New insights on cytotoxic activity of group 3 and lanthanide compounds: Complexes with [N,N,N]-scorpionate ligands

Article abstract of DOI:10.1111/jphp.12112

Objectives In this work was to evaluate the cytotoxic activity of a series of monomeric group 3 and lanthanide (N,N,N)-heteroscorpionate-triflate complexes (M (OTf) 2 (cybpamd) (THF)) (Ln = Sc (2), Y (3), La (4), Nd (5), Sm (6), Dy (7), Yb (8); OTf = SO3CF3; cybpamd = N, N′-dicyclohexyl-2,2-bis-(3,5- dimethyl-pyrazol-1-yl)-acetamidinate) having octahedral geometry around the metal atoms on the human epithelial lung adenocarcinoma (A549), human melanoma (A375), human cervical epithelial adenocarcinoma, human embryonic kidney (HEK-293) and murine macrophages (J774.A1) cell lines. Methods All the tested compounds were incubated with cells for 72 h and their growth inhibition assessed by using MTT assay. Key findings On the cell line HEK-293 complexes 5 and 7 show a reasonable activities, while the murine macrophage cell line (J774.A1), only the scandium 2 complex is not very active. All complexes tested are poorly active on human health adenocarcinoma lung epithelial (A549) and human melanoma (A375). Conclusions The group 3 and lanthanide (N,N,N)-heteroscorpionate triflate-complexes (M(OTf)2(cybpamd)(THF)) on murine macrophage (J774.A1) cell line, except that of scandium, show a reasonable activity. On human epithelial cervix adenocarcinoma (HeLa) complexes 3, 5 and 6 are significantly more active than cis-platinum, as well as complex 5 is more active on human embryonic kidney (HEK-293) cell line. All the tested complexes are poorly active on human epithelial lung adenocarcinoma (A549) and human melanoma (A375). The different behaviour of the complexes examined (2-8) let us hypothesize that the cytotoxic activity is related to the molecule as a whole and not only to the ligand or the metal ion separately.

Full text of DOI:10.1111/jphp.12112

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Research Paper
Journal of Pharmacy
And Pharmacology
New insights on cytotoxic activity of group 3 and
lanthanide compounds: complexes with
[N,N,N]-scorpionate ligands
Carmela Saturninoa, Marco Bortoluzzib, Mariagrazia Napolic, Ada Popoloa, Aldo Pintoa,
Pasquale Longoc and Gino Paoluccib
aDipartimento di Scienze Farmaceutiche, Università di Salerno, Fisciano, Italy, bDipartimento di Scienze Molecolari e Nanosistemi, Università Ca’
c
Foscari di Venezia, Venezia, Italy and Dipartimento di Chimica, Università di Salerno, Fisciano, Italy
Keywords
cytotoxic activity; HEK-293; HeLa; J774.A1;
Abstract
Objectives In this work was to evaluate the cytotoxic activity of a series of mono-
meric group 3 and lanthanide (N,N,N)-heteroscorpionate-triflate complexes
(M (OTf) 2 (cybpamd) (THF)) (Ln = Sc (2), Y (3), La (4), Nd (5), Sm (6), Dy (7),
Yb (8); OTf = SO3CF3; cybpamd = N, N'-dicyclohexyl-2,2-bis-(3,5-dimethyl-
pyrazol-1-yl)-acetamidinate) having octahedral geometry around the metal atoms
on the human epithelial lung adenocarcinoma (A549), human melanoma (A375),
human cervical epithelial adenocarcinoma, human embryonic kidney (HEK-293)
and murine macrophages (J774.A1) cell lines.
metal complexes
Correspondence
Carmela Saturnino, Dipartimento di Scienze
Farmaceutiche, Università di Salerno, Via
Ponte don Melillo, 84084 Fisciano (SA), Italy.
E-Mail: saturnino@unisa.it
Gino Paolucci, Dipartimento di Scienze
Molecolari e Nanosistemi, Università Ca’
Foscari di Venezia, Dorsoduro 2137, 30123
Venezia, Italy.
