New zinc(II), palladium(II) and platinum(II) complexes of dl-piperidine-2-carboxylic acid; X-ray crystal structure of trans-[Zn 2(μ-Ca)2(Hpa)2Cl6] and anticancer activity of some complexes

Article abstract of DOI:10.1016/j.molstruc.2012.09.045

New complexes of dl-piperidine-2-carboxylic acid (dl-H₂pa), [Zn(Hpa)(AcO)(H₂O)₂], trans-[Zn₂(μ-Ca) ₂(Hpa)₂Cl₆], [M(bpy)(Hpa)]Cl and [M(pa)(PPh₃)₂] (M(II) = Pd, Pt) have been prepared and characterized on the basis of elemental analyses, molar conductivity and thermal measurements, IR, Raman, UV-Vis, NMR (¹H and ³¹P) and mass spectroscopy. dl-Piperidine-2-carboxylic acids act as bidentate ligands, through the carboxyl oxygen and cyclic nitrogen atoms. The crystal structure of trans-[Zn₂(μ-Ca)₂(Hpa)₂Cl₆], obtained from the addition of ZnCl₂ to dl-H₂pa in either hard tap water or presence of CaCl₂, has been determined by X-ray diffraction. It crystallizes in a triclinic lattice with space group symmetry P1. The complex has two zinc atoms in tetrahedral geometry, each ligated by a carboxyl oxygen and three chlorine atoms. The other carboxyl oxygen atoms from the two Hpa^- ligands are bridged by two calcium atoms, i.e., there are two Zn(Hpa^-)Cl₃ units bridged by two calcium atoms. The free dl-H₂pa and its complexes, trans-[Zn₂(μ-Ca) ₂(Hpa)₂Cl₆], [Pd(bpy)(Hpa)]Cl and [M(pa)(PPh₃)₂] (M(II) = Pd, Pt) have been tested against the serous ovarian cancer ascites, OV 90 cell line.

Full text of DOI:10.1016/j.molstruc.2012.09.045

Journal of Molecular Structure 1036 (2013) 161–167
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
New zinc(II), palladium(II) and platinum(II) complexes of DL-piperidine-2-carboxylic
acid; X-ray crystal structure of trans-[Zn2(l-Ca)2(Hpa)2Cl6] and anticancer activity
of some complexes
Afaf A. Alie El-Deen a, Abd El-Monem E. El-Askalany a, Ruba Halaoui b, Bertrand J. Jean-Claude b,
Ian S. Butler c, Sahar I. Mostafa a,
⇑
a Chemistry Department, Faculty of Science, Mansoura University, Egypt
b Royal Victoria Hospital, Department of Medicine, Montreal, QC, Canada H3A 1A1
c Department of Chemistry, McGill University, Montreal, QC, Canada H3A 2K6
h i g h l i g h t s
"
"
"
We prepared and characterized new complexes of DL-piperidine-2-carboxylic acid (H2pa).
The addition of ZnCl2 to DL-H2pa in either hard tap water or in presence of CaCl2, obtained trans-[Zn2(m-Ca)2(Hpa)2Cl6].
The X-ray structure of trans-[Zn2(m-Ca)2(Hpa)2Cl6] shows two Zn(Hpa-)Cl3 units (each zinc atom ligates by carboxyl oxygen and three chlorine atoms)
bridged by two calcium atoms.
"
"
The free DL-H2pa and its complexes, trans-[Zn2(m-Ca)2(Hpa)2Cl6], [Pd(bpy)(Hpa)]Cl and [M(pa)(PPh3)2] (M(II) = Pd, Pt) have been tested against the
serous ovarian cancer ascites, OV90 cell line in comparison to cis-platin.
[Pt(PPh3)2(pa)] exhibits the highest growth inhibitory activity with mean IC50 43.13 lM.
a r t i c l e i n f o
a b s t r a c t
Article history:
New complexes of DL-piperidine-2-carboxylic acid (DL-H2pa), [Zn(Hpa)(AcO)(H2O)2], trans-[Zn2(l-Ca)2(-
Received 20 June 2012
Received in revised form 14 September
2012
Accepted 17 September 2012
Available online 26 September 2012
Hpa)2Cl6], [M(bpy)(Hpa)]Cl and [M(pa)(PPh3)2] (M(II) = Pd, Pt) have been prepared and characterized
on the basis of elemental analyses, molar conductivity and thermal measurements, IR, Raman, UV–Vis,
NMR (1H and 31P) and mass spectroscopy. DL-Piperidine-2-carboxylic acids act as bidentate ligands,
through the carboxyl oxygen and cyclic nitrogen atoms. The crystal structure of trans-[Zn2(l-Ca)2(Hpa)2-
Cl6], obtained from the addition of ZnCl2 to DL-H2pa in either hard tap water or presence of CaCl2, has been
determined by X-ray diffraction. It crystallizes in a triclinic lattice with space group symmetry P1. The
complex has two zinc atoms in tetrahedral geometry, each ligated by a carboxyl oxygen and three chlo-
rine atoms. The other carboxyl oxygen atoms from the two HpaÀ ligands are bridged by two calcium
atoms, i.e., there are two Zn(HpaÀ)Cl3 units bridged by two calcium atoms. The free DL-H2pa and its com-
Keywords:
Palladium
Zinc
DL-piperidine-2-carboxylic acid
Platinum
plexes, trans-[Zn2(
l-Ca)2(Hpa)2Cl6], [Pd(bpy)(Hpa)]Cl and [M(pa)(PPh3)2] (M(II) = Pd, Pt) have been tested
Anticancer
against the serous ovarian cancer ascites, OV 90 cell line.
Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction
Inomata et al. [4–6] have reported number of complexes with
piperidine-2-carboxylic acid (pipe-2), piperidine-3-carboxylic acid
(pipe-3) and piperidine-4-carboxylic acid (pipe-4). Also, the X-ray
crystal structures of the complexes, [Cu(pipe-2)2(H2O)2] [7], [CdCl2(-
Piperidine-2-carboxylic acid is known as a pharmaceutically ac-
tive compound [1]. The spectral data support its presence in a
Zwitterionic form, similar to common amino acids [2]. Over the
past few years, our laboratory has been actively involved in the
synthesis of various transition metal complexes of piperidine-2-
carboxylic acid [3]. Some of these complexes have been evaluated
as anticancer agents against Ehrlich ascites tumor cells (EACs) [3].
D-Hpipe-2)(H2O)]–[CdCl2(L-Hpipe-2)(H2O)], have been published [4].
