Synthesis, characterization and anticancer activity of new palladacycles derived from chiral α-diimines

Article abstract of DOI:10.1002/aoc.1570

Optically pure α-diimines quantitatively obtained in solvent-free conditions starting from 2,3-butanedione and (S)-(-)-1- phenylethylamine and (S)-(-)-1-(4-methylphenyl)ethylamine, respectively, yielded the new chiral mono-Pd complexes 2a-b, which have be

Full text of DOI:10.1002/aoc.1570

Full Paper
Received: 29 June 2009
Revised: 14 September 2009
Accepted: 15 September 2009
Published online in Wiley Interscience: 6 November 2009
(www.interscience.com) DOI 10.1002/aoc.1570
Synthesis, characterization and anticancer
activity of new palladacycles derived
from chiral α-diimines
a,b
c
d
a
`
Sandra Cruz , Sylvain Bernes , Pankaj Sharma , Rosa Vazquez ,
a
a
a∗
´
´
´
Guadalupe Hernandez , Roberto Portillo and Rene Gutierrez
Optically pure α-diimines quantitatively obtained in solvent-free conditions starting from 2,3-butanedione and (S)-(−)-1-
phenylethylamine and (S)-(−)-1-(4-methylphenyl)ethylamine, respectively, yielded the new chiral mono-Pd complexes 2a–b,
which have been partly characterized by IR, 1H- and 13C-NMR spectroscopies along with MS-FAB+ spectrometry. The crystal and
molecular structure for palladacycle 2a has been fully confirmed by single-crystal X-ray studies. Studies in vitro of 2a–b have
displayed growth inhibition against different classes of cancer: leukemia (K-562 CML), colon cancer (HCT-15), breast cancer
c
(MCF-7), central nervous system (U-251 Glio) and prostate cancer (PC-3) cell lines. Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Keywords: anticancer activity; chiral α-diimines; Pd complexes
Introduction
Results and Discussion
The chiral α-diimines 1a–b were synthesized in quantita-
tive yield in solvent-free conditions starting from (S)-(−)-1-
phenylethylamineand(S)-(−)-1-(4-methylphenyl)ethylaminewith
2,3-butanedione, respectively. The reaction between Na2PdCl4
and each of the ligands 1a–b in a MeOH solution at ambient
temperature gave a precipitate leading to the formation of the
corresponding complexes, 2a–b, and their structures were partly
established by spectroscopic analysis.
The complexes 2a–b, isolated as air-stable clear brown
crystalline solids in 94 and 91% yields, respectively, were given
structure 2 based on their spectroscopic features. Thus, the IR
spectra for 2a exhibited absorption at 1672 as well as at 1576 cm−1
for the CN group, with bands in the low-frequency IR region at
753 cm−1 assigned to the Pd–C bonds and at 468 cm−1 owing
to the Pd–N bonds, and a band at 334 cm−1 corresponding
to the absorption of the Pd–Cl bond was also observed. The
1H NMR (400 MHz, CDCl3) spectrum for complex 2a showed at
7.7–6.7 ppm a multiple signal (9H) owing to the phenyl groups:
at 5.4 and 5.1 ppm two quadruplets assigned to the protons
belonging to the chiral moieties; at 2.7 and 2.2 ppm two singulets
Nowadays, there is a growing interest in the synthesis, reactivity
and applications of organometallic complexes with interesting
ligands, and an important area of organometallic chemistry
is that of cyclopalladated compounds.[1–6] Such longstanding
interest in these compounds stems from their widespread utilities,
ranging from potential new applications in organic chemistry,
such as catalysts,[7–19] and as antitumor drugs,[20–25] and the
usual efforts in understanding fundamental chemistry. Among the
cyclometallatedcomplexesdescribed,thosederivedfromoptically
pure ligands[26–41] have attracted additional interest, since they
can be used for the resolution of mono- or bidentate ligands as
well as in chiral discrimination processes. So far, most attention
on this subject has been aimed at synthesizing novel complexes
derived from a wide-ranging assortment of functionalized ligands
and we are currently focusing our efforts on the synthesis of such
compounds derived from optically pure N-donor ligands owing
to their attractive features as potential catalysts and bioactive
compounds. In this regard, we have synthesized new chiral Pd
complexes derived from enantiopure α-ketoimines, which have
shown promising anticancer activity.[42]
Along this latter line, although cisplatin and carboplatin therapy
have achieved major improvements in some forms of cancer, in
some cases remissions are of limited duration and the former
can give rise to toxic side effects. We became interested in
developing chiral α-diimines as promising carrier ligands and,
by incorporation of a variety of selected functional groups into
these carrier ligands, it is hoped that the clinical properties of
the corresponding compounds can be modified systemically. We
report herein our results concerning the preparation of the chiral
mononuclear Pd complexes 2a–b, derived from the optically pure
α-diimines 1a–b, the crystal structure of 2a and anticancer activity
of 2a–b.
