Part 1: Experimental and theoretical studies of 2-cyano-2-isonitroso-N- piperidynylacetamide (HPiPCO), 2-cyano-2-isonitroso-N-morpholylacetamide (HMCO) and their Pt- and Pd-complexes

Article abstract of DOI:10.1016/j.ica.2011.12.005

The reaction between substituted cyan-acetamides NC-CH₂-C(O)X (X = N-piperidyne or N-morpholyl residues) and gaseous methylnitrite CH ₃ONO in isopropanol at room temperature in the presence of a base within minutes leads to colorless cyanoximes 2-cyano-2-isonitroso-N- piperidynylacetamide (further as HPiPCO), and 2-cyano-2-isonitroso-N- morpholylacetamide (HMCO) in 70-90% yield. The deprotonation of HPiPCO and HMCO with a base such as NaOEt affords anionic Na-salts, bright-yellow in color originated from n → π^* transitions in the nitroso-chromophore. Anionic cyanoximates react with aqueous solutions of K ₂MCl₄ (M = Pd, Pt) to form yellow-orange PdL₂ and dark blue-green polymeric [PtL₂]_n (L = PiPCO ^-, MCO^-), which upon treatment with DMSO or DMF breaks down to pale-yellow monomeric PtL₂. Synthesized metal complexes were characterized by spectroscopic methods (IR, UV-Vis), measurement of the electric conductivity and the X-ray analysis. Both PdL₂ and PtL₂ exhibit non-electrolyte behavior in DMSO and DMF. Crystal structures of Pd(PiPCO)₂ and Pt(PiPCO)₂ were determined and revealed the formation of the cis-complexes with nearly planar geometry around the metal core and an adoption of the cis-anti configuration by anions, in contrast to the trans-anti geometry in structures of uncomplexed HPiPCO and HMCO. Ab initio calculations were performed for all six compounds: two cyanoxime ligands and four Pd and Pt metal complexes. A very satisfactory agreement between the calculated and experimental values of geometrical parameters of all evaluated compounds was attained. The electron densities, energies of HOMO and LUMO orbitals and molecular electrostatic potentials were calculated as well.

Full text of DOI:10.1016/j.ica.2011.12.005

Inorganica Chimica Acta 385 (2012) 1–20
Contents lists available at SciVerse ScienceDirect
Inorganica Chimica Acta
journal homepage: www.elsevier.com/locate/ica
Part 1: Experimental and theoretical studies of 2-cyano-2-isonitroso-
N-piperidynylacetamide (HPiPCO), 2-cyano-2-isonitroso-
N-morpholylacetamide (HMCO) and their Pt- and Pd-complexes
c
d
Jessica Ratcliff a, Janina Kuduk-Jaworska b, , Henryk Chojnacki , Victor Nemykin ,
⇑
Nikolay Gerasimchuk a,
⇑
a Department of Chemistry, Missouri State University, Temple Hall 431, Springfield, MO 65897, USA
b Faculty of Chemistry, Wrocław University, F. Joliot-Curie 14, 50-383 Wroclaw, Poland
c Institute of Physical and Theoretical Chemistry, Wroclaw University of Technology, Wyb. Wyspianskiego 27, 50-370 Wroclaw, Poland
d Department of Chemistry and Biochemistry, University of Minnesota, Duluth, MN 55812, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction between substituted cyan-acetamides NC–CH2–C(O)X (X = N-piperidyne or N-morpholyl
residues) and gaseous methylnitrite CH3ONO in isopropanol at room temperature in the presence of a
base within minutes leads to colorless cyanoximes 2-cyano-2-isonitroso-N-piperidynylacetamide (fur-
ther as HPiPCO), and 2-cyano-2-isonitroso-N-morpholylacetamide (HMCO) in 70–90% yield. The depro-
tonation of HPiPCO and HMCO with a base such as NaOEt affords anionic Na-salts, bright-yellow in
color originated from n ? p⁄ transitions in the nitroso-chromophore. Anionic cyanoximates react with
aqueous solutions of K2MCl4 (M = Pd, Pt) to form yellow-orange PdL2 and dark blue-green polymeric
[PtL2]n (L = PiPCOꢀ, MCOꢀ), which upon treatment with DMSO or DMF breaks down to pale-yellow mono-
meric PtL2. Synthesized metal complexes were characterized by spectroscopic methods (IR, UV–Vis),
measurement of the electric conductivity and the X-ray analysis. Both PdL2 and PtL2 exhibit non-electro-
lyte behavior in DMSO and DMF. Crystal structures of Pd(PiPCO)2 and Pt(PiPCO)2 were determined and
revealed the formation of the cis-complexes with nearly planar geometry around the metal core and
an adoption of the cis-anti configuration by anions, in contrast to the trans–anti geometry in structures
of uncomplexed HPiPCO and HMCO. Ab initio calculations were performed for all six compounds: two
cyanoxime ligands and four Pd and Pt metal complexes. A very satisfactory agreement between the cal-
culated and experimental values of geometrical parameters of all evaluated compounds was attained. The
electron densities, energies of HOMO and LUMO orbitals and molecular electrostatic potentials were cal-
culated as well.
Received 11 September 2011
Received in revised form 15 November 2011
Accepted 3 December 2011
Available online 29 December 2011
Keywords:
Cyanoximes
Synthesis
X-ray analysis
Ab initio Calculations
Ó 2011 Elsevier B.V. All rights reserved.
1. Introduction
an ability to overcome the intrinsic or acquired resistance of
cancerous cells, and lesser side effects. In contrast, there are
Although the history of successful application of platinum
complexes in oncology (the chemotherapy) began three decades
ago, the complexes of platinum(II) and platinum(IV) continue to
serve as an abundant source of cytotoxic compounds. An early hit,
cisplatin, and the follow-on drugs carboplatin and oxalilplatin, are
still among the most frequently administered anticancer drugs of
the cisplatin family. They account for the treatment of 40–80% of
all cancer patients [1]. However, there has been limited progress
in the discovery of new active members of the cisplatin drug family,
particularly those with a broader or different spectrum of activity,
significant achievements in the development of active non-classical
compounds, such as trans-platinum complexes [2], multinuclear
complexes [3], and both Pt(II) and Pt(IV) complexes with non-
traditional ligands including polypeptides [4]. In line with the idea
of further exploration of new, non-traditional platinum complexes,
a few years ago we found several cytotoxic bivalent Pd and Pt com-
plexes with deprotonated MCOꢀ and PiPCOꢀ ligands that possess
in vitro activity comparable to cisplatin [5]. These square-planar
Pd and Pt complexes represent the first examples of a new group of
active oxime-based bis-chelates. However, prior to current studies,
no high-yield preparations of Pd,Pt-cyanoximates were developed,
no direct structural information about these complexes was avail-
able, and their electronic structure was not known as well.