In continuation of our search for potent active anticancer com-
plexes, it was considered worthwhile to synthesize new complexes
of DL-piperidine-2-carboxylic acid (DL-H2pa) with Zn(II), Pd(II) and
Pt(II). The structure of the resulting complexes have been investi-
gated on the basis of elemental analyses and spectral (IR, Raman,
UV–Vis, 1HNMR, mass), thermal and molar conductivity measure-
⇑
Corresponding author. Tel.: +20 100 8502625; fax: +20 50 2246781.
E-mail address: sihmostafa@yahoo.com (S.I. Mostafa).
ments. The X-ray crystal structure of trans-[Zn2(l-Ca)2(Hpa)2Cl6]
0022-2860/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2012.09.045

162
A.A. Alie El-Deen et al. / Journal of Molecular Structure 1036 (2013) 161–167
have been also determined. The anticancer activity of DL-H2pa and
its complexes, trans-[Zn2( -Ca)2(Hpa)2Cl6], [Pd(bpy)(Hpa)]Cl and
13.20 (s, 1H, NH), ESI-MS: m/z, 386.0 [Zn(Hpa)(AcO)(H2O)2]+;
256.0 [Zn(Hpa)(AcO)]+; 194.0 [Zn(Hpa)]+; 178.0 [Zn(HpaAO)]+.
l
[M(pa)(PPh3)2] (M(II) = Pd, Pt) have been tested against the serous
ovarian cancer ascites, OV 90 cell line.
2.3.2. Trans-[Zn2(l-Ca)2(Hpa)2Cl6]Á1/3H2O
An aqueous solution of zinc chloride (0.136 g, 1 mmol; 15 mL)
was added to an aqueous solution of DL-H2pa (0.129 g, 1 mmol;
15 mL). The resulting solution was stirred with gentle heating for
5 h. Upon reducing the volume, white crystals separated out. These
were filtered off, washed with water and dried in vacuo. Yield: 65%.
Anal. Calcd. for C12Cl6H18.6N2O4.3Ca2Zn2: C, 21.0; Ca, 11.7; Cl, 31.0;
H, 3.0; N, 4.1; Zn, 19.1%, Found: C, 21.2; Ca, 11.8; H, 2.9; N, 3.9; Cl,
31.3; Zn, 19.3%. (The calcium content present in this complex
comes from using hard water by mistake.) Conductivity data
2. Experimental
2.1. Materials and measurements
All reagents and solvents were purchased from Alfa/Aesar and
all manipulations were performed under aerobic conditions using
materials and solvents as received. [M(PPh3)2Cl2] and [M(bpy)Cl2]
(M(II) = Pd, Pt) were prepared by the literature methods [8,9].
DMSO-d6 was used for the NMR measurements, which were refer-
enced against TMS.
The human serous ovarian cancer ascites, OV 90 cell line was
obtained from the American Type Culture Collection (ATCC catalog
number). Cells were maintained in Dulbecco’s Modified Eagle Med-
ium (Wisent Inc., St-Bruno, Canada) supplemented with 10% FBS,
(10À3
as(COOÀ) 1733, 1633;
1548;
(ZnAO) 510 cmÀ1
1440; d(NH) 1545; (ZnAO) 517;
(d6-DMSO/TMS, ppm), d: 3.50 (d, H, H
M
in DMF): KM = 3.0 ohmÀ1
s(COOÀ) 1378;
Raman:
as(COOÀ) 1734; s(COOÀ)
,
(ZnACl) 375 cmÀ1 1HNMR
. ) m(NH) 3156;
IR (cmÀ1
m
m
m(CAO) 1310; d(NH)
m
.
m
m
m
m
a
); 2.50 (m, 2H, Hb); 2.04
(m, 2H, Hc); 1.43 (m, 2H, Hd); 3.25, 2.74 (m, 2H, He); 13.22 (s, 1H,
NH), ESI-MS: m/z, 339.3 [CaZn(Hpa)Cl3]+; 306.0 [CaZn(Hpa)Cl2]+;
10 mM HEPES, 2 mM L-glutamine and 100 lg/mL penicillin/strep-
tomycin (GibcoBRL, Gaithersburg, MD). In all assays cells were pla-
268.0 [CaZn(Hpa)Cl]+; 170.0 [Ca(Hpa)] +; 128.0 [(Hpa)]+.
ted 24 h before drug treatment.
2.3.3. Trans-[Zn2(l-Ca)2(Hpa)2Cl6]
2.2. Instrumentation
Calcium chloride (0.11 g, 1 mmol) in water (15 mL) was added
to an aqueous solution containing zinc chloride (0.136 g, 1 mmol)
and DL-H2pa (0.129 g, 1 mmol; 25 mL). The resulting solution was
stirred and heated gently for 5 h. Upon reducing the volume, white
crystals were separated out. They were filtered off, washed with
water and dried in vacuo. Yield: 76%. Anal. Calcd. for C12Cl6H18N2-
O4Ca2Zn2: C, 21.2; Ca, 11.8; Cl, 31.4; H, 2.7; N, 4.1; Zn, 19.3%,
Found: C, 21.1; Ca, 11.7; Cl, 31.2; H, 2.6; N, 4.0; Zn, 19.3%. Conduc-
Elemental analyses and X-ray crystallography were performed
in the Department of Chemistry, Montreal University. The crystal
structure was measured at the X-ray crystal structure unit, using
a Bruker Platform diffractometer, equipped with a Bruker MART
4 K Charger-Coupled Device (CCD) Area Detector using the pro-
gram APEX II and a Nonius Fr591 rotating anode (Copper radiation)
equipped with Montel 200 optics. The crystal-to-detector distance
was 5 cm and the data collection was carried out in 512 Â 512 pix-
el mode. The initial unit cell parameters were determined by the
least-squares fit of the angular setting of strong reflections, col-
lected by a 10.0° scan in 33 frames over three different parts of
the reciprocal space (99 frames total) and one complete sphere
of data was collected. Infrared spectra were recorded on a Nicolet
6700 Diamond ATR spectrometer in the 4000–200 cmÀ1 range. Ra-
man spectra were measured on an In-via Renishaw spectrometer
using 785-nm laser excitation. NMR spectra were recorded on
VNMRS 500-MHz spectrometer in DMSO-d6 using TMS as refer-
ence. Mass spectra, ESI-MS and EI-MS were recorded using LCQ
Duo and double-focusing MS25RFA instruments, respectively.
