Synthesis, structural characterization and cytotoxic activity against tumor cells of heteroleptic copper (I) complexes with aromatic diimines and phosphines

Article abstract of DOI:10.1016/j.ica.2017.06.050

Copper coordination complexes are increasingly recognized as potential drugs for therapeutic use in various diseases, especially in cancer. In an attempt to find new leaders for the development of antitumor Cu compounds, heteroleptic Cu(I) complexes with

Full text of DOI:10.1016/j.ica.2017.06.050

Accepted Manuscript
Synthesis, structural characterization and cytotoxic activity against tumor cells
of heteroleptic copper (I) complexes with aromatic diimines and phosphines.
Natalia Alvarez, Carolina Noble, María H. Torre, Eduardo Kremer, Javier
Ellena, Marcio Peres de Araujo, Antonio J. Costa-Filho, Luis Felipe Mendes,
M. Gabriela Kramer, Gianella Facchin
PII:
S0020-1693(17)30472-3
http://dx.doi.org/10.1016/j.ica.2017.06.050
ICA 17699
DOI:
Reference:
To appear in:
Inorganica Chimica Acta
Received Date:
Revised Date:
Accepted Date:
24 March 2017
9 June 2017
21 June 2017
Please cite this article as: N. Alvarez, C. Noble, M.H. Torre, E. Kremer, J. Ellena, M. Peres de Araujo, A.J. Costa-
Filho, L. Felipe Mendes, M. Gabriela Kramer, G. Facchin, Synthesis, structural characterization and cytotoxic
activity against tumor cells of heteroleptic copper (I) complexes with aromatic diimines and phosphines., Inorganica
Chimica Acta (2017), doi: http://dx.doi.org/10.1016/j.ica.2017.06.050
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Synthesis, structural characterization and cytotoxic activity against tumor
cells of heteroleptic copper (I) complexes with aromatic diimines and
phosphines.
Revised version
a
a
a
a
b
Natalia Alvarez , Carolina Noble , María H. Torre , Eduardo Kremer , Javier Ellena ,
c
d
d
Marcio Peres de Araujo , Antonio J. Costa-Filho , Luis Felipe Mendes , M. Gabriela
e
a*
Kramer , Gianella Facchin .
a
Facultad de Química, General Flores 2124, UdelaR, Montevideo, Uruguay
*gfacchin@fq.edu.uy
b
Instituto de Física de São Carlos, Universidade de São Paulo, C.P. 369, 13560-970,
São Carlos (SP), Brasil
c
Departamento de Química, Centro Politécnico, Universidade Federal do Paraná,
Curitiba (PR), Brasil
d
Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São
Paulo, Av. Bandeirantes, 14040-901, Ribeirão Preto (SP), Brasil
e
Department of Biotechnology, Instituto de Higiene, Facultad de Medicina,
Universidad de la República (UdelaR), Av.Alfredo Navarro 3051, Montevideo,
Uruguay.
Key words
Cu(I) coordination compounds, X-ray structure, cytotoxic activity.

