Bis(dimethylsulfoxide)carbonateplatinum(II), a new synthon for a low-impact, versatile synthetic route to anticancer Pt carboxylates

Article abstract of DOI:10.1039/c6dt01689h

The work describes a new low-impact synthetic route to Pt(ii)-carboxylate complexes, a class of compounds provided with established anticancer activity. The process is based on the ligand substitution on [PtCO₃(Me₂SO-S)₂] (1), a new synthon that can be easily prepared in water with high yield, is stable as a solid, and is reactive in solution where all its ligands can be easily replaced. It reacts with acidic O-donors releasing CO₂ as the only side-product, whose development also supplies a driving force toward the products. The substitution of carbonate led to new Pt-DMSO carboxylate complexes 2-4, while the total substitution of the ligands of complex 1 gave new Pt-phosphino carboxylates 5-9 in high yields. The X-ray crystal structures of complexes [Pt(d(-)-quinate-O,O′)(Me₂SO-S)₂] (3), [Pt(salicylate)(Me₂SO-S)₂] (4) and [Pt(salicylate)(PPh₃)₂] (6) were determined. The tests of the antiproliferative activity of complexes 1-9 on two human tumoral cell lines, A2780 (cisplatin-sensitive) and SKOV-3 (cisplatin-resistant), showed that the PTA (PTA = 1,3,5-triaza-7-phosphaadamantane) complexes 7-9 were the most active on both cell lines.

Full text of DOI:10.1039/c6dt01689h

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Bis(dimethylsulfoxide)carbonateplatinum(II), a new synthon for a
low-impact, versatile synthetic route to anticancer Pt
carboxylates.
Received 00th xxxxxxx20xx,
Accepted 00th xxxxxxx 20xx
Paola Bergaminia*, Lorenza Marvellia, Valeria Ferrettia, Chiara Gemmob, Roberto Gambarib,
Yekatsiaryna Hushchaa and Ilaria Lamprontib.
DOI: 10.1039/x0xx00000x
www.rsc.org/
The work describes a new low-impact synthetic route to Pt(II)-carboxylate complexes, a class of compounds provided with
established anticancer activity. The process is based on the ligand substitution on [PtCO3(Me2SO-S)2] (1), a new synthon
that can be easily prepared in water with high yield, is stable as a solid, and is reactive in solution where all its ligands can
be easily replaced. It reacts with acidic O-donors releasing CO2 as the only side-product, whose development also supplies
a driving force toward the products.
The substitution of the carbonate led to the new Pt-DMSO carboxylate complexes 2-4, while the total substitution of the
ligands of complex 1 gave the new Pt-phosphino carboxylates 5-9 in high yields.
The x-ray crystal structures of complex [Pt(D(-)-quinate-O,O’)(Me2SO-S)2] (3), [Pt(salicylate)(Me2SO-S)2] (4) and
[Pt(salicylate)(PPh3)2] (6) were determined.
The tests of the antiproliferative activity of complexes 1-9 on two human tumoral cell lines, A2780 (cisplatin-sensitive) and
SKOV-3 (cisplatin-resistant), showed that the PTA complexes 7-9 were the most active on both cell lines.
characterized by chemical stability and by the presence of easily
replaceable ligands. Emblematically, [PtMe2(1,5-cod)] reacts in
organic solvent with coordinating acids (e.g. carboxylic acids) via Pt-
Introduction
The coordination chemistry of Pt(II) was deeply explored, both with
the aim of understanding fundamental reaction mechanisms and
for its valuable practical applications in the fields of catalysis and
medicine.1-3 Most of the known Pt(II) complexes were prepared by
ligand substitutions from a few versatile key intermediates. A huge
number of cisplatin analogues reported in the literature have been
synthesized starting from the ready accessible key compound cis-
[PtCl2(Me2SO-S)2], where coordinated Me2SO can be replaced by a
variety of N-donors, both mono-dentate and chelating, giving the
corresponding dichlorides cis-[PtCl2(NN’)].4-6
Me bonds protonolysis, and with neutral ligands (e.g. phosphines)
by 1,5-cod substitution.7-10 No similar synthon is available for
reactions in water, which would be valuable above all for the
preparation of Pt complexes with O-donor ligands for
pharmaceutical applications.11
The presence of O-donors as anionic ligands is the common
character of Pt-drugs provided with a better therapeutic index than
cisplatin, namely carboplatin, oxaliplatin, nedaplatin and
lobaplatin.12-13 Among thousands of cisplatin analogues prepared
since the late seventies, only this group has achieved international
approval and has found wide clinical use.
