Novel platinum(II) complexes of 3-(aminomethyl)naphthoquinone Mannich bases: Synthesis, crystal structure and cytotoxic activities

Article abstract of DOI:10.1039/c0dt00572j

The first examples of platinum(II) complexes of 3-(aminomethyl) naphthoquinone Mannich bases have been synthesised and their crystal structures are described. Neutral and charged complexes have been obtained, fully characterised and their cytotoxic activi

Full text of DOI:10.1039/c0dt00572j

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www.rsc.org/dalton | Dalton Transactions
Novel platinum(II) complexes of 3-(aminomethyl)naphthoquinone Mannich
bases: synthesis, crystal structure and cytotoxic activities†
Amanda P. Neves,a Gustavo B. da Silva,a Maria D. Vargas,*a Carlos B. Pinheiro,b Lorenzo do C. Visentin,c
Jose´ D. B. M. Filho,d Ana J. Arau´jo,d Let´ıcia V. Costa-Lotufo,d Cla´udia Pessoad and Manoel O. de Moraesd
Received 28th May 2010, Accepted 21st July 2010
DOI: 10.1039/c0dt00572j
The first examples of platinum(II) complexes of 3-(aminomethyl)naphthoquinone Mannich bases have
been synthesised and their crystal structures are described. Neutral and charged complexes have been
obtained, fully characterised and their cytotoxic activities have also been investigated.
3-[(R1-amino)(pyridin-2-yl)methyl]-2-hydroxy-1,4-naphthoquinones (R1 = n-Bu, HL1; Bn, HL2;
furfuryl, HL3; n-heptyl, HL4 and n-decyl, HL5) coordinate to platinum(II) through the two nitrogen
atoms. The neutral complexes cis-[Pt(HL)Cl2] 1a–5a are analogous to cisplatin with the bidentate ligand
HL and two chlorine atoms occupying cis positions. In the charged complexes cis-[Pt(L-)(NH3)2]NO3
1b–5b the deprotonated form of the ligand L- also coordinates via the nitrogen atoms, and the other
two positions around the platinum(II) ion are completed with NH3 ligands. The cytotoxic activities of
all compounds have been tested for six different cancer cell lines: MDA-MB-435 (melanoma), HL-60
(promyelocytic leukaemia), HCT-8 (colon), SF-295 (brain), OVCAR-8 (ovary) and PC-3 (prostate).
Proligands HL4 and HL5 have exhibited high activity against HL-60 (IC50 = 1.9 and 3.8 mmol L-1,
respectively), HCT-8 (IC50 = 1.6 and 1.7 mmol L-1, respectively) and SF-295 (IC50 = 1.1 and 1.7 mmol
L-1, respectively). The chlorido complexes 1a–5a have shown high to moderate cytotoxic activities,
complex 4a (R1 = n-heptyl) being more active than proligand HL4 against melanoma (IC50 = 6.4 and
> 40 mmol L-1, respectively) and more active than cisplatin against all tested cell lines. Among the
amine charged complexes only 4b and 5b have exhibited significant cytotoxic activity against the tested
cell lines, although they were only moderately active against the PC-3 cell line (IC50 = 29.9 and
15.6 mmol L-1, respectively). In general the compounds with the longest carbon chains (R1 = n-heptyl
and n-decyl) have exhibited the highest activities.
cyclohexane-1,2-diamine](ethanedioato-O,O¢)platinum(II)) which
have achieved widespread clinical use.4,5
Introduction
Platinum-based drugs have been extensively investigated since
the first report of the tumour inhibiting properties of cisplatin
[cis-diamminedichloridoplatinum(II)] by Rosenberg in 1969.1 This
drug is widely used in chemotherapy to treat a variety of
cancers.2 Despite its success in the treatment of certain tumours,
cisplatin has shown severe side effects, such as nephrotoxicity
and neurotoxicity, as well as the development of resistance,
which have been limiting its effectiveness.3,4 Several “second-
generation” drugs have been designed and shown, in some cases,
improvement in the toxicity and/or potential use against cisplatin-
resistant tumours such as carboplatin (cis-diammine(cyclobutane-
1,1-dicarboxylate-O,O¢)platinum(II)) and oxaliplatin ([(1R,2R)-
Although most of the early platinum drugs are based on the
cisplatin structure, many non-traditional platinum compounds,6
including platinum(IV), trans and multinuclear compounds have
been synthesised and shown promising results. For example, BBR-
3464, with two reactive platinum centres, exhibits high cytotoxicity
and overcomes acquired cisplatin resistance.7
Even four decades after the discovery of cisplatin as an antitu-
mour drug, the desire to find new platinum-based compounds
exhibiting high cytotoxicity, low side effects and that are able
to overcome clinical resistance to the currently used drugs still
motivates research in this area.8
A wide variety of molecules have been attached to platinum(II),
from simple amines9 to bioactive compounds, such as porphyrins,
hormones and anthraquinones.10 Quinone derived compounds,
such as naphthoquinones, are well known for their pharmacolog-
ical activities.11,12a The quinone nucleus is present in many drugs,
e.g. in anthracyclines, doxorubicin and mitomycin, which are used
in the therapy of solid cancers.13
The cytotoxic activity of naphthoquinones is still not totally
clear but studies have shown that it could be associated with factors
such as inhibition of topoisomerase,14 intercalation on DNA15
and generation of reactive oxygen species (ROS) in a process
known as quinone redox cycling.16 In this context, the design of
complexes which have two biologically active fragments (ditopic
aInstituto de Qu´ımica, Campus do Valonguinho, Universidade Federal
Fluminense, 24020-150, Nitero´i, RJ, Brazil. E-mail: mdvargas@vm.uff.br
bDepartamento de F´ısica, ICEX, Universidade Federal de Minas Gerais,
31270-901, Belo Horizonte, MG, Brazil
cInstituto de Qu´ımica, Universidade Federal do Rio de Janeiro, Ilha do
Funda˜o, 21945-970, Rio de Janeiro, RJ, Brazil
dDepartamento de Fisiologia e Farmacologia, Centro de Cieˆncias da Sau´de,
Universidade Federal do Ceara´, 60430-270, Fortaleza, CE, Brazil
† Electronic supplementary information (ESI) available: 1H, 13C and 195Pt
NMR spectra and cyclic voltammograms (CVs). CCDC reference numbers
766250 and 766251. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c0dt00572j
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Scheme 1 Chlorido 1a–5a and amino complexes 1b–5b of platinum(II) and 2-(aminomethyl)naphthoquinones.
complexes) can be an alternative approach to obtain compounds
Results and discussion
with improved cytotoxic activity.17
Synthesis of the compounds
To our knowledge, there is no example in the literature
of a 3-(aminomethyl)naphthoquinone platinum(II) complex, al-
though copper complexes were recently described12 and a few
platinum(II) complexes of aminonaphthoquinone-derivatives have
been reported.18
We report herein the synthesis, crystal structures and the
cytotoxic activities of a series of chlorido and amino platinum(II)
complexes of the Mannich base proligands 3-[(R1-amino)(pyridin-
2-yl)methyl]-2-hydroxy-1,4-naphthoquinone (R1 = n-Bu, HL1; Bn,
HL2; furfuryl, HL3; n-heptyl, HL4 and n-decyl, HL5, Scheme 1).
Proligands
3-[(R1-amino)(pyridin-2-yl)methyl]-2-hydroxy-1,4-
naphthoquinones (R1 = n-Bu, HL1; Bn, HL2; furfuryl, HL3; n-
heptyl, HL4 and n-decyl, HL5) were synthesised from the Mannich
reactions19 of 2-hydroxy-1,4-naphthoquinone (lawsone) with the
respective primary amines and 2-pyridinecarboxyaldehyde,
in ethanol, under stirring, at room temperature (Scheme 2).
According to analytical and spectroscopic data (see Experimental)
the compounds were obtained in a pure state and thus did not
need to be recrystallised after precipitation in solution. They are
Scheme
2
Synthesis of 3-(aminomethyl)naphthoquinones HL1–HL5 and their respective chlorido, cis-[Pt(HL1–5)Cl2] 1a–5a, and amino,
cis-[Pt(L1-5)(NH3)2]NO3 1b–5b, complexes.
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stable in the solid state, but undergo decomposition when kept in
solution for long periods of time.
The reactions of equimolar amounts of HL1–HL5 and cis-
[Pt(DMSO)2Cl2]20 (Scheme 2) in dimethylformamide (DMF)
yielded the chlorido complexes cis-[Pt(HL1–5)Cl2] 1a–5a as yellow
solids. These analogues of cisplatin are stable in the solid state and
in solution, insoluble in water, but very soluble in polar solvents,
such as alcohols, acetone, DMSO and DMF.
The amino complexes cis-[Pt(L1–5)(NH3)2]NO3 1b–5b were ob-
tained as orange powders from the reactions of the solid proligands
21
HL1–HL5 with a solution of cis-[Pt(NH3)2(DMF)2](NO3)2 in
DMF (Scheme 2). These complexes are soluble in water and
hygroscopic, with the exception of 4b, that is partially soluble
in water, and 5b, insoluble in water due to the large carbon side
chain (R1 = C10H25).
The proligands and complexes have been characterised by
1
IR, UV-Vis and H, 13C and 195Pt NMR spectroscopy, and the
structures of 1a and 3b, determined by X-ray diffraction analyses.