Abstract
Copper coordination complexes are increasingly recognized as potential drugs for
therapeutic use in various diseases, especially in cancer. In an attempt to find new
leaders for the development of antitumor Cu compounds, heteroleptic Cu(I)
complexes with triphenylphosphine (PPh
phenanthroline (phen) or neocuproine (neo) were prepared and characterized. The
compounds [CuCl(dmbpy)(PPh )] (1), [CuCl(phen)(PPh )]0,25H (2) and
CuCl(neo)(PPh )] (3) were obtained. The crystal structures of compounds 2 and 3
3
) and dimethylbipyridine (dmbpy),
3
3
2
O
[
3
were determined. In both complexes, the Cu(I) centre presents distorted tetrahedral
coordination. All complexes present cytotoxic activity, against tumor cell lines, being
more active than Cisplatin, with IC50 in the low micromolar range. This activity
augments in the order 123, following the same order as the lipophilicity.
1
Introduction
Copper coordination complexes are increasingly recognized as potential drugs for
therapeutic use in various diseases. In particular, triggered by the success of
Cisplatin for the treatment of cancer, and under the hypothesis that endogenous
metals may be less toxic than Pt, several copper complexes were studied looking for
cytotoxic activity [1-3]. As a consequence, a variety of Cu(II)-complexes were found
to present good antitumor activity, as tested in vitro on several cancer cell lines, and
a few of them on in vivo experiments including ongoing preclinical studies [1-5].
Cu(I) is the chemical form of Cu accepted to be relevant in the active internalization
of copper in mammalians [1-3]. In spite of that, relatively few studies report on the
antitumor activity of Cu(I) complexes, probably due to the difficulty in obtaining stable
Cu(I) complexes in aqueous media. Cu(I)-phosphine complexes were studied

following the discovery of the in vivo antitumor activity of the anti-arthritic Au(I)-
phosphine complex Auranophine, and of [Au(dppe) ][Cl] (dppe: 1,2-
2
bis(diphenylphosphino)ethane). Cu(I) complexes with phosphine ligands that present
cytotoxic activity have been reported [4, 6-8]. An outstanding example is
[
Cu(thp)
4
][PF ] (thp= tris(hydroxymethyl)phosphine), which has strong cytotoxic
6
effects. It is more active than Cisplatin and presents activity even against Cisplatin
resistant cells with high selectivity to tumor cells. The proposed mechanism of action
for the latter is parapoptotic cell death [9, 10]. Recently a Cu(I) compound with both
cytotoxic and antiangiogenic activity was also reported [11]. Review studies suggest
that the presence of a labile ligand is necessary for Cu complexes to exhibit cytotoxic
activity [1].
Heteroleptic Cu(I) complexes with general formula Cu(N-N)(PPh
3
)
2
X [12-19] and

Cu(N-N)(PPh )X [20-23], where N-N represents an aromatic di-imine, P a
3
monodentate phosphine and X an halogen, were previously studied due to the
luminescent properties of these complexes or as catalysts [24, 25].
Our research group has developed several Cu(II) complexes with different sets of
ligands looking for compounds with antitumor activity [26-41]. Special attention has
been given to ternary complexes Cu(L-dipeptide)(phenanthroline) with dipeptides
and different phen derivatives, finding compounds with elevated cytotoxic activity, as

Cu(L-ala-phe)(phen) [40]. In an attempt to obtain complexes with stronger activity,
we widened our studies to phosphine-Cu(I) compounds, keeping the Cu-di-imine
core which proved active to the date, therefore preparing Cu-di-imine-phosphine
(
where di-imine: dimethylbiyridine, phenanthroline or neocuproine) mixed ligand
complexes. In this paper we report the synthesis and characterization of

[
CuCl(dmbpy)(PPh
3
)], [CuCl(phen)(PPh
3
)]0,25H
2
O and [CuCl(neo)(PPh )] which to
3
the best of our knowledge is the first report on the cytotoxic activity of this group of
complexes.
2
Experimental
Reagents for synthesis and biochemical studies were used as commercially
available: CuSO 5H O, NaCl and Na SO (Fluka); ligands: dimethylbiyridine
dmbpy), 1,10-phenanthroline (phen), neocuproine (neo) and triphenylphosphine
PPh ) (SIGMA).
4
2
2
3
(
(
3
2
.1 Synthesis of the complexes and analytical characterization
The complexes were synthesized under Ar atmosphere using standard Schlenck
techniques: 0.15 mmol of CuCl (previously synthesized according to Jolly [42]) , 0.15
mmol of di-imine ligand (where di-imine: dmbpy, phen or neo) and 0.15 mmol PPh
3
were dissolved in dichloromethane, to a final volume of 5 mL. The yellow resulting
solution was further stirred for 1 h at room temperature. A yellow amorphous solid
was obtained after addition of hexane. Yield: 50-60 %.
Small crystals were obtained by slow evaporation of a dichloromethane solution of
the compounds in dichloromethane at -5 °C for 2 and 3.
Elemental analysis: [CuCl(dmbpy)(PPh
6.05%, %N 5.13%, 4.99 found: 66.67%,
CuCl(phen)(PPh )]0,25H O (2) Calc. for CuN
.13%, H 4.34 found: 66.16%, N 4.83%, H 4.57 %, [CuCl(neo)(PPh
27PCl: %C 67.48%, %N 4.92%, H 4.78 found: 67.31%, N 4.83%, H 5.08%.
3 2 30
)] (1) Calc. for CuN C H27PCl: %C
6
H
N
4.78%,
H
5.42%,
[
3
2
2
C H23PClO0,25: %C 66.99%, %N
30
5
3
)] (3). Calc. for
CuN
C H
2 32
2
.2 Physical measurements