⇑
Corresponding authors. Tel.: +1 417 836 5165 (N. Gerasimchuk).
E-mail addresses: janina.kuduk@gmail.com (J. Kuduk-Jaworska), NNGerasimchuk@
In the first part of this work we present: (a) developed experi-
mental procedures for the synthesis of complexes; (b) data of the
MissouriState.edu (N. Gerasimchuk).
0020-1693/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.ica.2011.12.005

2
J. Ratcliff et al. / Inorganica Chimica Acta 385 (2012) 1–20
Table 1
O
O
N
N
Crystal data for the synthesized Pd(II) and Pt(II) N-piperidine-cyanoximates.
C
C
N
N
Parameter
Pd(PiPCO)2
Pt(PiPCO)2
O
N
N
Empirical formula
Formula weight
Wavelength, k, Å
Diffractometer
C16H20N6O4Pd
466.78
0.71073
C16H20N6O4Pt
555.47
0.71075
Rigaku RAXIS, image
plate
HO
HO
Bruker APEX2, CCD
HPiPCO
HMCO
Temperature, K
Crystal system
Space group
120(2)
293(2)
Scheme 1. Used cyanoximes and their common abbreviations.
Monoclinic
C 2/c (#15)
a = 18.266(2)
b = 8.5792(11)
c = 11.3612(14)
Orthorhombic
Pbca (#61)
a = 6.79700(10)
b = 17.6365(4)
c = 30.652(2)
Unit cell dimensions, Å,°
X-ray crystallographic studies of the monomeric Pd(PiPCO)2 and
Pt(PiPCO)2 complexes that we used then for in vitro cytoxicity
studies; and (c) results of our theoretical investigations of both
uncomplexed, ‘‘free’’ ligands HMCO and HPiPCO, and their respec-
tive Pd(II) and Pt(II) complexes (Scheme 1).
a
= 90
b = 92.008(2)
= 90
a
= 90
b = 90
= 90
c
c
Volume, Å3
1779.3(4)
4
1.743
1.080
944
3674.4(3)
8
2.008
76.664
Z
Density (calc.), Mg/m3
2. Experimental
Absorption coeff.,
F(000)
l
, mmꢀ1
2144
2.1. Equipment and reagents
Crystal habit, color
Crystal size, mm
2hmax,o
pale yellow plate
0.21 x 0.09 x 0.06
61.6
lemon-yellow needle
0.03 x 0.05 x 0.46
55.0
Precursors for the synthesis of HPiPCO and HMCO were cyano-
ethylacetic ester, NC–CH2–C(O)OC2H5, morpholine and piperidine
– all from Sigma Aldrich chemical company and were used as re-
ceived without additional purification. Gaseous methyl nitrite
was freshly prepared in situ during the nitrosation reaction accord-
ing to a recently published procedure [6], also described below.
Melting points were determined using open capillary tubes in a
Mel-Temp apparatus, and are uncorrected. The TLC was carried
out on silicagel plates (Merk) with a UV-indicator (254 nm) and a
mobile phase 1:2 = hexane:ethyl acetate. An elemental analysis
on C, H and N content was performed at Atlantic Microlab (Nor-
cross, Georgia). Electrical conductivity of 1 mM solutions of M(PiP-
CO)2 and M(MCO)2 (M = Pd, Pt) in an anhydrous DMSO was
measured at 296 K using the YSI Conductance–Resistance meter
Model 34. Solutions of ammonium bromide, tetrabutylammonium
bromide, and tetraphenyl-phosphonium bromide (as 1:1 electro-
lytes), and hydrazinium dichloride (as 1:2 electrolyte) were used
for the electrode calibration.
Structure Solution
Direct methods
(BRUKER APEX2
Suite)
Patterson Method
(DIRDIF99 PATTY)
Refinement
Reflections collected
Independent reflections
- Full-matrix least-squares on F2-
11947
2706
24437
4005 [R(int) = 0.039]
[R(int) = 0.0356]
semi-empirical
0.7461 and 0.6355
2706 / 0 / 123
1.062
R1 = 0.0258
wR2 = 0.0538
wR2 = 0.0575
0.556 and ꢀ0.549
Absorption correction
Lorentz polarization
0.216 and 0.102
3992 / 70 / 304
1.010
T
max. and Tmin.
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I>2
r(I)]
R1 = 0.0328
wR2 = 0.0432
wR2 = 0.0575
1.84 and ꢀ1.64
R indices (all data)
Larg. diff. peak/hole, e.Åꢀ3
rections were applied based on crystal face indexing obtained
using actual images recorded by the video-microscope camera.
The data reduction [9] and the following data processing was per-
formed using the SADABS program that was included in the Bruker
AXS software package [10]. The first structure was solved by direct
methods and refined by the least squares method on weighted F2
values for all reflections using the SHELXTL program [10]. All atoms
received assigned anisotropic displacement parameters and were
refined without positional constraints. Crystals of the second com-
plex – Pt(PiPCO)2 – were too small to study using the APEX2 dif-
fractometer, and, therefore, they were examined on a Rigaku
RAXIS image plate diffractometer, which is especially suitable for
small crystalline specimens. The data were collected at 293 1 °C
to a maximum 2h value of 55.0°. A total of 90 oscillation images
2.2. Spectroscopic measurements
A Nicolet Magna 500 FTIR spectrometer equipped with win-
dows OMNIC 1.20 software was used for recording IR spectra of
synthesized compounds in KBr pellets. The IR spectra were ob-
tained in a range of 400–4000 cmꢀ1 at 4 cmꢀ1 resolution using
64 repetitions. UV–Vis spectra were recorded at 293 K on the HP
8354 diode array spectrophotometer in the range of 200–
1100 nm, in 1 and 10 mm quartz cuvetts (Starna Cells), while spec-
tra from solid powdery samples of M(PiPCO)2 and M(MCO)2 were
recorded as fine suspensions in mineral oil squeezed between
two quartz plates of 1 ꢁ 4 cm dimensions.
were collected. A sweep of data was done using
98.0° to 188.0° in 2.0° steps. The exposure rate was also 450.0 [s/°],
and oscillations from 98.0° to 188.0° in 2.0° steps. The exposure
rate was 450.0 [s/°]. A third sweep was performed using oscilla-
tions from 98.0° to 188.0° in 2.0° steps. The exposure rate was
450.0 [s/°]. A fourth sweep was performed using oscillations
x oscillations from
2.3. X-ray crystallography
x
x
Crystal structures were determined for two metal complexes
Pd(PiPCO)2 and Pt(PiPCO)2. Single crystals of the first compound,
suitable in size and quality, were mounted on a thin glass fiber
placed on the goniometer head of the Bruker APEX 2 diffractome-
ter, equipped with a SMART CCD area detector. The intensity data
x
from 98.0° to 188.0° in 2.0° steps. The exposure rate was 450.0
[s/°]. The crystal-to-detector distance was 127.40 mm. Readout
was performed in the 0.100 mm pixel mode. Of the 24,437 reflec-
tions that were collected, 4005 were unique (Rint = 0.039); equiva-
lent reflections were merged. The data was corrected for Lorentz
and polarization effects. A correction for a secondary extinction
[11] was applied (coefficient = 0.000420). The structure was solved
by heavy-atom Patterson methods [12] and expanded using
were collected in
x scan mode using the Mo tube (Ka radiation;
k = 0.71073 Å) with a highly oriented graphite monochromator.