Description of the structures
Single crystals of 1a and 3b were obtained by slow evaporation
of their ethanol/isopropanol solutions. Compounds 1a and 3b
crystallise in the monoclinic system in P21/n and C2/c space
groups, respectively. The asymmetric unit of 3b is composed
by one cis-[PtL3)(NH3)2]+ cation, one NO3 counter ion and
-
3.5 H2O molecules. The asymmetric unit of compound 1a
is composed by two cis-[Pt(HL1)Cl2] molecules and one iso-
propanol solvent molecule. Differently from compound 1a the
2-(aminomethyl)naphthoquinone ligand of compound 3b is de-
protonated. The molecular structures and numbering schemes for
cis-[Pt(HL1)Cl2] and cis-[Pt(L3)(NH3)2]NO3 are shown in Fig. 1
and 2, respectively. Details of the structure determinations and
refinements are given in the Experimental. Selected bond lengths
and angles are given in Table 1.
Fig. 1 (a) View of the cis-[Pt(HL1)Cl2] 1a molecule with the labelling
scheme shown in (3 4 18) direction. The second molecule in the asymmetric
unit as well as the isopropanol solvent molecule were omitted for the
sake of simplicity. (b) View of the asymmetric unit of the cis-[Pt(HL1)Cl2]
structure (compound 1a) along a direction. Abnormal large displacement
parameter values for C39 and C40 carbon atoms suggested that this
group is disordered and they were refined with split positions. Atomic
displacement ellipsoids at the 50% level. Hydrogen atoms are represented
by open circles.
In complex 1a, both symmetry independent platinum(II) ions
(Pt1 and Pt2) are coordinated in a cis conformation to two
chloride ions and to one chelating ligand HL1 which binds
through the N2 of the pyridine ring and the aliphatic NH group,
forming five membered quelate rings N1/C11/C12/N2/Pt1 and
N3/C32/C31/N4/Pt2. The atoms N1, C11, C12, N2 and Pt1 are
situated in a plane and the deviation of the fitted least-squares
˚
plane through these atoms (r.m.s.) is about 0.106 A, C11 being the
˚
˚
most distant atom (-0.162(5) A). The atoms N3, C32, C31, N4 and
squares plane through these atoms (r.m.s.) is about 0.141 A, C31
˚
Pt2 are also situated in a plane and the deviation of the fitted least-
being the most distant atom (-0.208(7) A). The Pt–N and Pt–Cl
◦
˚
Table 1 Selected bond lengths (A) and angles ( ) for cis-[Pt(HL1)Cl2] 1a and cis-[Pt(L3)(NH3)2]NO3 3b in the crystals asymmetric units
[Pt(HL1)Cl2] 1a
[Pt(L3)(NH3)2]NO3 3b
Pt(1)–N(1)
Pt(1)–N(2)
Pt(1)–Cl(1)
Pt(1)–Cl(2)
N(1)–Pt(1)–N(2)
N(1)–Pt(1)–Cl(1)
N(2)–Pt(1)–Cl(1)
N(1)–Pt(1)–Cl(2)
N(2)–Pt(1)–Cl(2)
Cl(1)–Pt(1)–Cl(2)
2.074(7)
2.008(8)
2.310(2)
2.313(3)
82.6(3)
176.2(2)
95.0(2)
93.1(2)
174.2(2)
89.56(9)
Pt(2)–N(3)
Pt(2)–N(4)
Pt(2)–Cl(3)
Pt(2)–Cl(4)
N(3)–Pt(2)–N(4)
N(3)–Pt(2)–Cl(3)
N(4)–Pt(2)–Cl(3)
N(3)–Pt(2)–Cl(4)
N(4)–Pt(2)–Cl(4)
Cl(3)–Pt(2)–Cl(4)
2.073(7)
2.015(8)
2.301(2)
2.309(3)
83.0(3)
177.2(2)
94.2(2)
94.2(2)
176.2(2)
88.64(9)
Pt–N(1)
Pt–N(2)
Pt–N(3)
Pt–N(4)
N(1)–Pt–N(2)
N(1)–Pt–N(3)
N(2)–Pt–N(3)
N(1)–Pt–N(4)
N(2)–Pt–N(4)
N(3)–Pt–N(4)
2.043(7)
2.031(7)
2.050(7)
2.040(7)
82.2(3)
179.2(3)
97.7(3)
94.2(3)
176.0(3)
85.8(3)
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parameters values for C39 and C40 carbon atoms of the HL1
ligand suggesting that this group is disordered. Thus, atoms C39
and C40 were refined with split positions (Fig. 1(b)).
In the amino complex 3b, the platinum centre is surrounded
by the quelate ligand in its deprotonated form L3-, coordinated
through both Namine and Npyridine, and by two amino ligands.
The charge of the cis-[Pt(L3-)(NH3)2]+ monocation is neutralised
-
by a NO3 counter ion. The Pt–Namine and Pt–NH3 distances
are in the normal range when compared to those observed
for other platinum(II) complexes containing an N4 coordination
environment.23 The atoms N1, N2, N3, N4 and Pt are situated
in a plane and the deviation of the fitted least-squares plane
˚
through these atoms (r.m.s.) is about 0.021 A, N2 being the
˚
most distant atom (0.025(5) A). The packing of the molecules
is assured by a complex 3D network of hydrogen bonds between
cis-[Pt(L3)(NH3)2]+, NO3 and H2O molecules in which the latter
-
˚
occupy a cavity of approximately 7 A of diameter observed in
the structure projection along the c axis (Fig. 4). The structure
-
refinements indicated that the H2O molecules and NO3 ions are
all ordered.
Fig. 2 View of the asymmetric unit of the cis-[Pt(L3)(NH3)2]NO3 3b
structure with the labelling scheme. Crystallisation H2O solvents (Ow)
are also indicated despite the lack of precision in their hydrogen atoms
positions. Atomic displacement ellipsoids at the 50% level. Hydrogen
atoms are represented by open circles.
distance values can be considered typical and are similar to those
found in other cis-[Pt(amine)2Cl2] complexes.22 Strong hydrogen
bonds between symmetry related naphthoquinone groups as well
as between naphthoquinone and the isopropanol molecule assure
the crystal packing (Fig. 3). Indeed, from the packing point of
view, thetwoindependent cis-[Pt(HL1)Cl2]molecules aredifferent.
Atom O2 makes hydrogen bonds towards the O7i atom (i = 1 - x,
-y, 1 - z) of the isopropanol solvent molecule (O2–H2A ◊ ◊ ◊ O7i =
ii
˚
2.596(10) A) whereas atom O5 bonds to atom O4 (ii = 1 - x,
-1 - y, -z) from a symmetry related [Pt(HL1)Cl2] molecule (O5–
Fig. 4 cis-[Pt(L3)(NH3)2]NO3 3b structure projection along c direc-
tion. Grey areas indicate the channels in which only H2O solvent
molecules can be found. A complex 3D hydrogen bond network between
ii
˚
H5A ◊ ◊ ◊ O4 = 2.673(10) A), nevertheless, as mentioned before,
packing does not change the Pt atoms coordination. The structure
refinements of complex 1a indicated abnormal large displacement
cis-[Pt(L3)(NH3)2]+, NO3 and H2O assure the crystal packing.
-
Fig. 3 Packing of the structure of 1a indicating the most relevant hydrogen bonds between symmetry related cis-[Pt(HL1)Cl2] molecules and between
cis-[Pt(HL1)Cl2] molecule and the isopropyl alcohol solvent molecule. Symmetry operations: i = 1 - x, -y, 1 - z; ii = 1 - x, -1 - y, -z; iii = x, -1 + y,
-1 + z.
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Table 2 Electrochemical data at a scan rate of 100 mV s-1 obtained for HL1–HL5, 1a–5a and 1b–5b in CH3OH + 0.1 mol L-1 n-Bu4NClO4, at 25 ◦
C
E
pIc/V
E
pIa/V
E
pIIc/V
E
pIIa/V
EpIIaa/V
E
pIIIc/V
E
pIIIa/V
DEp/V
HL1
HL2
HL3
HL4
HL5
1a
—
—
-1.036
—
—
—
-0.707
—
—
—
-1.200
—
—
—
-0.807
—
—
—
—
—
-1.141
-1.156
—
-1.183
-1.218
—
—
—
—
—
-1.116
-1.068 (-0.848)c
-1.067
-1.158
-1.146
-0.811
-0.755
—
-0.816
-0.831
—
—
—
—
—
-0.966
-0.848
-0.890
-0.923
-0.930
0.330
0.401
0.329 (0.393)b
0.367
—
—
—
—
—
0.387
-0.652
-0.598
-0.640
-0.653
-0.639
—
—
—
—
—
-0.021
-0.102
-0.068
-0.003
-0.066
—
—
—
—
—
-1.158
-1.128
-1.145
-1.172
-1.151
—
—
—
—
—
-1.117
-0.977
-1.009
-0.976
-0.981
—
—
—
—
—
hidden
-1.090
-0.917
hidden
-0.912
—
—
—
—
—
0.631 (0.041)b
0.496 (0.151)b
0.572 (0.136)b
0.650 (0.196)b
0.573 (0.170)b
0.150
2a
3a
4a
5a
1b
2b
0.220
0.177
0.235
0.216
3b
4b
5b
a Data from voltammetric experiments in an anodic scan; potential values are reported vs. FcH/FcH+. b Data in parentheses correspond to the DEp of
the second process. c Data in parentheses correspond to peak IIIc* (Fig. S36, ESI†).
In both complexes, the coordination polyhedron around the
platinum(II) ion corresponds to a square-planar geometry with
only small angular distortions. Their unit cells contain a racemic
mixture of S/R enantiomeric pairs due to chiral C11 carbon
atom.