Other Pt-containing starting materials undertake complete ligands
substitution, e.g. [PtMe2(1,5-cod)] (1,5-cod = 1,5 cyclooctadiene),
Still today, research in the field of Pt-based anticancer drugs is
oriented towards Pt-carboxylates with innovative properties, like
the Pt(IV) complexes satraplatin which is orally active14 and
aDipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Ferrara, v
Fossato di Mortara 17, 44121 Ferrara, Italy.
mitaplatin
which
contains
the
pro-apoptotic
anion
b Dipartimento di Scienze della Vita e Biotecnologie, Sezione di Biochimica e Biologia
Molecolare, Università degli Studi di Ferrara, Via Fossato di Mortara 74, 44121 Ferrara,
Italy.
dichloroacetate.15-16
In new drug design, a great variety of carboxylate ligands were
considered, while the neutral carrier ligands are mostly limited to
NH3 or primary amines like 1,2-diaminocyclohexane (1,2-DACH) and
cyclohexylamine. The change of neutral ligands could open new
perspectives in terms of therapeutic index, distribution and route of
administration.
*Corresponding Author e-mail: bgp@unife.it
Electronic Supplementary Information (ESI) available:
Selected NMR and ESI-MS spectra, data of known products, crystallographic
information is reported as Supporting Information.
Crystallographic data for the structural analysis of 3, 4 and 6 have been deposited with
the Cambridge Crystallographic Data Center, 12 Union Road, Cambridge, CB2 1EZ, UK,
and are available on request, free of charge, from the Director on quoting deposit
numbers CCDC 1438939, 1438940 and 1438941 for 3, 4 and 6, respectively.
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The main purpose of this work is to develop of a new, simple Synthesis and characterization of [PtCO3(Me2SO-S)2] (1)
and eco-friendly synthetic path to Pt-carboxylate complexes, that
By treating the dichloride cis-[PtCl2(Me2SO-S)2] with Ag2CO3 in
may be suitable for complexes with non aminic carrier ligands,
water (Scheme 2), we have prepared and isolated the new
based on a new Pt-containing synthon.
carbonate complex [PtCO3(Me2SO-S)2] (1). Complex 1 has been
The insertion of hard O-donors, e.g. the deprotonated form of
characterized by NMR in D2O.
dicarboxylic acids or hydroxy-carboxylic acids, is not straightforward
on the soft acid Pt(II)17 and needs to be assisted by one or more
driving forces like: a) the presence of easily replaceable leaving
O
S
O
S
-
O
O
Cl
Cl
groups (e.g. H2O, NO3 ) in the reagent complex, b) the formation of
Ag2CO3
Pt
Pt
O
a 5 or 6-membered chelate ring in the product, c) the formation of
volatile or precipitating side-products.
S
O
S
2AgCl
1
O
Pt(II) dicarboxylated bearing NH3 or 1,2-DACH as neutral ligands
are routinely obtained from the corresponding dihalo complexes by
precipitation of the halides as water insoluble silver or barium
salts.18-19 These reactions occur in water where both the starting
dihalo and the final dicarboxylate complexes are soluble. With
poorly water-soluble reagents like several complexes of
phosphines, DMSO, tertiary and aromatic amines, this route (being
in practice an heterogeneous process) takes long time and gives low
yields due to part of the product being co-precipitated with the
silver salt.
Scheme 2
In 1H NMR, the coordinated DMSO is found at 3.27 ppm as a singlet
with broad satellites (3JPtH of 20.5 Hz), due to the superposition of
the spectra of two isotopomers, one containing non-active Pt which
produces the central signal and the other containing 195-Pt (33.7%)
which gives a doublet (Pt-satellites).
The difference in line broadening between the central signal (sharp)
and its satellites (broad) can be ascribed to the relaxation of 195Pt
via the chemical shift anisotropy mechanism.23 This signal is clearly
distinguishable from the corresponding signal in its precursor cis-
We are proposing here the use of complex [PtCO3(Me2SO-S)2] (1) as
a new synthon for Pt(II) coordination chemistry, whose ligands can
all undergo substitution: the anionic carbonate via protonolysis
with acids, DMSO by nucleophilic substitution at Pt(II). The side
products are respectively CO2 and DMSO, both of which are easy to
remove (Scheme 1).
