Synthesis, cytotoxic effect, and structure-activity relationship of Pd(II) complexes with coumarin derivatives

Article abstract of DOI:10.1021/ic0605569

We report the influence of the substituent at the N atom of the ligands on the synthesis, biological activity, and stability of Pd(II) complexes of the general formula PdL₂. The compounds adopt a cis or trans configuration with respect to the substituent at the nitrogen atom. Sterically hindered substituents promote the formation of trans isomers, whereas when the nitrogen atom is unsubstituted, cis isomers are formed. The compounds were characterized by elemental analysis, infrared and ¹H NMR spectroscopies, and electrospray mass spectrometry. The complexes were also studied using X-ray diffraction and computational DFT methods. Both complexes cis-3a and trans-3c exhibit square-planar geometries around the Pd(II) atom. The cytotoxic effects of these complexes were examined on two human leukemia cell lines, HL-60 and NALM-6. Pd complex cis-3a showed significant cytotoxic activity. The effects exhibited by this complex were comparable to those reported for carboplatin. Loigand 2a was not cytotoxic. Computational analysis carried out at the PB/B3LYP/LACVP**//mPW1PW91/LanL2DZ level showed excellent correlation between the energy difference of the cis and trans isomers and the cytotoxic activity, rendering computations a useful predictive tool for the design of new drugs.

Full text of DOI:10.1021/ic0605569

Inorg. Chem. 2006, 45, 9688−9695
Synthesis, Cytotoxic Effect, and Structure
Complexes with Coumarin Derivatives
−Activity Relationship of Pd(II)
Elz
Piotr Paneth,| Urszula Krajewska, and Marek Ro´zalski
3
bieta Budzisz,*,† Magdalena Małecka,‡ Ingo-Peter Lorenz,§ Peter Mayer,§ Renata A. Kwiecien´,|
Departments of Cosmetic Raw Materials Chemistry and Pharmaceutical Biochemistry,
Faculty of Pharmacy, Medical UniVersity of Ło´dz´, Muszyn´skiego 1, 90-151 Ło´dz´, Poland,
Department of Crystallography and Crystal Chemistry, UniVersity of Łodz´, Pomorska 149/153,
90-236 Łodz´, Poland, Department of Chemistry and Biochemistry, Ludwig Maximilians UniVersity,
Butenandtstrasse 5-13 (D), D-81377 Munich, Germany, and Institute of Applied Radiation
Chemistry, Department of Chemistry, Technical UniVersity of Ło´dz´,
Zeromskiego116, 90-924 Łodz´, Poland
Received April 3, 2006
We report the influence of the substituent at the N atom of the ligands on the synthesis, biological activity, and
stability of Pd(II) complexes of the general formula PdL2. The compounds adopt a cis or trans configuration with
respect to the substituent at the nitrogen atom. Sterically hindered substituents promote the formation of trans
isomers, whereas when the nitrogen atom is unsubstituted, cis isomers are formed. The compounds were
characterized by elemental analysis, infrared and 1H NMR spectroscopies, and electrospray mass spectrometry.
The complexes were also studied using X-ray diffraction and computational DFT methods. Both complexes cis-3a
and trans-3c exhibit square-planar geometries around the Pd(II) atom. The cytotoxic effects of these complexes
were examined on two human leukemia cell lines, HL-60 and NALM-6. Pd complex cis-3a showed significant
cytotoxic activity. The effects exhibited by this complex were comparable to those reported for carboplatin. Loigand
2a was not cytotoxic. Computational analysis carried out at the PB/B3LYP/LACVP**//mPW1PW91/LanL2DZ level
showed excellent correlation between the energy difference of the cis and trans isomers and the cytotoxic activity,
rendering computations a useful predictive tool for the design of new drugs.
Introduction
Over the past several years, inorganic chemistry has played
an important role in modern medicine. The development of
metal-based therapeutics has been stimulated by the discov-
ery of cisplatin [cis-diamminedichloroplatinum(II), Figure
1a], which is widely used as a drug in chemotherapy,1,2 yet
* To whom correspondence should be addressed: Dr. hab. Elz˘bieta
Budzisz, Department of Cosmetic Raw Materials Chemistry, Faculty of
Pharmacy, Medical University of -Lo´dz´, 90-151 -Lo´dz´, Muszyn´skiego1, Poland.
E-mail: elora@ich.pharm.am.lodz.pl.
† Department of Cosmetic Raw Materials Chemistry, Faculty of Phar-
macy, Medical University of -Lo´dz´.
‡ University of -Lo´dz´.
Figure 1. Structures of (a) cisplatin, (b) carboplatin, and (c) Pd(II)
complex.
§ Ludwig Maximilians University.
| Technical University of -Lo´dz´.
Department of Pharmaceutical Biochemistry, Faculty of Pharmacy,
Medical University of -Lo´dz´.
exhibits a wide range of side effects.3 In recent years,
investigations have been directed toward searching for new
(1) Jakupec, M. A.; Galanski, M.; Keppler, B. K. ReV. Physiol. Biochem.
Pharmacol. 2003, 146, 1-53.
(2) Heim, M. E. In Metal Complexes in Cancer Chemotherapy; Keppler,
B. K., Ed.; VCH: Weinheim, Germany, 1993; p 9.
(3) Daugaard, G.; Abildgaard, C. Cancer Chemother. Pharmacol. 1989,
1, 25.
9688 Inorganic Chemistry, Vol. 45, No. 24, 2006
10.1021/ic0605569 CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/24/2006

Pd(II) Complexes with Coumarin DeriWatiWes
antitumor transition metal derivatives with better therapeutic
properties than cisplatin. Both platinum and nonplatinum
complexes have been screened. Clinical application of the
second-generation drug carboplatin [cis-diammine(1,1-cy-
clobutanedicarboxylato)platinum(II), Figure 1b] resulted in
a significant decrease in the toxic side effects.4 Metal
complexes that contain coumarin as a ligand show antico-
agulant properties5,6 and antitumor activity.7,8 In particular,
complexes with cerium(III), zirconium(IV), copper(II), zinc(II),
bismuth(III), and cadmium(II) exhibit pronounced in vitro
cytotoxicity.9,10 On the basis of the structural and thermo-
dynamic analogy between platinum(II) and palladium(II)
complexes,11 a variety of studies on palladium(II) derivatives
as potential anticancer drugs have been carried out.12 The
cytotoxic or antitumor activities of many palladium(II)
complexes have been investigated.13 As a result, relatively
weak ligand binding and a predominant tendency to form
trans isomers were found.14 Only a few examples of cis
conformers have been reported.15
lipophilicities and electronic density distributions on atoms
that participate in coordination.