Intensities were integrated from four series of 364 exposures, each
covering 0.5° in
x within 60 s of acquisition time, and the total
data set being a sphere [7]. The space group determination was
done with the aid of XPREP software [8]. Numerical absorption cor-

J. Ratcliff et al. / Inorganica Chimica Acta 385 (2012) 1–20
3
Table 2
Selected bond lengths in the structure of Pd(PiPCO)2: comparison of experimental and theoretical values.
Numbering scheme in
the X-ray structure*
1
Bond lengths in the
X-ray structure (Å)
2
Calculated bond
lengths (Å)
3
Differences in exp. and
calc. bond lengths: (2–3) (Å)
4
Relative
error (%)
5
Pd1–O2
Pd1–N1
C8–N3
N2–C2
O2–C3
O1–N1
C4–N3
C3–C1
C1–N1
C1–C2
C3–N3
C7–C8
C5–C4
C6–C5
2.017(12)
1.977(15)
1.470(2)
1.148(2)
1.280(2)
1.250(19)
1.476(2)
1.469(2)
1.353(2)
1.426(3)
1.320(2)
1.517(3)
1.514(3)
1.527(3)
2.088
2.032
1.471
1.155
1.262
1.218
1.469
1.465
1.355
1.419
1.346
1.530
1.528
1.533
ꢀ0.071
ꢀ0.055
ꢀ0.001
ꢀ0.007
0.018
0.032
0.007
0.004
3.4
1.9
0.07
0.6
1.4
2.6
0.5
0.3
0.14
0.5
1.9
0.9
0.9
0.4
ꢀ0.002
0.007
ꢀ0.026
ꢀ0.013
ꢀ0.014
ꢀ0.006
*
From Fig. 2.
Table 3
Selected valence angles in the structure of Pd(PiPCO)2: experimental and ab initio calculated angles (°).
Numbering in the
X-ray structure*
1
Angles in the
X-ray structure
2
Calculated
angles
3
Differences in the exp
and calc angles: (2–3)
4
Relative
errors (%)
5
Pd1–O2–C3
Pd1–N1–O1
Pd1–N1–C1
O2–Pd1–N1
O2–C3–C1
O2–C3–N3
C3–C1–N1
C3–C1–C2
C1–N1–O1
C1–C2–N2
C1–C3–N3
N1–C1–C2
C7–C8–N3
C7–C6–C5
C6–C7–C8
C6–C5–C4
C4–N3–C8
C5–C4–N3
O2–Pd1–N1a
N1–Pd1–N1a
113.21(11)
126.27(12)
113.38(12)
81.12(6)
116.41(16)
118.74(16)
114.18(16)
127.96(16)
120.34(15)
178.4(2)
124.84(17)
117.58(16)
108.40(15)
111.21(17)
110.84(16)
110.87(18)
111.90(15)
109.51(16)
175.58(6)
103.04(9)
113.13
123.65
114.25
79.39
0.08
2.62
0.1
2.1
ꢀ0.87
ꢀ0.8
1.73
2.2
117.74
118.56
114.91
127.27
122.03
178.77
123.69
117.45
110.12
110.95
111.68
110.99
113.14
110.84
178.99
99.88
ꢀ1.33
0.18
ꢀ1.1
0.15
ꢀ0.6
0.5
ꢀ1.4
ꢀ0.2
0.9
ꢀ0.73
0.69
ꢀ1.69
ꢀ0.36
1.15
0.13
0.1
ꢀ1.72
ꢀ1.5
0.26
0.2
ꢀ0.84
ꢀ0.12
ꢀ1.24
ꢀ1.33
ꢀ3.41
3.16
ꢀ0.7
ꢀ0.1
ꢀ1.1
ꢀ1.2
ꢀ1.9
3.16
*
See Fig. 2 and Table 2.
Table 4
Selected bond lengths in the structure of Pt(PiPCO)2: comparison of experimental and theoretical values.
Numbering in the
X-ray structure*
1
Angles in the
X-ray structure
2
Calculated
angles
3
Differences in the exp
and calc angles: (2–3)
4
Relative
errors (%)
5
Pt1–O2
Pt1–N1
C8–N3
N2–C2
O2–C3
O1–N1
C4–N3
C3–C1
C1–N1
C1–C2
C3–N3
C7–C8
C5–C4
C6–C5
2.015(4)
1.944(5)
1.469(8)
1.122(8)
1.292(7)
1.257(6)
1.483(8)
1.457(8)
1.342(8)
1.439(9)
1.317(8)
1.490(10)
1.513(10)
1.519(11)
2.109
2.008
1.472
1.155
1.275
1.221
1.469
1.455
1.365
1.415
1.343
1.530
1.529
1.532
ꢀ0.094
ꢀ0.064
ꢀ0.003
ꢀ0.033
0.017
0.036
0.014
0.002
4.7
3.3
0.20
2.9
1.3
2.9
0.9
0.1
1.7
1.7
2.0
2.7
1.1
0.85
ꢀ0.023
0.024
ꢀ0.026
ꢀ0.04
ꢀ0.016
ꢀ0.013
*
From Fig. 3.

4
J. Ratcliff et al. / Inorganica Chimica Acta 385 (2012) 1–20
Table 5
Selected valence angles in the structure of Pt(PiPCO)2: experimental and ab initio calculated angles (°).
