oma cell line U251 [29]. The combination of two Hdpa
units by a flexible butyl-linker resulted in the two presented
dinuclear isotypic complexes Pd2(C4H8(dpa)2)Cl4 and
Pt2(C4H8(dpa)2)Cl4. The bridging alkyl chain offers a wide
operating range for DNA binding and enables an optimized
adjustment of the molecule to the DNA topology.
8.30 (ddd, 4H, CHPy
)
Synthesis of the complexes
Pd(Bzdpa)Cl2, Pd2(C4H8(dpa)2)Cl4
0.326 g (1 mmol) K2[PdCl4] were dissolved in 50 ml of water and
stirred for 10 min. The respective ligand was dissolved in a small
amount of ethanol and added to the light brown solution (mono-
nuclear complex: 1 mmol, dinuclear complex: 0.5 mmol). The reac-
tion mixture was stirred overnight at room temperature. The
resulting precipitates were collected, washed with water and dried
in vacuum. Diffusion of diethyl ether into a solution of complex 1
in DMF yielded pale yellow single crystals after three weeks at
ambient temperature. Single crystals of compound 2 were obtained
by diffusion of diethyl ether into a solution of the complex in aceto-
nitrile/methanol after one week at ambient temperature.
Pd(Bzdpa)Cl2: Yellow powder. Yield: 377 mg (0.86 mmol, 86 %).
[C17H15Cl2N3Pd] (Mr ϭ 438.7 g/mol): C: 46.41 (calc. 46.54); H:
3.53 (3.44); N: 9.54 (9.58) %
Experimental
General methods
All starting materials were obtained from commercial sources
(Aldrich, Fluka, Merck) and used as received. Elemental analyses
were performed on an ELEMENTAR VARIO EL III instrument.
IR spectra were obtained on a Bruker Fourier-Transform IFS 48
spectrometer (4000Ϫ400 cmϪ1) from KBr pellets of the newly syn-
thesized compounds. FIR spectroscopy of the complexes was per-
formed on a Bruker IF 113v spectrometer (400Ϫ80 cmϪ1). NMR
spectra were recorded on a BRUKER AMX 300 NMR spec-
trometer.
IR (KBr, 4000Ϫ400 cmϪ1): 3083 w, 3037 w, 1599 s, 1487 s, 1459 s, 1445 s,
1345 m, 1265 m, 1228 m, 1144 m, 1053 w, 1003 w, 915 w, 878 w, 790 s, 773 s,
698 s, 528 m, 502 w, 448 w, 435 w
FIR (PE, 400Ϫ80 cmϪ1): 393 m, 339 s, 302 m, 243 w, 199 w, 169 m, 120 m
Pd2(C4H8(dpa)2)Cl4: Light orange powder. Yield: 170 mg
(0.23 mmol, 23 %). [C24H24Cl4N6Pd2] (Mr ϭ 751.1 g/mol): C: 37.97
(calc. 38.38); H: 3.13 (3.22); N: 11.27 (11.19) %
IR (KBr, 4000Ϫ400 cmϪ1): 3081 br, 3055 w, 3008 w, 2940 m, 1574 s, 1469 s,
1424 s, 1378 m, 1317 w, 1273 s, 1183 s, 1148 w, 1080 w, 988 m, 865 m, 775 s,
737 w, 609 w, 531 w
Due to a low crystal yield analytical measurements (elemental
analyses, IR) of the metal complexes were exclusively carried out
on the amorphous complex powder. Insufficient solubility of the
complexes in any solvent or solvent mixture strongly limited NMR
studies, which are therefore not separately discussed.
FIR (PE, 400Ϫ80 cmϪ1): 431 s, 409 s, 341 m, 330 m, 225 w, 143 m, 129 m,
92 m
Pt2(C4H8(dpa)2)Cl4
0.415 g (1 mmol) K2[PtCl4] were dissolved in 50 ml of water. After
stirring the solution for 10 min 0.200 g C4H8(dpa)2 (0.5 mmol) were
dissolved in a small amount of ethanol and added to the red solu-
tion. The reaction mixture was stirred overnight at 50 °C. The re-
sulting precipitate was collected, washed with water and dried in
vacuum. Diffusion of diethyl ether into a solution of the complex
in acetonitrile yielded pale yellow single crystals of compound 3
after one week at ambient temperature.