Experimental Section
Materials and Methods. Bis(benzonitrile)palladium(II) chloride
was purchased from Sigma. Solvents used in the syntheses were
of reagent grade or better quality and were dried according to
standard methods. The melting points were determined using an
Electrothermal 1A9100 apparatus and are reported as uncorrected
values. The IR spectra were recorded on a Pey-Unicam 200G
spectrophotometer in KBr or CsI. The 1H NMR spectra were
recorded using a 300-MHz Varian Mercury spectrometer. The MS
data were obtained on an LKB 2091 mass spectrometer (70 eV
ionization energy), and the ESMS were recorded on a 5989A mass
spectrometer with a 59980B particle-beam LCMS interface (Hewlett-
Packard). For the new compounds, satisfactory elemental analyses
((0.4% of the calculated values) were obtained in the Microana-
lytical Laboratory of the Department of Bioorganic Chemistry
(Medical University, Lodz, Poland) using a Perkin-Elmer PE 2400
CHNS analyzer. Ethyl 2-phenyl-4-oxo-4H-chromene-3-carboxylate
(1a), methyl 2-methyl-4-oxo-4H-chromene-3-carboxylate (1b), 3-(1-
methylaminoethyl)-4-hydroxychromen-2-one (2d), and 3-(1-ben-
zylaminoethyl)-4-hydroxychromen-2-one (2e) were prepared ac-
cording to literature procedures.18,19
Synthesis of the Ligands. Synthesis of 3-(1-Aminobenzylidene)-
2H-chromene-2,4(3H)-dione (2a). A 25% aqueous ammonia
solution (0.31 mL, 2 mmol) in ethanol (0.5 mL) was added at room
temperature to a solution of ethyl 2-phenyl-4-oxo-4H-chromene-
3-carboxylate (1) (588.6 mg, 2 mmol) in ethanol (10 mL). After
24 h, the precipitated solid crude product was filtered off, dried,
and recrystallized from methanol (10 mL).
Compound 2a was obtained as a white solid (482.7 mg, 91.0%);
mp 236.3-237.4 °C (lit.20 223-226 °C). 1H NMR (DMSO-d6): δ
7.22-7.97 (m, 9H, aromatic), 10.12 (s, 1H, OH), 12.00 (s, 1H,
NH). 13C NMR (DMSO-d6): δ 94.77, 116.02, 120.04, 123.21,
125.91, 126.78, 127.55, 129.57, 133.73, 136.08, 153.10, 160.89,
175.14, 179.17 (CdO). MS m/z (%): 266 (100, M+). C16H11NO3
(265.26): calculated C 72.44, H 4.18, N 5.28; found C 72.23, H
3.85, N 5.32%.
In a recent article, we reported the synthesis and biological
activity of the complex of 3-(1-aminoethyl)-4-hydroxy-
chromen-2-one with palladium(II) (Figure 1c), where the
environment of the Pd atom is similar to that in carboplatin.16
This complex has a 7800-times higher cytotoxicity than
carboplatin. In contrast, the Pd(II) and Pt(II) complexes17
with 3-(1-aminoethylidene)-2-methoxy-2-oxo-2,3-dihydro-
2λ5-benzo[e][1,2]-oxaphosphinin-4-one exert effects com-
parable to those reported for cisplatin and carboplatin. The
present report includes five newly prepared palladium(II)
complexes of the general formula PdL2, where L represents
unsubstituted or N-alkylated (methyl or benzyl group)
coumarin derivatives. Synthetic, structural, and preliminary
biological studies were carried out to analyze the structure-
activity relationships for systems involving palladium(II)
centers. We discuss the influence of substituents at the
nitrogen atom and at the C3 position of coumarin on the
configurations and their biological activity of the complexes.
We also used quantum chemical calculations to evaluate the
stabilities of the obtained complexes, as well as their
General Procedure for Compounds 2b,c. A solution of methyl-
or benzylamine (20 mmol) in methanol (1.0 mL) was added at room
temperature to a solution of 2-phenyl-4-oxo-4H-chromene-3-
carboxylic acid ethyl ester (1a) (20 mmol) in methanol (5 mL).
The solid crude product, which precipitated after several minutes,
was filtered off, dried, and recrystallized from methanol. Com-
pounds 2b and 2c were obtained as white solids.
(4) Shehata, M. R. Transition Met. Chem. 2001, 26, 198-204.
(5) Jiang, D.; Deng, R.; Wu, J. Wuji Huaxue 1989, 5, 21-28.
(6) Deng, R.; Wu, J.; Long, L. Bull. Soc. Chim. Belg. 1992, 101, 439-
443.
(7) Kostova, I.; Manolov, I.; Konstantinov, S.; Karaivanova, M. Eur. J.
Med. Chem. 1999, 34, 63-68.
(8) Manolov, I.; Kostova, I.; Netzeva, T.; Konstantinov, S.; Karaivanova,
M. Arch. Pharm. Pharm. Med. Chem. 2000, 333, 93-98.
(9) Kostova, I.; Malonov, I.; Karaivanova, M. ArchiV. Pharm. Pharm.
Med. Chem. 2001, 334, 157-162.
(10) Karaivanova, V. D.; Malonov, I.; Minassyan, M. L.; Danchev, N. D.;
Samurova, S. M. Pharmazie 1994, 49, 856-857.
(11) Rau, T.; van Eldik, R. In Metal Ions in Biological Systems; Sigel, A.,
Sigel, H., Eds.; Marcel Dekker: New York, 1996; Vol. 32, p 339.
(12) Al-Allaf, T. A.; Rashan, L. J. Boll. Chim. Farmac. 2001, 140, 205-
210.
(13) Kuduk-Jaworska, J.; Puszko, A.; Kubiak, M.; Pelczynska, M. J. Inorg.