Chemical analyses for carbon, nitrogen, hydrogen and sulfur were performed with a
Thermo Scientific Flash 2000 analyzer. Infrared spectra were recorded with a
Shimadzu IR Prestige 21 spectrophotometer from 4000 to 400 cm−1 using KBr
disks.
UV–visible (UV–vis) spectra of the complexes´ solutions were carried out with a
Thermo Scientific Evolution 60 spectrophotometer, using 1 cm path length quartz
cells.
X-band (9.5 GHz) EPR measurements were carried out on DMSO/aqueous solutions
(
3:1) using a JEOL JES-FA200 spectrometer and a cavity with 100 kHz field
modulation. Measurements were performed at room temperature and experimental
parameters were adjusted to avoid signal saturation and line shape distortions.
2
.3 Crystal structure determination
Data from suitable single crystals were collected at 293.0(2) K for complexes 2 and 3
on an Enraf-Nonius FR590 Kappa-CCD diffractometer using graphite
monochromated MoKα radiation (0.71073 Å) and a Bruker D8 Venture diffractometer
using mirror-layered monochromated CuKα radiation (1.54178 Å), respectively. Data
collection and processing software used for 2 were Bruker AXS Collect software and
HKL Denzo-Scalepack program suite. Whereas for 3 Bruker Apex2 was used for
data collection and processing. The structures were solved by direct methods using
the SIR-92 [43] in the case of complex 2 and intrinsic phasing within Apex2 for 3.
Model refinement was performed with SHELXL [44] within Shelxle [45]. Gaussian
absorption correction was applied for complex 2 and semi-empirical from equivalents
for 3 [46, 47]. Molecular structure graphics were prepared using Mercury [48].

All non-hydrogen atoms were refined using anisotropic displacement parameters.
Hydrogen atoms of C-H groups were stereochemically positioned and refined
isotropically with the riding-model setting their thermal parameter as 1.2 times the
equivalent isotropic displacement parameter of the C atom they are bonded to.
Water hydrogen atoms were found in the difference Fourier map, positionally fixed
and their thermal parameters set to 1.5 times the equivalent Uiso. Summary of the
crystallographic data, experimental details and refinement results are listed in Table
1
.
Table 1. Summary of crystallographic data, experimental details and refinement
results.
Identification code
Empirical formula
Formula weight
Temperature
CuClphenPPh3
C120 H94 Cl4 Cu4 N8 O P4
2183.87
CuClneoPPh3
C32 H27 Cl Cu N2 P
569.51
293(2) K
293(2) K
Crystal system
Space group
Triclinic
Monoclinic
P-1
C 2/c
Unit cell dimensions
a = 9.7780(5) Å
b = 15.6430(6) Å
c = 18.3840(8) Å
α= 109.140(3)°
β= 103.430(2)°
γ = 92.068(3)°
2564.5(2) Å3
a = 23.9819(6) Å
b = 9.3905(2) Å
c = 24.6018(6) Å
α= 90°
β= 98.1830(10)°
γ = 90°
Volume
5484.0(2) Å3
Z
1
8
Density (calculated)
Absorption coefficient
F(000)
1.414 Mg/m3
1.041 mm-1
1.380 Mg/m3
2.747 mm-1
1122
2352
Crystal size
0.272 x 0.108 x 0.094 mm3
2.991 to 25.355°.
0.820 x 0.198 x 0.066 mm3
3.63 to 74.79°.
Theta range for data
collection
Index ranges
-11<=h<=11, -18<=k<=17, -
-29<=h<=29, -10<=k<=11, -
30<=l<=30
20<=l<=22
Reflections collected
24557
64609
Independent reflections
9325 [R(int) = 0.0769]
99.4 %
5615 [R(int) = 0.0510]
99.8 %
Completeness to theta =
25.242°
Max. and min. transmission
Refinement method
Data / restraints /
0.949 and 0.825
0.84 and 0.55
2
Full-matrix least-squares on F
5615 / 0 / 337
9325 / 0 / 640