Electronic spectra were measured in DMF using a Hewlett–Packard
8453 spectrophotometer. Thermal analysis studies were made in
the 20–800 °C range at a heating rate of 20 °C minÀ1 using Ni and
NiCo as references, on a TA instrument TGA model Q500Analyzer
TGA-50. Molar conductivity measurements were carried out at
room temperature on a YSI Model 32 conductivity bridge.
tivity data (10À3 M in DMF): KM = 5.0 ohmÀ1. IR (cmÀ1
3155; (CAO) 1313;
as(COOÀ) 1734, 1636; s(COOÀ) 1381;
d(NH) 1550;
(ZnAO) 515 cmÀ1. Raman: as(COOÀ) 1736; s(COOÀ)
1442; d(NH) 1544; (ZnAO) 520;
(ZnACl) 379 cmÀ1 1HNMR (d6-
DMSO/TMS, ppm), d: 3.48 (d, H, H ); 2.51 (m, 2H, Hb); 2.05 (m, 2H,
) m(NH)
m
m
m
m
m
m
m
m
,
a
Hc); 1.42 (m, 2H, Hd); 3.26, 2.77 (m, 2H, He); 13.32 (s, 1H, NH), ESI-
MS: m/z, 678.8 [Ca2Zn2(Hpa)2Cl6]+; 339.7 [CaZn(Hpa)Cl3]+; 304.0
[CaZn(Hpa)Cl2]+; 269.0 [CaZn(Hpa)Cl]+; 128.0 [(Hpa)]+.
2.3.4. [Pd(Hpa)(bpy)]ClÁ2H2O
Solid [Pd(bpy)Cl2] (0.166 g, 0.5 mmol) was added to DL-H2pa
(0.064 g, 0.5 mmol) in ethanol (8 mL) containing triethyl amine
(0.05 g, 0.5 mmol). The mixture was stirred for 72 h. The yellow-
beige precipitate was filtered off, washed with ethanol and air-
dried. Yield: 45%. Anal. Calcd. for C16ClH22N3O4Pd: C, 41.6; H, 4.8;
N, 9.1; Cl, 7.7; Pd, 23.0%, Found: C, 41.5; H, 4.4; N, 9.0; Cl, 7.6;
Pd, 23.1%. Conductivity data (10À3 M in DMF):KM = 97.0 ohmÀ1
.
IR (cmÀ1):
521;
(PdAN) 471 cmÀ1. Raman:
d(NH) 1560; (PdAO) 529;
DMSO/TMS, ppm), 3.73 (d, H, H
m
(NH) 3106;
m
as(COOÀ) 1659;
m
s(COOÀ) 1411;
m
(PdAO)
m
m
as(COOÀ) 1598;
m
;
s(COOÀ) 1402;
1HNMR (d6-
m
m
(PdAN) 450 cmÀ1
2.3. Preparations
a
); 2.50 (m, 2H, Hb); 2.07 (m, 2H,
Hc); 1.30 (m, 2H, Hd); 3.45, 3.10 (m, 2H, He); 13.19 (s, H, NH),
2.3.1. [Zn(Hpa)(AcO)(H2O)2]
ESI-MS: m/z, 816.7 {Pd(Hpa)(bpy)]2Cl}+, 780.7 {[Pd(bpy)(Hpa)]2}+,
Zinc acetate (0.054 g, 0.25 mmol) in methanol (10 mL) was
added to DL-H2pa (0.032 g, 0.25 mmol) in methanol (10 mL). The
reaction mixture was stirred for 4 h. Upon reducing the volume,
a white precipitate was obtained, which was filtered off, washed
with methanol and air-dried. Yield: 80%. Anal. Calcd. for C8H17NO6-
Zn: C, 33.3; H, 5.9; N, 4.9; Zn, 22.7%, Found: C, 33.2, H, 5.8; N, 5.0;
Zn, 22.5%. Conductivity data (10À3 M in DMF): KM = 10.0 ohmÀ1. IR
390.0 [Pd(bpy)(Hpa)]+, 263.0 [Pd(bpy)]+.
2.3.5. [Pt(Hpa)(bpy)]Cl
Solid [Pt(bpy)Cl2] (0.211 g, 0.5 mmol) was added to DL-H2pa
(0.064 g, 0.5 mmol) in methanol (10 mL) containing KOH
(0.028 g, 0.5 mmol). The mixture was stirred for 72 h, upon which
a yellow precipitate was obtained. It was separated out, washed
with methanol and air-dried. Yield: 70%. Anal. Calcd. for C16ClH18-
N3O2Pt: C, 37.3; H, 3.5; N, 8.2; Cl, 6.9%, Found: C, 37.4, H, 3.4 N, 8.4;
Cl, 6.8%. Conductivity data (10À3 M in DMF): KM = 91.0 ohmÀ1. IR
(cmÀ1
)
m
(NH) 3125;
(ZnAO) 510;
(ZnAN) 470 cmÀ1
s(COOÀ) 1410; d(NH) 1540;
(ZnAO) 532;
m
as(COOÀ) 1625;
m
s(COOÀ) 1369; d(NH) 1560;
Raman:
as(COOÀ) 1632;
(ZnAN) 410 cmÀ1
); 2.48 (m, 2H,
); 1.44 (m, 2H, Hd); 3.21, 2.70 (m, 2H, H );
m
m
m
.
m
m
m
;
1HNMR (d6-DMSO/TMS, ppm), d: 3.41 (d, 2H, H
a
(cmÀ1):
m
(NH) 3106;
m
as(COOÀ) 1659;
m
s(COOÀ) 1419;
m
(PdAO)
Hb); 2.03 (m, 2H, H
c
e
521;
m
(PdAN) 471 cmÀ1
;
Raman: m
m
as(COOÀ) 1608; s(COOÀ)

A.A. Alie El-Deen et al. / Journal of Molecular Structure 1036 (2013) 161–167
163
1420; d(NH) 1558;
(d6-DMSO/TMS, ppm), 3.73 (d, H, H
m
(PtAO) 512;
m
(Pt-N) 400 cmÀ1 cmÀ1
;
1HNMR
β
O
a
); 2.35 (m, 2H, Hb); 2.04 (m,
γ
C
2H, Hc); 1.62 (m, 2H, Hd); 3.54 (m, 2H, He); 13.10 (s, H, NH),
α
ESI-MS: m/z, 465.0 [Pt(Hpa-1/2N2)(bpy)]+, 419.0 [Pt(bpy)(Hpa-
δ
H2CO2N)]+, 379.0 [Pt(bpy)(Hpa–Hpa-H6C4O2N)]+.
OH
N
ε
2.3.6. [Pd(PPh3)2(pa)]
H
A suspension of [Pd(PPh3)2Cl2] (0.175 g, 0.25 mmol) in CH2Cl2
(15 mL) was added to DL-H2pa (0.032 g, 0.25 mmol). The reaction
mixture was stirred under reflux for 48 h. The yellow precipitate
was filtered off, washed with CH2Cl2 and air-dried. Yield: 50%. Anal.
Calcd. for C42H37NO2P2Pd: C, 66.5; H, 5.1; N, 1.9; Pd, 14.0%, Found:
C, 66.2; H, 4.9; N, 1.8; Pd, 13.8%. Conductivity data (10À3 M in
Fig. 1. Structure of H2pa.