Electrochemistry studies
The electrochemical behaviour of proligands HL1–HL5 and their
respective platinum complexes 1a–5a and 1b–5b was investigated
in methanol solutions (at 1.0 ¥ 10-3 mol L-1) containing 0.1 mol
L-1 n-Bu4NClO4 as the supporting electrolyte, under an argon
atmosphere. Electrochemical data are summarised in Table 2. The
aim of this study was the search for possible correlations between
General characterisation
redox potential (i.e. the ease of reduction represented by Epc, E 1 or
The FT-IR spectra of all compounds show similar profiles, with
the O–H and N–H stretching bands appearing around 3400 and
3200 cm-1, respectively, and the aliphatic and aromatic C–H bands,
in the 3100–2800 cm-1 range. The carbonyl nCO absorptions appear
as a single band around 1680 cm-1 in the ligands spectra, and as two
bands around 1680 and 1645 cm-1, in the spectra of the complexes.
The electronic spectra, recorded in methanol, are characterised
by one intense absorption around 270 nm attributed to the p–p*
transitions of the naphthoquinone ring, and three ligand based
transitions in the 330–495 nm range.12,24
Significant changes in the 1H-NMR spectra of the proligands are
observed upon coordination to the platinum(II) ion. The strongest
evidence of complexation is the shift of hydrogen H14, in the ortho
position to the pyridine nitrogen. This trend is observed in the
spectra of all chlorido complexes (see Experimental and ESI†),
when compared with the free ligands, e.g., this hydrogen appears
at d 8.48 in the spectrum of HL1 and is shifted to d 9.42 in that
of its chlorido complex 1a. In the spectra of some complexes it is
also possible to observe the N–H hydrogen (as a doublet around
d 6.4) and the coupling with its neighbour proton H11, which also
appears as a doublet (Fig. S16, S22, S25, S28, S31, S40 and S43,
ESI†). These observations indicate that coordination to the metal
occurs through both nitrogen atoms. The other peaks were found
in the expected regions.
2
E
redox) and cytotoxic activity (given by IC50 values – see below). Few
examples of positive correlations between the ease of reduction of
naphthoquinones and biological activities have been described in
the literature.27,11b
In general, naphthoquinones exhibit two classical one-electron
transfer processes corresponding to the conversion of quinone
into semiquinone (process I – Scheme 3) and semiquinone into
cathecol (process II – Scheme 3), in aprotic media.27,28 However, in
protic solvents these systems can undergo two rapid one-electron-
transfer processes, which are close enough to merge into one CV
wave29–31(process III – Scheme 3).
The cyclic voltammograms (CVs) of the proligands showed
one two-electron-transfer redox couple (except that of HL3, see
below), attributed to the conversion of the quinone into cathecol29
and labeled IIIc (cathodic) and IIIa (anodic) in the voltammogram
of HL1 in Fig. 5.
Wave IIIc is associated with the formation of the respective
double-oxidised species. This behaviour, usually observed for
naphthoquinone systems in protic solvents, is explained by the
fact that protic solvents are capable of making stronger hydrogen-
bonding interactions with the cathecol species than with the
semiquinone radical, therefore favouring reduction to the cathecol
species.29,30 In addition, if the hydrogen of the naphthoquinone
OH group is abstracted, the negative charge is delocalized in the
quinone ring. As a consequence the second redox process is so
rapid that the two processes merge into a single one.28 In the
absence of a protic solvent or delocalised negative charge effect,
however, the two one-electron-transfer processes are slow and
clearly observed, since it should be harder to add an electron
to a species that is already negatively charged.
The 195Pt NMR spectra of the chlorido complexes 1a–5a were
measured in CDCl3 or DMF-d7 and gave a single peak from d
-2148 to -2113 ppm corresponding to a cis-N2Cl2 environment.25
Those of the charged amino complexes 1b–5b were recorded in
D2O or DMF-d7, and yielded a single peak from d -2532 to
-2510 ppm, confirming an N4 environment around the platinum
atom.26
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Scheme 3 Redox behaviour of the 3-(aminomethyl)naphthoquinones (ANQ) in protic solvents: process I: conversion of the 2-(aminomethyl)-
naphthoquinone (ANQ) into semi-2-(aminomethyl)naphthoquinone (SANQ); process II: conversion of SANQ into aminomethyl-cathecol (ACAT);
process III: conversion of the ANQ zwitterion into ACAT zwitterion.
processes approach electrochemical low reversibility at slow scan
rates33 (Table 2).
The CVs of the chlorido and amino platinum complexes 1a and
1b are shown in Fig. 6. For the chlorido complexes, coordination
of the 3-(aminomethyl)naphthoquinone was expected to prevent
intramolecular phenolic hydrogen deprotonation and therefore
two one-electron-transfer redox processes were anticipated and
indeed were observed according to the classical quinone redox
behaviour.27–29,34
Fig. 5 Cyclic voltammograms of HL1 and HL3 obtained with a glassy
carbon electrode (3 mm) in 0.1 mol L-1 n-Bu4NClO4/CH3OH. The
potential scan was initiated in the anodic direction. The cathodic (Ic,
IIc, IIIc) and anodic (Ia, IIa, IIIa) peaks are indicated.
Considering that the 3-(aminomethyl)naphthoquinones
HL1–HL5 may be found in their zwitterionic form in protic
solvents,19 the kinetics of the redox processes is strongly
influenced by the intramolecular phenolic hydrogen dissociation
constant.32 The fact that only one CV wave is observed for
compounds HL1, HL2, HL4 and HL5 and two one-electron
transfer processes are clearly observed in the CV of HL3
Fig. 6 Cyclic voltammograms of complexes 1a and 1b obtained with a
(Fig. 5 and Table 2), indicates that the equilibrium between the
glassy carbon electrode (3 mm) in 0.1 mol L-1 n-Bu4NClO4/CH3OH. The
zwitterionic and neutral species is shifted towards the neutral form
potential scan was initiated in the anodic direction. Both cathodic and
anodic peaks are indicated.
in HL3,19 most probably due to a decrease in the basicity of the
amine nitrogen as the result of a hydrogen-bonding interaction
with the furfuryl oxygen.
The observed DEp = Epa - Epc values are larger than 90 mV
For the amino complexes that contain
3-(aminomethyl)naphthoquinone ligand (supported by X-ray
a deprotonated
for all processes, at scan rates of 100 mV s-1, indicating that the
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Fig. 7 (A) Cyclic voltammogram of 1b in the absence and presence of HCl(aq). (B) Cyclic voltammogram of 1a in the absence and presence of NaOH(aq)
.
CVs were obtained with a glassy carbon electrode (3 mm) in 0.1 mol L-1 n-Bu4NClO4/CH3OH. The potential scan was initiated in the anodic direction.
Both cathodic and anodic peaks are indicated.
crystallographic data), only one two-electron-transfer redox pro-
cess was expected and observed in all cases (Fig. 6).32
Biological studies
The cytotoxicity of HL1–HL5, 1a–5a, 1b–5b and cisplatin, for
comparison, has been investigated against six tumour cell lines:
MDA-MB-435 (melanoma), HL-60 (promyelocytic leukaemia),
HCT-8 (colon), SF-295 (brain), OVCAR-8 (ovary) and
PC-3 (prostate). Doxorubicin was used as a positive control. The
experimental data are presented in Table 3.
A comparison between the electrochemical data obtained for the
proligands HL1–HL5 and the cationic amino platinum complexes
1b–5b shows a positive shift of the cathodic waves and a negative
shift of the anodic waves upon complexation. This observation
indicates that electron density is withdrawn from the negatively
charged quinone nucleus by the platinum(II) cation via hydrogen
bonding of the amine hydrogen with the phenoxide oxygen. As
a consequence, the ligand becomes more susceptible to reduction
which is expected to result in increased cytotoxic activity as the
result of easier generation of reactive oxygen species (ROS).16 In
addition, the redox processes become more reversible as shown
by the decrease in the DEp values observed in the CVs of the
complexes.
According to the IC50 values, proligands HL1–HL5 exhibited
moderate to good activities against the tested cell lines. Exceptions
were: HL1 (R1 = n-Bu) that was inactive against melanoma,
ovary, prostate and leukaemia; HL2 (R1 = Bn) and HL3 (R1 =
furfuryl) that were inactive against melanoma and prostate, and
HL4 (R = n-heptyl) and HL5 (R = n-decyl) that were inactive
and little active against melanoma, respectively. In contrast,
compounds HL4 and HL5 exhibited high activities against the
other cell lines tested, with IC50 values around 1.5 mmol L-1
against human colon (HCT-8) and human brain (SF-295) cell
lines. These data indicate clearly that activity depends strongly on
the nature of R1, the highest values being observed, in all cases, for
the derivatives containing long aliphatic carbon chains (n-heptyl,
HL4, and n-decyl, HL5). Interestingly, the differences in the
equilibrium constant between the zwitterionic and neutral species
observed for HL3 ¥ other proligands showed no effect in the IC50
values.
The chlorido complexes 1a–5a were also active against the
tested cell lines, with the exception of 1a that was inactive against
prostate, and 2a and 3a, inactive against prostate and ovary cell
lines. In contrast, the charged complexes 1b–5b were inactive
against all cells tested, except 4b and 5b, that exhibited low and
moderate activities (IC50 = 29.9 and 15.6 mmol L-1, respectively)
against the prostate cell line.