Numbering in the
X-ray structure*
1
Angles in the
X-ray structure
2
Calculated
angles
3
Differences in the exp.
and calc. angles: (2–3)
4
Relative
error (%)
5
Pt1–O2–C3
Pt1–N1–O1
Pt1–N1–C1
O2–Pt1–N1
O2–C3–C1
O2–C3–N3
C3–C1–N1
C3–C1–C2
C1–N1–O1
C1–C2–N2
C1–C3–N3
N1–C1–C2
C7–C8–N3
C7–C6–C5
C6–C7–C8
C6–C5–C4
C4–N3–C8
C5–C4–N3
O2–Pt1–N4
N1–Pt1–N4
113.1(4)
125.2(4)
115.5(5)
80.56(19)
116.2(6)
119.0(6)
113.2(6)
126.5(6)
119.2(5)
179.0(9)
124.8(6)
119.1(5)
111.2(6)
110.7(6)
110.0(6)
111.0(7)
112.0(5)
107.8(6)
175.4(2)
103.9(2)
113.2
124.5
114.6
79.2
ꢀ0.1
0.7
0.9
0.09
0.6
0.78
1.69
1.03
0.76
1.6
0.71
1.34
0.17
0.24
1.51
0.99
0.27
1.45
0.1
1.4
117.4
118.1
115.0
127.4
120.8
178.7
124.5
117.3
110.1
111.0
111.6
111.1
113.2
110.8
178.4
100.8
ꢀ1.2
ꢀ0.9
ꢀ1.8
ꢀ0.9
ꢀ1.6
ꢀ0.3
0.3
1.8
1.1
ꢀ0.3
ꢀ1.6
0.1
ꢀ1.2
1.07
2.78
1.71
2.98
ꢀ3
ꢀ3
3.1
*
From Fig. 3 and Table 4.
Fourier techniques. The non-hydrogen atoms were refined aniso-
tropically. Hydrogen atoms were refined using the riding model.
Neutral atom scattering factors were taken from Cromer and Wab-
er [13]. Anomalous dispersion effects were included in Fcalc [14];
their geometry. Figures for the crystal structures of these com-
plexes were drawn using MERCURY 4.1.2 and ORTEP 32 software [19]
at a 50% thermal ellipsoids probability level. The PLATON checks of
crystallographic data and actual CIF files for reported structures
can be found in the Electronic Supplementary Information.
the values for
D D
f0 and f00 were those of Creagh and McAuley
[15]. The values for the mass attenuation coefficients are those of
Creagh and Hubbell [16]. All calculations were performed using
the CrystalStructure [17] crystallographic software package except
for refinement, which was performed using SHELXL-97 [18]. Crystal
data for two studied compounds are presented in Table 1, while se-
lected bond lengths and valence angles are summarized in Tables
2–5 together with the results of the theoretical optimization of
2.4. Syntheses of compounds
2.4.1. Organic compounds
The general synthetic route for obtaining the desired cyanoxi-
mes, HPiPCO and HMCO is represented by a three-step procedure
shown in Scheme 2. It was published previously [5] for alkylnitrites,
step 1
O
O
+ N , R.T.
2
N
N
HN
+
+
ROH
N
N
C
C
R
N
N
C
C
X
neat liquids
O
N
X
step 2
O
O
O
+ N , R.T.
2
+
C3H7OH
+
NaOC3H7
Na
X
X
step 3
O
N
+ N , R.T.
2
N
+
CH3OH
C
C
+
CH3ONO
N
N
Na
X
X
N
NaO
+ HCl, diluted, R.T.
- NaCl
O
N
C
R = CH3, C2H5
N
X = CH2, for HPiPCO
N
X
HO
X = O,
for HMCO
Scheme 2. Synthetic route to cyanoximes.

J. Ratcliff et al. / Inorganica Chimica Acta 385 (2012) 1–20
5
and will not be described in detail. However, we would like to point
out that the gaseous methylnitrite CH3ONO was found to be the
most convenient nitrosating agent for the synthesis of cyanoximes,
the procedure we patented recently [6].
2.5.2. Syntheses of M(MCO)2
An aqueous solution of Na(MCO) 0.195 g (0.954 mmol) in 5 mL
of water was added dropwise within one hour to an aqueous solu-
tion of K2PtCl4 (0.198 g; 0.477 mmol) in 5 mL of water in a 25 mL
Erlenmeyer flask. The reaction mixture became red, but then
slowly within ꢂ2 h gained a green color, and turned to a dark,
blue-green, very fine suspension after about five hours. The precip-
itate was filtered off, washed with 5 mL of water and dried in a vac-
uum dessicator charged with H2SO4 (conc.). The yield of dry
Pt(MCO)2 was 0.152 g (76%). For C14H16N6O6Pt calculated (found),
%: C – 30.06 (29.71), H – 2.88 (2.93), N – 15.02 (14.82). The com-
plex is hygroscopic. A synthesis of the Pd(MCO)2 was conducted
in an analogous fashion and led to a canary-yellow precipitate in
80% yield. Anal. Calc. For C14H16N6O6Pd: C, 35.72; H, 3.43; N,
17.85. Found: C, 35.95; H, 3.69; N, 17.68%. This complex is not
hygroscopic.
2.4.2. Preparation of methylnitrite
CH3ONO. The methylnitrite is a heavy gas and was prepared in
the fume hood by mixing two solutions: a 2:1 mixture of
H2O:H2SO4 cooled to 0 °C, and an excess of NaNO2 dissolved in a
1:1 mixture of H2O and methanol. As the H2O:H2SO4 solution is
added dropwise to the NaNO2 solution, gaseous CH3ONO is rapidly
evolved and then bubbled into solutions of respective substituted
acetonitriles – NC–CH2–C(O)N(CH2)4O and NC–CH2–C(O)N(CH2)5
– in PrOH in the presence of the base (NaOC3H7), as depicted in
Schemes 2 and ESI 1 (Electronic Supporting Information). The
workup procedure for isolation of the target HMCO and HPiPCO
compounds consisted of removal of solvent under vacuum, drying
off solid yellow crude Na-salts of cyanoximes in high vacuum, their
re-dissolving in water with the following precipitation of oximes at
pH 3 upon acidification of solutions with diluted HCl (1:5, by
volume).
2.5.3. Syntheses of M(PiPCO)2
An aqueous solution of NaPiPCO of 0.199 g (0.982 mmol) in
5 mL of water was added dropwise to a 5 mL solution of K2PdCl4
(0.161 g; 0.493 mmol) in a 25 mL Erlenmeyer flask. The reaction
mixture within ꢂ5 min turned to an orange-yellow followed by a
thick precipitate of Pd(PiPCO)2. The precipitate was filtered off,
washed with water, and dried in a vacuum dessicator charged with
H2SO4 (conc.). The yield of dry Pd(PiPCO)2 was 0.205 g (89%). Anal.
Calc. For C16H20N6O4Pd: C, 41.17; H, 4.32; N, 18.00. Found: C,
41.03; H, 4.46; N, 18.09%. This complex is not moisture sensitive.
Preparation of Pt(PiPCO)2 was carried out in a similar way and re-
sulted in a very fine dark-green precipitate obtained in 70% yield.
Anal. Calc. For C16H20N6O4Pt: C, 34.60; H, 3.63; N, 15.13. Found:
C, 34.72; H, 3.80; N, 15.04%.
2.5. Metal derivatives of substituted acetamide-cyanoximes
Bivalent Pd and Pt complexes of cyanoximes were prepared in
sufficiently good yield from Na+ salts of the latter and tetrachloro-
metallates K2[MCl4] (M = Pd, Pt), as shown in Scheme 3.