Biochem. 2004, 98, 1447-1456.
(14) Acquaye, J. H. K. A.; Richardson, M. F. Inorg. Chim. Acta 1992,
201, 101-107.
3-(1-Methylaminobenzylidene)-2H-chromene-2,4(3H)-dione
(2b). Yield: 480.3 mg, 86.5%; mp 134.5-135.9 °C. 1H NMR
(DMSO-d6): δ 2.85 (s, 3H, N-CH3) 7.21-7.97 (m, 9H, aromatic),
13.37 (s, 1H, OH). 13C NMR (DMSO-d6): δ 32.31 (N-CH3), 95.89,
116.23, 120.16, 125.43, 128.40, 153.95, 160.35, 174.98, 179.36 (Cd
O). MS m/z (%): 280 (100, M+). C17H13NO3 (279.28): calculated
C 73.10, H 4.69, N 5.02%; found C 72.74, H 4.64, N 5.02%.
3-(1-Benzylaminobenzylidene)-2H-chromene-2,4(3H)-dione (2c).
Yield: 494.7 mg, 69.6%; mp 144.2-146.1 °C. 1H NMR (DMSO-
d6): δ 4.41 (d, 2H, N-CH2Ph), 7.21-7.96 (m, 14H, aromatic),
13.92 (s, 1H, OH). 13C NMR (DMSO-d6): δ 48.44 (CH2), 96.17,
116.25, 123.53, 125.50, 126.06, 127.33, 153.41, 160.45, 179.91
(15) Petit, L. D.; Bezer, M. Coord. Chem. ReV. 1985, 61, 97-114.
(16) Budzisz, E.; Keppler, B. K.; Giester, G.; Woz´niczka, M.; Kufelnicki,
A.; Nawrot, B. Eur. J. Inorg. Chem. 2004, 4412-4419.
(17) Budzisz, E.; Krajewska, U.; Rozalski, M. Pol. J. Pharmacol. 2004,
56, 473-478.
(18) Coppola, G. M.; Dodsworth, R. W. Synthesis 1981, 7, 523-524.
(19) Budzisz, E.; Brzezinska, E.; Krajewska, U.; Rozalski, M. Eur. J. Med.
Chem. 2003, 38, 597-603.
(20) Kloss, R. A.; Wiener, C. J. Org. Chem. 1963, 28, 1671-1673.
Inorganic Chemistry, Vol. 45, No. 24, 2006 9689

Budzisz et al.
Figure 2. Single-crystal X-ray structures with the atom-numbering schemes of 3a and 3c. Displacement ellipsoids are drawn at the 30% probability level.
(CdO). MS m/z (%): 355 (100, M+). C23H17NO3 (355.37):
calculated C 77.73, H 4.82, N 3.94%; found C 77.67, H 4.71, N
3.98%.
38 [R(int) ) 0.0400], of which 5898 were observed with I > 2σ(I).
In the data reduction step, intensities were corrected for Lorentz
and polarization effects but not for absorption.21 Structures were
solved by direct methods using the SHELXS8622 program and
refined by full-matrix least-squares calculations on F2 using
SHELXL97.23 After the refinement with isotropic displacement
parameters, the refinement was continued with anisotropic displace-
ment parameters for all non-hydrogen atoms. Positions of all H
atoms attached to phenyl groups were determined geometrically
and refined using a riding model with Uiso(H) ) -1.2Ueq(C), where
the C-H distance was fixed at 0.93 Å. Positions of H atoms for
NH groups were found on a Fourier map and refined isotropically.
General Procedure for Compounds 3a-e. A methanolic
solution of 2 (0.5 mmol, in 15 mL of MeOH) was added to a
solution of [Pd(C6H5CN)2Cl2] (95.9 mg, 0.25 mmol) in chloroform/
methanol (1:1, v/v, 6 mL). The mixture was stirred at room
temperature for 24 h, after which time the resulting yellow crystals
were filtered off, washed with water and diethyl ether, and dried
overnight in a vacuum over anhydrous silica gel.
1
Compound 3a. Yield: 103.5 mg (65%); mp >360 °C dec. H
NMR (DMSO-d6): δ 7.20-7.96 (m, 18H, aromatic), 12.4 (sbroad
,
2H, NH). ESMS m/z: 637. C32H20N2O6Pd (636.93): calculated C
60.53, H 3.17, N 4.41%; found C 60.67, H 2.91, N 4.48%.
Compound 3b. Yield: 121.5 mg (73.3%); mp 263.5-264.8 °C.
1H NMR (DMSO-d6): δ 2.84 (2 × s, 6H, N-CH3), 7.20-7.96
(m, 18H, aromat.). ESMS m/z: 662. C34H24N2O6Pd‚1.5 H2O
(689.99): calculated C 59.18, H 3.94, N 4.06%; found C 59.04, H
3.59, N 4.13%.
Compound 3c. Yield: 138.8 mg (68.1%); mp 245.1-245.3 °C.
1H NMR (DMSO-d6): δ 4.54 (d, 4H, N-CH2Ph), 7.22-8.14 (m,
18H, aromatic). ESMS m/z: 815. C46H32N2O6Pd (815.06): calcu-
lated C 67.77, H 3.96, N 3.44%; found C 67.68, H 3.75, N 3.48%.
Compound 3d. Yield: 101.0 mg (75%); mp 261.2-263.0 °C.
1H NMR (DMSO-d6): δ 2.64 (2 × s, 6H, C-CH3), 2.95 (2 × s,
6H, N-CH3) 7.29-8.16 (m, 8H, aromatic). ESMS m/z: 538.
C24H20N2O6Pd‚0.5 H2O (547.84): calculated C 52.61, H 3.83, N
5.11%; found C 52.58, H 3.93, N 5.11%.
The final refinement gave R1 ) 0.0264, wR2 )0.0646, and S
) 1.029 for the observed reflections. The maximum peak on the
final ∆F map was 0.351 e/A3, and the minimum was -0.789 e/A3.
The molecular geometry was calculated using PLATON.24 The
drawings were generated using PLATON and are presented in
Figure 2. The crystal data and X-ray details are given in the
Supporting Information, and the geometric parameters are reported
in Table 2 below. Further experimental details have been deposited
at the Cambridge Crystallographic Data Centre, CCDC 297227.