In addition, white crystals of the same complex, trans-[Zn2(l-
Ca)2(Hpa)2Cl6] were obtained from the addition of CaCl2 to a mix-
ture of ZnCl2 and DL-H2pa in distilled water. These crystals were
mounted on the diffractometer and the unit cell dimensions and
intensity data were measured at 150 K. The structure was solved
by least-squares fit of the angular setting of strong reflections
based on F2. The relevant crystal data and experimental conditions
along with the final parameters are summarized in Table 1.
DMF): KM = 6.0 ohmÀ1
.
IR (cmÀ1):
(PdAO) 514 cmÀ1
Raman:
(PdAO) 523; (PdAN) 431;
m
m
as(COOÀ) 1653;
as(COOÀ) 1640;
(PdAP) 392 cmÀ1
m
m
s(COOÀ)
s(COOÀ)
1HNMR
1409;
1440;
m
m
;
m
m
;
(d6-DMSO/TMS, ppm), 1HNMR (d6-DMSO/TMS, ppm), d 3.41 (d,
H, H
a
); 2.48 (m, 2H, Hb); 2.03 (m, 2H, H
c
); 1.44 (m, 2H, Hd);
3.21, 2.70 (m, 2H, H
e
), ESI-MS (m/z): 758.0 [Pd(pa)(PPh3)2]+,
631.0 [Pd(PPh3)2]+.
3.1. Vibrational spectra
2.3.7. [Pt(pa)(PPh3)2]ÁCH2Cl2
A similar procedure as for the [Pd(PPh3)2(Hpa)]Cl was applied in
using [Pt(PPh3)2Cl2] (0.197 g, 0.25 mmol) and bright yellow precip-
itate was obtained. Yield: 70%. Anal. Calcd. for C43Cl2H41NO2P2Pt: C,
55.4; Cl, 3.8; H, 4.4; N, 1.5%, Found: C, 56.0; Cl, 3.6; H, 4.8; N, 1.4%.
Conductivity data (10À3 M in DMF): KM = 9.0 ohmÀ1. IR (cmÀ1):
The characteristic IR and Raman bands and vibrational assign-
ments observed for DL-piperidine-2-carboxylic acid (DL-H2pa) com-
plexes are reported in the experimental section. The spectral data
of DL-H2pa support its Zwitterionic form, similar to common amino
acids (Scheme 1) [3,13]. This conclusion is supported by the pres-
m
m
m
as(COOÀ) 1646;
as(COOÀ) 1584;
m
m
s(COOÀ) 1384;
s(COOÀ) 1340;
m
(PtAO) 509 cmÀ1
(PtAO) 537; (PtAN) 447;
; Raman:
ence of the mas(COO) and ma(COO) stretching modes at 1617 and
m
m
1397 cmÀ1, respectively [3,13]. The nature of the coordination of
the carboxylate groups have been classified on the basis of the dif-
(PtAP) 390 cmÀ1 1HNMR (d6-DMSO/TMS, ppm), d 3.43 (d, H,
Ha); 2.50 (m, 2H, Hb); 2.09 (m, 2H, Hc); 1.46 (m, 2H, Hd); 3.54
ference (
[3,13–16]. In monodentate complexes, the (
greater than those in the ionic complexes. In chelating complexes
D
m) in the positions of the
m
as(COO) and
ms(COO) bands
(m, 2H,
He
), ESI-MS (m/z): 847.0 [Pt(pa)(PPh3)3]+ 719.0
,
D
m
) values are much
[Pt(PPh3)2]+, 457.0 [Pt(PPh3)]+.
the (
the (
D
D
m
) values are significantly lower than the ionic values; and
2.4. Biological assay
m) values for bridging complexes are greater than those of
chelating (bidentate) complexes, and close to the ionic values.
In the reported complexes, the separation between the two
Growth inhibition assay; ovarian cancer ascites, OV 90 cells
were plated at 3000 cells/well in 96-well (100 lL/well) flat-bot-
tomed microliter plates (Costar, Corning, NY). After 24 h incuba-
tion, the cells were exposed to different concentrations of each
compound continuously for 5 days. Briefly, following drug treat-
vibrational bands
{
D
m
=
m
as(COOÀ) À
m
s(COOÀ) > 220 cmÀ1
}
is
Table 1
ment, the cells were fixed using 50 lL of cold trichloroacetic acid
Crystal data and structure refinement for C6H10CaCl3NO2Zn (using hard water).
(50%) for 2 h at 4 °C, washed with water, stained with sulforhoda-
mine B (SRB 0.4%) overnight at room temperature, rinsed with 1%
acetic acid and allowed to dry overnight [10]. The resulting colored
Empirical formula
Formula weight
Temperature
C6H10CaCl3NO2Zn
339.95
150 K
Wavelength
Crystal system
Space group
1.54178 Å
Triclinic
P1
a = 7.5291(10) Å a = 87.489(6)°
b = 7.7410(10) Å b = 77.799(7)°
residue was dissolved in 200 lL Tris base (10 mM, pH 10.0) and
optical density was recorded at 490 nm using a microplate reader
ELx808 (BioTek Instruments). The results were analyzed by Graph-
Pad Prism (GraphPad Software, Inc., San Diego, CA) and the sigmoi-
dal dose response curve was used to determine 50% cell growth
inhibitory concentration (IC50). Each point represents the average
of two independent experiments performed in triplicate [10].
Unit cell dimensions
c = 10.8126(14) Å
615.09(14) Å3
2
c = 87.794(8)°
Volume
Z
Density (calculated)
Absorption coefficient
F(000)
Crystal size
Theta range for data collection
Index ranges
Reflections collected
Independent reflections
Absorption correction
Max. and min. transmission
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2sigma(I)]
R indices (all data)
Largest diff. peak and hole
1.835 g/cm3
12.238 mmÀ1
340
3. Results and discussion
0.06 Â 0.04 Â 0.02 mm
5.72–69.95°
The experimental section described the synthesis of new com-
plexes of Zn(II), Pd(II) and Pt(II) with DL-piperidine-2-carboxylic
À8 6 h 6 6, –8 6 k 6 9, À13 6 ‘ 6 13
7665
2202 [Rint = 0.067]
(DL-H2pa; Fig. 1). The elemental analyses of the complexes are in
Semi-empirical from equivalents
0.7829 and 0.5324
excellent agreement with the assigned formulae. The molar con-
ductivities (KM) in DMF at room temperature suggest all com-
plexes to be non-electrolytes except for, [M(bpy)(Hpa)]Cl
(M(II) = Pd, Pt), which appear to be 1:1 electrolytes [11,12].