Anionic cyanoximes are much better nucleophiles in substitu-
tion reactions with tetrachlorometallates and the reaction times
for the Lꢀ are shorter than those for the protonated HL ligands.
Complexes of the ML2 composition (M = Pd, Pt; L = PiPCOꢀ, MCOꢀ)
poorly soluble in water and precipitate out of solutions in an
acceptable yield.
All four ML2 transition metal complexes (M = Pd, Pt; L = MCOꢀ,
PiPCOꢀ) are sparingly soluble in CH3CN and benzonitrile, not solu-
ble in chlorohydrocarbons and alcohols, but are readily soluble in
donor solvents such as DMF, DMSO, pyridine and picolines. More-
over, complexes are non-conducting in DMF and DMSO, but slowly
become 1:1 electrolytes in pure pyridine and 2-picoline due to par-
tial substitution of the cyanoxime in the inner sphere of complexes
with solvent molecules.
2.5.1. Preparation of Na+ salts
The typical procedure for the preparation of Na(MCO) was as
follows: 0.065 g (2.84 mmol) of thinly sliced metallic sodium was
dissolved in 5 mL of dry ethanol under N2 protection. The HMCO
(0.521 g; 2.84 mmol) was dissolved with stirring in 80 mL of dry
ether in a 125 mL Erlenmeyer flask. A solution of NaOEt was added
dropwise to the cyanoxime solution within several minutes with
intensive stirring. The resulting amorphous yellow precipitate
was filtered off, washed with ether, and dried in a vacuum desica-
tor over H2SO4 (conc.). Yield was 0.454 g (78%). The Na(PiPCO) was
obtained in a similar fashion in 80% yield. Both salts are ionic,
highly hygroscopic, soluble in dry CH3CN, Py, DMF and DMSO,
and insoluble in ether, hexane and chlorohydrocarbons. Detailed
description of the preparation of Pd and Pt complexes is given be-
low for two compounds.
2.6. Computational procedure
The quantum chemical calculations have been performed for
four experimentally studied molecular systems: HMCO, HPiPCO,
Pd(PiPCO)2 and Pt(PiPCO)2. In the initial step the preliminary
optimization was done at the semiempirical MOPAC2009 (PM6
version) level [20]. In the next step, the all-electron procedure
and the density hybrid functional B3LYP have been used with the
6-311⁄⁄G(2d,2p) basis set except for the Pd and Pt atoms where
colorless
bright yellow
NaL
ether, R.T.
+ NaOC H
HL
+
NaOC2H5
+
C2H5OH
2
5
HL = HPiPCO, HMCO
H O, R.T.
2
H O, R.T.
2
2
+ K [PtCl ]
2
4
+ K [PdCl ]
4
DMSO, R.T.
[PtL2]
[PdL2]
[PtL2]n
yellow-orange
blue-green,
pale-yellow,
monomeric
1D polymeric
Scheme 3. Preparation of Na-salts and transition metals derivatives of cyanoximes.

6
J. Ratcliff et al. / Inorganica Chimica Acta 385 (2012) 1–20
Huzinaga or WTBS [21] sets were employed. In the last case the to-
tal energies were lower, pointing out that the WTBS basis is pre-
ferred to the Huzinaga Gaussians [22]. The full geometry
optimization was performed for all considered systems with C1
symmetry for HMCO, HPiPCO and Ci point groups, in the case of
Pd(PiPCO)2 and Pt(PiPCO)2. In all cases the molecular geometry,
i.e. bond lengths and angles, HOMO and LUMO, as well as Mulliken
atomic charges, have been evaluated and, if possible, compared
with the respective experimental results. The ionization energies
and the relevant electron affinities were evaluated according to
the Koopmans theorem [23]. Most of the numerical computations
have been performed GAUSSIAN-09 (Rev. A.02) package [24]. The
change from blue-green to pale yellow due to the breakdown of 1D
coordination polymeric structures and the formation of mono-
meric compounds [28] (Fig. 1 and ESI 2 and 3). Apparently, Pd-cya-
noximates do not have extended polymeric structures and the
dissolution of complexes does not lead to the color change. Hence,
yellow-orange solutions of these complexes are consistent with
square-planar geometries around metal centers.
The IR spectra of the ML2 complexes (M = Pd, Pt; L = PiPCOꢀ,
MCOꢀ) indicate coordination of anions to metal centers via oxygen
atoms of the amide groups and nitrogen atoms of the nitroso-groups
with the formation of the five-membered chelate rings. This conclu-
sion is based on the decrease of the
m
(C@O) amide-I vibrational fre-
(CNO)
electrostatic potential images were generated with the MOLEKEL
-
quencies in ML2 complexes and an increase in the m
5.4.0 computer program [25].
frequencies in comparison to uncomplexed anions in HL and NaL
due to the redistribution of electron density in the coordinated an-
ion (ESI 4). Similar spectral changes were previously observed for
transition metals complexes of nitrosodicyanmethanide [36],
amide-cyanoximes [31,32,37], and cyanoximes containing aromatic
and heterocyclic groups [29,30,34].
3. Results and discussion
Palladium(II) complexes of cyanoximes are soluble in pyridine
(furter Py), 2-methylpipidine (2-pic), DMF and DMSO; and spar-
ingly soluble in CH3CN and benzonitrile. Palladium(II) complexes
do not change yellow-orange color in solutions, which is the evi-
dence of their square-planar structure. Synthesized Pt-cyanoxi-
mates are intensely green-blue, which is a rare occasion among
bivalent platinum complexes. The Magnuss’ salt – [Pt(NH3)4][PtBr4] –
is one of the few examples of green complexes [26], and has the
structure of a 1D coordination polymer. It adopts a ‘‘poker chips’’
stacked motif with close intermetallic separations. Platinum(II)
cyanoximates dissolve in DMSO, Py and 2-Pic, with a very signifi-
cant color change from dark blue-green to a light-yellow, indicating
the loss of solid state coordination-polymeric structure. Surpris-
ingly, PtL2 solutions in CH3CN and in DMF remain dark green, which
suggests that their 1D polymeric structure is largely intact. The
solution’s electrical conductivity of all the synthesized ML2 com-
plexes (M = Pd, Pt; L = PiPCOꢀ, MCOꢀ) in DMSO and DMF at 1 mM
concentrations supports their non-electrolytic nature. However,
being left for several hours the DMSO solutions show increase in
electrical conductivity, which is in accord with the compounds’ par-
tial solvolysis [27] the latter leads to the liberation of anions in solu-
tion due to the substitution reactions.