3
[PtCl2(Me2SO-S)2], which falls at 3.42 ppm in D2O and JHPt = 25.3
Hz.24
The 13C signal of the coordinated DMSO is at 42.69 ppm with JCPt
=
2
38.4 Hz (in D2O). It is possible to observe also the signal of
coordinated carbonate at 165.65 ppm, which is too weak to detect
the Pt satellites. The 195Pt NMR in D2O shows a single signal at
-
O
O
3155.3 ppm.
O
O
HX
HX
S
S
X
X
Complex 1 is soluble in water, slightly soluble in DMSO, CH3OH and
O
Pt
Pt
acetone.
S
S
CO2, H2O
1
O
O
Equilibria of complex 1 in aqueous solution
2L
While in the solid state complex 1 can be stored for a long time
2 DMSO
1
without modification (unchanged H NMR signal after 5 months), in
L
L
X
X
solution it gives rise to two consecutive transformations: O/S
isomerization and DMSO/H2O exchange.
Pt
O/S isomerization25-26: in the 1H-NMR spectrum of a freshly
prepared solution in D2O (1.5 .10-2 M), the main signal for DMSO is a
singlet at 3.10 ppm with no satellites and the minor is at 3.27 ppm
with 3JPtH 20.5 Hz (2.7:1 ratio); we attribute the first signal to the O-
coordinated isomer O-1, which turns almost completely to the S-
isomer 1 (1:20 ratio) (Scheme 3) in 2 hours (Fig. 1). The signals of a
mixed S/O-coordinated species have not been observed.
Scheme 1
The reactivity of complex 1 parallels that of the above described
[PtMe2(1,5-cod)], enhanced by environment-friendly characters: in
fact 1 is prepared in a reactor open to the laboratory atmosphere,
with high yields, and is soluble and reactive in water. The Pt
coordinated carbonate can deprotonate the incoming acidic ligands
giving CO2 as a harmless side product, which also leaves two vacant
coordinative sites on Pt and supplies a driving force toward the
products.
The presence of small residual amounts of the O-isomer does not
influence the subsequent substitution reactions.
O
O
O
O
O
S
S
S
A few carbonate Pt complexes have been described before, e.g.
[PtCO3(PPh3)2]20-21 and [PtCO3(1,2-DACH)]22 and used as convenient
starting materials in organic solvents.
O
Pt
O
Pt
S
O
O
O
O-1
1
Scheme 3
Results and discussion
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and the aquo species 1a, which does not preclude the possibility for
complex
1
to react with acids (Scheme 5).
2+
O
O
O
S
S
OH2
OH2
2 H2O
2-
O
Pt
CO3
Pt
S
S
O
O
O
1
1a
HX
HX
HX
HX
Fig. 1 – O-bonded/S-bonded isomerization observed by 1H-NMR
O
S
X
X
signals of coordinated DMSO (at 400 MHz):
min; , 2 hours.
a, after 2 min; b, 18
CO2
H2O
CO2
3H2O
Pt
c
S
O
The O-bonded/S-bonded isomerization of Pt-coordinated DMSO
could be due to the conversion of the kinetically favoured O-
bonded isomer into the thermodynamically favoured S-isomer
occurring at a rate compatible with the NMR-scale. 27-29
Scheme 5
In the MS-ESI spectrum, the major peak M+ at 734.87 is consistent
with an O-bridged dinuclear species [(Me2SO-S)4Pt2µ(O)µ(OH)]+,
which is probably originated from
1 via the aquo species 1a,
DMSO/H2O exchange: [PtCO3(Me2SO-S)2] (1) is soluble in water,
followed by dimerization. Although it cannot be excluded that this
species is produced under specific electrospray conditions, the MS-
ESI supports the hypothesis described above.
but it slowly undertakes a partial replacement of DMSO by water
(Scheme 4).