The intermediate shoulders IIa*, present in the CVs of some of
the chlorido complexes (Fig. 21, 24 and 30, ESI†), and IIIc*, in 2b
CV (Fig. S36, ESI†), are related to the oxidation and reduction of
hydrogen-bonded intermediates.28
The CV of the amino complex 1b was also taken in the presence
of a proton source (Fig. 7A). As expected, the electrodic mecha-
nism is strongly affected. The 3-(aminomethyl)naphthoquinone is
protonated and two one-electron-transfer redox couples appear,
in accord with the classical quinone electrochemistry behaviour.27
The two couples observed are indicated as Ic¢/Ia¢ and IIc¢/IIa¢
at potential values of -0.688/0.122 and -1.023/-0.729V vs.
FcH/FcH+, respectively. Considering the acidic nature of endo-
cytic compartments such as endosomes (pH 5–6) and lysosomes
(pH 4–5) this information may be valuable in the interpretation of
cytotoxic activity data.
The electrodic mechanism is also affected by the presence
of OH- (Fig. 7B) that leads to deprotonation of the 2-
(aminomethyl)naphthoquinone in complex 1a and therefore, to
the presence of one two-electron-transfer redox couple in the CV.32
This couple is indicated as IIIc¢ and IIIa¢ at potential values of
-1.169 and -1.116 V vs. FcH/FcH+, respectively. The negative
shift of the waves and the presence of only one couple of waves
confirm the influence of the hydroxyl proton on the electrodic
reduction mechanism.27
In general, the chlorido complexes exhibited lower activity when
compared with their respective proligands, however, chlorido com-
plexes 1a–5a were more active against melanoma than proligands
HL1–HL5, respectively. For instance, the increase in the activity
of HL4, against melanoma, after coordination with platinum(II)
was quite pronounced (IC50 > 40 mmol L-1 for HL4 and 6.4 mmol
L-1 for 4a). Furthermore, complexes 4a and 5a (IC50 = 6.4 and
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Table 3 IC50 values in mmol L-1 of HL1–HL5, 1a–5a and 1b–5b, after 72 h incubation, compared to cisplatin
MDA-MB-435
HL-60
HCT-8
SF-295
OVCAR-8
PC-3
HL1
>40
>40
>40
>40
23.6 (19.2–28.6)
19.7 (17.9–25.6)
21.1 (17.3–25.6)
27.6 (24.6–30.8)
6.4 (5.1–7.8)
9.0 (7.4–11.1)
>40
>40
>40
>40
>40
15.3 (11.3–20.7)
0.86 (0.62–1.2)
>40
12.0 (9.2–15.7)
2.3 (1.9–2.7)
3.9 (2.5–5.8)
1.6 (1.3–1.9)
1.7 (1.4–1.9)
21.0 (17.9–24.9)
20.7 (13.7–31.3)
29.7 (26.5–31.8)
11.5 (10.1–13.3)
15.9 (14.0–18.2)
>40
>40
>40
>40
>40
12.3 (9.3–16.7)
0.07 (0.05–0.09)
9.0 (7.7–11.9)
1.4 (1.1–1.9)
2.5 (1.9–3.3)
1.1 (1.0–1.3)
1.7 (1.2–1.9)
17.4 (13.9–21.9)
25.8 (21.2–31.3)
26.2 (21.4–31.8)
7.9 (7.1–8.7)
11.8 (10.0–14.0)
>40
>40
>40
>40
>40
26.7 (17.3–41.0)
0.42 (0.35–0.46)
>40
>40
>40
>40
7.7 (5.3–10.8)
3.3 (2.1–4.8)
>40
>40
>40
23.0 (19.4–27.2)
28.0 (22.7–34.5)
>40
>40
>40
29.9 (20.2–45.8)
15.6 (12.8–19.0)
>40
HL2
4.7 (3.7–5.9)
5.3 (3.9–6.9)
1.9 (1.3–2.6)
3.8 (2.8–5.3)
7.1 (2.8–17.9)
9.4 (4.2–21.2)
19.5 (16.4–23.2)
5.7 (3.3–10.2)
12.5 (9.5–16.6)
>40
>40
>40
>40
>40
5.7 (5.1–6.2)
16.9 (13.0–22.2)
5.5 (5.0–6.0)
4.0 (2.4–5.5)
21.4 (18.6–24.7)
>40
HL3
HL4
HL5
1a
2a
3a
>40
4a
14.3 (13.2–15.8)
22.9 (19.4–27.5)
>40
>40
>40
>40
>40
>40
0.44 (0.3–0.52)
5a
1b
2b
3b
4b
5b
cisplatin
Doxorubicin
28.6 (21.3–39.0)
0.04 (0.02–0.04)
0.44 (0.39–0.50)
Data are presented with 95% of confidence interval for MDA-MB-435 (melanoma), HL-60 (promyelocytic leukaemia), HCT-8 (colon), SF-295 (brain),
OVCAR-8 (ovary) and PC-3 (prostate) cancer cells lines. Doxorubicin was used as a positive control. Experiments were performed in triplicate.
9.0 mmol L-1, respectively) exhibited higher activity than cisplatin
(IC50 = 15.3 mmol L-1).
(Aldrich) were used as supplied. Dimethylformamide (DMF)
(Vetec) was distilled prior to use. cis-[Pt(DMSO)2Cl2],20 cis-
[Pt(DMF)2(NH3)2](NO3)2 and cisplatin41 were prepared as de-
21
If the cytotoxicity of these compounds resulted only from
oxidative stress and therefore were based only on their redox
potential values, the cisplatin analogues 1a–5a would be expected
to show the highest cytotoxicity considering that these compounds
are more easily reduced than the proligands HL1–HL5 and the
cationic complexes 1b–5b (Table 2). However, a direct correlation
between the cyclic voltammetry results and the IC50 values
could not be established. Certainly other factors are involved
in the biological activity of the platinum complexes, which are
directly related with the uptake of the compounds such as
lipophilicity, solubility and membrane permeability that depend
on the nature of R1, and also reactivity, i.e., interaction with
DNA.
scribed in the literature.
Microanalyses were performed using a Perkin-Elmer CHN 2400
microanalyser at Central Anal´ıtica - Instituto de Qu´ımica, Univer-
sidade Federal de Sa˜o Paulo, Brazil. Melting points were obtained
with a Mel-Temp II, Laboratory Devices - USA apparatus and
are uncorrected. IR spectra (KBr pellets) were recorded on a FT-
1
IR Spectrum One (Perkin Elmer) spectrophotometer. H NMR
(300 MHz) and 13C NMR (75 MHz) spectra were recorded with
a Varian Unit Plus spectrometer in CDCl3, D2O, CD3OD or
DMSO-d6; chemical shifts are reported in parts per million (ppm)
relative to an internal standard of Me4Si. The hydrogen signals
1
1
were attributed through coupling constant values and H ¥ H –
COSY experiments. 195Pt NMR (64 MHz) spectra were recorded
on a Bruker spectrometer at Universidade Federal de Juiz de
Fora, Brazil, in CDCl3, D2O or DMF-d7. X-Ray data collection
was performed at the Laborato´rio de Cristalografia (LabCri)
of Universidade Federal de Minas Gerais (UFMG). Electronic
spectra were taken on a Cary 50 (Varian) spectrophotometer
using spectroscopic grade solvents (Tedia Brazil) in 10-4 mol L-1
solutions. Cyclic voltammograms were carried out with a BAS
Epsilon potentiostat–galvanostat system at room temperature in
methanol (spectroscopic grade – Tedia Brazil) solutions of the
compounds (at 1.0 ¥ 10-3 mol L-1) containing 0.1 mol L-1 n-
Bu4NClO4 (Aldrich) as the supporting electrolyte, under an argon
atmosphere. The electrochemical cell was a conventional one with
three electrodes: Ag/Ag+ was used as the reference electrode, a
platinum wire as the auxiliary electrode and glassy carbon as the
working electrode. The spectra were obtained at 100 mV s-1 scan
rate. The ferrocene/ferrocenium (FcH/FcH+) couple was used as
the internal standard. (E1/2 372 mV vs. Ag/Ag+; E1/2 0.40 V vs.
The nature of the leaving group as well as the type of interaction
of platinum(II) complexes with DNA have been related to their cy-
totoxic activities.35 It is known that chlorido complexes analogous
to cisplatin interact with DNA through covalent binding after
replacement of the chloride ions.36 Amino complexes, however,
are inert37 and therefore bind to DNA exclusively through nonco-
valent interactions38,39 i.e. electrostatic interactions and hydrogen
bonding, which are weaker than the covalent bonds exhibited by
cisplatin analogues.38
Finally, increase in the cytotoxic activity of the compounds was
observed upon increase of the R1 carbon chain length. Indeed,
only compounds with a large carbon chain (R1 ≥ 7) exhibited
significant activity against the PC-3 cell line. One can speculate
that a large organic portion enhances cellular penetration through
the membranes to the nucleus, as previously observed.40
Experimental
NHE).42 For the studies in the presence of HCl(aq) and NaOH(aq)
,
General Considerations
the conditions were the same as those described above but for
the sequential addition of 50 mL aliquots of HCl 0.02 mol L-1 (or
NaOH). Pure Argon was bubbled through the electrolytic solution
to remove oxygen in all experiments.
Solvents (Vetec), 2-hydroxy-1,4-naphthoquinone (Aldrich), 2-
pyridinecarboxyaldehyde (Aldrich), butylamine (Aldrich), ben-
zylamine (Aldrich), furfurylamine (Aldrich) and K2PtCl4
10210 | Dalton Trans., 2010, 39, 10203–10216
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1
13C { H} NMR (75 MHz, DMSO-d6): d 184.2, 178.7, 171.1, 156.9,
147.7, 146.1, 144.0, 137.4, 134.8, 133.8, 131.7, 130.9, 125.5, 125.2,
122.8, 121.6, 112.1, 111.0, 109.6, 57.3, 55.9 ppm. Found: C, 70.2;
H, 4.7; N, 7.3. Calc. for C21H16N2O4: C, 70.0; H, 4.5; N, 7.8%.