parameters
Goodness-of-fit on F2
Final R indices [I>2sigma(I)]
R indices (all data)
1.013
1.145
R1 = 0.0529, wR2 = 0.1003
R1 = 0.1143, wR2 = 0.1193
R1 = 0.0414, wR2 = 0.1021
R1 = 0.0511, wR2 = 0.1065
-
3
-3
Largest diff. peak and hole
0.413 and -0.348 e.Å
0.380 and -0.255 e.Å
2
.4 Lipophilicity
Lipophilicity was determined by reverse phase thin layer chromatography, using
ALUGRAM® RP-18W/UV254 plates. Solutions of the complexes were prepared in
methanol. Samples were run in methanol: aqueous buffer (Tris pH=7.4 buffer) 9:1.
UV-light was used to reveal the complexes. Caffeine was used as a control in all
runs. Lipophilicity is expressed as R
M
(where R =log10[(1/Rf)-1]).
M
2
.5 Cytotoxic activity studies
Cell lines were obtained from the American Type Culture Collection (ATCC): HeLa
CCL-2™, human cervical adenocarcinoma), MDA MB 231 (HTB-22™, human
(
metastatic breast adenocarcinoma) and A549 (CCL185 ™, human lung epithelial
carcinoma). HeLa cells were grown in high glucose (4.5 g/L) Dulbecco's Modified
Eagle Medium (DMEM), A549 and MDA-MB-231cells were grown in RPMI Medium
containing stable L-Glutamine and supplemented with 10% Fetal Bovine Serum
(
FBS, GE Healthcare). Cells were removed enzymatically from flasks using 0.01%
Trypsin-EDTA solution. Cultured cells were incubated at 37°C on 5% CO
2
atmosphere for 48 h, containing aqueous solutions of the Cu complexes (final
concentrations ranging from 1 to 50 M). Cell viability in response to the complexes
was determined by colorimetric assay using Cell Counting Kit – 8 (Fulka) on 15.000
cells grown in 96-well plates. The kit utilizes a water-soluble tetrazolium salt that is
reduced by cells to give a colored product (formazan). Therefore, formazan
concentration is directly proportional to the number of living cells. Absorbance of

converted dye was measured at 450 nm using a microplate reader. The IC50 was
estimated from the semi logarithmic dose-response curves. Cu-complexes solutions
were prepared by dissolving the corresponding solid complexes, in DMSO and then
sterilized by filtration.
3
Results
3
.1 Crystal structures
In both complexes, the Cu(I) ion is in the centre of a distorted tetrahedral
coordination polyhedron, bonded to two N atoms from phen or neocuproine, one P
-
from the phosphine and one Cl (Figures 1 and 2). Bonding distances and angles are
similar to those reported for related compounds as confirmed by statistical analysis
using Mogul [49]. Selected bond lengths and angles are presented in Table 2.
Figure 1. ORTEP representation of the asymmetric unit of
[
CuCl(phen)(PPh
3
)]0,25H O (2).
2