Syntheses
Synthesis of the ligands
(2,2Ј-Dipyridyl)benzylamine (Bzdpa)
To a suspension of 5.20 g potassium hydroxide in 30 ml of DMSO
3.42 g (0.02 mol) 2,2Ј-dipyridylamine were added. The suspension
was stirred at room temperature over night and 2.30 ml (0.02 mol,
2.53 g) benzyl chloride were added subsequently. After stirring for
another hour the reaction was quenched with 30 ml of water. The
precipitated crude product was collected, washed with water and
dried in vacuum. For purification the Bzdpa ligand was then dis-
solved in hot n-hexane and precipitated again as a yellow crystalline
powder after cooling of the solution.
Pt2(C4H8(dpa)2)Cl4: Yellow powder. Yield: 490 mg (0.53 mmol,
53 %). [C24H24Cl4N6Pt2] (Mr ϭ 928.5 g/mol): C: 30.94 (calc. 31.05);
H: 2.72 (2.61); N: 8.97 (9.05) %
IR (KBr, 4000Ϫ400 cmϪ1): 3078 w, 3008 w, 2948 w, 2856 w, 1637 w, 1577 s,
1520 w, 1469 s, 1436 s, 1385 m, 1302 m, 1184 s, 1156 m, 1079 m, 988 m,
956 w, 865 m, 777 s, 738 m, 639 w, 608 w, 532 w, 509 w
FIR (PE, 400Ϫ80 cmϪ1): 433 m, 410 s, 335 s, 227 w, 135 m, 91 w
Yield: 2.30 g (8.80 mmol; 44.0 %)
1H-NMR (300 MHz, CDCl3): δ ϭ 5.43 (s, 2H, CH2), 6.93 (m, 2H, CHPy),
7.24 (m, 5H, CHar), 7.66 (m, 2H, CHPy), 8.28 (d, 2H, CHPy
)
Single crystal structure analyses
1,4-N,NЈ-Di-(2,2Ј-dipyridylamine)butane (C4H8(dpa)2)
To a suspension of 5.20 g potassium hydroxide in 30 ml of DMSO
3.42 g (0.02 mol) 2,2Ј-dipyridylamine were added. The suspension
was stirred at room temperature over night and 1.32 ml (0.01 mol,
3.10 g) 1,4-diiodobutane were added subsequently. After stirring
for another 5 hours the reaction was quenched with 70 ml of water
and the solution repeatedly extracted with diethylether (4 x 30 ml).
The combined organic extracts were dried over MgSO4. The sol-
vent was removed in vacuum to yield C4H8(dpa)2 as a yellow pow-
der.