UV-Vis [CH3OH; l/nm (log e)]: 270 (4.38), 330 (3.64), 440 (3.71),
493 (3.55).
Synthesis of pro-ligands HL1–HL5. The novel Mannich bases
HL1–HL5 were synthesised according to the methodology de-
scribed recently in the literature.12 General procedure: to a
suspension of lawsone (870 mg, 5 mmol) in ethanol (15 mL), kept
under stirring at 22 ◦C, were added the amine (5.5 mL) and, after
about 5 min, 2-pyridinecarboxyaldehyde (0.574 mL, 6 mmol). The
mixture was stirred at this temperature for 5 h, the bright orange
solid was filtered, extensively washed with ethanol and dried under
vacuum. For the synthesis of HL4, it was necessary to use half the
amount of ethanol in order to obtain a precipitate.
3-[(Heptylamino)(pyridin-2-yl)methyl]-2-hydroxy-1,4-naphtho-
quinone, HL4. Yield: 1.60 g (85%). m.p. 109–110 ◦C. IR (KBr):
n = 3424 (O–H), 3052 (C–H), 2927 (C–H), 2857 (C–H), 1678
(C O), 1590 (C C/C N), 1525 (d N–H), 1466 (C C), 1372
1
(C C), 1273 (C–O/C–N). H NMR (300 MHz, CDCl3): d 8.47
3-[(Butylamino)(pyridin-2-yl)methyl]-2-hydroxy-◦1,4-naphtho-
quinone, HL1. Yield: 1.18 g (70%). m.p. 142–143 C (dec.). IR
(KBr): n = 3446 (O–H), 3148 (N–H), 2964 (C–H), 2932 (C–H),
2865 (C–H), 1682 (C O), 1590 (C C/C N), 1560 (C C), 1520
(d N–H), 1472 (C C), 1372 (C C), 1277 (C–O/C–N), 1219 (C–
O/C–N). 1H NMR (300 MHz, CDCl3): d 8.48 (ddd, J = 4.9, 1.7,
0.9 Hz, 1H, H14), 7.84–7.79 (m, 2H, H5/H8), 7.59 (td, J = 7.4,
1.7 Hz, 1H, H16), 7.48 (td, J = 7.5, 1.5 Hz, 1H, H6 or H7), 7.42–
7.35 (m, 2H, H7 or H6/H17), 7.17 (ddd, J = 7.4, 4.9, 0.8 Hz, 1H,
H15), 5.75 (s, 1H, H11), 3.35–3.23 (m, 1H, H19), 3.18–3.05 (m,
1H, H19¢), 1.99–1.84 (m, 2H, H20), 1.58–1.43 (m, 2H, H21), 0.99
(d, J = 4.7 Hz, 1H, H14), 7.82–7.77 (m, 2H, H5/H8), 7.59 (td, J =
7.6, 1.7 Hz, 1H, H16), 7.46 (td, J = 7.5, 1.2 Hz, 1H, H6 or H7),
7.40–7.35 (m, 2H, H7 or H6/H17), 7.16 (dd, J = 7.6, 4.7 Hz, 1H,
H15), 5.73 (s, 1H, H11), 3.32–3.24 (m, 1H, H19), 3.13–3.06 (m,
1H, H19¢), 1.92 (q, J = 7.6 Hz, 2H, H20), 1.49–1.41 (m, 2H, H21),
1.39–1.32 (m, 2H, H22), 1.31–1.25 (m, 4H, H23/H24), 0.87 (t, J =
6.9 Hz, 3H, H25). 13C { H} NMR (75 MHz, CDCl3): d 184.7,
1
180.9, 170.5, 155.5, 147.6, 137.2, 134.1, 133.5, 131.1, 130.8, 126.0,
125.3, 122.6, 122.2, 111.4, 58.6, 46.9, 31.4, 28.6, 26.6, 26.4, 22.4,
13.9 ppm. Found: C, 72.8; H, 7.1; N, 7.4. Calc. for C23H26N2O3: C,
73.0; H, 6.9; N, 7.4%. UV-Vis [CH3OH; l/nm (log e)]: 269 (4.48),
332 (3.88), 440 (3.91), 488 (3.82).
1
(t, J = 7.3 Hz, 3H, H22). 13C { H} NMR (75 MHz, DMSO-d6): d
184.4, 178.7, 171.4, 157.4, 147.8, 137.4, 134.9, 133.9, 131.8, 131.0,
125.6, 125.3, 122.8, 121.5, 109.9, 57.6, 44.9, 27.7, 19.4, 13.6 ppm.
Found: C, 71.3; H, 5.9; N, 8.4. Calc. for C20H20N2O3: C, 71.4;
H, 6.0; N, 8.3%. UV-Vis [CH3OH; l/nm (log e)]: 270 (4.28), 330
(3.48), 440 (3.57), 485 (3.46).
3-[(Decylamino)(pyridin-2-yl)methyl]-2-hydroxy-1,4-naphtho-
quinone, HL5. Yield: 1.57 g (75%). m.p. 141–142 C (dec.). IR
◦
(KBr): n = 3430 (O–H), 3126 (N–H), 2926 (C–H), 2855 (C–H),
1682 (C O), 1585 (C C/C N), 1514 (d N–H), 1434 (C C),
1389 (C C), 1273 (C–O/C–N), 1233 (C–O/C–N). 1H NMR
(300 MHz, CDCl3): d 8.46 (ddd, J = 4.9, 1.4, 0.8 Hz, 1H, H14),
7.77 (dd, J = 7.6, 0.8 Hz, 1H, H5 or H8), 7.75 (dd, J = 7.6, 0.8 Hz,
1H, H8 or H5), 7.57 (td, J = 7.7, 1.7 Hz, 1H, H16), 7.43 (td, J = 7.6,
1.3 Hz, 1H, H6 or H7), 7.38–7.33 (m, 2H, H7 or H6/H17), 7.14
(dd, J = 7.7, 4.9 Hz, 1H, H15), 5.73 (s, 1H, H11), 3.30–3.24 (m,
1H, H19), 3.11–3.05 (m, 1H, H19¢), 1.93 (q, J = 7.6 Hz, 2H, H20),
1.44 (q, J = 7.6 Hz, 2H, H21), 1.37–1.19 (m, 12H, H22–H27), 0.87
3-[(Benzylamino)(pyridin-2-yl)methyl]-2-hydroxy-1,4-naphtho-
◦
quinone, HL2. Yield: 1.57 g (85%). m.p. 140–141 C (dec.). IR
(KBr): n = 3447 (O–H/N–H), 3065 (C–H), 2949 (C–H), 1684
(C O), 1611 (C C/C N), 1590 (C C/C N), 1557 (C C),
1519 (d N–H), 1470 (C C), 1389 (C C), 1272 (C–O/C–N), 1261
1
(C–O/C–N). H NMR (300 MHz, DMSO-d6): d 8.66 (ddd, J =
4.8, 1.7, 1.2 Hz, 1H, H14), 8.06 (dd, J = 7.6, 1.4 Hz, 1H, H5 or
H8), 7.96 (dd, J = 7.6, 1.4 Hz, 1H, H8 or H5), 7.86 (td, J = 7.7,
1.7 Hz, 1H, H16), 7.84 (td, J = 7.6, 1.4 Hz, 1H, H6 or H7), 7.72 (td,
J = 7.6, 1.4 Hz, 1H, H7 or H6), 7.60–7.47 (m, 5H, Ph), 7.47–7.40
(m, 2H, H15/H17), 5.82 (s, 1H, H11), 4.37 (d, J = 13.0 Hz, 1H,
(t, J = 7.0 Hz, 3H, H28). 13C { H} NMR (75 MHz, DMSO-d6): d
1
184.7, 180.8, 170.4, 155.5, 147.6, 137.2, 134.0, 133.5, 131.1, 130.8,
126.0, 125.2, 122.6, 122.2, 111.4, 58.7, 46.9, 31.7, 29.3, 29.2, 29.1,
28.9, 26.6, 26.4, 22.5, 13.9 ppm. Found: C, 74.1, H, 7.4, N, 6.5.
Calc. for C26H32N2O3: C, 74.3; H, 7.7; N, 6.7%. UV-Vis [CH3OH;
l/nm (log e)]: 270 (4.47), 334 (3.73), 438 (3.78), 492 (3.62).
1
H19), 4.25 (d, J = 13.0 Hz, 1H, H19¢). 13C { H} NMR (75 MHz,
DMSO-d6): d 184.4, 179.2, 171.6, 157.2, 148.0, 137.8, 135.0, 134.1,
132.7, 132.0, 131.3, 130.4, 129.2, 128.9, 125.8, 125.5, 123.2, 122.0,
109.9, 57.8, 48.9 ppm. Found: C, 74.1; H, 5.1; N, 7.4. Calc. for
C23H18N2O3: C, 74.6; H, 4.9; N, 7.6%. UV-Vis [CH3OH; l/nm
(log e)]: 270 (4.44), 330 (3.68), 440 (3.76), 495 (3.60).
Synthesis of the chlorido platinum complexes 1a–5a. To a
suspension of the proligand (HL1–HL5, 0.50 mmol) in 5 mL
of DMF, was added cis-[Pt(DMSO)2Cl2] (232 mg, 0.55 mmol).
The orange reaction mixture was stirred at room temperature for
48 h in the dark. The resulting orange solution was evaporated
under reduced pressure. The orange oily product was washed with
water to obtain a yellow solid which was isolated by filtration.