Single crystals of compound 3c were obtained by slow evapora-
tion of a chloroform/methanol solution of 3c. The data were
collected on a Nonius Kappa CCD instrument equipped with a
rotating anode generator (Mo KR radiation). The structure was
solved with SHELXL9725 using direct methods and refined with
SHELXL-97. All non-hydrogen atoms were refined anisotropically;
the hydrogen atoms were located in the Fourier map and refined
without any restraints. The drawings were generated using PLATON
and are shown in Figure 2a. Crystallographic data for 3c have been
deposited with the Cambridge Crystallographic Data Centre as
CCDC 299066. Copies of the data can be obtained free of charge
Compound 3e. Yield: 110.4 mg (64%); mp 228.1-229.3 °C.
1H NMR (DMSO-d6): δ 2.58 (2 × s, 6H, C-CH3), 4.43 (d, 4H,
N-CH2Ph), 7.18-8.10 (m, 18H, aromatic). ESMS m/z: 691.
C36H28N2O6Pd (691.02): calculated C 62.56, H 4.08, N 4.06%;
found C 62.48, H 3.75, N 3.96%.
Crystallographic Analysis of Palladium(II) Complexes. Single
crystals of compound 3a were obtained by slow evaporation of a
solution of 3a in chloroform/methanol. Data for a yellow crystal
of size 0.4 × 0.05 × 0.05 mm were measured at 150 K on a STOE
IPDS diffractometer. The unit cell parameters were determined from
36223 reflections in the θ range 1.65-29.33°. 33994 intensities
were collected using graphite-monochromatized Mo KR radiation
in θ range 1.65-29.39°. 6994 independent reflections were
measured in the range -17 e h e 17, -10 e k e 10, -37 e l e
(21) Software for IPDS-II; Stoe and Cie: Darmstadt, Germany, 2000.
(22) Sheldrick, G. M. SHELXS86: Program for Crystal Structure Solution;
University of Go¨ttingen: Go¨ttingen, Germany, 1986.
(23) Sheldrick, G. M. SHELX97: Programs for Crystal Structure Analysis;
University of Go¨ttingen: Go¨ttingen, Germany, 1997.
(24) Spek, A. L. PLATONsMolecular Geometry Program; University of
Utrecht: Utrecht, The Netherlands, 1998.
(25) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.; Giaco-
vazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna,
R. J. Appl. Crystallogr. 1999, 32, 115-119.
9690 Inorganic Chemistry, Vol. 45, No. 24, 2006

Pd(II) Complexes with Coumarin DeriWatiWes
Scheme 1. Synthesis of Coumarin Derivatives 2a-e
upon application to the CCDC, 12 Union Road, Cambridge CB2
1EZ, U.K. E-mail: deposit@ccdc.cam.ac.uk.
Cell and Cytotoxicity Assay. The cytotoxicity was determined
on two human leukemia cell lines, promyelocytic HL-60 and
lymphoblastic NALM-6. The NALM-6 cell line was purchased from
the German Collection of Microorganisms and Cell Cultures. Cells
were cultured in an RPMI 1640 medium supplemented with 10%
fetal calf serum in a 5% CO2/95% air atmosphere. Exponentially
growing cells were seeded at 3 × 105 per well of 24-well plate
(Nunc), and cells were then exposed to the tested compounds for
48 h. Stock solutions were freshly prepared in DMSO, and then
dilutions from 10-3 to 10-7 M in complete culture medium were
made.
The number of viable cells was counted in a Buˆrker hemocy-
tometer using the trypan-blue exclusion assay. The values of IC50
(the concentration of test compounds required to reduce the cell
survival fraction to 50% of the control) were calculated from dose-
response curves and used as a measure of cellular sensitivity to a
given treatment. All data are expressed as mean ( standard
deviation.
Scheme 2. Synthesis of Pd(II) Complexes 3a-e
Computational Details. All gas-phase geometry optimizations
were performed with the Gaussian 03 package26 using the
mPW1PW91 functional27 in the ECP LanL2DZ basis set.28,29
Optimization of the cis-3a structure was also carried out using the
family of PMx semiempirical Hamiltonians (PM3-d,30 PM5,31
PM632) as implemented in the Mopac2002 program.33 log P values
were obtained from the free Gibbs energy in water and 1-octanol.
Solvation effects of the structures optimized at the mPW1PW91/
LanL2DZ level were calculated by the Poisson-Boltzmann (PB)
method as implemented in the Jaguar v.6.0 program.34 These energy
calculations were carried out at the B3LYP theory level using the
LACVP** basis set for palladium and the 6-31G(d,p) basis set for
the other atoms. For 1-octanol, the dielectric constant of 10.3 and
the solvent probe molecule radius of 3.14 were used. All calcula-
tions were carried out using default convergence criteria.
according to our published methods,20 using the reaction of
2-phenyl-4-oxo-4H-chromene-3-carboxylic acid ethyl ester
(1a) and 2-methyl-4-oxo-4H-chromene-3-carboxylic acid
methyl ester (1b) with primary amines. The compounds were
obtained in excellent yields (70-95%). The structures of
compounds 2a-e (Scheme 1) were confirmed by elemental
Results
Chemistry. Derivative 2a was first synthesized by Kloss35
via the reaction of 3-benzoilo-4-hydroxycoumarin with
ammonium acetate. We have synthesized ligands 2a-e
1
and spectral (IR, H, 13C NMR, MS) analyses (see Experi-
mental Section).
(26) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin,
K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone,
V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G.
A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai,
H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R.
E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J.
W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari,
K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.;
Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
Gaussian 03, revision D01; Gaussian, Inc.: Pittsburgh, PA, 2003.
(27) Adamo, C.; Barone, V. J. Chem. Phys. 1998, 108, 664-675.
(28) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270-283.
(29) Wadt, W. R.; Hay, P. J. J. Chem. Phys. 1985, 82, 284-298.
(30) Lopez, X.; York, D. M. Theor. Chem. Acc. 2003, 109-148.
(31) Stewart, J. J. P. Fujitsu Limited, Tokyo, Japan, MOPAC 2002.