The unit cell data and diffraction intensities of 1 were collected on
a SIEMENS-P3 diffractometer with graphite monochromated
˚
Mo-Kα radiation (λ ϭ 0.71073 A) at 293 K, intensity data of com-
pound 2 and 3 on a BRUKER AXS SMART 6000 with mono-
chromated Cu-Kα radiation (Göbel mirror, λ ϭ 1.54178 A) at
˚
110 K. The complete data collection parameters and details of the
structure solutions and refinements are summarized in Table 1. The
structure of 1 was solved by direct methods (SHELXS 97 [30])
while the structure of 2 was determined by Patterson synthesis
(SHELXS 97 [30]). The structure of compound 3 was solved by
Yield: 2.41 g (6.08 mmol; 60.8 %)
1398
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim
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Z. Anorg. Allg. Chem. 2005, 631, 1397Ϫ1402

Dinuclear and Mononuclear Platinum(II) and Palladium(II) Complexes
Table 1 Crystal data and structure refinement for 1Ϫ3
1
2
3
Empirical formula
Formula weight, g/mol
Crystal color and shape
Crystal system
Space group
Unit cell dimensions
C17H15Cl2N3Pd
438.62
C28H30Cl4N8Pd2
833.20
yellow plates
triclinic
C28H30Cl4N8Pt2
1010.57
pale yellow cuboids
triclinic
pale yellow cuboids
orthorhombic
Pna21 (No.33)
P-1 (No.2)
P-1 (No.2)
˚
˚
˚
a
b
c
13.722(3) A
7.8427(2) A
7.831(5) A
˚
˚
˚
13.457(3) A
8.7940(2) A
8.814(5) A
˚
˚
˚
9.483(2) A
11.7645(3) A
11.817(5) A
Ͱ
β
γ
90°
79.219(2)°
79.271(5)°
83.571(5)°
88.063(5)°
796.3(8)
90°
84.033(2)°
90°
1751.1(6)
4
87.744(2)°
792.58(3)
1
3
˚
Volume, A
Formula units/cell
1
Dc, g/cm3
1.664
1.746
2.107
˚
Diffractometer (wavelength, A)
SIEMENS-P3
(Mo-Kα, λϭ0.71073)
Graphite
293(2)
BRUKER AXS SMART 6000
(Cu-Kα, λϭ1.54187)
Göbel mirror
110(2)
BRUKER AXS SMART 6000
(Cu-Kα, λϭ1.54187)
Göbel mirror
110(2)
Monochromator
Temperature, K
Absorption coefficient, mmϪ1
Data collection range
1.366
12.526
9.144
4.24° < 2θ < 53.96°
Ϫ17 Յ h Յ 17
Ϫ17 Յ k Յ 17
Ϫ10 Յ l Յ 12
7731
7.68° < 2θ < 142.58°
Ϫ9 Յ h Յ 8
Ϫ10 Յ k Յ 9
Ϫ14 Յ l Յ 14
4650
3.52° < 2θ < 51.80°
Ϫ8 Յ h Յ 7
Ϫ9 Յ k Յ 10
Ϫ13 Յ l Յ 13
4549
Indices
Reflections collected
Independent reflections
Program for structure solution
Program for structure refinement
Goodness-of-fit on F2
2368
SHELXS-97
2658
2644
SIR 97
SHELXS-97
SHELXL-97, Full matrix on F2
1.034
R1 ϭ 0.0425,
wR2 ϭ 0.1099b
R1 ϭ 0.0450,
wR2 ϭ 0.1114b
1.102; Ϫ1.126
0.997
1.019
Final R values (I>2σ(I))
R1 ϭ 0.0320,
wR2 ϭ 0.0775a
R1 ϭ 0.0359,
wR2 ϭ 0.0761a
0.0385; Ϫ1.226
R1 ϭ 0.0624,
wR2 ϭ 0.1606c
R1 ϭ 0.0688,
wR2 ϭ 0.1635c
3.455; Ϫ3.099
Final R value (all data)
Ϫ3
(Δ/ρ)max; (Δ/ρ)min, eϪ
A
˚
2
w ϭ 1/[σ2(Fo2) ϩ (xP)2 ϩ yP], P ϭ (Fo ϩ 2Fc2)/3; a) x ϭ 0.0551, y ϭ 0; b) x ϭ 0.0834, y ϭ 0; c) x ϭ 0.1201, y ϭ 0.
SIR 97 [31]. All structures were refined in full-matrix least-squares
methods on F2o using the program SHELXL 97 [32]. Anisotropic
displacement parameters were used to refine the positions of all
non-hydrogen atoms. Hydrogen atoms were placed at calculated
positions according to a riding model with group isotropic tem-
perature factors. The residual value wR2 in Table 1 is defined as
[w(F2o Ϫ F2c)2 / w(F2o)2]1/2. Selected bond lengths and angles are re-
ported in Tables 2 and 3. Atomic coordinates, thermal parameters,
and all bond lengths and angles have been deposited with the
Cambridge Crystallographic Data Center (CCDC). Copies of the
data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html or on application to the Director, CCDC,
12 Union Road, Cambridge CB2 1EZ, UK, Fax: (international)
ϩ 44 -1223/336-033; e-mail: deposit@ccdc.cam.ac.uk on full quot-
ing the journal citation and deposition number CCDC 144494 (1),
CCDC 265544 (2), CCDC 265543 (3).