Complexes 1a, 4a and 5a were recrystallised from a mixture of
ethanol/petroleum ether or isopropanol/petroleum ether while
2a and 3a were purified by recrystallisation in CHCl3.
3 - [(Furfurylamino) (pyridin - 2 - yl) methyl] - 2 - hydroxy - 1, 4 -
naphthoquinone, HL3. Yield: 1.51 g (84%). m.p. 128–129 ◦C
(dec.). IR (KBr): n = 3446 (O–H), 3059 (C–H), 2950 (C–H), 1681
(C O), 1612 (C C/C N), 1589 (C C/C N), 1567 (C C),
1521 (d N–H), 1471 (C C), 1385 (C C), 1275 (C–O/C–N), 1262
1
(C–O/C–N). H NMR (300 MHz, DMSO-d6): d 8.66 (ddd, J =
4.8, 1.7, 1.2 Hz, 1H, H14), 8.04 (ddd, J = 7.5, 1.4, 0.4 Hz, 1H, H5
or H8), 7.95 (ddd, J = 7.6, 1.4, 0.4 Hz, 1H, H5 or H8), 7.85 (td, J =
7.8, 1.8 Hz, 1H, H16), 7.83 (td, J = 7.5, 1.4 Hz, 1H, H6 or H7),
7.78 (dd, J = 1.8, 0.8 Hz, 1H, H23), 7.77 (td, J = 7.5, 1.4 Hz, 1H,
H7 or H6), 7.46–7.40 (m, 2H, H15/H17), 6.65 (dd, J = 3.3, 0.8 Hz,
1H, H21), 6.57 (dd, J = 3.3, 1.8 Hz, 1H, H22), 5.84 (s, 1H, H11),
4.44 (d, J = 14.5 Hz, 1H, H19), 4.35 (d, J = 14.5 Hz, 1H, H19¢).
[Pt(HL1)Cl2] 1a. Yield: 180 mg (60%). m.p. 188–190 ◦C.
IR (KBr): n = 3393 (O–H/N–H), 2957 (C–H), 2958 (C–H),
2930 (C–H), 2870 (C–H), 1680 (C O), 1641 (C O), 1590
(C C/C N), 1528 (d N–H), 1478 (C C), 1459 (C C), 1374
(C C), 1351 (C C), 1274 (C–O/C–N), 1227 (C–O/C–N). H
NMR (300 MHz, CDCl3): d 9.42 (d, J = 6.1 Hz, 1H, H14), 8.14
1
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©

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(d, J = 7.6 Hz, 2H, H5/H8), 7.88–7.73 (m, 2H, H16/H6 or H7),
7.75 (td, J = 7.6, 1.4 Hz, 1H, H7 or H6), 7.29 (t, J = 6.1, 1H, H15),
7.09 (d, J = 7.9 Hz, 1H, H17), 6.26 (d, J = 8.7 Hz, 1H, NH), 5.81 (d,
J = 8.7 Hz, 1H, H11), 3.40–3.30 (m, 1H, H19), 2.46–2.35 (m, 1H,
H19¢), 1.95–1.76 (m, 2H, H20), 1.42–1.24 (m, 2H, H21), 0.89 (t,
J = 7.3 Hz, 3H, H22). 195Pt NMR (64 MHz, CDCl3): d -2142 ppm.
Found: C, 40.4; H, 3.5; N, 4.5. Calc. for C20H20N2O3Cl2Pt: C, 39.9;
H, 3.4; N, 4.7%. UV-Vis [CH3OH; l/nm (log e)]: 261 (4.37), 348
(3.26), 416 (3.21), 442 (2.93).
1644 (C O), 1591 (C C/C N), 1538 (d N–H), 1522 (C C),
1459 (C C), 1374 (C C), 1351 (C C), 1275 (C–O/C–N), 1228
(C–O/C–N). 1H NMR (300 MHz, CDCl3): d 9.43 (d, J = 5.4 Hz,
1H, H14), 8.15 (d, J = 7.7 Hz, 2H, H5/H8), 7.88–7.80 (m, 2H,
H16/H6 or H7), 7.76 (t, J = 7.7 Hz, 1H, H7 or H6), 7.29 (t,
J = 6.8, 1H, H15), 7.07 (d, J = 8.0 Hz, 1H, H17), 6.29 (d, J =
8.6 Hz, 1H, NH), 5.83 (d, J = 8.6 Hz, 1H, H11), 3.38–3.30 (m, 1H,
H19), 2.45–2.35 (m, 1H, H19¢), 1.92–1.82 (m, 2H, H20), 1.35–1.15
(m, 14H, H21–H27), 0.84 (t, J = 7.0 Hz, 3H, H28). 195Pt NMR
(64 MHz, CDCl3): d -2148 ppm. Found. C, 43.1; H, 4.5; N 3.8.
Calc. for C26H32N2O3Cl2Pt·1.7H2O: C, 43.5; H, 5.0; N, 3.9%. UV-
Vis [CH3OH; l/nm (log e)]: 271 (4.34), 338 (3.69), 436 (3.73), 476
(3.13).
[Pt(HL2)Cl2] 2a. Yield: 260 mg (82%). m.p. > 243 ◦C (dec.).
IR (KBr): n = 3347 (N–H), 3190 (N–H), 3110 (N–H), 3069
(C–H), 1679 (C O), 1649 (C O), 1632 (C C/C N), 1592
(C C/C N), 1577 (C C), 1476 (C C), 1454 (C C), 1363
1
(C C), 1351 (C C), 1284 (C–O/C–N), 1213 (C–O/C–N). H
Synthesis of the amino platinum complexes 1b–5b. The pro-
ligand HL1–HL3 (1.1 mmol) was added as a solid to a previously
NMR (300 MHz, DMF-d7): d 9.37 (d, J = 5.7 Hz, 1H, H14), 8.23
(d, J = 7.1 Hz, 2H, H5/H8), 8.05 (d, J = 7.4 Hz, 1H, Ph), 8.01–7.97
(m, 2H, Ph), 7.91 (td, J = 7.5, 1.3 Hz, 1H, H16), 7.86 (td, J = 7.4,
1.2 Hz, 1H, Ph), 7.47–7.43 (m, 2H, H15, Ph), 7.43–7.39 (m, 1H,
NH), 7.33–7.24 (m, 3H, H17/H6/H7), 5.74 (d, J = 7.6 Hz, 1H,
H11), 4.77 (dd, J = 13.4, 4.2 Hz, 1H, H19), 4.14 (dd, J = 13.4,
2.6 Hz, 1H, H19¢). 195Pt NMR (64 MHz, DMF-d7): d -2113 ppm.
Found: C, 42.8; H, 2.8; N, 4.2. Calc. for C23H18N2O3Cl2Pt·0.4H2O:
C, 42.9; H, 2.9; N, 4.4. UV-Vis [CH3OH; l/nm (log e)]: 266 (4.26),
349 (3.43), 433 (3.46), 480 (3.35).
21
prepared solution of cis-[Pt(NH3)2(DMF)2](NO3)2 (1 mmol) in
10 mL of DMF and the orange reaction mixture was left stirring
at room temperature in the dark. After 72 h the resulting orange
solution was evaporated under vacuum and the product, extracted
with water. After evaporation of the water, the complex was
obtained as an orange solid after precipitation in a mixture of
ethanol/petroleum ether. Same procedure was followed for the
synthesis of complexes 4a and 5a, except for the amount of
proligands HL4 and HL5 (0.8 mmol). After 72 h, the DMF was
evaporated and the complexes were obtained as orange solids after
addition of water to the residue. The compounds were extensively
washed with water, filtered off and dried under vacuum.
[Pt(HL3)Cl2] 3a. Yield: 241 mg (77%). m.p. > 225 ◦C (dec.).
IR (KBr): n = 3445 (O–H), 3220 (N–H), 3116 (N–H), 2923 (C–
H), 2851 (C–H), 1674 (C O), 1646 (C O), 1592 (C C/C N),
1533 (d N–H), 1478 (C C), 1372 (C C), 1275 (C–O/C–N), 1225
(C–O/C–N). 1H NMR (300 MHz, DMF-d7): d 9.40 (d, J = 5.9 Hz,
1H, H14), 8.08–8.00 (m, 3H, H5/H8/H6 or H7), 7.91 (td, J = 7.4,
1.5 Hz, 1H, H16), 7.87 (td, J = 7.4, 1.4 Hz, 1H, H7 or H6), 7.55 (d,
J = 8.0 Hz, 1H, H17), 7.51 (t, J = 6.7 Hz, 1H, H15), 7.42 (dd, J =
1.8, 0.7 Hz, 1H, H23), 7.17–7.12 (m, 1H, NH), 6.89 (d, J = 3.2 Hz,
1H, H21), 6.29 (dd, J = 3.2, 1.8 Hz, 1H, H22), 5.88 (d, J = 8.0 Hz,
1H, H11), 4.63 (dd, J = 14.6, 6.1 Hz, 1H, H19), 4.51 (dd, J = 14.6,
2.4 Hz, 1H, H19¢). 195Pt NMR (64 MHz, DMF-d7): d -2120 ppm.
Found: C, 40.5; H, 2.6; N, 4.4. Calc. for C21H16N2O4Cl2Pt: C, 40.3;
H, 2.6, N, 4.5. UV-Vis [CH3OH; l/nm (log e)]: 272 (4.37), 343
(3.68), 443 (3.75), 481 (3.24).