White sheets, suitable for X-ray crystallography, of trans-
Full-matrix least-squares on F2
2202/0/131
1.091
R1 = 0.0684, wR2 = 0.1988
R1 = 0.0731, wR2 = 0.2032
1.092 and À0.890 e/Å3
[Zn2(l-Ca)2(Hpa)2Cl6] were obtained from the addition of ZnCl2
to DL-H2pa in hard tap water used by mistake in the preparation.

164
A.A. Alie El-Deen et al. / Journal of Molecular Structure 1036 (2013) 161–167
Scheme 1. Zwitter-ionic form of H2pa.
greater than that of the free DL-H2pa, indicating monodentate coor-
dination of the carboxylate group [3,16,17]. Moreover, the carbonyl
oxygen does not play any role in coordination, as no bands near
1700 cmÀ1 are observed [18]. The bands at 3140 and 1570 cmÀ1
N
Ph3P
Ph3P
arise from
m(NH) and d(NH) vibrations, respectively and, as
Pt
expected, these bands are shifted to lower wavenumber upon
complex formation [3,4,15]. Raman and IR spectral data suggest
N,O-mononegative bidentate coordination of DL-piperidine-2-
carboxylate anion (HpaÀ) (Fig. 2), except in case of trans-[Zn2
C
O
O
Fig. 3. Structure of [Pt(pa)(PPh3)2].
(
l
-Ca)2(Hpa)2Cl6] and [M(PPh3)2(pa)] (M(II) = Pd, Pt) complexes
(Fig. 3). In the complexes, [M(PPh3)2(pa)] (M(II) = Pd, Pt), bands
at 3140 and 1570 cmÀ1 in the free ligand due to
(NH) and d(NH)
stretches are missing, while that arising from (CAN) is shifted
m
m
two Ca(II) ions seem to connect two carboxylato oxygen atoms in
a bridging manner. The IR and Raman spectra show strong bands
to lower wavenumber [19,20]. The same feature have been re-
ported in the X-ray crystal structures of [Au(Gly–Gly–His-HÀ2)]Cl
and [Pd(Gly–Gly–His-HÀ2)], in which the terminal NH2 and two
deprotonated amide nitrogens are involved in coordination. More-
over, the potentiometric measurements of Pd(II) against Gly–Gly–
His peptide support the deprotonation of pyrrole nitrogen center at
pKa 8.63, which further confirmed by 1HNMR spectroscopy [21].
These observations support the coordination of pa2À via the depro-
tonated carboxylato oxygen and deprotonated cyclic nitrogen cen-
ters in a binegative manner.
near 1735 cmÀ1 that may be assigned to
m(C@O) stretches, indicat-
ing that the ligand is linked via its carbonyl oxygen atom to Zn(II)
[5,6,18]. This conclusion is further supported by the results ob-
tained from the X-ray diffraction. The same behavior has been ob-
served for [CdCl2(Hpipe-3)] (Hpipe-3 = piperidine-3-carboxylic
acid) [22].
As expected, the presence of coordinated PPh3 in the
[M(PPh3)2(pa)] (M(II) = Pd, Pt) complexes is indicated by strong
bands near 1100 and 755 cmÀ1 due to
m(PAC) and d(CCH) vibra-
tions, respectively [23,24]. Also, the IR bands near 840, 750 and
725 cmÀ1 in the [M(bpy)(Hpa)]Cl (M(II) = Pd, Pt) complexes, are
due to bpy stretching vibrations [25]. These bands are at higher
wavenumbers compared with those for the free bpy ligand indicat-
ing the coordination to the central metal ions [26].
On the other hand, the dimeric complex, trans-[Zn2(
l-Ca)2
(Hpa)2Cl6], illustrates two coordination manners of HpaÀ, since
the
D
m
value is slightly smaller than that of free H2pa, i.e., the
H2O
Finally, the Raman spectra of the complexes show several bands
near 500, 420 and 281 cmÀ1 attributable to
m(MAO), m(MAN) and
H
N
m
(ZnACl) stretches, respectively [3,5,6,23].
O
Zn
H3C
3.2. NMR spectra
C
O
O
O
The 1HNMR spectra of the reported complexes provide some
information on the coordination mode and chelate ring conforma-
H2O
tion that DL-H2pa ligand adopts. The 1HNMR data for the free DL
-
H2pa ligand and some of its complexes in DMSO-d6 are given in
the experimental section; they are in a good agreement with pre-
viously reported data [3]. On coordination of NH and COOÀ groups,
(a)
the protons attached to carbon atoms (Ca) become more deshield-
O
O
ed than the NH in the Zwitterion because of the donation of elec-
tron pairs to the metal ion [3]. In the 1HNMR spectra of the
complexes, the proton bound to the nitrogen atom (NH) is clearly
shown as a broad signal at d13.10–13.22 ppm. The two doublets at
C
N
N
H
Pd
Cl
d 3.41–3.73 ppm region are assigned to H
3.54 ppm which appear as two multiplets overlapped by two
quartets, respectively, are due to the two H protons. The multi-
plets at d2.35–2.51, 2.03–2.09 and 1.30–1.62 ppm region are attrib-
uted to the Hb, H , Hd protons, respectively. The upfield shift of the
NH and H signals compared to that in the free ligand (Zwitterion)
a, while those at d 3.20–
N
e
c
a
supports the coordination of DL-H2pa to the metal ion through the
NH and carboxylate oxygen centers [3,27,28]. In the 1HNMR spec-
tra of, the [M(PPh3)2(pa)] (M(II) = Pd, Pt) complexes, the NH proton
signal is missing supporting the coordination of pa2À through the
(b)
Fig. 2. Structures of [Zn(Hpa)(AcO)(H2O)2] (a) and [Pd(Hpa)(bpy)]Cl (b).

A.A. Alie El-Deen et al. / Journal of Molecular Structure 1036 (2013) 161–167
165
deprotonated cyclic nitrogen and the deprotonated carboxylate
oxygen atoms [21].
(TG) technique. The complexes, [Zn(Hpa)(AcO)(H2O)2] and
[Zn2(
-Ca)2(Hpa)2Cl6]Á1/3H2O show endothermic behavior with
l
The 1HNMR spectra of the [M(bpy)(Hpa)]Cl and [M(PPh3)2(pa)]
(M(II) = Pd, Pt) complexes show complicated multiplets in the d
7.6–8.4 and 7.2–7.8 ppm regions, which are assigned to bpy and
PPh3 protons, respectively. The bpy and PPh3 protons show upfield
shifts in comparison to those of [M(bpy)Cl2] and [M(PPh3)Cl2]. This
observation is interpreted in terms of strong binding of HpaÀ or
paÀ2 to M(II) as compared to binding of chloride ion [3,27].