(32) Stewart, J. J. P. Fujitsu Limited, Tokyo, Japan. Personal communica-
tion, MOPAC 2002.
Synthesis and Spectral Characteristics of Pd(II) Com-
plexes. The palladium(II) complexes of coumarin ligands
(2a-e) were synthesized by the addition of a methanol
solution of 2a-e to a chloroform/methanol solution (1:1) of
bis(benzonitrile)dichloropalladium(II) in a 1:2 molar ratio.
The reaction was carried out at room temperature for 24 h
(Scheme 2). The compositions and structures of the resulting
complexes 3a-e were confirmed by elemental analysis, IR
spectroscopy, ES mass spectrometry, and X-ray diffraction.
The structures were also confirmed by 1H NMR analysis
of the samples dissolved in DMSO-d6. DMSO was selected
as the solvent because of the very limited solubility of all
complexes in other solvents. Some characteristic IR spectral
data for the complexes 3a-e and ligands 2a-e are reported
in Table 1.
Significant differences in the IR spectra of complexes
3a-e were observed in comparison with the spectra of
ligands 2a-e, predominantly in the valency vibrations of
the NH group. The νNH band shifted toward higher frequen-
(33) Fujitsu Limited, Tokyo, Japan, MOPAC 2002.
(34) Jaguar, version 6.0; Schrodinger, LLC: New York, 2005.
(35) See ref 20.
Inorganic Chemistry, Vol. 45, No. 24, 2006 9691

Budzisz et al.
Table 1. Selected IR Bands for Ligands 2a-e and Complexes 3a-e
Table 3. Hydrogen Bonding Geometry (Å, deg)
ν (cm-1
)
NH
sCdO
sNdCs
MsNs
MsO
D-H
H‚‚‚A
D‚‚‚A
D-H‚‚‚A
2a
3a
2b
3b
2c
3c
2d
3d
2e
3e
3238
3329
3458
-
1685
1709
1711
1708
1710
1721
1701
1701
1698
1701
1607
1600
1606
1600
1588
1601
1607
1607
1613
1615
-
446
-
-
506
-
N20-H20‚‚‚O12i
N10-H10‚‚‚O12i
0.77(3)
0.78(3)
2.25(1)
2.32(1)
2.976(2)
3.065(2)
157(1)
159(1)
443
-
512
-
formed by two N atoms and two O atoms, and the PdN2O2
square adopts a cis configuration. The corresponding Pd-N
and Pd-O bond distances (Table 2) are almost equal,
whereas the Pd-O distances are 2.0012(2) and 1.999(2) Å
and are therefore shorter than the literature values.38 The
geometry about the Pd atom deviates little from an ideal
square plane; the O(2)-Pd(1)-O(1) angle is slightly smaller
than 90°. As a consequence, the corresponding N(20)-
Pd(1)-N(10) angle is slightly larger than 90°.
3448
-
460
-
520
-
3393
-
3382
-
459
-
527
-
461
524
Table 2. Selected Geometric Parameters of 3a and 3c (i ) 2 - x, -y,
2 - z)
cis-PdL2 (3a)
trans-PdL2 (3c)
Bond Lengths (Å)
The Pd atom is almost exactly coplanar with the plane
defined by the four atoms bonded to it, with a deviation from
the “best” plane of -0.0023(1) Å. Ligand 3-(1-aminoben-
zylidene)-2H-chromene-2,4(3H)-dione (2a) connected to the
central Pd atom forms two six-membered rings, which have
conformation between boat and twisted-boat. The puckering
parameters39 are QT ) 0.369(2) Å, æ2 ) 14.7(3)°, θ2 )
71.8(3)°, QT ) 0.360(2) Å, æ2 ) -171.8(3)°, and θ2 )
105.1(3)°, corresponding to the Pd1, O2, C3, C2, C1, N20
and Pd1, O1, C4, C5, C6, N10 atom sequences, respectively.
According to Nardelli,40 the asymmetry parameters are ∆2
) 0.048(1) and ∆2 ) 0.048(1) for two 2-fold pseudo-axes
passing through the midpoint of the Pd1-O2 bond and the
C3 atom and ∆s ) 0.033(1) and ∆s ) 0.049(1) for the mirror
plane passing through the Pd1 atom and the midpoint of the
O1-C4 bond, corresponding to the atom sequences men-
tioned above. Bond distances and angles for both molecules
are in good agreement with the expected values.41
O(1)-Pd(1)
N(20)-Pd(1)
O(2)-Pd(1)
N(10)-Pd(1)
2.012(1) O(1)-Pd(1)
1.961(2) N(1)-Pd(1)
1.999(1) O(1)i-Pd(1)
1.962(2) N(1)i-Pd(1)
1.990(2)
2.022(2)
1.990(2)
2.022(2)
Bond Angles (deg)
O(2)-Pd(1)-O(1)
N(20)-Pd(1)-N(10)
N(20)-Pd(1)-O(1)
N(10)-Pd(1)-O(2)
87.43(5) O1-Pd-O1i
91.78(7) Ni-Pd-N
177.41(6) O1-Pd-N
177.77(6) O1-Pd-Ni
179.999(1)
179.999(1)
87.87(9)
92.13(9)
Torsion Angles (deg)
Pd(1)-O(1)-C(4)-C(5) -12.0(2)
Pd1-O1-C1-C9 36.2(2)
Pd1-N-C10-C9 -0.1(2)
Pd(1)-N(10)-C(6)-C(5)
Pd(1)-O(2)-C(3)-C(2)
2.9(3)
18.8(2)
Pd(1)-N(20)-C(1)-C(2) -1.6(3)
cies: from 3238 cm-1 for compound 2a to 3329 cm-1 for
complex 3a. For the other complexes, this band disappeared.
This observation can be explained by the participation of
the nitrogen atom in the coordination with the metal ions in
3a complexes. The N-Pd band peaks were observed at
∼443-461 cm-1 for complexes 3a-e. Within the range
between 600 and 500 cm-1, the bands for the of O-Pd group
were observed at ∼506 cm-1 for complex 3a and 520 cm-1
for complex 3c.
An examination of the hydrogen bonds present shows
conventional N-H‚‚‚O interactions. The geometry of the
hydrogen bond present is presented in Table 3.