Figure
2.
ORTEP
representation
)] (3).
of
the
asymmetric
unit
of
[
CuCl(neocuproine)(PPh
3
Table 2. Selected bond distances (Å) and angles (°) for [CuClphenPPh
CuClneoPPh ].
3
] and
[
3
[
CuClphenPPh
3
]
[CuClneoPPh ]
3
Bond distances
Cu1-N1
Cu1-N2
Cu1-P1
Cu1-Cl1
Cu1-N1
Cu1-N2
Cu1-P1
Cu1-Cl1
2.086(3)
Cu2-N3
2.102(3)
2.137(2)
2.115(2)
2.2070(8)
2.3258(8)
2.091(3)
Cu2-N4
Cu2-P1
Cu2-Cl2
2.094(3)
2.1813(11)
2.2998(11)
2.1902(11)
2.2713(13)
Bond angles
N1-Cu1-N2
N1-Cu1-P1
N2-Cu1-P1
N1-Cu1-Cl1
N2-Cu1-Cl1
P1-Cu1-Cl1
N1-Cu1-N2
N1-Cu1-P1
N2-Cu1-P1
N1-Cu1-CL1
N2-Cu1-CL1
P1-Cu1-CL1
80.34(13)
118.65(9)
120.39(9)
106.53(9)
108.38(9)
116.68(4)
N3-Cu2-N4
N3-Cu2-P2
N4-Cu2-P2
N3-Cu2-Cl2
N4-Cu2-Cl2
P2-Cu2-Cl2
79.77(12)
111.45(9)
121.78(9)
109.15(10)
105.15(9)
121.61(4)
79.34(8)
124.99(6)
123.61(6)
103.60(6)
103.71(6)
115.07(3)
The distortion of the coordination tetrahedron was analyzed using the ,  and 
angles, as defined by Starosta et. al [23] and explained in Fig. 3.

Figure 3. Definition of ,  and  angles as tetrahedral distortion evaluation
parameters, where  is the angle between the di-imine plane and the plane defined
by the CuCl and CuP bonds. For a perfect tetrahedron  = 90°, and deviation from
this value is considered a flattening distortion.  and  are the angles between the
line of intersection of the former planes and the Cu-Cl and Cu-P bonds, respectively.
The difference  -  for a perfect tetrahedron is 0°, deviations are considered a
rocking distortion [23].
Values of α, β and  angles for the presented structures are presented in Table 3.
Table 3. α, β and  angles as defined in Fig. 3.
Compound
α (°)
β (°)
 (°)
2
3
(Cu1/Cu2) 88,33/82,31 131,02/112,84 112,30/125,45
89,49
146,21
98,72
From the parameters listed in Table 3 it can be inferred that neither 2 nor 3 present
significant flattening distortion. However, the addition of the methyl groups in the 2
and 9 positions of the phenanthroline in 3 results in an increased rocking distortion.
Intramolecular C-H···π interactions (distance 2,70 Å ) and a weak C-H···Cl (distance
3
.11 Å) hydrogen bond constrain the tetrahedral geometry in 3. As a consequence, 3
presents only one molecule per asymmetric unit as opposed to two molecules in 2.
Crystal packing in 2 presents a unidimensional chain along the a axis with molecules
bound through O-H···Cl (H···Cl distance 2.35 Å), C-H···O (H···O distance 2.53 Å)