O
O
O
O
O
H2O
H2O
S
S
2 H2O
Reactivity of [PtCO3(Me2SO-S)2] (1)
O
O
Pt
Pt
Protonolysis and substitution of CO32-: a series of [Pt(Me2SO-
S)2(dicarboxylate)] have been obtained by Pierpont et al30 by
exploiting the reaction of cis-[PtCl2(Me2SO-S)2] with the silver salt of
the dicarboxylic acid in water. We obtained some of the products
1
O
2 DMSO
Scheme 4
In a 1.5·10-2 M solution, the ratio of free to coordinated DMSO was
estimated from the integrals ratio of the 1H NMR signals at 2.58
ppm and 3.27 (3JPtH 20.5 Hz ppm), respectively. It increases from
1:22 (ratio 0.045) in a fresh solution to an equilibrium state of
1:10.5 (ratio 0.095) in 6 days, as reported in Fig 2.
reported in ref. 30 from the reaction of
acids, which produced H2CO3 (CO2) as the only side-product.
[Pt(CBDC)(Me2SO-S)2] ( ) and [Pt(malonate)( Me2SO-S)2] ( ) were
identified by comparison with the NMR data of ref. 30, while
[Pt(oxalate)( Me2SO-S)2] ( ) was indirectly identified after the
1 with the appropriate
A
B
C
exchange of DMSO with PPh3 in CDCl3 which gave
[Pt(oxalate)(PPh3)2] (31P NMR: 7.73 ppm, 3780 Hz), as showed by
comparison with the reported 31P NMR data (7.7 ppm, 3770 Hz).31
The reaction of [PtCO3(Me2SO-S)2] with one equivalent of L-
10
8
carnitineBF4 gave the chelate complex
O,O’)(Me2SO-S)2]BF4, as we already reported.32
(D) [Pt(L-carnitina-
6
4
These reactions showed that
1 can react with bicarboxylic acids
2
(CBDA, malonic, oxalic) giving Pt/DMSO/carboxylate complexes. We
then focussed on α and β hydroxyacids whose coordination to Pt is
relevant because a large number of such molecules are natural,
biocompatible or even provided with various therapeutic activities
which could improve the performance of Pt-based drugs.
0
0
50
100
150
200
Time (h)
Fig 2. Kinetic plot for DMSO release from complex 1.
The coordination of alcoholic-O to Pt is quite rare, due to the low
Due to this reactivity, the use of freshly prepared solution is affinity of soft Pt to hard O-donors, and occurs exclusively when
recommended when is used for reactions in water. favoured by a side driving force like the formation of a chelate ring
CO32-/H2O exchange. Complex [PtCO3(Me2SO-S)2] is very soluble and/or the development of a volatile side product.33
in water (unlike the parent dichloride complex). This unexpected The reaction of
with α-hydroxycarboxylic acids produces DMSO-Pt
high water solubility suggested the hypothesis that the real nature complexes containing a five-membered chelate ring where the
1
1
of complex
1
in water is an equilibrium state between carbonate donors are a COO- and an RO- group. The same pattern is present in
the platinum-based drug nedaplatin.34
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The α-hydroxycarboxylic L(+)-mandelic acid has been used in
medicine as an antibacterial, particularly in the treatment of urinary
The reaction of
1
with ß-hydroxycarboxylic acids produces
tract infections. It is a useful precursor to various drugs and Pt DMSO-Pt complexes containing a six- membered chelate ring with a
complexes.35 COO- group and an RO- as donor groups; for example, complex
The reaction of complex with 1 eq of L(+)-mandelic acid in [Pt(salicylate)(Me2SO-S)2] was obtained by treating in water with
water produced the new complex [Pt(L(+)-mandelate)(Me2SO-S)2], salicylic acid, a well-known anti-inflammatory drug.39
, in 2 hours in high yield, with CO2 and water as the only side The 1H NMR of complex
in acetone shows two signals of
product. coordinated DMSO at 3.46 (19.0 Hz) and 3.54 (20.5 Hz) due to two
In the 1H NMR in D2O, the CH signal of coordinate mandelate was DMSO in trans to different O-donors. Crystals of
suitable for x-ray
4
,
1
1
2
4
4
found at 5.13 (4JPtH 41 Hz). It is also possible to observe four signals diffractometric determination were obtained from an acetone
for the methyl groups of DMSO (3.31, 3.34, 3.39, 3.40 ppm with solution (Fig. 4).
satellites, coupling constants not computable), while the 13C shows
three singlets (probably due to a fortuitous coincidence of two
signals) at 42.70, 42.97, 43.47 ppm. The inequivalence of the four
CH3 groups of coordinated DMSO is due to two different O donors
in trans to coordinated DMSO and to the presence of a chiral center
which makes the methyl groups of each coordinated DMSO
diastereotopic.