3.2. Crystal structures
Crystal data for two new cyanoxime complexes Pd(PiPCO)2 and
Pt(PiPCO)2 reported in this work are presented in Table 1. The crys-
tal structures of HPiPCO and HMCO were determined earlier [19],
and the values of their geometric parameters (bond lengths and va-
lence angles) were used for comparison to the results of quantum-
chemical calculations, in order to validate their accuracy in the
optimization of molecular geometry. The molecular structures
and numbering schemes for both cyanoximes are presented in
ESI 5, while the experimental geometry (found by X-ray analysis)
and calculated one are summarized in ESI 6–8. It is important to
note that both protonated cyanoximes adopt the most favorable
trans–anti configuration: the oxime C@N bond is in the trans-posi-
tion to the carbonyl group in the amide fragment (ESI 5). The
deprotonation of cyanoximes leads to the anionic species that bind
the transition metal in a step-wise fashion, changing the configura-
tion to cis-anti. In the process the rotation around the C–C bond oc-
curs and leads to the formation of the five-membered chelate rings,
Scheme 4.
3.1. UV-visible and IR spectra
3.2.1. Pd(PiPCO)2
The molecular structure and numbering scheme for this com-
plex is shown in Fig. 2. Selected bond lengths and valence angles
are presented together with the data of in silico molecular geome-
try optimization in Tables 4 and 5. The complex has cis-geometry
with two cyanoxime ligands forming five-membered chelate rings
(Fig. 2). The metal atom occupies the special position (two fold
axis), and, therefore, the ASU of the complex consists of only half
of the molecule. Hence, the numbering scheme for the symmetry
related part has atoms labeled with a indices (Fig. 2). The Pd1–
N1–N1a–O2–O2a core is planar. However, the five atom fragment
Pd1–N1–C1–C3–O3 in the chelate claw has the shape of a shallow
‘‘semi-chair’’ (or envelope), similar to that in the THF molecule. The
dihedral angle between planes N1–C1–C3–O2 and Pd1–N1–O2 is
10.29o. The ‘‘bite’’ angle O2–Pd1–N1 is 81.12° and is within a range
for the cyanoxime chelates with other transition metal complexes
[29–32]. The cyanoxime anion in the Pd(PiPCO)2 complex is in the
nitroso form judging by much shorter length of O1–N1 bond
(1.250 Å) in comparison to C1–N1 bond (1.353 Å) (Table 4). The
bond lengths Pd1–N1 and Pd1–O1 are 1.977 Å and 2.017 Å. The
first of, being significantly shorter than the sum of ionic radii for
the metal–nitrogen pair (ca 2.51 Å) [33], points out to the covalent
character.
Dissolution of dark-green Pt(PiPCO)2 and Pt(MCO)2 complexes
in strong donor solvents (Py, 2-Pic and DMSO) results in a fast color
319 nm
1.6
383 nm
1.2
0.8
330 s
570 s
789 nm
0.4
0.0
200
400
600
Wavelength, nm
800
1000
Fig. 1. Change in the UV–Vis spectrum of Pt(MCO)2 in DMF treated with one drop of
DMSO; T = 293 K, 1 cm cuvette. The PtꢃꢃꢃPt CT band at ꢂ790 nm of aggregated into
1D ‘‘poker chip’’ stacks rapidly disappears: the solutions turns from green to yellow.
(For interpretation of the references in color in this figure legend, the reader is
referred to the web version of this article.)
In contrast, the metal–oxygen bond is only slightly shorter than
the sum of ionic radii of involved elements (ca 2.12 Å) [33], which

J. Ratcliff et al. / Inorganica Chimica Acta 385 (2012) 1–20
7
O
O
N
N
+ NaOH, H O
2
C
C
N
Na
X = CH2 for PipCO-,
X = O for MCO-,
M = Pd, Pt
N
X
R.T.
N
X
N
O
HO
+ K [MCl ]
2
4
H O, R.T.
2
X
O
O
N
N
N
N
C
C
C
N
N
O
X
X
N
N
N
O
O
O
M
M
M
Scheme 4. Formation of cyanoxime anions and changes in their conformation during chelate complexes formation with transition metals.
Fig. 2. Molecular structure and numbering scheme for Pd(PiPCO)2 in GROW mode. The ASU contains half of the molecule with palladium(II) atom being in a special position:
symmetry operations for the a positions, generated due to the two-fold axis: ꢀx, y, ½ ꢀ z. (A) View from above, (B) side view.
is important when considering of the chelate ring opening in the
presence of biological substrates inside the cell. The ring opening
is likely to lead to the monodentate coordination of the cyanoxime
to the Pd-atom, with two other sites on the metal becoming avail-
able for other donor atoms to occupy. The piperidine rings of the
amide fragment adopt the most favorable chair conformation in
the solid state. The central atom Pd1 occupies a special position –
a two-fold proper rotation axis – in this structure. The amide
fragment is not planar and the dihedral angle between planes
C8–N3–C4 and O2–C3–N3 is 21.73°. Other functional groups in this
molecule have normal values of bond lengths and angles (Tables 4
and 5).
3.2.2. Pt(PiPCO)2
The molecular structure and numbering scheme for this com-
pound is snown in Fig. 3, while selected bond lengths and valence
angles are presented in Tables 4 and 5 together with the data of in
silico computations. This complex also adopts cis-geometry similar
to that of the analogous Pd-complex discussed above, with two
five-membered chelate rings providing the tetracoordinated
square-planar environment for Pt(II) center. The overall core
structure in Pt(PiPCO)2 is noticeably flattened in comparison to
the Pd-cyanoximate above: the dihedral angle between mean
planes C1–C3–N1–O2–Pt1 and C9–C11–N4–O4–Pt1 is 5.46°. The
‘‘bite’’ angles in these two chelate rings are 80.54° and 80.09°,

8
J. Ratcliff et al. / Inorganica Chimica Acta 385 (2012) 1–20
Fig. 3. Molecular structure and numbering scheme of Pt(PipCO)2: view from above (A) and side view (B).
respectively. The bond lengths Pt1–N1, Pt1–N4 and Pt1–O2, Pt1–
O4 are 1.944, 1965 and 2.014, 2.010 Å, respectively, which is signif-
icantly shorter than the sum of ionic radii of metals and nitrogen
(2.51 Å) [33], and only slightly less than the sum M–O (M = Pd,
Pt) ionic radii (2.15 Å). Therefore, the degree of covalency in the
M–N (M = Pd, Pt) bond and its strength is much greater than that
for almost ionic M–O bonds. This implies that the latter can be
cleaved easier in solutions during intracellular interactions, leading
to the formation of the monodentate-binding of cyanoxime anions.