[Pt(L1)(NH3)2]NO3, 1b. Yield: 180 mg (29%). m.p. > 221 ◦C
(dec.). IR (KBr): n = 3484 (O–H), 3163 (N–H), 2958 (C–H),
2928 (C–H), 2871 (C–H), 1676 (C O), 1612 (C C/C N), 1587
(C C/C N), 1533 (d N–H), 1484 (C C), 1373 (C C/N O),
1333 (C C), 1280 (C–O/C–N), 1242 (C–O/C–N). 1H NMR
(300 MHz, D2O): d 8.33 (d, J = 6.1 Hz, 1H, H14), 8.03 (td, J =
8.0, 1.3 Hz, 1H, H16), 7.89 (dd, J = 7.6, 1.3 Hz, 1H, H5 or H8),
7.84 (dd, J = 7.6, 1.3 Hz, 1H, H8 or H5), 7.73 (td, J = 7.6, 1.3 Hz,
1H, H7 or H6), 7.63 (td, J = 7.6, 1.3 Hz, 1H, H6 or H7), 7.46 (t,
J = 6.1 Hz, 1H, H15), 7.38 (d, J = 8.0 Hz, 1H, H17), 6.50 (d, J =
6.4 Hz, 1H, NH), 5.80 (d, J = 6.4 Hz, 1H, H11), 2.93–2.84 (m, 2H,
H19), 1.96–1.83 (m, 2H, H20), 1.44–1.28 (m, 2H, H21), 0.88 (t,
J = 7.4 Hz, 3H, H22). 195Pt NMR (64 MHz, D2O): d -2530 ppm.
Found: C, 36.7; H, 4.0; N, 10.6. Calc. for C20H25N4O3Pt·1.5H2O:
C, 36.8; H, 4.3; N, 10.7%. UV-Vis [CH3OH; l/nm (log e)]: 268
(4.41), 328 (3.63), 434 (3.65), 472 (3.61).
◦
[Pt(HL4)Cl2] 4a. Yield: 284 mg (79%). m.p. 138–140 C. IR
(KBr): n = 3195 (N–H), 2953 (C–H), 2925 (C–H), 2854 (C–
H), 1680 (C O), 1642 (C O), 1591 (C C/C N), 1534 (d
N–H), 1479 (C C), 1459 (C C), 1383 (C C), 1370 (C C),
1351 (C C), 1276 (C–O/C–N), 1224 (C–O/C–N). 1H NMR
(300 MHz, CDCl3): d 9.44 (d, J = 5.6 Hz, 1H, H14), 8.16 (dd,
J = 7.4, 0.9 Hz, 1H, H5 or H8), 8.15 (dd, J = 7.6, 1.1 Hz, 1H, H8
or H5), 7.87–7.81 (m, 2H, H16/H6 or H7), 7.77 (td, J = 7.6, 1.1 Hz,
1H, H7 or H6), 7.30 (t, J = 6.8, 1H, H15), 7.07 (d, J = 8.0 Hz,
1H, H17), 6.27 (d, J = 8.7 Hz, 1H, NH), 5.82 (d, J = 8.7 Hz, 1H,
H11), 3.36–3.33 (m, 1H, H19), 2.44–2.37 (m, 1H, H19¢), 1.92–1.82
(m, 2H, H20), 1.35–1.17 (m, 8H, H21-H24), 0.83 (t, J = 6.9 Hz,
3H, H25). 195Pt NMR (64 MHz, CDCl3): d -2147 ppm. Found: C,
43.4; H, 4.6; N, 4.0. Calc. for C23H26N2O3Cl2Pt·CH3CH2OH: C,
43.5; H, 4.7; N, 4.1%. UV-Vis [CH3OH; l/nm (log e)]: 271 (4.54),
334 (3.72), 431 (3.78), 481 (3.28).
[Pt(L2)(NH3)2]NO3, 2b. Yield: 250 mg (38%). m.p. > 158 ◦C
(dec.). IR (KBr): n = 3458 (O–H), 3147 (N–H), 1678 (C O),
1643 (C O), 1614 (C C/C N), 1587 (C C/C N), 1520 (d
N–H), 1318 (C C/N O), 1275 (C–O/C–N), 1234 (C–O/C–N).
1H NMR (300 MHz, D2O): d 8.21 (d, J = 6.4 Hz, 1H, H14), 7,91
(td, J = 8.0, 1.2 Hz, 1H, H16), 7.70–7.65 (m, 2H, H5/H8), 7.61 (td,
J = 7.4, 1.4 Hz, 1H, H6 or H7), 7.39–7.50 (m, 1H, H7 or H6/3H
(Ph)), 7.34 (t, J = 6.4 Hz, 1H, H15), 7.20 (d, J = 8.0 Hz, 1H, H17),
7.08–6.99 (m, 2H, Ph), 5.70 (s, 1H, H11), 4.15 (d, J = 18.6 Hz,
2H, H19). 195Pt NMR (64 MHz, D2O): d -2510 ppm. Found: C,
38.3; H, 3.9; N, 10.3. Anal. Calc. for C23H23N5O6Pt·3H2O: C, 38.7;
H, 4.1; N, 9.8%. UV-Vis [CH3OH; l/nm (log e)]: 266 (4.35), 332
(3.68), 431 (3.66), 491 (3.58).
◦
[Pt(HL5)Cl2] 5a. Yield: 240 mg (70%). m.p. 136–137 C. IR
(KBr): n = 3144 (N–H), 2923 (C–H), 2852 (C–H), 1679 (C O),
10212 | Dalton Trans., 2010, 39, 10203–10216
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[Pt(L3)(NH3)2]NO3, 3b. Yield: 170 mg (26%). m.p. > 193 ◦C
(dec.). IR (KBr): n = 3452 (O–H), 3160 (N–H), 1680 (C O),
1642 (C O), 1633 (C C/C N), 1613 (C C/C N), 1587
(C C/C N), 1527 (d N–H), 1477 (C C), 1376 (C C/N O),
1335 (C C), 1277 (C–O/C–N), 1236 (C–O/C–N). 1H NMR
(300 MHz, D2O): d 8.22 (d, J = 6.2 Hz, 1H, H14), 7.97–7.86
(m, 3H, H16/H5 or H8/H23), 7.80 (d, J = 7.6 Hz, 1H, H8 or
H5), 7.71 (t, J = 7.6 Hz, 1H, H6 or H7), 7.61 (t, J = 7.6 Hz,
1H, H7 or H6), 7.36 (t, J = 6.2 Hz, 1H, H15), 7.27–7.19 (m, 1H,
H17), 6.51–6.47 (m, 1H, H21), 6.19 (dd, J = 4.8, 2.5 Hz, 1H, H22),
5.69 (s, 1H, H11), 4.17–4.12 (m, 2H, H19). 195Pt NMR (64 MHz,
DMF-d7): d -2532 ppm. Found: C, 36.3; H, 3.3; N, 10.7. Calc. for
C21H21N5O7Pt·2H2O: C, 36.7; H, 3.7; N, 10.2%. UV-Vis [CH3OH;
l/nm (log e)]: 267 (4.18), 331 (3.60), 430 (3.54), 486 (3.45).
1a an empirical absorption correction was carried out using
intensity measurements implemented in SCALE3 ABSPACK
scaling algorithm.43
The structures were solved by direct methods using the
SHELXS45 program. The positions of all atoms could be un-
ambiguously assigned on consecutive difference Fourier maps.
Refinements were performed using SHELXL45 based on F2
through full-matrix least square routine. All but hydrogen atoms
were refined with anisotropic atomic displacement parameters.
Hydrogen atoms were added in the structure in their typical
distances to the neighbour atoms and were further refined
according to the riding model.46
Fourier difference maps of both compounds present quite high
peaks around the platinum atoms. The height of these peaks was
not influenced by the choice of parameters in the absorption model
correction neither by the ionisation number of the platinum atoms
and indeed similar structural features were observed in many
platinum structures investigated recently.47
Final structure refinement of compound 1a was performed
considering split positions for carbon atoms C39 and C40. The
C–C distances and the atomic displacement parameters of the
split atoms were restrained in order to keep the correct molecule
geometry. The high noise level in the final electron density maps
due the peaks around the platinum atoms made the placement of
the hydrogen atoms around the H2O molecules a quite complicated
task. In particular, the hydrogen atoms of these molecules in
compound 3b were added manually in the structure and then
refined according to riding model with anti-bumping constraints
what did not provide a satisfactory structural model as far as the
H2O hydrogen bonds is concerned.
[Pt(L4)(NH3)2]NO3, 4b. Yield: 180 mg (34%). m.p. > 217 ◦C
(dec.). IR (KBr): n = 3438 (O–H), 3176 (N–H), 2954 (C–H),
2925 (C–H), 2855 (C–H), 1680 (C O), 1643 (C O), 1634
(C C/C N), 1614 (C C/C N), 1587 (C C/C N), 1527
(d N–H), 1477 (C C), 1380 (C C N-1 O), 1276 (C–O/C–N),
1236 (C–O/C–N) cm-1. 1H NMR (300 MHz, CD3OD): d 8.40 (d,
J = 5.7 Hz, 1H, H14), 8.04 (td, J = 7.8, 1.2 Hz, 1H, H16), 7.94 (d,
J = 7.5 Hz, 1H, H5 or H8), 7.85 (d, J = 7.5 Hz, 1H, H8 or H5),
7.68 (td, J = 7.5, 1.0 Hz, 1H, H7 or H6), 7.55 (td, J = 7.5, 1.0 Hz,
1H, H6 or H7), 7.46–7.40 (m, 2H, H15/H17), 6.75 (d, J = 5.2 Hz,
1H, NH), 5.81 (d, J = 5.2 Hz, 1H, H11), 2.97–2.86 (m, 2H, H19),
2.00–1.85 (m, 2H, H20), 1.43–1.20 (m, 8H, H21–H24), 0.85 (t, J =
6.9 Hz, 3H, H25). 195Pt NMR (64 MHz, DMF-d7): d -2522 ppm.
Found. C, 41.5; H, 4.5; N, 10.2. Calc. for C23H31N5O6Pt: C, 41.3;
H, 4.7; N, 10.5. UV-Vis [CH3OH; l/nm (log e)]: 266 (4.43), 331
(3.92), 440 (3.88), 495 (3.82).