Methods All the tested compounds were incubated with cells for 72 h and their
growth inhibition assessed by using MTT assay.
E-mail: paolucci@unive.it
Key findings On the cell line HEK-293 complexes 5 and 7 show a reasonable
activities, while the murine macrophage cell line (J774.A1), only the scandium 2
complex is not very active. All complexes tested are poorly active on human health
adenocarcinoma lung epithelial (A549) and human melanoma (A375).
Conclusions The group 3 and lanthanide (N,N,N)-heteroscorpionate triflate-
complexes (M(OTf)2(cybpamd)(THF)) on murine macrophage (J774.A1) cell
line, except that of scandium, show a reasonable activity. On human epithelial
cervix adenocarcinoma (HeLa) complexes 3, 5 and 6 are significantly more active
than cis-platinum, as well as complex 5 is more active on human embryonic
kidney (HEK-293) cell line. All the tested complexes are poorly active on human
epithelial lung adenocarcinoma (A549) and human melanoma (A375).
The different behaviour of the complexes examined (2–8) let us hypothesize
that the cytotoxic activity is related to the molecule as a whole and not only to the
ligand or the metal ion separately.
Received July 2, 2012
Accepted June 15, 2013
doi: 10.1111/jphp.12112
Introduction
After the great success as antitumour drug of cis-platin, (cis-
(NH3)2PtCl2), especially in the clinical treatment of ovarian,
testicular, neck and head cancers, considerable research
activity has been developed to obtain new organometallic
compounds that do not present the limits of applicability
of the cis-platin and of its analogues.[1] In fact, cis-platin
gives severe toxic side effects, comprising nephrotoxicity
and neurotoxicity, which limit the dose that can be
given to patients. So, a second generation of platinum
drug, carboplatin (1,1-cyclobutanedicarboxylato(2-)-O,O’-
platinum(II)), was introduced in clinic in mid-1980s. The
compound is devoid of nephrotoxicity along with reduced
gastrointestinal tract toxicity and neurotoxicity. Further-
more, carboplatin allows treatment with higher doses of the
drug because of its lower toxicity.[2,3]
The third generation of platinum drugs includes oxali-
platin, which overcomes cis-platin resistance and is specific
for common cancer diseases (colon or rectal that has
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Carmela Saturnino et al.
Cytotoxic studies of group 3 complexes
metastasized, testicular and ovarian), it has less ototoxicity
and nephrotoxicity than cisplatin and carboplatin.[4]
Complexes of many metals in the periodic table have
been studied up to now, including those of group 3, which
have shown a significant biological activity.[5]
reported the synthesis and characterization of scandiu-
m(III), yttrium(III), samarium(III) and neodymium(III)
chloro- or triflate-complexes with tridentate mono-
anionic quinoline-phenoxy-amine, quinoline-phenoxy-
imine and ansa-monocyclopentadienyl-imino-pyridine
ancillary ligands, and their cytotoxic activity was evaluated
on rat glioma (C6), murine fibroscarcoma (WHEI-164) and
human embryonic kidney (HEK-293) cell lines.[24]
Hence, the complexation of lanthanides with heterocyclic
ligands having more than one donor atom is of great inter-
est in the chemistry of coordination compounds, as the
complexation can lead to compounds with significant cyto-
toxic effects.
Homoscorpionate and heteroscorpionate compounds
have shown to be very interesting species for the synthesis
of a wide range of stable group 3 elements and lanthanide
derivatives. Scorpionates represent attractive and versatile
ligands because of their fine-tuning of the electronic and
steric properties and consequently for the control of the
metal coordination sphere.[25–34]
In a previous study, our group reported the synthesis and
characterization of a series of group 3 and lanthanide (N,N,N)-
heteroscorpionate complexes with k3-NNN-coordination of
the heteroscorpionate ligand N,N’-dicyclohexyl-2,2-bis-(3,5-
dimethyl-pyrazol-1-yl)-acetamidinate (cybpamd).[35] In this
study, we detail on cytotoxic screening and further investiga-
tion of (Ln(OTf)2(cybpamd)(THF)) (where Ln = Sc (2), Y
(3), La (4), Nd (5), Sm (6), Dy (7), Yb (8); OTf = SO3CF3) and
THF = tetrahydrofuran.