The 31PNMR spectra of the [M(PPh3)2(pa)] (M(II) = Pd, Pt) com-
plexes in DMSO-d6 display two sharp signals near d 14.15 and
16.00 ppm, indicating the presence of the two PPh3 groups in a
cis-configuration [29].
mass losses between 190 and 290 °C, and 90 and 130 °C, respec-
tively [31–33]. The percentages of mass loss for the two complexes
in these decompositions are in good agreement with the values
which are calculated by assuming that initially two molecules
and then a third molecule of water are released. The dehydration
temperatures suggest that these are coordinated and hydrated
water, respectively [4,31].
The thermogram of [Zn(Hpa)(AcO)(H2O)2], shows three endo-
thermic TG inflections in the 192–294, 295–362 and 363–503 °C
regions. These weight losses may arise from the release of coordi-
nated water molecules and acetate (AcO) (Calcd. 32.9, Found 33.4),
C2H9N fragment (Calcd. 16.3, Found 17.0%) and an HCOH fragment
(Calcd. 10.0, Found 9.8%), leaving a residue of zinc oxide and car-
3.3. Electronic spectra
bide (28.25%). The thermogram of [Zn2(l-Ca)2(Hpa)2Cl6]Á1/3H2O,
The electronic spectra of the complexes were recorded in DMSO
in the 200–800 nm range. The electronic spectra of the diamag-
netic [M(bpy)(Hpa)]Cl and [M(PPh3)2(ap)] (M(II) = Pd, Pt) com-
plexes show bands near 470 and 335 nm due to 1A1g ? 1B1g and
1A1g ? 1E1g transitions in a square-planar configuration [3,19,30].
The absorption band near 375 nm is assigned to combination of
charge-transfer transitions from the M(II) d-orbital to the pÃ-orbi-
tal of bpy or PPh3 [31].
is characterized by four weight losses in the 93–128, 276–391,
392–517 and 587–796 °C regions. These weight losses are due to
the elimination of hydrated water (Calcd. 0.9, Found 0.9%) [28],
two Cl2 and 1/2N2 (Calcd. 22.7, Found 22.3%), 1/2N2 and H2 (Calcd.
2.3, Found 2.7%) and two C6H9Cl and CaO (Calcd. 42.1, Found
42.5%) fragments, respectively, leaving a mixture of CaO and two
ZnO residues at 800 °C (27.8%) [6,22]. The TG thermogram of
[Pt(bpy)(Hpa)]Cl shows the first endothermic weight loss step be-
tween 340 and 437 °C, corresponding to the release of 1/2Cl2, 1/2
N2 and HCOH fragments (Calcd. 16.8, Found 16.4%). The second
decomposition step occurs between 510 and 677 °C, this weight
loss is attributed the loss of ½ bpy and C5H10 fragments (Calcd.
28.3, Found 28.6%), leaving PtO and carbide residue representing
(52.9%). In some reported transition metal complexes, the thermal
decomposition residue is mainly metal or metal oxide, but in the
presence of non-stoichiometric oxide, unburned carbon or nitrogen
is observed [33].
The thermal decomposition of the complex [Pd(PPh3)2(pa)],
shows two TG inflections in the ranges of 184–250 and 251–
350 °C. The exothermic weight losses may arise from the release
of a fragment (Calcd. 11.2, Found 11.7%), and PPh3 and three phe-
nyl (Ph; C6H5) fragments (Calcd. 65.0, Found 65.5), respectively,
leaving a PdO residue (16.2%) [33].
The TG thermogram of the complex [Pt(pa)(PPh3)2]ÁCH2Cl2, dis-
plays three TG weight losses in the ranges 188–251 °C, 252–346
and 413–537 °C. The first exothermic weight loss may arise from
the release of dichloromethane and three Ph fragments (Calcd.
33.8, Found 33.9%). The second one is due to the loss of one P
and C6H9NO fragments (Calcd. 15.4, Found 15.5%) while the third
is indicating the loss of a PPh fragment (Calcd. 11.6, Found
12.2%), leaving a PtO residue (22.7%) [6].
3.4. Mass spectra
Mass spectra of the complexes are reported in the experimental
section and their molecular ion peaks are in agreement with their
assigned formulae. The mass spectrum of [Zn(Hpa)(AcO)(H2O)2]
shows fragmentation patterns corresponding to the successive
degradation of the complex. The first peak at m/z 286.0 with 20%
abundance represents the molecular ion (Calcd. 288.5). The peaks
at 256.0 and 194.0 correspond to [Zn(pa)(AcO)]+ and [Zn(pa)]+ frag-
ments, respectively. The mass spectrum of [Zn2(l-Ca)2(Hpa)2Cl6]
shows a peak at m/z 339.3 (Calcd. 340.0), in agreement with the
molecular ion of the complex, [ZnCa(Hpa)Cl3]+, with 7.6% abun-
dance. There are signals which represent stepwise loss of Cl frag-
ments; [ZnCa(Hpa)Cl2]+ (Calcd. 304.5), [ZnCa(Hpa)Cl]+ (Calcd.
269.0) and [Ca(Hpa)]+ (Calcd. 168.0) [3,32]. The mass spectrum of
[Pd(bpy)(Hpa)]Cl displays a signal at m/z 816.7 (Calcd. 816.3) with
100% abundance, in agreement with the dimeric molecular ion of
the complex, {[Pd(bpy)(Hpa)]2Cl}+. The fragmentation patterns
indicate formation of the fragments, {[Pd(bpy)(Hpa)]2}+ at 780.7
(Calcd. 780.8), [Pd(bpy)(Hpa)]+ at 390.0 (Calcd. 390.4) and
[Pd(bpy)]+ at 264.0 (Calcd. 262.4) [33,34].
The mass spectrum of [Pt(bpy)(Hpa)]Cl shows a signal at m/z
465.0 (Calcd. 465.0) with 100% abundance, corresponding to the
molecular ion of the complex, [Pt(bpy)(Hpa-N)]+. The spectrum
exhibits two more peaks at 419.0 and 379.0 corresponding to
[Pt(bpy)(pa-CH2NO2)]+ (Calcd. 419.0) and [Pt(bpy)(pa-C4H4NO2)]+
(Calcd. 379.0) fragments [30].