∗
´
´
´
Correspondence to: Rene Gutierrez, Universidad Autonoma de Puebla, Lab.
Síntesis de Complejos, PO Box 1067, C.P. 72001, Puebla, Mexico.
E-mail: jrgutie@siu.buap.mx
´
Lab. Síntesis de Complejos. Fac. Ciencias Químicas, Universidad Autonoma de
Puebla, PO Box 1067, C.P. 72001, Puebla, Pue., Mexico
a
b
c
´
´
Departamento Ing. Química, Universidad Politecnica de Tlaxcala, Calle 21, no.
´
´
611, Col. La Loma Xicohtencatl, Tlaxcala, Tlax. Mexico
˜
DEP, Faculdad Ciencias Químicas, UANL Guerrero y Progreso S/N Col. Trevino
´
64570, Monterrey, N.L. Mexico
´
d
Instituto de Química-UNAM, Circuito exterior, Cd. Universitaria, Coyoacan, C.P.
´
04510, D.F., Mexico
c
Appl. Organometal. Chem. 2010, 24, 8–11
Copyright ꢀ 2009 John Wiley & Sons, Ltd.

New palladacycles derived from chiral α-diimines
Table 1. Summary of crystallographic results for 2a
Formula
C20H23ClN2Pd
433.25
fw
Crystal size (mm)
Color, shape
0.52 × 0.48 × 0.12
Orange plate
1.570
ρ (calc) (g cm−3
)
Space group
a (Å)
P212121
8.0580(4)
9.6843(5)
23.4813(10)
1832.39(15)
4
b (Å)
c (Å)
V (Å3)
Figure 1. Molecular structure of complex 2a with thermal ellipsoids for
non-H atoms at the 50% probability level.[44]
.
Z
µ (mm−1
)
1.162
2θ range (deg)
3.5–60.0
Table 2. Selected bond lengths (Å) and angles (deg) for 2a
Reflns coll.
5808
a
Unique reflns (Rint
)
4918 (0.035)
3983
Pd1–N8
Pd1–N11
C7–N8
1.976(3)
2.176(3)
1.494(5)
1.274(5)
1.508(6)
Pd1–C1
Pd1–Cl1
N8–C9
1.980(4)
2.3207(11)
1.283(5)
1.489(5)
Reflns with Fo > 4σ(Fo)
Transmission factors
Data/parameters
GOFa on F2
R indicesa [I > 2σ(I)]
R indicesa (all data)
Max. residence density (e Å−3
System used
0.601–0.868
4918/221
1.031
C10–N11
C9–C10
N11–C12
0.037, 0.085
0.051, 0.092
0.68, −0.78
SHELXTL-Plus[44]
N8–Pd1–C1
C1–Pd1–N11
C1–Pd1–Cl1
C9–N8–C7
83.43(14)
160.93(14)
94.94(12)
123.1(3)
N8–Pd1–N11
N8–Pd1–Cl1
N11–Pd1–Cl1
C9–N8–Pd1
77.50(12)
172.70(12)
103.93(9)
119.0(3)
)
ꢀ
ꢀ
|Fo2 − ꢁFo2ꢂ|
||Fo| − |Fc||
C7–N8–Pd1
C10–N11–Pd1
117.3(2)
C10–N11–C12
C12–N11–Pd1
121.4(3)
a Rint
=
,
R1
=
,
wR2
=
ꢀ
ꢀ
Fo2
|Fo|
111.9(3)
126.7(3)
ꢄ
ꢁ
ꢀ
ꢀ
ꢂ
ꢂ
ꢃ
w(Fo2 − Fc2)2
w(Fo2 − Fc2)2
m − n
ꢀ
, S =
w(Fo2)2
In spite of the fact that the free ligand potentially belongs to
the C2 point group, this does not coordinate in a symmetric
manner: one benzene group is bonded to the metal center,
with the expected bond length Pd1–C1 = 1.980(4) Å, while the
other is free of coordination. As a consequence, the diimino
fragment is also asymmetrically coordinated, with significantly
different Pd–N distances of 1.976(3) and 2.176(3) Å. However,
the geometry of the diimino functionality is unaffected by
coordination, with formal N8–C9 and N11–C10 localized double
bonds and a central C9–C10 σ-bond (see Table 2). The Pd(II) atom
liesalmostperfectlyintheplaneofthetwofive-memberedchelate
rings formed by the coordination. Unexpectedly, dimerization of
the mononuclear complex did not occur, although favorable
conditions were available for the formation of a centrosymmetric
dinuclear complex: the presence of chlorine, which commonly is
bonded to Pd in a (µ2-Cl)2 bridging mode, and the use of a C2
ligand containing two coordinating N atoms.[43] However, in the
present case, the formation of a dinuclear complex seems to have
been avoided because an entropic factor favored the formation
of a Pd–C bond (five-membered ring) and because of the steric
hindrance produced by the other benzene group.