Many of the pharmacological properties of the metals of
group 3 are due to their affinity for Ca2+ sites in biological
molecules and to the formation of a stronger bond with
water molecules. Moreover, they can also replace the metal
ions Mg2+, Mn2+ and Fe3+ in the biological processes.[5,6]
The lanthanides can replace calcium in the protein, and
so calcium-dependent enzymes can be inhibited or be acti-
vated by lanthanides. It has been proposed that the stimula-
tion or the inhibitory effect of the lanthanides may be a
function of role of calcium in the native enzyme. If calcium
plays a catalytic role, its substitution with a group 3 ion
leads to the deactivation of the enzyme, and the degree of
inhibition depends on the ionic radius of metal. Instead, if
calcium plays a structural role, the replacement with a M3+
ion gives, at least, the maintenance of the activity.[5,6]
Accordingly, the mode of action of anticancer-active
group 3 metals is related to their possible inhibition of
function of ions essential for cells cycle regulation, and anti-
tumour activity is significantly enhanced by complexation
with various ligands.
In fact, lanthanide complexes with coumarins exhibited
superior activity in various tumour models as compared
with the corresponding inorganic salts. Coumarins are an
important group of organic compounds that show a wide
variety of biological activity as antitumour and antiprolif-
erative effects.[7–10] Complexes of rare earth metal as
cerium(III), lanthanum(III) and neodymium(III), having
coumarines as ligand, were examined on different cell
lines.[11]
Results and Discussion
Chemistry
Rogers and coworkers reported the cytotoxic activity of
acenocumarol samarium(III) and gadolinium(III) com-
plexes against melanoma B16 and fibrosarcoma L929 cell
lines.[12]
Lanthanide complexes having macrocyclic monoanionic
ligands containing five coordinating nitrogen atoms in the
central core, the texaphyrins, have progressed into clinical
trials.[13,14]
Furthermore, it has been reported that a series of ceriu-
m(III) complexes with bipyridyl or phenanthroline ligands
showed an interesting antiproliferative activity against
tumoral cell lines. Recently, the lanthanum complex of
phenanthroline derivative (KP772) has shown to exert com-
parable activity with that of cis-platin and methotrexate
against a wide range of tumour cell lines in vitro and a
colon carcinoma xenograft model in vivo.[15,16]
Synthesis of N,N’-dicyclohexyl-2,2-bis-(3,5-dimethyl-
pyrazol-1-yl)-acetamidine (cybpamd-H) (1) and (Ln(OTf)2
(cybpamd)(THF)) complexes (Ln = Sc (2), Y (3), La (4), Nd
(5), Sm (6), Dy (7), Yb (8); OTf = SO3CF3) were carried out
as follows.
The organic compound N,N’-dicyclohexyl-2,2-bis-(3,5-
dimethyl-pyrazol-1-yl)-acetamidine (cybpamd-H) (1) was
prepared, according to Otero et al.,[36] by reacting bis-(3,5-
dimethyl-pyrazol-1-yl)methane with butyllithium in THF
at low temperature to form in situ the corresponding
lithium salt, which was subsequently reacted with one
equivalent of dicyclohexylcarbodiimide. The quench of the
reaction mixture with cold water allowed the formation of
the final product, which was purified following common
procedures and isolated in high yield (see Figure 1).
The neutral triflate complexes (Ln(OTf)2(cybpamd)
(THF)) (Ln = Sc (2), Y (3), La (4), Nd (5), Sm (6), Dy (7),
Yb (8); OTf = SO3CF3) were all prepared as reported in
the literature[35] in ca. 70% yield by allowing to react
Recently, it has been evaluated the cytotoxic activity of a
significant number of new complexes of metals of group 3
and lanthanides with heterocyclic ligands,[17–23] and we have
© 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 65, pp. 1354–1359
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Cytotoxic studies of group 3 complexes
Carmela Saturnino et al.