Crystal structure and refinement data for compounds 1a and 3b
are summarised in Table 4.
[Pt(L5)(NH3)2]NO3, 5b. Yield: 283 mg (50%). m.p. > 171 ◦C
(dec.). IR (KBr): 3438 (O–H), 3163 (N–H), 2953 (C–H), 2923 (C–
H), 2853 (C–H), 1679 (C O), 1645 (C O), 1634 (C C/C N),
1613 (C C/C N), 1587 (C C/C N), 1528 (d N–H), 1476
(C C), 1378 (C C/N O), 1276 (C–O/C–N), 1236 (C–O/C–
Biological studies
(a) Cells and culture conditions. The human cell lines used
in this work were HL-60 (promyelocytic leukaemia), HCT-8
(colon), MDA-MB-435 (melanoma) and SF-295 (brain), OVCAR-
8 (ovary), PC3 (prostate), which were all obtained from the
National Cancer Institute (Bethesda, MD, USA). The cells were
maintained in RPMI 1640 medium supplemented with 10% fetal
bovine serum, 2 mmol L-1 gluta◦mine, 100 U/mL penicillin, and
100 mg mL-1 streptomycin at 37 C with 5% CO2.
1
N) cm-1. H NMR (300 MHz, CD3OD): d 8.39 (d, J = 5.7 Hz,
1H, H14), 8.03 (t, J = 7.8 Hz, 1H, H16), 7.94 (d, J = 7.6 Hz,
1H, H5 or H8), 7.85 (d, J = 7.6 Hz, 1H, H8 or H5), 7.68 (t, J =
7.6 Hz, 1H, H7 or H6), 7.55 (t, J = 7.6, 1.0 Hz, 1H, H6 or H7),
7.45–7.39 (m, 2H, H15/H17), 6.74 (d, J = 5.0 Hz, 1H, NH), 5.80
(d, J = 5.0 Hz, 1H, H11), 2.96–2.85 (m, 2H, H19), 2.02–1.85 (m,
2H, H20), 1.43–1.17 (m, 14H, H21-H27), 0.87 (t, J = 7.0 Hz, 3H,
H28). 195Pt NMR (64 MHz, DMF-d7): d -2521 ppm. Found. C,
43.9; H, 5.4; N, 9.8. Calc. for C26H37N5O6Pt: C, 43.9; H, 5.3; N,
9.9%. UV-Vis [CH3OH; l/nm (log e)]: 269 (4.60), 328 (3.89), 437
(3.85), 482 (3.74).
(b) Proliferation assays. The cytotoxicity of the com-
pounds and cisplatin41 were tested against HL-60 (promyelocytic
leukaemia), HCT-8 (colon), MDA-MB-435 (melanoma), SF-295
(brain), OVCAR-8 (ovary) and PC3 (prostate) cell lines. For all
experiments, cells were plated in 96-well plates (105 cells/well
for adherent cells or 0.5 ¥ 105 cells/well for suspended cells in
100 mL of medium). After 24 h, the compounds (0.06 to 77.0 mmol
L-1) dissolved in 1% DMSO were added to each well using
a high-throughput screening system (Biomek 3000 - Beckman
Coulter, Inc. Fullerton, California, EUA), and the cultures were
incubated for 72 h. Doxorubicin (Zodiac) was used as a positive
control. Control groups received the same amount of DMSO.
Tumour cell growth was quantified by the ability of living cells to
reduce the yellow dye 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-
2H-tetrazolium bromide (MTT) to a purple formazan product.48
At the end of the incubation, the plates were centrifuged and
X-Ray crystallography†
X-Ray diffraction data collections were performed on
a
Oxford-Diffraction GEMINI CCD diffractometer using mirror-
˚
monochromatised Cu-Ka radiation (l = 1.54184 A) at 120 K.
Final unit cell parameters were based on the fitting of all reflections
positions integrated during the data reduction. Data Integration
and scaling of the reflections were performed with the CrysalisPRO
suite.43 For compound 3b an analytical numeric absorption correc-
tion was performed using a multifaceted crystal model based on
expressions derived by Clark and Reid,44 whereas for compound
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The Royal Society of Chemistry 2010
Dalton Trans., 2010, 39, 10203–10216 | 10213
©

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Table 4 Crystal data and structure refinement for 3b and 1a
Identification code
3b
1a
Empirical formula
Formula weight
Temperature/K
C21 H28 N5 O10.50 Pt
713.5
120(2)
C43 H48 Cl4 N4 O7 Pt2
1264.83
120(2)
˚
Wavelength/A
1.54178
1.54184
Crystal system
Space group
Monoclinic
C2/c
Monoclinc
P21/n
Unit cell dimensions
˚
a/A
31.7768(12)
9.4926(2)
19.6173(14)
90
122.01
90
16.5463(6)
13.2528(5)
20.6428(8)
90
103.106(4)
90
˚
b/A
˚
c/A
a/◦
b/◦
g /◦
3
˚
Volume/A
5018.0(4)
4408.7(3)
Z
8
1.87
11.058
2808
0.13 ¥ 0.06 ¥ 0.04
3.28 to 66.26
-37 < = h < = 36
-11 < = k < = 9
-23 < = l < = 23
11 925
4
1.9
14.378
2448
0.10 ¥ 0.09 ¥ 0.03
3.10 to 62.65
-19 < = h < = 18
-14 < = k < = 13
-23 < = l < = 23
18 998
Density (calculated)/Mg m-3
Absorption coefficient/mm-1
F(000)
Crystal size/mm3
Theta range for data collection/◦
Index ranges
Reflections collected
Independent reflections
Completeness to q = 66.26◦/62.65◦
Max. and min. transmission
Refinement method
4197 [R(int) = 0.0337]
6877 [R(int) = 0.0495]
95.3%
97.4%
0.673 and 0.391
Full-matrix least-squares on F2
4197/7/339
1.057
R1 = 0.0490
wR2 = 0.1313
R1 = 0.0616
wR2 = 0.1405
3.764 and -0.774
0.672 and 0.327
Full-matrix least-squares on F2
6877/28/549
1.006
R1 = 0.0509
wR2 = 0.1307
R1 = 0.0798
wR2 = 0.1452
2.686 and -1.356
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2s(I)]
R indices (all data)
-3
˚
Largest diff. peak and hole/e A
the medium was replaced with fresh medium (150 mL) containing
MTT (0.5 mg mL-1). Three hours later, the plates were centrifuged,
the MTT formazan product was dissolved in 150 mL DMSO, and
the absorbance was measured using a multiplate reader (Spectra
Count, Packard, Ontario, Canada). The drug effect was quantified
as the percentage of the control absorbance of the reduced dye at
595 nm.
large organic side chains showed the highest IC50 values, and
amino cationic complexes were generally inactive. Poor activity
of the amino compounds compared to the chlorido complexes
may be associated to the different types of interactions complexes-
DNA-cisplatin type, covalent, for the chlorido complexes and non-
covalent for the amino cations. Detailed biophysical and cellular
studies on interaction with DNA and cellular uptake are under
way, as well as the investigation of the platinum(IV) analogues
aiming at complexes with better IC50 values.
Conclusions
In summary, we have synthesised and fully characterised five novel
3-(aminomethyl)naphthoquinones HL1–5 and their chlorido-
cis-[Pt(HL1–5)Cl2] and amino cis-[Pt(L3)(NH3)2]NO3 platinum
complexes, and evaluated their cytotoxicity against MDA-MB-
435, HL-60, HCT-8, SF-295, OVCAR-8 and PC-3 cancer cell lines.
Spectroscopic and voltammetric studies have evidenced that the 3-
(aminomethyl)naphthoquinone ligand is present in the protonated
HL form in the chlorido complexes and in the deprotonated form
in the amino-complexes. Furthermore, X-ray diffraction studies
have confirmed that in both cases these ligands coordinate through
the nitrogen atoms forming a five membered chelate ring around
the platinum(II) ions which exhibit square planar geometry. The
results of the cytotoxic activity have demonstrated that proligands
and chlorido complexes exhibit high to moderate activities,
whereas the amino complexes are mostly inactive. Lipophilicity
is an important factor to be considered, since compounds with
Acknowledgements
The authors thank the Brazilian agencies ‘Conselho Na-
cional de Desenvolvimento Cient´ıfico e Tecnolo´gico’ (CNPq),
‘Coordenac¸a˜o de Aperfeic¸oamento de Pessoal de N´ıvel Superior’
(CAPES) and ‘Fundac¸a˜o de Amparo a` Pesquisa do Estado do
Rio de Janeiro’ (FAPERJ) for financial support. Pronex-FAPERJ
(grant number E-26/171.512/2006) is acknowledged. M. D. Var-
gas and A. P. Neves are recipients of CNPq research fellowships.
We also thank Dr Ana Paula S. Fontes of Universidade Federal
de Juiz de Fora (UFJF) for the 195Pt NMR spectra.
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10214 | Dalton Trans., 2010, 39, 10203–10216
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©

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