Compound 3c crystallizes in space group P21/n with two
formula units per unit cell. In the centrosymmetric complex,
the Pd(II) is bound by two chelating ligands, resulting in a
square-planar coordination sphere. As a consequence of the
inversion symmetry, the Pd-N2-O2 core exhibits a trans
configuration. The Pd-O1 bond distance is 1.990(2) Å and
is slightly shorter than the Pd-N bond distance at 2.022(2)
Å. The O-Pd-N1 angle is 87.87(9)°, resulting in a small
deviation from an ideal square plane. The chelate formation
leads to a six-membered ring Pd-O1-C1-C9-C10-N
with the puckering parameters Q ) 0.5969(21) Å, θ )
110.45(25)°, and æ ) 199.3(3)°, giving a B1,4 boat confor-
1
In the H NMR spectra of the complexes, one of the
exchangeable protons (at 10.12 ppm), attributed to the OH
enol group of 2a, was not present in the complex, and the
NH signal was observed at 12.4 ppm.
Electrospray mass spectrometry (ESMS) is considered one
of the most powerful analytical techniques in the field of
coordination compounds.36 The spectra obtained by ESMS
analysis can show patterns that correspond to [M + H]+,
[2M + H]+, or adducts with solvent molecules.37 ESMS
analyses were performed for all complexes in positive-ion
mode. ESMS analysis for complex 3a showed the expected
isotope pattern ion at m/z ) 538.
X-ray Structure. Single-crystal X-ray crystal studies of
compound 3a were undertaken to elucidate the coordination
sphere of the palladium(II) center. The molecular structures
of the palladium(II) complexes with the atomic numbering
scheme are shown in Figure 2, and selected bond lengths
and angles are reported in Table 2. In addition to the
complex, there one-half molecule of water in the unit cell.
The environments of the Pd(II) atom are square-planar,
2
mation that is twisted toward S4.
Computational Results. The superior performance of the
mPW1PW91/LanL2DZ theory level in comparison with
other DFT functionals for the calculation of geometries and
vibrations for cisplatin and carboplatin has been docu-
(38) Orpen, A. G.; Brammer, L.; Allen, F. H.; Kennard, O.; Watson, D.
G.; Taylor, R. J. Chem. Soc., Perkin. Trans. 1987, 2, S1-S19.
(39) Cremer, D.; Pople, J. A. J. Am. Chem. Soc. 1975, 97, 1354-1358.
(40) Nardelli, M. J. Appl. Crystallogr. 1996, 29, 296-300.
(41) Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen, A.
G.; Taylor, R. J. Chem. Soc., Dalton Trans. 1989, S1-S83.
(36) Plattner, D. A. Int. J. Mass Spectrom. 2001, 207, 125-144.
(37) Henderson, W.; Evans, C. Inorg. Chim. Acta 1999, 294, 183-192.
9692 Inorganic Chemistry, Vol. 45, No. 24, 2006

Pd(II) Complexes with Coumarin DeriWatiWes
Table 4. Selected Geometrical Parameters Obtained for Ligands 2a-2e
from DFT Calculations at the MPW1PW91/LanL2DZ Theory Level
Table 6. Partial Atomic Charges (δ) Calculated for Compound 2a at
the B3LYP/LACVP**//MPW1PW91/LanL2DZ Level
compd
N-H (Å)
N-H-O (deg)
H-O (Å)
population scheme
δN
δH
δO
2a
2b
2c
2d
2e
1.033
1.043
1.042
1.043
1.044
135.8
141.4
140.5
142.6
141.3
1.695
1.636
1.648
1.621
1.635
gas phase
-0.41
-0.59
0.69
Mulliken
ESP
NBO
0.27
0.39
0.44
-0.45
-0.56
-0.64
1-octanol
-0.38
-0.57
-0.66
Mulliken
ESP
NBO
0.29
0.41
0.44
-0.49
-0.60
-0.68
Table 5. Values of LogP Calculated from Solvation-Free Energies
Obtained at the B3LYP/LACVP**//MPW1PW91/LanL2DZ Theory
Level Using the PB Continuum Solvent Model
water
-0.38
-0.57
-0.65
solvation-free
energy (kcal/mol)
Mulliken
ESP
NBO
0.29
0.42
0.45
-0.49
-0.61
-0.68
compd
2a
2b
2c
2d
2e
cis-3a
gas-phase energy (a.u.)
1-octanol
water
log P
-897.242 216 152 36
-936.570 447 282 65
-1167.748 033 014 83
-744.738 894 207 86
-975.915 337 149 67
-1920.120 733 787 47
-14.41
-13.21
-16.90
-13.55
-15.65
-24.42
-21.77
-22.34
-20.55
-22.55
-22.05
-19.79
-19.85
-20.46
-19.68
-17.84 2.51
-16.85 2.66
-18.77 1.34
-14.73 0.86
-16.71 0.77
-31.96 5.51
-28.98 5.27
-30.02 5.61
-28.78 6.02
-31.81 6.77
-31.27 6.74
-25.87 4.44
-24.89 3.68
-27.41 5.08
-26.66 5.10
Table 7. Basic Geometrical Features and ESP Partial Atomic Charges
on Palladium at the B3LYP/LACVP**//MPW1PW91/LanL2DZ Level
compd
N-Pd (Å)
Pd-O (Å)
N‚‚‚Pd‚‚‚O (deg)
δPd
cis-3a
trans-3a
cis-3b
trans-3b
cis-3c
trans-3c
cis-3d
trans-3d
cis-3e
trans-3e
1.978
1.988
2.021
2.025
2.037
2.019
2.022
2.035
2.036
2.033
2.028
2.006
2.020
2.021
2.027
2.029
2.020
2.024
2.023
2.022
88.8
89.6
87.7
88.2
85.4
87.5
87.5
87.6
87.4
88.0
0.62
0.67
0.60
0.58
0.70
0.65
0.62
0.59
0.69
0.63
trans-3a -1920.160 542 477 92
cis-3b -1998.766 339 879 11
trans-3b -1998.766 278 883 66
cis-3c -2461.110 998 662 73
trans-3c -2461.117 045 322 92
cis-3d -1615.098 524 661 74
trans-3d -1615.099 697 833 61
cis-3e -2077.448 947 822 58
trans-3e -2077.453 512 391 60
mented42 in the literature. This level was, therefore, used for
the optimization of the geometries of ligands 2a-e in the
gas phase. In the structures of the isolated ligands, the most
interesting result of the geometry optimization is the position
of the proton in the N‚‚‚H‚‚‚O bridge. Although enol forms
were used as the initial structures, as indicated in Table 4,
the optimized structures show that the proton is close to the
nitrogen atom in the optimized structures, indicating that the
keto forms are more stable even in the gas phase in all cases.