(3H) corresponding to methyl groups; and finally at 1.9 and 1.5
two doublets ascribed to the methyl groups of chiral entities. The
13C NMR spectrum (300 MHz, CDCl3) displayed two signals at 174
and 171 ppm ascribed to the imine carbons; at 155–120 ppm the
signals of the phenyl groups; and at 68 and 62 ppm as well as at
22 and 20 ppm the peaks assigned to the methyne and methyl
carbons, respectively. By high-resolution mass spectrometry with
FAB ion mode technique, the molecular weight of the complex
was observed at m/z 433, suggesting a mononuclear complex.
This fact was unequivocally established by single-crystal X-ray
diffraction studies (Table 1) and the molecular structure is given
in Fig. 1. For complex 2b, almost identical spectroscopic data
were obtained (see Experimental), the only differences being the
additional signals owing to the methyl groups in the para- position
for the benzene rings of the ligand, and the distinctive features
being the position of the signals in NMR for the protons of the
chiral entities. Attempts to grow crystals of 2b suitable for X-ray
crystallography failed.
Solid-state Structure
Anticancer Results
Selected geometric parameters for complex 2a are reported in
Table 2. The asymmetric unit of the orthorhombic cell contains
one molecule with all atoms in general positions. The complex is
mononuclear, with the Pd(II) center adopting a distorted square
planar Pd[N2CCl] coordination geometry, as expected for a d8
ion. The distortion from an ideal geometry mainly arises from
the bite angle of the diimino moiety, N8–Pd1–N11 = 77.50(12)◦.
IC50 values (µM) of complexes 2a–b and cisplatin against U251
(CNS), PC-3 (prostate), K562 (leukemia), HCT-15 (colon) and MCF-7
(breast) human cancer cells are displayed in Table 3. The assays
were performed, in the case of complex 2a, with the crystalline
solid. The data show that both complexes were cytotoxic towards
the panel of cultured cell lines, mainly against U251 (CNS) and
K562 (leukemia) cancer cells, with complex 2b performing better
c
Appl. Organometal. Chem. 2010, 24, 8–11
Copyright ꢀ 2009 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/aoc

S. Cruz et al.
CDCl3): δ 7.4–7.2 (m, 10H, Ar), 4.8 (q, 2H, J = 6.6 Hz, N–CH),
2.2 (s, 6H, H3C–C N), 1.45 (d, 6H, J = 6.6 Hz, H3C–CH). 13C NMR
(300 MHz, CDCl3): δ 166.3 (C N), 146 (ArC-ipso), 128.2, 126.7, 125.6
(Ar), 60.2 (Ar–CH), 24.7 (H3C–C N), 12.6 (H3C–CH). EI-MS (m/z):
292 M+. [α25D] −80 (c = 1, HCCl3).
Table 3. IC50 (µM)a values of complexes 2a–b and cisplatin against
U251(CNS), PC-3(prostate), K562(leukemia), HCT-15(colon)andMCF-7
(breast) human cancer cells
U251
(CNS)
PC-3
K562
HCT-15
MCF-7
(breast)
Complex
(prostate) (leukemia) (colon)
2a
23.6 1.5
>100
25.4 1.3
>100
88.5 1.3
N1,N2-di[(S)-(−)-1-(4-methylphenyl)ethyl]-2,3-butanediimine 1b
2b
19.8 1.4 51.5 1.3 22.5 1.1 54.3 1.1 93.3 1.2
ND 10.5 0.05 3.1 1.2 4.6 1.2 2.52 0.6
Cisplatin
A mixture of 2,3-butanedione (0.2 g, 2.3 mmol) and (S)-(−)-1-(4-
methylphenyl)ethylamine (0.6 g, 4.6 mmol) was treated as above.