N
C
1) BuLi 2)
N
N
NH
N
N
N
N
N
N
N
THF
N
1) Ln(OTf)3
2) BuLi
3) H2O
N
THF
N
N
N
N
N
TfO
Ln
TfO
THF
Ln = Sc (2), Y (3), La (4), Nd (5), Sm (6), Dy (7), Yb (8)
Figure 1 Sunthetic route for the preparation of metal complexes 2–8.
cybpamd-H with a stoichiometric amount of anhydrous
Ln(OTf)3 salt in THF and subsequent addition of diluted
butyllithium (see Figure 1).
that affords a 50% reduction in cell growth as compared
with control cells, reported in Table 1. Cis-platin is also
included for comparison, and it was chosen for testing the
susceptibility of our cell lines to cytotoxicity.
All the tested compounds, as detailed into experimental
part, were incubated with cells for 72 h and their growth
inhibition assessed by using 3-(4,5-dimethylthiazol-2-yl)-
2,5-phenyl-2H-tetrazolium bromide (MTT) assay.[37]
As previously reported,[35] in these complexes, the anionic
ligand cybpamd acts as tridentate with the two pyrazole
rings, and only one amidinate nitrogen atom strongly
bonded to the metal centre. The coordination mode of the
1
2
two triflate groups appears comprised between k and k ,
while the THF molecule results only weakly bonded.
It is important to note that the cell lines used in this
study are very different from each other, as denoted by the
different response to cis-platin (Table 1). No cytotoxic activ-
ity was exerted by Ln(OTf)3 (Ln = Sc, Y, La, Sm, Nd, Dy, Yb)
on any of the cell lines used. The free ligand cybpamd-H is
active only on HeLa cells. In fact, on this cell line, the free
ligand showed a cytotoxic activity comparable with that of
cis-platin. However, the IC50 values of complexes 2–5 and 6
were lower than that of the free ligand, demonstrating that
the presence of metal potentiates the activity. Human
embryonic kidney (HEK-293) cell lines are poorly sensitive
to the examined compounds, and only complex 7 has a
cytotoxic effect comparable with that of cis-platin. This
result suggests that the cytotoxic activity on HEK-293 cells
is strongly dependent upon the ionic radius of the metal
ion. Also on murine macrophage (J774.A1) cell lines, a role
Cytotoxicity studies
The cytotoxic activity of complexes 2–8 have been evaluated
on human epithelial lung adenocarcinoma (A549), human
melanoma (A375), human epithelial cervix adenocarci-
noma (HeLa), human embryonic kidney (HEK-293) and
murine macrophage (J774.A1) cell lines. The same studies
have been carried out also on the simple lanthanide triflate
and on the free ligand, which is N,N’-dicyclohexyl-2,2-bis-
(3,5-dimethyl-pyrazol-1-yl)-acetamidine (cybpamd-H) (1)
at the pH value of the biological experiments. Complexes 4
and 8 were tested against only one cell lines: that is, HEK-
293. The IC50 (the half maximal inhibitory concentration)
value, expressed as mm, is the concentration of compound
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Carmela Saturnino et al.
Cytotoxic studies of group 3 complexes
Table 1 Effect of complexes 2–8 and of 1 on several cell lines viability
Cell lines
A375
Compound
HEK
J774.A1
A549
HeLa
Sc 2
Y 3
>100
>100
>100
97 Ϯ 1.3
>100
76 Ϯ 5.77***
>100
38 Ϯ 3
—
>100
>100
—
>100
6.2 Ϯ 0.95***
La 4
Nd 5
Sm 6
Dy 7
Yb 8
—
—
85 Ϯ 4.3***
73 Ϯ 1.5***
70 Ϯ 3.7***
—
>100
>100
>100
—
62 Ϯ 4.3
12 Ϯ 1.8***
5.7 Ϯ 0.2***
22 Ϯ 1.2
—
>100
56 Ϯ 1.12*
>100
>100
>100
>100
43 Ϯ 4.2
—
a
Ln(OTf)3
>100
>100
>100
>100
>100
0.49 Ϯ 0.05
>100
>100
6.5 Ϯ 0.2
>100
18 Ϯ 1.6
cybpamd-H 1
Cis-Pt
67 Ϯ 4.2
15 Ϯ 1.2
aLn = Sc, Y, La, Sm, Nd, Dy, Yb. The viability of control cells was designated as 100%, and results were expressed as the concentration (mM) of each
complex able to induce the 50% of mortality in each cell line (IC50). Results are expressed as mean Ϯ SEM from at least three independent experi-
ments. Kruskal–Wallis test was used for statistical analysis. *denotes P < 0.05, and ***denotes P < 0.0001 versus cis-Pt on the same cell line.