Another example of α-hydroxycarboxylic acid is the D(-)-quinic
acid, which is exploited as a versatile chiral starting material for the
synthesis of new pharmaceuticals36 and is also known as an
effective carrier for some metal ions, due to the formation of
coordination compounds.37
Fig. 4 ORTEPIII view38 and atom numbering scheme for complex 4,
The reaction of complex
complex [Pt(D(-)-quinate-O,O’)(Me2SO-S)2],
characterization is reported in the Experimental section.
1
with D(-)-quinic acid in water gave
[Pt(salicylate)(Me2SO-S)2]. Thermal ellipsoids are drawn at the 40%
3
,
whose
probability level.
Total substitution of the ligands in [PtCO3(Me2SO-S)2] (1): the
O
O
S
total substitution of the ligands in complex
1 can be obtained via
S
S
O
O
O
O
OH
two possible sequences: i) substitution of DMSO with neutral
Pt
Pt
2-
S
O
O
O
ligands followed by the protonolysis of CO3 by the incoming acids
OH
H
O
or ii) protonolysis of
1 with the desired acid followed by the
2
3
OH
substitution of DMSO. Several experiments showed that the more
convenient sequence is ii), which avoids the formation of side
products probably due to the DMSO trans effect, which we
observed using sequence i).
O
S
O
O
Pt
S
O
O
In most cases, these syntheses can be carried out in one pot,
4
saving time and chemicals. For example, the new complex
5,
bearing the chelating diphosphine dppe, was prepared starting
from [PtCO3(Me2SO-S)2] treated with one equivalent of L(+)-
mandelic acid in water. One equivalent of dppe dissolved in acetone
was then added to the previous solution, triggering the immediate
The slow evaporation of a solution of
3 in MeOH gave crystals
suitable for the acquisition of the x-ray crystal structure (Fig. 3).
precipitation of
5
5
as a white solid.
in acetone shows two doublets coupled with 195Pt
The 31P NMR of
1
at 28.4 (d, JPPt 3671 Hz, trans to COO, PA) ppm and 33.3 ppm (d,
1JPPt 3113 Hz, trans to OR, PB), due to two inequivalent P, coupled
each other with a 2JPP 10.7 Hz.40
On the contrary, the preparation of the known complex
6
requires a two-steps procedure: after the formation of [Pt(Me2SO-
S)2(salicylate)] in water, it is necessary to change the solvent (to
acetone) because PPh3 is insoluble in water.
Fig. 3 - ORTEPIII view38 and atom numbering scheme for complex 3, [Pt(D(-)-
quinate-O,O’)(Me2SO-S)2]. Thermal ellipsoids are drawn at the 40%
probability level. The intramolecular hydrogen bond is drawn as a dashed
line.
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The 31P NMR of
9
in CH3OH shows two doublets coupled with 195Pt
O
PB
PA
O
O
Ph3PB
Ph3PA
O
at -61.88 (1JPPt 3018 Hz, trans to OR, PB) and -58.63 (1JPPt 3692 Hz,
trans to COO, PA) ppm, due to two inequivalent P, coupled each
other with a 2JPP 24.3 Hz.
Pt
Pt
O
O
H
5
6
Test of inhibition of cellular proliferation on human tumoral cell
lines. Activity of complexes 1-9.
Complex
6
has been reported before41
,
but has not been
characterized by a crystal structure, which we determined on
crystals of grown in acetone (Fig. 5).
The Pt complexes
1-9 together with their precursor cis-
6
[PtCl2(Me2SO-S)2] were tested in vitro for antiproliferative activity
on two human tumoral cell lines, A2780 (cisplatin-sensitive) and
SKOV-3 (cisplatin-resistant) at 0.01 μM, 0.1 μM, 1 μM, 10 μM, 100
μM and 400 μM.
The cell growth %, for each complex at each dose, was determined
in three independent experiments. The results, obtained by using a
Coulter counter after 72 h treatment, and expressed as IC50, are
reported in Table 1.
The results in Table 1 indicate a low activity of DMSO
complexes 1-4 on both cell lines. The dppe complex
5 shows a
remarkable activity on the A2780 cell line and an even better
activity on the cisplatin-resistant SKOV-3 cell line, where it seems to
be more active than cisplatin. The PPh3 complex
6 shows a low
antiproliferative effect on A2780 cell line, but its activity
interestingly increases on SKOV-3 cells.