and C-H···Cl (H···Cl distances 2.86-2.92 Å) hydrogen bonds, as well as, C-H···π
interactions between the phenyl groups in the triphenylphoshpine ligand. These
chains are arranged in an antiparallel fashion bound by  stacking through the phen
moiety (interplanar distance 3.5 Å). Even though the same intermolecular
interactions are observed for 3, the packing diagram in this case shows intercalated
zig zag chains, with C-H···Cl (H···Cl distances 2,87-3,28 Å) hydrogen bonding and
weak  stacking (interplanar distance 3.7 Å) within and C-H···π (H···π distance 3.09
Å) bonds between adjacent chains.
Hirshfeld surfaces and their corresponding 2D fingerprint plots were constructed
using CrystalExplorer software [50] and used to interpret intermolecular interactions
semiquantitatively [51, 52]. Fingerprint plots are included as supplementary material.
The shape of the fingerprint plots confirms the presence of the interactions
discussed above. It is worth highlighting that the most polar intermolecular bonds
found in these structures are non classic hydrogen bonds. Particularly, in the
fingerprint plot H···Cl contacts correspond to 10.5% and 8.9% of the total contacts in
2
and 3, respectively. In 2 there is also a contribution of 2.3% due to H···O contacts.
Being 2 the structure with the most and the shorter polar contacts, it could be
expected to be more polar than 3.
3
.2 Infrared spectra
The infrared spectra of the complexes present similar features, as shown in figure 4.
-
1
Vibrations in the range of 2900-3500 cm are attributed to C-H stretching vibrations
in the ligands for all complexes. Other distinctive bands, like the ones due to C-N, C-
-
1
C stretching and C-H rocking appear around 1585 and 1150-1260 cm , respectively
[
53]. Absorption bands typical of the triphenylphosphine ligand appear in the range
-
1
5
00-525 cm [54]. These common features of the infrared spectra of the complexes
suggest that 1 presents a coordination scheme similar to that observed for 2 and 3.
Figure 4. Infrared Spectra of 1, 2 and 3.

-
1
Table 4. Wavenumber (cm ) of representative absorption bands in the complexes,
as well as their tentative assignment.
v (O–H)
v (C–H)
3428
v (C–C), v (C–N)
1585
ν(P-C), ρ(C-H)
1091
ρ(C-H), δ(C–C–C), δ(C–C–N)
1
2
3
851
858
845
3476
3414
1584
1092
3431
1588
1090
3
.3 Stability of the Cu(I) compounds in solution.
EPR was used to check whether copper compounds remained as Cu(I) or were
rapidly oxidized to Cu(II) in solution. DMSO solutions present no EPR signal, even
after several weeks. As an approach to biological studies conditions, water was
added to the DMSO solution and the EPR spectrum was repeatedly registered
during 48h. Compounds 1 and 2 show a slow apparition of the characteristic Cu(II)
signal in 48 h, meanwhile compound 3 shows no EPR signal in 48 hours. Therefore
Cu remains mainly in the Cu (I) oxidation state in DMSO/water solution in the
biological assays time frame. EPR spectra of the solutions are included as
supplementary material.
3
.4 Lipophilicity

Lipophilicity is a relevant parameter as it influences the pharmacodinamic of a drug,
specially its ability to permeate cellular membranes. Table 5 shows the lipophilicity
(
expressed as R ) of the complexes. All complexes are more lipophilic than both
M
ligands. This fact is in agreement with the observed coordination, where the
hydrophilic groups are bonded to the Cu(I) and hindered from the solution. The
lipophilicity of the complexes follows the same order found for the di-imine ligand.
Table 5.
Compound
PPh3
dmb
R
M
-0,09
-0,25
-0,19
-0,14
0,27
phen
neo
[
[
[
CuCl(PPh
CuCl(PPh
CuCl(PPh
3
)(dmb)]
)(phen)]
)(neo)]
3
0,30
0,45
3
3
.5 Cytotoxic activity
Table 6 presents the IC50 values for the studied complexes. All the complexes
present higher cytotoxic activity (lower IC50) on HeLa, MDA MB 231 and A459 cells
than Cisplatin and according to Santini et al.[1] may be classified as very active (IC50
in the low micromolar range). The cytotoxic activity increases in the same order as
observed for the lipophilicity, being [CuCl(neo)(PPh
This observation is in agreement with the hypothesis that the complexes act as
copper ionophores” that deliver copper inside the cell [10, 55].
3
)] the most lipophilic and active.
“
In other series of Cu(II) mixed ligand complexes containing di-imines, a similar
relation between the aromatic di-imine ligand and the cytotoxic activity was
observed, being the Cu-neocuproine-coligand system the most active of the series
[
56]. This highlights the pharmacological potential of the Cu-neocuproine moiety.