to the ionic radius can be ascribed, having the scandium
complex a very high IC50 (>100 mm), whereas the other
examined complexes have an activity superior (P < 0.001)
Experimental Section
Chemistry
to that of cis-platin. Finally, human epithelial lung adeno-
carcinoma (A549) and human melanoma (A375) are poorly
responsive to synthesized compounds 2–8, and a concentra-
tion almost 10 times higher than that of cis-platin was
required.
The ligand cybpamd-H 1 and the complexes 2–8 were pre-
pared as reported in the literature.[35] All manipulations
were carried out under oxygen- and moisture-free atmos-
phere in a MBraun MB 200 glove-box (MBraun GmbH,
Garching, Germany). All the solvents were thoroughly
deoxygenated and dehydrated under argon by refluxing
over suitable drying agents, while NMR deuterated solvents
(Euriso-Top products, Euriso-Top, C.E. Saclay, France) were
kept in the dark over molecular sieves. The anhydrous
triflate salts M(OTf)3 (M = Sc, Y, La, Nd, Sm, Dy, Yb;
OTf = CF3SO3) (Strem Chemicals Inc., Kehl, Germany;
Sigma-Aldrich Chemie GmbH, Steinheim, Germany) were
used as received, as the organic reactants (Aldrich) required
for the synthesis of 1. The synthesis of the desired products
was verified by recording their 1H and 13C (1H) NMR
spectra, using a Bruker Avance 300 spectrometer (Bruker
Spectrospin, Zuerich, Switzerland) operating at 300 MHz
(1H) and 75 MHz (13C).
The stability of 1 was tested by dissolving 50 mg of the
neutral compound in 30 ml of DMSO and 3 ml of water.
The solution was left under stirring for 72 h, then water
(100 ml) was added and the product was extracted with
dichloromethane (50 ml). The traces of water were removed
from the organic solution by addition of anhydrous sodium
sulfate. After removal of the solvent by evaporation under
reduced pressure, the 1H NMR was recorded in CDCl3.
By considering that Ln3+ ions are hard acid and that they
preferably coordinate hard donor atoms such as oxygenated
species, we had the suspect that in the medium used for the
tests (dimethylsulfoxide (DMSO)/H2O), the complexes
could not maintain the coordination with the ligand con-
taining only N-donor atoms (less hard then O-donor
atoms). The different cytotoxic activity between the free
ligand and the corresponding complexes, in particular on
the HEK, J774.A1, A375 and A549 cells, suggests that the
ligand-metal bonds are almost partially maintained in bio-
logical media. On considering that the negative charge of
the tridentate ligand is located on the acetamidinate group
and that the lanthanide ions give stronger bonds with nega-
tively charged nitrogen atoms, probably, the complexes
maintain in solution the acetamidinate–Ln3+ interaction,
while the coordination sphere is saturated by water and
dimethylsufoxide molecules. We have also verified that the
acetamidine group is not hydrolysed under the experimen-
tal conditions used. To do this, cybpamd-H has been main-
tained in a DMSO solution containing the 10% of water for
72 h at room temperature. The subsequent extraction
(water/CH2Cl2) has led to the initial product, as verified by
Nuclear Magnetic Resonance (NMR) spectroscopy.
Antiproliferative activity
Thus, the different behaviour of the complexes exam-
ined (2–8) shows that the cytotoxic activity is related to
the molecule as a whole and not only to the ligand or the
metal ion.