Pale yellow oil (93% yield). FT-IR νmax (film)/cm−1: 1637 (C N). 1H
NMR (400 MHz, CDCl3): δ 7.3 (d, 4H, Ar), 7.1 (d, 4H, Ar), 4.8 (q, 2H,
J = 6.6,N–CH),2.3(s,6H,CH3 –Ar),2.2(s,6H,CH3 –C N),1.4(d,6H,
J = 6.6 Hz, H3C–CH). 13C NMR (300 MHz, CDCl3): δ 173.1 (C N),
130.7 and 128.7 (ArC-ipso), 129, 126 (Ar), 60.4 (CH3 –CH), 28.0
(H3C–Ar), 21.1 (H3C–C N), 14.2 (H3C–CH). EI-MS (m/z): 320 M+.
[α25D] −87 (c = 1, HCCl3).
ND, Not determined.
a IC50 corresponds to the concentration required to inhibit a 50% of
the cell growth when the cells are exposed to the compounds during
48 h. Each value is the average of three independent experiments.
results in view of the relatively smaller amounts required in both
cell lines (IC50 = 19.8 and 22.5 µM for 2b compared with 23.6
and 25.4 µM for 2a, respectively) and, in this regard, the results of
2b with prostate and colon cell lines (IC50 = 51.5 and 54.3 µM,
respectively) are also salient when taking into account those of
complex 2a (>100 in both cases).
Palladacycle 2a
A solution of MeOH (30 ml) containing the ligand (1 mmol)
and Na2PdCl4 (300 mg, 1 mmol) was stirred for 2 h at room
temperature, and a brown precipitate was formed. The solid
was filtered and washed with hexane. The solid was crystallized
from a mixture of CH2Cl2 and EtOH (1 : 3 ratio).
Conclusion
Yield: 770 mg (94%), brown solid, m.p. 198–200 ◦C. FT-IR νmax
(KBr)/cm−1: 1672 (C NPd), 1576 (C N), 753 (Pd–C), 468 (Pd–N),
The synthesis of new chiral palladacycles along with their
characterization are reported. Also, anticancer activity has been
registered. Work is in progress with other optically pure α-diimines
to increase the scope and fine-tune the cytotoxic activity by
varying the functional groups. Applications of these compounds
in asymmetric synthesis are also being investigated.
1
334 (Pd–Cl). H NMR (400 MHz, CDCl3): δ 7.7–6.7 (m, 9H, H–Ar),
5.4 (q, 1H, HC–N), 5.1 (q, 1H, HC–N), 2.7 (s, 3H, C–CH3), 2.2
(s, 3H, C–CH3), 1.9 (d, 3H, NC–CH3), 1.5 (d, 3H, NC–CH3). 13C
NMR (300 MHz, CDCl3): δ 174.0, 171.5 (C N–Pd), 155.0–120.1
(C–Ar), 68.5, 62.2 (N–CH), 22.0, 20.5 (HCCH3). MS-positive FAB
(m/z): 433 M+. [α25D] −148 (HCCl3). Anal. calcd for C20H23N2PdCl:
C, 56.78; H, 6.71; N, 6.02. Found: C, 56.63; H, 6.67; N, 6.01.
Experimental Section
General Methods
Palladacycle 2b
1H NMR and 13C NMR spectra were recorded on a Varian
400S spectrometer, using CDCl3 as solvent and TMS as internal
reference. IR spectra were performed on a Perkin–Elmer 283 B or
1420 spectrometer. The FAB spectra were obtained on a Jeol JMS
SX 102A mass spectrometer operated at an accelerating voltage of
10 kV. Samples were desorbed from a nitrobenzyl alcohol matrix
using6 keVxenonatoms.Theelectronicimpact(EI)ionizationmass
spectra were acquired on a Jeol JMS-AX505 HA mass spectrometer
operated in the positive ion mode. The acquisition conditions
were ion source temperature 230 ◦C, ionization energy 70 eV,
emission current 0.14 µA and ionization current 100 µA. Mass
measurements in FAB were performed at 10 000 resolution using
electrical field scans, and polyethylene glycol ions were used as
the reference material. Melting points were measured using a
Mel-Temp II apparatus and are uncorrected. Elemental analyses
were recorded on a Euro EA elemental analyzer. Reagents were
obtained from commercial suppliers and used as received.