Henceforth, two vacant coordination sites provide an opportunity
for the biological substrate binding to fulfill the metal center
requirement for four-coordinated square-planar geometry. The
cyanoxime anion PiPCOꢀ in the complex is in the nitroso form as
judged by the shorter N–O than N–C bond length in the CNO frag-
ment (Table 5). The amide groups in both anions in the structure of
Pt(PiPCO)2 are not planar, but are less distorted than the group in
the structure of Pd(PiPCO)2. The values of dihedral angles between
mean planes O2–C3–N3 and C8–N3–C4, and between O4–C11–N6
and C12–N6–C16 are 16.94° and 9.94°, respectively. The piperidine
ring adopts the chair conformation, and other functional groups
possess geometries normal for them.
[5]. The molecular structures and numbering schemes are shown
in ESI 5. At the time of commencement of this work the only crystal
structure known was that of Pd(MCO)2ꢁDMSO solvate [5]. When
two more solid state structures were determined for Pd(PiPCO)2
(Fig. 2) and for Pt(PiPCO)2 (Fig. 3), it became possible to compare
their actual geometries with the calculated ones. The molecular
geometry of the DMSO solvated Pd(MCO)2 is depicted in the Sup-
porting Information section of this paper (ESI 11). The structural
parameters of free ligands were calculated at the B3LYP/6-311G
(2d,2p) level of theory. In the case of Pt and Pd compounds the
WTBS basis set was used, as it provided the best accessible accu-
racy. Computed structures refer to the gas phase, whereas the X-
ray diffractions were recorded on the solid samples, therefore no
perfect agreement of between these is expected. Nevertheless, the dif-
ferences between the experimental values of bond lengths and valence
angles are insignificantly small for the purpose of the compounds’
geometry comparison and the electronic structure description.
3.3.1. Geometry of HMCO
The calculated interatomic distances and bond angles are sum-
marized in the table in ESI 7 and 8 together with the corresponding
experimental data obtained from the crystal data [5] for the HMCO
molecule. The values of measured and calculated geometrical
parameters are very similar, and the differences for the interatomic
distances are close to their standard deviations, with the maximum
relative error not exceeding 1.7% (ESI 7 and 8). The calculated and
experimentally found values of bond angles are generally also in a
good agreement, with one exception: 6.6% of the relative error for
the oxime group. Perhaps this deviation is caused by a different
spatial orientations of the O–H bond calculated in the gas phase
and in the crystal, where it participates in the H-bonding. Thus,
the position of H at O3 in the HMCO X-ray structure (ESI 5) is
different from the position of H14 at O5 in HMCO calculated for
the gas phase (Fig. 4A, ESI 13). In the gas phase the proton of the
Prior to the discussion of the results of theoretical studies it is
important to note that dihedral angles described above are largely
the product of crystal packing and cannot be used for the compar-
ison with data obtained from quantum-chemical calculations on a
single molecule in a gas phase at 0 K. Therefore, only the values of
bond lengths and valence angles will be used for a meaningful com-
parison and data analysis.
3.3. Quantum calculations (QM): geometry optimization
In order to verify the accuracy of the theoretical studies, molec-
ular geometries of uncomplexed cyanoximes HMCO and HPiPCO
were compared with their crystal structures determined earlier

J. Ratcliff et al. / Inorganica Chimica Acta 385 (2012) 1–20
9
O
O
O-H group lies towards the CN-group, whereas in the crystal struc-
ture it points to a different direction due to the intermolecular H-
bonding. Other structural features of the molecule, such as the
trans orientation of the oxime C@N and the carbonyl C@O bonds,
the anti-configuration of the oxime group, and the chair-conforma-
tion of the morpholine ring, were found to be the same the calcu-
lated and solid state structure.
N
N
C
C
N
N
N
X
N
X
HO
OH
trans-syn
trans-anti
X
X
X = CH2 for HPiPCO
X = O for HMCO
3.3.2. Geometry of HPiPCO
N
N
N
N
Small differences in geometriy of free ligand HPiPCO (shown in
ESI 6) determined by the X-ray analysis and calculated quantum
mechanically are comparable to those found for the HMCO (ESI 7
and 8). Two structures have almost identical geometrical parame-
ters, with the maximum relative error for the interatomic distance
not exceeding 2.0% (ESI 6). There is also a satisfactory agreement
between the calculated and experimental values of bond angles,
although the calculated valence angles for the oxime group differ
from the experimental values by 5.6–7.5%. The reason for such dif-
ferences is the same as discussed above in the description of the
HMCO geometry.
It should be especially mentioned that despite the structural
flexibility and the possibility for several alternative geometries
(such as, for instance, cis-anti, cis–syn, or trans–syn configurations
[34,35] Scheme 5), the actual trans-anti conformation of the
oxime-group in both HMCO and HPiPCO molecules, as well as
the chair conformation of the piperidine ring, were accurately
reproduced by the QM calculations.
C
C
O
O
N
N
HO
OH
cis-anti
cis-syn
Scheme 5. Geometrical isomerism of N-substituted amide-cyanoximes.
3.3.3. Geometry of Pd(PiPCO)2
The calculated geometrical parameters for this complex are
shown in Tables 2 and 3 together with experimental values ob-
tained from the single crystal X-ray diffraction. The crystal struc-
ture and calculated MEP results for Pd(PiPCO)2 are presented in
Figs. 2 and 4C, respectively. An agreement between the experimen-
tal and theoretical values is remarkably close, perhaps, due to the
presence of a heavy metal atom. Thus, the difference of experimen-
tal and calculated interatomic distances in Table 2 is generally be-
low 1%; with only near the Pd center the deviations are slightly
higher, as indicated by the value of relative errors: 3.4% for Pd1 –
Fig. 4. The electrostatic potential maps prepared with the MOLEKEL: (A) HMCO; (B) HPiPCO; (C) Pd(PiPCO)2; (D) Pt(PiPCO)2.

10
J. Ratcliff et al. / Inorganica Chimica Acta 385 (2012) 1–20
O2, 1.9% for Pd1 – N1, and 2.6% for N1 – O1 bonds. This fact is a
manifestation of the crystal packing phenomenon, which lead to
a distortion of the PdO2N2 planar structure in solid state. At the
same time, the isolated molecule in the gas phase, which was stud-
ied in computations, is free from such intermolecular interactions.
Satisfactory results were obtained also for the values of valence an-
gles in Pd(PiPCO)2 (Table 3). The only noticeable differences be-
tween the experimental and calculated data were observed for
the angles around the metal center with highest relative errors in
the range of 2–3% (Table 3). Upon coordination to the metal center
the cyanoxime ligand changes its conformation from trans-anti to
cis-anti (Schemes 4 and 5; Fig. 2), which assures its tight binding
and the formation of the five-membered chelate ring system.
ligands HMCO and HPiPCO. The crystal structure of the latter
complex is the first known for Pt-cyanoximates in general.
(3) Ab initio calculations were performed for six compounds:
two cyanoxime ligands and four Pd and Pt metal complexes.