Human epithelial lung adenocarcinoma (A549), human
melanoma (A375), human epithelial cervix adenocarci-
noma (HeLa), human embryonic kidney (HEK-293) and
© 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 65, pp. 1354–1359
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Cytotoxic studies of group 3 complexes
Carmela Saturnino et al.
murine macrophage (J774.A1) cell lines (3.5 ¥ 104 cells/
well) were plated on 96-well microtitre plates and allowed
to adhere at 37 °C in a 5 % CO2 atmosphere for 2 h.
Thereafter, the medium was replaced with 50 ml of fresh
medium, and a 75-ml aliquot of serial dilution of each test
compound was added and then the cells were incubated
for 72 h. In some experiments, serial dilutions of cis-platin
were added. Mitochondrial respiration, an indicator of
cell viability, was assessed by the mitochondrial-dependent
reduction of MTT to formazan, and cells viability was
assessed accordingly to the method of Mosmann.[37]
Briefly, 25 ml of MTT (5 mg/ml) were added, and the cells
were incubated for an additional 3 h. Thereafter, cells were
lysed and the dark blue crystals solubilized with 100 ml of a
solution containing 50% (v:v) N,N-dimethylformamide,
20% (w:v) SDS (sodium dodecyl sulphate) with an adjusted
pH of 4.5 (Opipari et al., 1992).[38] The OD of each well was
measured with a microplate spectrophotometer (Titertek
Multiskan MCC/340, Toronto, Canada) equipped with a
620-nm filter. The viability of each cell line in response to
treatment with tested compounds and 6-mercaptopurine
was calculated as: % dead cells = 100-(OD treated/OD
control) ¥ 100.
(THF)) (M = Sc (2), Y (3), La (4), Nd (5), Sm (6), Dy
(7), Yb (8); OTf = SO3CF3; cybpamd = N,N’-dicyclohexyl-
2,2-bis-(3,5-dimethyl-pyrazol-1-yl)-acetamidinate), having
octahedral geometry around the metal atoms, have been
tested to evaluate their cytotoxic activity on: human epithe-
lial lung adenocarcinoma (A549), human melanoma
(A375), human epithelial cervix adenocarcinoma (HeLa),
human embryonic kidney (HEK-293) and murine macro-
phage (J774.A1) cell lines. On murine macrophage
(J774.A1) cell line, all tested complexes, except that of scan-
dium, show a reasonable activity. On human epithelial
cervix adenocarcinoma (HeLa) complexes 3, 5 and 6 are sig-
nificantly more active than cis-platinum, as well as complex
5 is more active on human embryonic kidney (HEK-293)
cell line. All the tested complexes are poorly active on
human epithelial lung adenocarcinoma (A549) and human
melanoma (A375).
It is worth emphasize that the lanthanide triflate com-
pounds show no cytotoxic activity on any of the cell
lines tested, and N,N’-dicyclohexyl-2,2-bis-(3,5-dimethyl-
pyrazol-1-yl)-acetamidine (cybpamd-H), the used ligand,
shows a quite good activity only on human epithelial cervix
adenocarcinoma (HeLa), however lower than the complexes
3, 5 and 6.
Statistical methods
Thus, the different behaviour of the complexes examined
(2–8) let us hypothesize that the cytotoxic activity is related
to the molecule as a whole and not only to the ligand or the
metal ion separately.
The IC50 was calculated, as described earlier and in the
caption of the Table 1, by evaluating the average of three
different experiments, each performed in triplicate. Results
are expressed as mean Ϯ SEM (standard error of the mean).
Kruskal–Wallis test was used for statistical analysis. A value
of P < 0.05 was considered as statistically significant.
Acknowledgements
We wish to thank Italian Ministry of University and
Research for financial support of this work. The authors are
grateful to Dr. I. Immediata and Dr. P. Oliva for helpful
technical support.
Conclusion
A series of monomeric group 3 and lanthanide (N,N,N)-
heteroscorpionate triflate-complexes (M(OTf)2(cybpamd)
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