Fig. 1 Ellipsoid plot of 1 (50 % probability); hydrogen atoms
omitted for clarity
Results and Discussion
Crystal structure of Pd(Bzdpa)Cl2 (1)
The mononuclear palladium complex 1 crystallizes in the
space group Pna21 (No. 33) with four neutral Pd(Bzdpa)Cl2
complex molecules in the orthorhombic unit cell. The struc-
ture of 1 is presented in Figure 1 with thermal ellipsoids
(50 % probability). Figure 2 shows the unit cell of the com-
plex.
The metal center of 1 is coordinated by a N2Cl2 donor
set provided by the two aromatic pyridine systems and two
chlorine ions in cis-position to complete the first coordi-
nation sphere. A square-planar coordination is generated
from which the centered palladium ion deviates only by
Z. Anorg. Allg. Chem. 2005, 631, 1397Ϫ1402
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© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim
1399

S. Fakih, W. C. Tung, D. Eierhoff, C. Mock, B. Krebs
Fig. 2 Unit cell of 1, view along [001]
˚
0.003 A. Together with the bidentate Bzdpa ligand the
palladium atom closes a six membered chelate ring adopt-
ing a boat conformation. The planes through the hetero-
cyclic rings of the ligand include a dihedral angle of 55.8°
which corresponds to commonly observed values for 2,2Ј-
dipyridiylamine-based ligand systems. All bond lengths and
angles are well within expected ranges. Selected values are
reported in Table 2. The packing of the neutral complex
molecules in the crystal structure results in a shortest
Fig. 3 Ellipsoid plot of 2 (50 % probability); hydrogen atoms
omitted for clarity
˚
intermolecular metal-metal distance of 6.212(1) A
(Pd(1)···Pd(1b); b ϭ Ϫ1Ϫx, 1Ϫy, Ϫ0.5ϩz), thus indicating
no intermetallic interactions.
˚
Table 2 Selected bond lengths [A] and angles [°] in 1
atoms
bond length
atoms
angles
Pd(1)-Cl(1)
Pd(1)-Cl(2)
Pd(1)-N(1)
Pd(1)-N(2)
2.312(1)
2.314(1)
2.045(4)
2.057(4)
Cl(1)-Pd(1)-Cl(2)
Cl(1)-Pd(1)-N(1)
Cl(2)-Pd(1)-N(2)
N(1)-Pd(1)-N(2)
90.5(1)
90.7(1)
92.2(1)
86.8(2)
Crystal structures of Pd2(C4H8(dpa)2)Cl4·2CH3CN
(2) and Pt2(C4H8(dpa)2)Cl4·2CH3CN (3)
The isotypic compounds 2 and 3 crystallize in the triclinic
¯
space group P1 (No. 2) with a dinuclear neutral complex
Fig. 4 Unit cell of 2, view along [100]
molecule and two acetonitrile molecules in each unit cell.
The structure of the complex molecule in 2 is presented in
Figure 3 with thermal ellipsoids (50 % probability). Figure
4 displays the unit cell of 2.