With relation to the mechanisms underlying the biological activity of Cu-complexes
they are, to the date, not completely known [11, 57]. Taken into account our results
and the information in the literature it can be proposed that the cytotoxic activity of
Cu-di-imine -phosphine complexes is due to:
-
DNA interaction in an alternative way than observed for Cisplatin. We have
previously study several Cu-phen containing complexes that intercalate
isolated DNA though the di-imine moiety [40, 41] . It has been also observed
in several Cu-phen-derivatives containing complexes [1].
-
Generation of reactive oxygen species (ROS) which oxidize and degrade
DNA [58]. ROS production in vitro has been observed for related complexes.
Our complexes are likely to degrade DNA. We tried to determine its DNA
binding but this measurement was hampered as we systematically had
evidence of DNA degradation (data not published).
-
-
Mitochondrial toxicity as observed in the literature for related Cu-complexes
[
59].
Cellular death by an apoptotic mechanism induced by the molecular events
previously described as observed for Cu-bi-imine complexes [1, 59]. In spite
of that cellular death by a parapoptotic mechanism can´t be ruled out as it has
been reported for Cu-phosphine complexes [9, 10].
Table 6. Cytotoxic activity (expressed by IC50) of the studied complexes against
HeLa (human cervical adenocarcinoma), MDA MB 231 (human metastatic breast
adenocarcinoma) and A459 (human lung epithelial carcinoma) cell lines.
Compound
IC HeLa (M) IC MDA MDB 231(M)
IC50
A459
50
50

(
M)
[
[
[
CuCl(dmbpy)(PPh
CuCl(phen)(PPh )]0,25H2O
CuCl(neo)(PPh )]
3
)]
4
3
2
8.4
4.3
1.4
4.5
3.5
3
.6
.8
3
1.3
50
Cisplatin
30
5
0
Conclusions
Three new Cu(I)-complexes were prepared an characterized, including two new
crystal structures. Complex [CuCl(neo)(PPh
DMSO/water solution.
3
)] is particularly redox-stable in
The complexes present high cytotoxic activity on the studied tumor cells, being the
CuCl(neo)(PPh )] the most active.
[
3
Supplementary material
Supplementary crystallographic data can be obtained free of charge from The
Cambridge Crystallographic Data on request, quoting deposit numbers:
CCDC 1479605 (C2), and CCDC 1479606 (C3). Fingerprint plots and EPR spectra
are presented in Figs. S1 and S2 respectively.
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[
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[
[
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To find new leaders for the development of antitumor Cu compounds, heteroleptic Cu(I) complexes
with triphenylphosphine (PPh ) and dimethylbipyridine (dmbpy), phenanthroline (phen) or
neocuproine (neo) were prepared and characterized. The crystal structures of compounds 2 and 3
3
were determined. [CuCl(neo)(PPh
being more active than Cisplatin.
3
)] (figure) presents high cytotoxic activity against tumor cell lines,

To find new leaders for the development of antitumor Cu compounds, heteroleptic Cu(I) complexes
with triphenylphosphine (PPh ) and dimethylbipyridine (dmbpy), phenanthroline (phen) or
3
neocuproine (neo) were prepared and characterized.
The crystal structures of compounds 2 and 3 were determined.
[
CuCl(neo)(PPh
3
)] presents high cytotoxic activity against tumor cell lines, being more active than
Cisplatin.