Yield: 420 mg, (91%), brown solid, m.p. 271–273 ◦C. FT-IR νmax
(KBr)/cm−1: 1607 (C NPd), 1512 (C N), 744 (Pd–C), 441 (Pd–N),
1
334 (Pd–Cl). H NMR (400 MHz, CDCl3): δ 7.6–6.6 (m, 7H, H–Ar),
5.4 (q, 1H, HC–N), 4.9 (c, 1H, HC–N), 2.3 (s, 3H, Ar–CH3), 2.2
(s, 3H, Ar–CH3), 2.2 (s, 3H, N C–CH3), 2.1 (s, 3H, N C–CH3),
1.9 (d, 3H, HC–CH3), 1.48 (d, 3H, HC–CH3). 13C NMR (300 MHz,
CDCl3): δ 179.0, 174.7 (C N–Pd), 136.3–120.0 (C–Ar), 69.2, 62.3
(N–CH), 24.7 (Ar–CH3), 21.1, 21.0 (N C–CH3), 18.3 (HCCH3). MS-
positive FAB (m/z): 460 M+. [α25D] −270 (HCCl3). Anal. calcd for
C22H29N2PdCl: C, 58.42; H, 7.15; N, 5.68. Found: C, 58.39; H, 7.14; N,
5.64.
Crystallographic Study
Single crystals suitable for X-ray structure determination of 2a
were obtained by slow evaporation and were handled in a non-
controlled atmosphere. A summary of crystallographic results is
presented in Table 1. Diffraction data were collected at 300 K on
a Bruker P4 diffractometer, using graphite monochromatized Mo-
Kα radiation (λ = 0.71073 Å), following a standard procedure.[45]
Absorption effects were corrected using 12 ψ-scans. The structure
was solved by direct methods and completed with difference
Fourier maps.[44] Non-H atoms were refined anisotropically us-
ing full-matrix least squares, without constraints or restraints on
the geometry, using an appropriate weighting scheme in the
N1,N2-di[(S)-(−)-1-phenylethyl]-2,3-butanediimine 1a
A mixture of 2,3-butanedione (0.2 g, 2.3 mmol) and (S)-(−)-1-
phenylethylamine (0.55 g, 4.6 mmol) was heated under focused-
microwave irradiation in solvent-free conditions for 5 min. After
cooling, the oily product was diluted with CH2Cl2, washed three
times with water, and dried with sodium sulfate. Pale yellow oil
(97% yield). FT-IR νmax (film)/cm−1: 1637 (C N). 1H NMR (400 MHz,
c
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Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2010, 24, 8–11

New palladacycles derived from chiral α-diimines
last cycles. H atoms were placed in idealized positions and re-
fined using a riding model with fixed isotropic displacement
parameters. The configurations of the chiral centers S-C7 and
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Colon cancer (HCT-15), breast cancer (MCF-7), leukemia (K-562
CML), central nervous system (U-251 Glio) and prostate cancer
(PC-3) cell lines were supplied by the National Cancer Institute
(USA). Cytotoxicity of the tumors cells with the test compounds
was determined using the protein-binding dye sulforhodamine
B (SRB) in microculture assay to measure cell viability and cell
growth., as described in Monks et al.[47] The cell lines were
cultured in RPMI-1640 supplemented with 10% fetal bovine
serum, 2 mM L-glutamine, 100 IU ml−1 penicillin G, 100 µg ml−1
streptomycin sulfate and 0.25 µg ml−1 amphotericin B (Gibco).
They were maintained at 37 ◦C in a 5% CO2 atmosphere with
95% humidity. For the assay, cells were detached with 0.1%
trypsin-EDTA to make single-cell suspension, and viable cells were
counted using a hematocytometer and diluted with medium to
give5×104 cells ml−1 (K562, MCF-7), 7.5×104 cellsperwell(U251,
PC-3) and 10 × 104 cells per well (HCT-15). In 96-well microtiter
plates, 100 µl per well of these cell suspensions were seeded and
incubated to allow for cell attachment. After 24 h the cells were
treated with logarithmic concentrations of the test products and
the positive control, doxorubicin. They were initially dissolved in
DMSO (40 mM) and further diluted in medium to produce five
concentration test solutions (100, 31, 10, 3.1 and 1 µM). Aliquots
of 100 µl of each test solution with the compound for evaluation
were added to each well. After 48 h, adherent cell cultures were
fixed in situ by adding 50 µl of cold 50% (w/v) trichloacetic acid
(TCA) and incubated for 60 min at 4 ◦C. The supernatant was
discarded and the plates were washed three times with water and
air-dried. Cultured fixed with TCA were stained for 30 min with
100 µl of SRB solution (0.4% w/v in 1% acetic acid). Unbound
SRB was removed by four washes with 1% acetic acid and
protein-bound dye was extracted with 10 mM unbuffered tris
base (tris[hydroxymetryl] aminomethane); the optical densities
were read on an automated spectrophotometric plate reader at
a single wavelength of 515 nm. The IC50 (concentrations required
to inhibit cell growth by 50%) was calculated according to the
protocol previously established.[47] Mean and standard error (SE)
of three independent experiments are reported for each selected
concentration of the studied compound.
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