Fig. 5 ORTEPIII view38 and atom numbering scheme for complex 6,
[Pt(Me2SO-S)2(salicylate)]. Thermal ellipsoids are drawn at the 40%
probability level.
N
N
N
N
O
One of the problems in using phosphines as ligands for Pt and
other metal ion complexes aimed to pharmaceutical applications is
the lack of solubility in water, which is particularly relevant with
aromatic phosphines like PPh3. The water soluble phosphine PTA
PB
PA
N
PB
PA
N
O
O
O
7
O
OH
Pt
Pt
N
N
O
OH
N
N
N
N
8
OH
has been proposed by us42 and others43-47 as
a convenient
alternative.
N
N
BF4
Therefore, we prepared the PTA analogue of
by a one-pot reaction from complex by addition of salicylic acid (1
eq) followed by PTA (2 eq) in acetone.
6, the new complex 7,
NMe3
PA
PB
N
O
O
9
1
Pt
N
The 31P NMR of the product in DMSO shows two doublets coupled
with 195Pt at -64.55 (1JPPt 3156 Hz, trans to OR, PB) and -63.12 (1JPPt
3416 Hz, trans to COO, PA) ppm, due to two inequivalent P atoms,
coupled each other with a 2JPP 25.5Hz.
O
N
N
The PTA complexes
active on SKOV-3, the best being complex
complex , [Pt(salicylate-O,O’)(Me2SO-S)2], (not active on SKOV-3)
. In the same and complex
, [Pt(salicylate-O,O’)(PTA)2], the most active on the
same cell line, underlines how much the activity is affected by the
is based on 31P neutral ligands on Pt.
7
and
8
are quite active on A2780 and very
7
. A comparison between
The new complex 8, [Pt(D(-)quinate-O,O')2(PTA)2], was also
4
obtained by a one-pot synthesis in CH3OH, starting from
was converted into the DMSO intermediate complex
solvent, two equivalents of PTA were added and complex
isolated after one hour. The characterization of
1
which
was
3
7
8
8
NMR in DMSO, showing two doublets coupled with 195Pt at -63.33 The remarkable activity of the here described phosphinic
(1JPPt 2995 Hz, trans to OR, PB) and -62.04 (1JPPt 3340 Hz, trans to
complexes confirms that this group of Pt complexes deserves
COO, PA) ppm, due to two inequivalent P atoms, coupled each other renewed attention, especially when the presence of hydrophilic
with a 2JPP 24.0 Hz.
phosphines like PTA improves their solubility in water.
The new complex [Pt(L-carnitine)(PTA)2]BF4, 9, was prepared
from the DMSO intermediate [Pt(L-carnitine)(Me2SO-S)2]BF4, D32
,
which was treated with two equivalents of PTA in acetone.
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Table 1. IC50 of complexes 1-10 on A2780 and SKOV-3 cell lines
.
A2780
SKOV-3
IC50 μM
Complexes
IC50 μM
96.03
111.97
42.07
101.30
49.03
6.60
sd
sd
7.14
1.34
0.71
14.92
9.55
1.84
0.35
0.19
0.05
0.14
0.08
[PtCl2(Me2SO-S)2]
1.78
10.90
1.63
15.27
7.98
1.73
9.27
2.54
2.42
1.10
0.15
186.05
42.45
327.50
176.35
205.25
4.70
1
2
3
4
5
6
7
8
9
DMSO
complexes
dppe
PPh3
55.07
6.37
7.55
0.77
PTA
complexes
13.97
3.07
0.89
3.90
cisplatin
2.93
5.94
DMSO), 165.65 ppm (s, CO3). 195Pt NMR (D2O): - 3155.3 ppm. MS-
ESI: m/z = 734.87 (C8H25O6S4Pt2)+, m/z = 656.80 (C6H19O5S3Pt2)+.
S25°C (H2O): 470 g L-1.