The C4H8(dpa)2 ligand derives from 2,2Ј-dipyridylamine
by substitution of the hydrogen at the bridging amine. The
dipyridyl units coordinate the particular metal centers via
their two nitrogen donor atoms. Two chloride ions in cis-
position complete the coordination sphere resulting in a
square-planar coordination around the metal cations. The
palladium atoms as well as the platinum atoms deviate only
marginally from the planes through the first coordination
˚
˚
spheres (0.010 A in 2 and 0.001 A in 3) not distorting the
virtually ideal square-planar structure. Each metal center
closes a six membered chelate ring which adopts a distinct
boat conformation. Within the structures of both dinuclear
complexes an inversion center is located in the middle of
the bridging butyl chain generating one half of each mol-
1400
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim
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Z. Anorg. Allg. Chem. 2005, 631, 1397Ϫ1402

Dinuclear and Mononuclear Platinum(II) and Palladium(II) Complexes
(FCI) for financial support and the W.C. HERAEUS GmbH for
substantial support of their work. S. F. thanks the International
Graduate College “Template Directed Chemical Synthesis” for a
graduate fellowship and W. C. T. gratefully acknowledges a re-
search fellowship from the Erasmus-Program. D. E. would like to
thank the Westfälische Wilhelms-Universität for a graduate fellow-
ship.
ecule. The planes through the heterocyclic aromatic ring
systems of the coordinating C4H8(dpa)2 ligand form a di-
hedral angle of 52.7° in 2 and 53.5° in 3. All bond lengths
and angles are well within the expected ranges. Selected val-
ues are reported in Table 3. The intramolecular metal-metal
˚
˚
distances amount in 2 to 9.172(1) A and in 3 to 9.180(3) A.
The shortest intermolecular metal-metal distance for the
˚
palladium complex is 4.27(1) A and for the platinum com-
References
˚
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Pd, Pt). Intermetallic interactions can thus be excluded.
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Table 3 Selected bond lengths [A] and angles [°] in 2 and 3
2
bond length
3
bond length
Pd(1)-Cl(1)
Pd(1)-Cl(2)
Pd(1)-N(1)
Pd(1)-N(2)
2.292(1)
2.297(1)
2.017(4)
2.023(4)
Pt(1)-Cl(1)
Pt(1)-Cl(2)
Pt(1)-N(1)
Pt(1)-N(2)
2.292(3)
2.312(4)
2.004(9)
1.999(9)
2
angles
3
angles
Cl(1)-Pd(1)-Cl(2) 91.2(1)
Cl(1)-Pd(1)-N(1) 90.6(1)
Cl(2)-Pd(1)-N(2) 91.9(1)
Cl(1)-Pt(1)-Cl(2) 90.7(1)
Cl(1)-Pt(1)-N(1) 91.1(3)
Cl(2)-Pt(1)-N(2) 91.8(3)
N(1)-Pd(1)-N(2)
86.5(2)
N(1)-Pt(1)-N(2)
86.4(4)
The potential use of dinuclear platinum complexes in
cancer chemotherapy is expected to offer important advan-
tages over the clinically applied mononuclear compounds.
A more efficient DNA interaction of two DNA-bound
platinum centers is not only believed to result in a higher
cytostatic activity but to overcome intrinsic or acquired re-
sistances of tumor cells towards platinum chemotherapeu-
tics. The presented structures show the extension of well
investigated and highly cytostatic mononuclear 2,2Ј-dipyri-
dylamine metal complexes to their dinuclear correspon-
dents. The mononuclear 2,2Ј-dipyridylamine compounds
tightly fit into the DNA structure due to a lack of sterical
hindrance of the flat aromatic systems around the metal
center. Variable extensions of the ligand system at the bridg-
ing secondary amine strongly influence the cytostatic ac-
tivity of the compound by introducing electronic interac-
tions of different alkyl groups or intercalation effects
through additional aromatic ring systems as it is shown in
complex 1. However, the operating range of these mononu-
clear compounds is limited to only one selective DNA le-
sion. Consequently, the introduction of a second metal
binding unit which can also interfere with the DNA will
significantly enhance the cytotoxic effect. To optimize the
DNA binding capacity of two 2,2Ј-dipyridylamine units the
butyl-linker in the complex molecules in 2 and 3 was chosen
to cover a wide range of the duplex and to be highly flexible
in order to adapt to the DNA structure. In contrast to the
selective intrastrand cross-link of the mononuclear complex
the dinuclear platinum compound is expected to adopt pre-
ferred long range intra- and interstrand cross-linking
modes, thus leading to a more efficient DNA distortion.
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