The effect is most pronounced in compound 2a and increases
with the polarity of the solvent (data not shown), e.g., the
N-H bond becomes shorter and the O-H bond becomes
longer.
In calculations incorporating solvent effects, we followed
a recent report43 indicating that solvation effects can be
reliably obtained by the Poisson-Boltzmann (PB) method
at the B3LYP/LACVP** theory level. log P values, reported
in Table 5, were obtained using this approach from the free
energies of solvation in water and 1-octanol. For the example
of 2a, we tested the influence of the reoptimization of the
geometry within the solvent model. It was found that the
solvation-free energy differences do not change significantly;
the log P values at the B3LYP/LACVP** and B3LYP/
LACVP**//mPW1PW/LanL2DZ levels differ only by 0.07.
Because the partial atomic charges are also practically
unperturbed by the theory level at which the geometries were
obtained, we used the latter level in all subsequent calcula-
tions.
Table 6 summarizes the partial atomic charges on the
nitrogen, oxygen, and hydrogen atoms obtained from Mul-
liken, NBO, and electrostatic fitting (ESP) analyses. As can
be seen, the partial atomic charges depend significantly on
the population analysis scheme. Charges obtained from the
electrostatic potential fitting seem to be best balanced, and
we therefore used these values in the analysis of charges on
the palladium atom in its complexes.
For the ligands complexed with palladium, the optimized
geometries around the palladium atom are quite similar for
all of the studied compounds with the exception of 3a, which
shows significantly shorter N-Pd bonds in both conforma-
tions (see Table 7) and a slightly shorter Pd-O bond in the
case of the trans isomer, resulting in slightly larger N‚‚‚Pd‚
‚‚O angles.
Comparison of the calculated geometry of the cis-3a
isomer with the structure obtained from X-ray diffraction
indicates a very good agreement between the experimental
data and the computational results. The main difference, as
shown in Figure 3, lies in the torsional angle of the auxiliary
Three different schemes for obtaining partial atomic
charges were compared on the example of compound 2a.
(42) Wysokin´ski, R.; Michalska, D. J. Comput. Chem. 2001, 22, 901-12.
(43) Lau, J. K.-C.; Deubel, D. V. J. Chem. Theory Comput. 2006, 2, 103-
106.
Figure 3. Superposition of the structures of cis-3a obtained from DFT
calculations and X-ray diffraction.
Inorganic Chemistry, Vol. 45, No. 24, 2006 9693

Budzisz et al.
Table 8. Relative Cis-Trans Stabilitya
concentration range (from 10-7 to 10-3M). The activity is
expressed as the concentration required to reduce the cell
survival fraction to 50% after 48 h of exposure to the
compounds (IC50). The results are presented in Table 9.
compd
gas phase
1-octanol
water
3a
3b
3c
3d
3e
25.0
0.0
3.8
0.7
2.9
22.4
-1.8
3.3
0.8
2.1
22.0
-1.3
3.3
-0.2
2.1
Discussion. For many years, only cis isomers were used
in chemotherapy, and trans isomers were believed to be
inactive. In the past decade, many examples of trans-oriented
complexes that exhibit antitumor activity have been synthe-
sized.45-47 These complexes exhibit strong antitumor activity,
although the mechanism of their action differs from that of
their cis conterparts. We synthesized a series of ligands with
substituents such as H, CH3, or CH2Ph at the nitrogen or
benzylidene or ethylidene at the C3 atom. We observed that
the formation of the trans or cis isomer is governed by the
size of the substituent at the nitrogen atom, i.e., bulky groups
lead to the trans isomer, whereas compounds with unsub-
stituted nitrogen atoms exist as the cis isomer.
a Positive means that the trans isomer is more stable.
Table 9. Cytotoxic Activities (IC50, µM) of Compounds 2a-e and
3a-ea
compd
2a
3a
2b
3b
2c
3c
2d
HL-60
NALM-6
>1000
4.5 ( 0.6
784.0 ( 69.2
2.4 ( 0.4
387.9 ( 48.4
539.5 ( 16.6
47.2 ( 0.41
54.2 ( 4.30
408.0 ( 34.0
602.5 ( 44.3
801.0 ( 4.7
192.4 ( 45.8
4.3 ( 1.3
486.6 ( 62.3
548.6 ( 44.9
45.4 ( 0.98
51.7 ( 2.40
276.0 ( 64.0
84.5 ( 14.3
83.0 ( 13.3
209.9 ( 48.7
0.7 ( 0.2
3d
2e
3e
We observed that, for ligands 2a-c, the cytotoxic effect
increases with increasing size of the substituent at the
nitrogen atom, as the IC50 values were 784.0, 486.6, and 45.4,
respectively, for the NALM-6 cell line. For compounds 2d,e,
carrying the ethylidene group on the C3 atom of coumarin,
the cytotoxic effect increases in the same way. The synthe-
sized complexes were more toxic toward the NALM-6
leukemia cell lines than toward HL-60. The palladium cis
complex 3a exhibited the highest cytotoxicity toward the HL-
60 and NALM-6 cells, with IC50 coefficients of 4.5 and 2.4
µM, respectively, i.e., close to those for carboplatin. As
reported in Table 9, palladium complexes 3b-e have
somewhat lower cytotoxic activities than carboplatin. In
contrast to the cis complexes, the trans counterparts show
remarkable cytotoxicity to both cell lines. It is interesting to
note that ligand 2a exhibts a very low cytotoxic activity.
Initial antitumor studies show that the cytotoxic activity of
the synthesized palladium(II) complexes depends signifi-
cantly on the structure of the substituents at the nitrogen
atom.
carboplatin
a Data are expressed as mean ( SD (n ) 4).19
rings, which is not surprising given that crystal packing can
induce conformational features that are not present in the
gas phase.