3.6. X-ray crystallography
White sheets, suitable for X-ray crystallography of trans-
[Zn2(l-Ca)2(Hpa)2Cl6], obtained from the addition of ZnCl2 to
The mass spectrum of the [Pd(PPh3)2(pa)] complex shows first
the molecular ion peak at m/z 758.0 (Calcd. 757.4) with 100% abun-
dance, in agreement with the molecular ion, [Pd (PPh3)2(pa)]+. The
fragmentation patterns indicate the loss of pa, [Pd(PPh3)2]+ at 631
(Calcd. 630.4) [8,30]. The mass spectrum of [Pt(pa)(PPh3)2] exhibits
the first signal at m/z 846.0 (Calcd. 846.0) corresponding to
[Pt(pa)(PPh3)2]+ with two more signals at 719.0 (Calcd. 719.0)
and 457.0 (Calcd. 457.0) corresponding to [Pt(PPh3)2]+ and
[Pt(PPh3)]+fragments, respectively [8,30].
H2pa in presence of CaCl2 (in distilled water) or hard tap water
(as a source of Ca2+) by mistake in the preparation. These crystals
were shown to crystallize in a triclinic lattice with space group
symmetry P1. The crystal data and structure refinement details
for these complexes are identical and given in Table 1 (Table 1 Sup-
plementary data).
The structure of the dimeric, trans-[Zn2(l-Ca)2(Hpa)2Cl6] com-
plex with the atomic labeling is shown in Fig. 4 (X-ray obtained
from the use of CaCl2 in distilled water are present in Supplemen-
tary data). Selected bond angles (°) and bond lengths (Å) are listed
in Table 2. Each one of the two zinc(II) ion is four coordinated in
the center of tetrahedral geometry, ligated by one carbonyl oxygen
of carboxylate group and three chloride ions. The bond lengths of
ZnAO(2), ZnACl(1), ZnACl(2) and ZnACl(3) are 1.997(4),
3.5. Thermal measurements
The thermal stability and degradation behavior of some of the
reported complexes were studied using the thermogravimetric

166
A.A. Alie El-Deen et al. / Journal of Molecular Structure 1036 (2013) 161–167
Table 2
Selected bond lenghts (Å) and bond angles (°) for C6H10CaCl3NO2Zn.
Bond lenghts (Å)
Bond angles (°)
Zn(1)AO(2)
Zn(1)ACl(3)
Zn(1)ACl(2)
Zn(1)ACl(1)
Zn(1)ACa(1)
Ca(1)AO(1)
Ca(1)AO(1)#1
Ca(1)ACl(1)#2
Ca(1)ACl(2)#3
Ca(1)ACl(3)#1
Ca(1)ACl(2)
Ca(1)ACa(1)#1
Cl(1)ACa(1)#4
Cl(2)ACa(1)#3
Cl(3)ACa(1)#1
O(1)AC(6)
O(1)ACa(1)#1
O(2)AC(6)
N(1)AC(1)
N(1)AC(2)
C(1)AC(5)
C(1)AC(6)
C(2)AC(3)
C(3)AC(4)
C(4)AC(5)
1.997(4)
O(2)AZN1ACL3
O(2)AZN1ACL2
CL3AZN1ACL2
O(2)AZN1ACL1
CL3AZN1ACL1
CL2AZN1ACL1
O(2)AZN1ACA1
CL3AZN1ACA1
CL2AZN1ACA1
119.71(14)
108.33(15)
107.67(6)
103.11(14)
108.51(6)
109.16(6)
93.05(13)
66.42(5)
60.03(4)
163.09(5)
89.34(13)
161.57(13)
85.81(10)
84.95(11)
148.57(12)
108.14(5)
69.92(11)
66.24(11)
123.46(5)
82.83(5)
129.73(11)
48.99(11)
99.75(10)
114.45(5)
99.60(4)
117.97(4)
45.13(9)
44.21(9)
127.58(6)
122.91(6)
58.33(4)
107.36(5)
70.27(4)
97.59(6)
123.34(6)
82.87(5)
101.05(5)
103.46(6)
140.7(4)
2.2672(15)
2.2745(14)
2.2768(15)
3.7414(15)
2.698(4)
2.742(4)
3.1132(19)
3.1183(18)
3.258(2)
3.2663(19)
3.869(2)
3.1132(19)
3.1183(18)
3.258(2)
1.236(7)
2.742(4)
1.268(8)
1.485(8)
1.490(8)
1.501(10)
1.516(9)
1.494(11)
1.515(11)
1.524(11)
CL1AZN1ACA1
O(1)ACA1AO(1)#1
O(1)ACA1ACL1#2
O(1)#1ACA1ACL1#2
O(1)ACA1ACL2#3
O(1)#1ACA1ACL2#3
CL1#2ACA1ACL2#3
O(1)ACA1ACL3#1
O(1)#1ACA1ACL3#1
CL1#2ACA1ACL3#1
CL2#3ACA1ACL3#1
O(1)#1ACA1ACL2
O(1)ACA1AZN1
O(1)#1ACA1AZN1
CL1#2ACA1AZN1
CL2#3ACA1AZN1
CL3#1ACA1AZN1
O(1)ACA1ACA1#1
O(1)#1ACA1ACA1#1
CL1#2ACA1ACA1#1
CL2#3ACA1ACA1#1
CL3#1ACA1-CA1#1
CL2ACA1ACA1#1
ZN1ACA1ACA1#1
ZN1ACL1ACA1#4
ZN1ACL2ACA1#3
ZN1ACL2ACA1
Fig. 4. X-ray crystal structure of trans-[Zn2(l-Ca)2(Hpa)2Cl6].
2.2768(15), 2.2745(14) and 2.2672(15) Å, similar to those of the
corresponding bonds in [M(HPA)X2] (M(II) = Zn, Cd; HPA = piperi-
dine-2-carboxylic acid, piperidine-3-carboxylic acid, piperidine-4-
carboxylic acid; X = Cl, Br) [4,6]. The bond length of C(6)AO(2),
1.268(8) Å is longer than C(6)AO(1), 1.236(7) Å, as reported for
piperidine carboxylate complexes [6]. The two ZnCl3 are trans to
each other with O(2)AZnACl(1), O(2)AZnACl(2), O(2)AZnACl(3),
Cl(1)AZnACl(2), Cl(1)AZnACl(3) and Cl(2)AZnACl(3) bite angles
of 103.11(14)°, 108.33(15)°, 119.71(14)°, 109.16(6)°, 108.51(6)°
and 107.67(6)°, respectively.
In this complex, two carboxyl oxygen atoms from two HpaÀ
groups are bridged by two calcium atoms. The structure of this
complex consists of two Zn(HpaÀ)Cl3 units bridged by two calcium
atoms. The bond lengths of Ca(1)AO(1) and Ca(2)AO(1) are
2.698(4) and 2.742(4) Å, longer than that of ZnAO(2) (1.997(4) Å).
The bond angles of O(1)ACa(1)AO(1a) and Ca(1)AO(1)ACa(1a)
are 89.34(13)° and 90.66(13)°, respectively, similar to the data ob-
served for the bromide-bridged complex [Cd(HPA)Br2] [4]. The
strong coordination of Zn(II) to the two oxygen atom O(2), com-
pared to that of Ca(II) to O(1) may be attributed to the high basicity
of O(2) compared to O(1) [4,5,35].