A very satisfactory agreement between the calculated and
experimental values of the geometrical parameters of all
the evaluated compounds was obtained. The electron densi-
ties on atoms, as well as molecular electrostatic potentials,
play an important role in these transition metal complexes’
in vitro cytotoxicity, since they define the strength and the
site of interactions with bio-molecules inside the cell.
Acknowledgments
3.3.4. Geometry of Pt(PiPCO)2
Both sets of geometrical parameters (X-ray data and calculated
values) for this complex can be found in Tables 4 and 5. Similarly to
the Pd-analog, an agreement between the experimental and calcu-
lated data for Pt(PiPCO)2 is quite satisfactory. Again, the only
noticeable small differences in geometry were found at the metal
center where relative deviations in bond lengths were in the 2.9–
4.7% range (Table 4), while valence angle differens around Pt were
in the 1.69–2.98% range (Table 5).
N.G. is thankful to the ACS PRF foundation for the financial sup-
port of part of this work (award # 39079-B3), and to Ms. Alex Cor-
bett for technical help. J.R. greatly appreciates kind help from the
MSU Department of Chemistry and the Graduate College. The
numerical calculations have been performed in part at Wrocław
Networking and Supercomputing Center, whose work is greatly
appreciated.
In summary, the analysis of theoretical and experimental geom-
etry for both uncomplexed free cyanoximes HPiPCO and HMCO,
and their bivalent Pd and Pt complexes revealed a very good agree-
ment. This lays a foundation for the description of the electronic
structures of these compounds, which may lead to a better under-
standing of the origin of the pronounced cytotoxicity of the
M(MCO)2 (M = Pd, Pt) complexes.
Appendix A. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.ica.2011.12.005.
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3.4. Quantum-mechanical calculations (QM): electronic structures
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is 6.433 eV. The electron affinities are 2.894 and 4.998 eV, respec-
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ions, specifically, participation of the 4f orbitals in the latter case.
Within the Mulliken model, the most positively charged in both
cases are heavy atoms Pd (0.866) and Pt (0.830) whereas the most
negative charges are located on oxygen atoms and, to a lesser ex-
tent, on nitrogen atoms. A slight decrease of partial Mulliken
charges on N and O atoms of the nitroso-group in Pd,Pt complexes
in comparison with that for uncomplexed ligands has been ob-
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4. Conclusions
(1) Two cyanoximes – 2-cyano-2-isonitroso-N-piperidynylace-
tamide (HPiPCO) and 2-cyano-2-isonitroso-N-morpholylac-
etamide (HMCO) – were synthesized in a good yield at
room temperature using a gaseous methylnitrite. Four biva-
lent Pd and Pt complexes were synthesized in high yields
using fast reactions between K2MCl4 and sodium salts of
cyanoximes NaL (M = Pd,Pt; L = PiPCOꢀ, MCOꢀ). Synthesized
compounds were characterized by spectroscopic (IR, UV-vis-
ible) methods and X-ray analysis.
(2) Crystal structures were determined for Pd(PipCO)2 and
Pt(PiPCO)2 and revealed the complexes with cis-geometry
on the ligand and practically planar cores around transition
metal centers. Both anions adopt cis–anti configuration as
opposed to the trans-anti geometry in the uncomplexed
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Part 2: In vitro cytotoxicity studies of two ML2 complexes (M = Pd, Pt; L = 2-cyano-
2-isonitroso-N-morpholylacetamide, HMCO
Jessica Ratcliff a, Paul Durham b, Michael Keck c, Andriy Mokhir d, Nikolay Gerasimchuk a,
⇑
a Department of Chemistry, Missouri State University, Temple Hall 431, Springfield, MO 65897, USA
b Department of Biology, Missouri State University, Temple Hall 211, Springfield, MO 65897, USA
c Department of Chemistry, Emporia State University, Emporia, KS 66801, USA
d Anorganisches Chemie Institut, Ruprechts-Karls Universität, Neuenheimer Feld 270, Heidelberg D-69120, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
In recent years, many non-classical groups of Pt-compounds, including complexes with the trans-geom-
etry, polynuclear complexes, and compounds with a variety of extended heterocyclic ligands, were
obtained and studied. Part 1 of this work contains the results of our X-ray crystallographic and compu-
tational studies of a group of recently-discovered cytotoxic Pd and Pt complexes of the new cyanoxime
ligands HPipCO and HMCO. Here we present the results of our in vitro investigations of two M(MCO)2
(M = Pd, Pt) compounds against two morphologically different human cancer cell lines – epithelial cervi-
cal cancer HeLa cells, and WiDr solid tumor colon carcinoma. The Trypan Blue exclusion method was
used for the assessment of the complexes’ cytotoxicity. The data indicated a profound in vitro activity
of new M(MCO)2 (M = Pd, Pt) complexes, comparable to that of cisplatin, which was used as a positive
control. The palladium MCOꢀ complex was found to be consistently slightly more active than its corre-
sponding Pt-analog. Binding of the above compounds to a variety of the DNA was studied by UV–Vis spec-
troscopy, gel electrophoresis, fluorescent intercalator displacement (FID) assay, and the mitochondria
metabolism assay. No evidence of an interaction of either Pd(MCO)2 or Pt(MCO)2 complex with different
types of DNA was found, which infers a mechanism of cytotoxicity of these new metallo-cyanoximates dif-
ferent from one of the cisplatin family. This immediately suggests different active species involved in the
cellular interactions, as well as different metabolites. Consequently, it implies the absence of the negative
side effects so common to the cisplatin family of anticancer drugs.
Received 11 September 2011
Received in revised form 26 November 2011
Accepted 3 December 2011
Available online 29 December 2011
Keywords:
Cyanoximes
Synthesis
X-ray analysis
Ab initio Calculations
Ó 2011 Elsevier B.V. All rights reserved.
1. Introduction
neck tumors; and cervical, bladder and small cell lung cancer. Cis-
platin exerts its anticancer effects by binding to the DNA, inducing
cis-Dichlorodiammine platinum(II) (later cisplatin) was first
synthesized in 1847 by Peyrone [1] and is the most commonly
used and the most successful anticancer drug [2,3]. It is commonly
used in the treatment of testicular and ovarian cancer; head and
apoptosis [4]. This binding causes a distortion of the DNA helix,
leading to a damage repair pathway or apoptosis. Also, there are
several other active cis-complexes of Pt(II) with different organic
and inorganic groups: they are all members of the cisplatin family:
Although cisplatin has become a successful anticancer drug, it
also has serious drawbacks. One of them is a cascade of side effects
such as severe nausea, vomiting, nephrotoxicity, ototoxicity,
⇑
Corresponding author. Tel.: +1 417 836 5165.
E-mail address: NNGerasimchuk@MissouriState.edu (N. Gerasimchuk).
0020-1693/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.ica.2011.12.004