For the example of the cis-3a structure, we also tested
(data not shown) the performance of semiempirical methods
because they were reported to work very well for similar
cobalt complexes.44 Whereas the results obtained with PM3-d
and PM5 were unsatisfactory, the PM6 method proved very
good. The calculated geometry of the metal center is
practically the same as that obtained from the DFT calcula-
tions. This observation indicates that the PM6 parametrization
alone or as a part of QM/MM schemes might prove very
useful in future studies of palladium-containing complexes
within biological systems.
An interesting observation arises from a comparison of
the relative stabilities of the cis and trans complexes. Values
listed in Table 8 correlate very well with the biological
activities of the cis compounds listed in Table 9. The
significantly lower relative stability of cis-3a correlates very
well with its highest cytotoxic activity. This might be the
result of the highest destabilization of the cis isomer
(compared to the trans isomer) among all complexes studied,
making it more reactive. We were unable to find a transition
state corresponding to the torsional rotation that would result
in trans-cis isomerization. Because of the steric effects, it
seems more likely that such isomerization proceeds by a
dissociative mechanism. Obviously, more data are needed;
however, should these initial observations be substantiated,
it would suggest that calculations can provide a very useful
tool for predicting the biological activity of such complexes.
Cytotoxicity. The cytotoxicity of compounds 2a-c and
3a-e was evaluated on the two human leukemia cell lines
HL-60 and NALM-6. Carboplatin was used as a reference
compound. Cytotoxic activity was determined over a broad
Lipophilicity is one of the most important factor for the
design of new drugs.48 The mechanisms of resistance to
cisplatin have been identified as decreased drug accumula-
tion, increased cytoplasmic detoxification, and increased
DNA repair.49 Structure-cytotoxicity relationship studies
have also revealed that, for many compounds, increased
lipophilicity is often accompanied by increased cytotoxicity.50
In our investigations, we did not observe any correlation
between cytotoxicity and lipophilicity. Compounds 2a-c
exhibit a higher lipophilicity than compounds 2d,e. Calcula-
tions indicate that there is correlation between the relative
stabilities of the cis and trans complexes and the cytotoxicity.
(45) Kasparkova, J.; Marini, V.; Najareh, Y.; Gibson, D.; Brabec, V.
Biochemistry 2003, 42, 6321-6332.
(46) Natile, G.; Coluccia, M. Coord. Chem. ReV. 2001, 216-217, 383-
410.
(47) Radulovic, S.; Tesic, Z.; Manic, S. Curr. Med. Chem. 2002, 9, 1611-
1618.
(48) Hall, M. D.; Hambley, T. W. Coord. Chem. ReV. 2002, 232, 49-67.
(49) Welland, L. R. Eur. J. Cancer 1994, 30A, 725.
(50) Kupchan, S. M.; Eakin, M. A.; Thomas, A. M. J. Med. Chem. 1971,
14, 1147-1152.
(44) Kwiecien´, R.; Rostkowski, M.; Dyba-La-Defratyka, A.; Paneth, P. J.
Inorg. Biochem. 2004, 98, 1078-1086.
9694 Inorganic Chemistry, Vol. 45, No. 24, 2006

Pd(II) Complexes with Coumarin DeriWatiWes
On the basis of the observation that Pd(II) complexes
exchange their leaving groups 105 times more easily than
their Pt(II) analogues,51 the low antitumor activity of Pd
compounds has been attributed to the rapid hydrolysis of
the leaving groups, which dissociate readily in solution
leading to very reactive species that are unable to reach their
pharmacological targets.52,53 We investigated the stability of
the synthesized compounds. The significantly lower ther-
modynamic stability of cis-3a compared to trans-3c corre-
sponds to its highest cytotoxic activity. Obviously, more data
are needed to make sure that the correlation is not coinci-
dental. However, should it prove real, it would render
calculations a very strong predictive tool of biological
activity.
square-planar geometries around the Pd(II) atom. The results
clearly indicate coordination via N and O heteroatoms.
The present study demonstrates that the Pd(II) complexes
of the coumarin ligands 2a-e exhibit potential cytotoxic
activity toward HL-60 and NALM-6 leukemia cells, with
cytotoxicity coefficients IC50 similar to those of carboplatin.
Compound 3a seems to be promising as an anticancer agent
because of its high cytotoxic activity. Additionally, its ligand
2a is practically inactive. The computational analysis, carried
out at the PB/B3LYP/LACVP**//mPW1PW91/LanL2DZ
theory level, indicates that the cis complexes are thermody-
namically less stable than their trans counterparts and that
this difference seems to correlate well with the biological
activity.
Conclusions. In this article, we have shown a simple and
convenient route for the synthesis of cis- and trans-oriented
Pd complexes. The newly synthesized ligands 2a-e create
neutral complexes of the general ML2 type. We observed
that, depending on the size of the substituent on the nitrogen
atom, the trans or cis complexes are formed. The structures
of complexes 3a and 3c were confirmed using X-ray
diffraction. Both complexes cis-3a and trans-3c exhibit
Acknowledgment. Financial support from the Medical
University of L-o´dz´ (Grant 502-13-287 to E.B.), Technical
University of L-o´dz´, and University of Lodz (Grants 505/696
and 3T09A_138_26KBN to M.M.) and access to the super-
computing facilities at ICM Warsaw and PCSS Poznan are
gratefully acknowledged. The authors thank Prof. Werner
Massa from University of Marburg for skilful experimental
assistance.
(51) Shourky, A.; Rau, T.; Shourky, M.; van Eldik, R. J. Chem. Soc., Dalton
Supporting Information Available: Crystal data and positive-
ion ESMS spectrum of 3a. This material is available free of charge
via the Internet at http://pubs.acs.org.
Trans. 1998, 3105-3112.
(52) Macquet, J. P.; Butons, J. L. J. Natl. Cancer. Inst. 1983, 70, 899-
905
(53) Zhao, G.; Sun, H.; Lin, H.; Zhu, S.; Su, X.; Chen, Y. J. Inorg. Biochem.
1998, 72, 173-177.
IC0605569
Inorganic Chemistry, Vol. 45, No. 24, 2006 9695