CA1#3ACL2ACA1
ZN1ACL3ACA1#1
C(6)AO(1)ACA1
C(6)AO(1)ACA1#1
CA1AO(1)ACA1#1
C(6)AO(2)AZN1
C(1)AN(1)AC(2)
N(1)AC(1)AC(5)
N(1)AC(1)-C(6)
125.3(4)
90.66(13)
111.4(4)
113.3(5)
110.8(5)
110.5(5)
In the crystal structure, the complex molecules form hydrogen
bonded dimers via the nitrogen, N(1), and chlorine, Cl(1), atoms
of a symmetry related molecule. Table 3 shows the bond lengths
and bond angles related to the hydrogen bonding of the dimeric
complex.
C(5)AC(1)AC(6)
N(1)AC(2)AC(3)
C(2)AC(3)AC(4)
C(3)AC(4)AC(5)
C(1)AC(5)AC(4)
O(1)AC(6)AO(2)
O(1)AC(6)AC(1)
O(2)AC(6)AC(1)
114.7(5)
111.8(5)
110.3(6)
110.7(6)
111.8(6)
124.5(6)
117.8(6)
117.6(5)
3.7. Anticancer activity
Cisplatin is considered to be one of the best known small metal-
containing drug molecules. It acts as anticancer agent for several
human cancers, particularly, testicular and ovarian cancers
[19,36]. Generally, the side effects, especially nephrotoxicity, limit
its widespread use in high doses [37]. The need to develop new
complexes with reduced nephrotoxicity and higher activity has
stimulated the synthesis of many new complexes. Over the past
years, a renewed interest in Zn(II), Pd(II) and Pt(II) complexes as
potential anticancer agents has developed in our laboratory
[3,19,30,33,36,38].
Table 3
Bond lengths (Å) and angles (°) related to the hydrogen bonding for C6H10CaCl3NO2Zn.
DAH
A
d(DAH)
d(HÁ Á ÁA)
d(DÁ Á ÁA)
<DHA
N(1)AH(1A)
CL1#5
0.90(8)
2.39(8)
3.266(5)
163(7)
Symmetry transformations used to generate equivalent atoms.
#1 Àx, Ày, Àz #2 x À 1, y, z #3 Àx, Ày + 1, Àz.
#4 x + 1, y, z #5 Àx + 1, Ày + 1, Àz.
Piperidine-2-carboxylic acid
[Pd(Hpa)(pa)]Cl, [Pd(pa)(H2O)2]Cl,
(
DL-H2pa) and its complexes
[Pd(pa)(bpy)]Cl, [Pd(pa)
cer activity of the free DL-H2pa and its complexes; trans-[Zn2(l-
Ca)2(Hpa)2Cl6], [Pd(bpy)(Hpa)]Cl and [M(pa)(PPh3)2] (M(II) = Pd,
Pt) were tested against the serous ovarian cancer ascites, OV 90 cell
line in comparison to cis-platin as a reference (Table 4). The com-
plex, [Pt(PPh3)2(pa)] exhibits the highest growth inhibitor activity
with mean IC50 value of 43.13 lM. It is generally accepted that
binding of cis-platin to genomic DNA (gDNA) in the cell nucleus
(phen)Cl] and [Pd(pa)(pyq)Cl] have been tested as growth inhibitors
against Ehrlich ascites tumor cells (EAC) in Swiss albino mice and
were found to exhibit remarkable growth inhibitor activities [3].
The goal of this study was to develop new simple and mixed li-
gand complexes of piperidine-2-carboxylic acid (containing N and
P bases) with high efficacy against cancer cells. The in vitro antican-
is the main event responsible for its antitumor properties [39].

A.A. Alie El-Deen et al. / Journal of Molecular Structure 1036 (2013) 161–167
167
Table 4
Nadim Saade (Chemistry Department, McGill University, Montreal,
Canada) for obtaining the mass spectra.
Anticancer activity of H2pa and its complexes against the
human ovarian cancer ascites, OV 90 cell line.
Compound
H2pa
trans-[Zn2(l-Ca)2(Hpa)2Cl6]
[Pd(bpy)(Hpa)]Cl
[Pd(pa)(PPh3)2]
[Pt(pa)(PPh3)2]
Cis-platin
IC50 (lM)
Appendix A. Supplementary material
>100
>100
>100
>100
43.13
31.06
CCDC numbers: CCDC of the crystals obtained are 875432 and
875433 for trans-[Zn2(l-Ca)2(Hpa)2Cl6].
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.molstruc.2012.
09.045.
Thus, the damage induced upon binding of cisplatin to gDNA may
inhibit transcription, and/or DNA replication mechanisms. Subse-
quently, these alterations in DNA processing would trigger cyto-
toxic processes that lead to cancer cell death. The activity of
[Pt(pa)(PPh3)2] complex may be due to its square-planar geometry,
chelation of pa2À in binegative (O and N) manner as well as the
nature and position of the second ligand (cis-(PPh3)2) [3,19,38].
An important property of Pt(II) complexes is the fact that Pt-ligand
bonds (PtAP, PtAN, PtAO), which have thermodynamic strength of
a typical coordination bond, is much weaker than CAC, CAN or
CAO covalent bonds. However, the ligand exchanges behavior in
Pt complexes are quite slow, which gives them high kinetic stabil-
ity. Thus, ligand exchange reactions take place in minutes to days,
rather than microsecond to second as in case of Pd(II) complexes
[40]. Also, the kinetic trans effect is responsible for ligands ex-
change reactions; i.e., donor atoms located trans to other donors
with strong trans effect are more rapidly substituted than ligands
in cis positions [40]. On the other hand, the low activity of the other
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4. Conclusions
New complexes of DL-H2pa have been prepared and character-
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DL-H2pa
and
its
complexes;
trans-[Zn2(l-Ca)2(Hpa)2Cl6],
[Pd(bpy)(Hpa)]Cl and [M(pa)(PPh3)2] (M(II) = Pd, Pt) were tested
against the human serous ovarian cancer ascites, OV 90 cell line.
The complex, [Pt(PPh3)2(pa)] exhibits the highest growth inhibi-
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Acknowledgements
We are grateful to Mr. Joel Poisson (Chemistry Department,
McGill University, Montreal Canada) for running the NMR spectra,
Dr. Kelly Akers (ProSpect Scientific inc., Ontario, Canada) and Dr.
Morgan Thomas (Saskatchewan Structural Sciences Centre, Univer-
sity of Saskatchewan) for measuring the Raman spectra, and Mr.