Experimental
All the manipulations were carried out in atmosphere unless
otherwise noted. Commercial solvents and reagents were
purchased and used without further purification. cis-[PtCl2(Me2SO-
S)2] was prepared as described in the literature,48 as well as PTA.49
Elemental analyses were determined using a Carlo Erba instrument
model EA1110. The ESI mass spectra were acquired with a
Micromass LCQ Duo Finningan. NMR spectra were recorded on a
Varian Gemini 300 MHz spectrometer (1H at 300 MHz, 13C at 75.43
MHz, 31P at 121.50 MHz) or a Varian Mercury Plus (1H at 400 MHz,
13C at 100.58 MHz, 31P at 161.92 MHz, 195Pt at 85.64 MHz). The 13C ,
31P and 195Pt spectra were run with proton decoupling, 13C signals
are reported in ppm relative to external tetramethylsilane (TMS),
31P signals are reported in ppm relative to an external 85% H3PO4
standard and the reference for 195Pt NMR was Na2PtCl6 1M in D2O.
New Pt complexes obtained from 1
Synthesis of [Pt(L(+)mandelate-O,O’)(Me2SO-S)2] (2).
Complex [PtCO3(Me2SO-S)2], 1, (100 mg, 2.43·10-4 mol, MW 411.2
g/mol, 1 eq), solubilized in 10 mL of H2O, was kept under vigorous
stirring. L-mandelic acid (37 mg, 2.43·10-4 mol, MW 152.1 g/mol,
1eq), solubilized in 2 mL of H2O, was added to the first solution. No
change of color or precipitate was noted. The solution was left for
two hours under stirring, then taken to dryness leaving
yellow-white solid (112 mg, 2.23·10-4 mol, MW 501.5 g/mol, yield
2 as a
91%).
C12H18O5S2Pt (501.5): % found (% calc. for) C 28.73 (28.74), H: 3.52
(3.62), S 12.83 (12.79). 1H NMR (D2O): δ = 3.31, 3.34, 3.39, 3.40 (4s,
3JHPt unresolved, 12H, DMSO), 5.13 (s, 3JHPt = 41 Hz, 1H, CH), 7.2-7.4
(m, 5H, Ph) ppm. 13C NMR (D2O): δ = 42.70, 42.97, 43.47 (s, CH3,
DMSO), 81.28 (s, CH), 128.95, 128.63 and 126.50 (3s, Ph), 191.54 (s,
COO) ppm. 195Pt NMR (D2O): δ = - 3202 ppm. S25°C (H2O): 6.7 g L-1.
Synthesis of [PtCO3(Me2SO-S)2] (1).
A suspension of complex cis-[PtCl2(Me2SO-S)2] (422 mg, 1·10-3
mol, MW 422.1 g/mol) in 40 mL of H2O was kept under vigorous
stirring for 15 minutes and then solid Ag2CO3 (268 mg, 0.97·10-3
mol, MW 275.7 g/mol, 0.97 eq) was added. In order to avoid silver
carbonate aggregates, a very accurate mixing is essential. The
reaction mixture was kept in an oil bath at 40 °C in the dark for two
hours, and then it was filtered on Celite for eliminating the
Synthesis of [Pt(D(-)quinate-O,O’)(Me2SO-S)2]
(3).
Complex was prepared in the same way as complex 2, using the
3
following quantities: [PtCO3(Me2SO-S)2] 100 mg (2.43·10-4 mol,
MW 411.2 g/mol) in 10 mL of H2O and D(-)quinic acid, 47 mg
(2.43·10-4 mol, MW 192.2 g/mol, 1 eq) in 2 mL of H2O. A pale yellow
solid (107 mg, 1.98·10-4 mol, MW 541.5 g/mol, yield 81%) was
obtained.
precipitate of AgCl. The clear solution, taken to dryness, left
1 as a
pale yellow solid (373 mg, 0.91·10-3 mol, MW 411.2 g/mol, yield
C11H22O8S2Pt (541.5): % found (% calc. for) C 24.23 (24.40), H: 4.15
(4.09), S 12.03 (11.84).
93%).
1H NMR (D2O): δ = 1.42-1.78 (m, 2H, CH2), 2.0-2.32 (m, 2H, CH2),
3.2-3.5 (m, 13H, CHOH + DMSO), 3.85 (m, 1H, CHOH), 3.95 (m, 1H,
1 . 2H2O, C5H16O7S2Pt (447): % found (% calc. for) C 13.01 (13.42), H:
3.50 (3.57), S 14.55 (14.32). H NMR (D2O): δ = 3.27 (s,3JPtH 20 Hz,
12H, DMSO) ppm. 13C NMR (D2O): δ = 42.69 (s, C, JPtC 38.42 Hz,
1
1
2
CHOH) ppm. H NMR (CD3OD): δ = 1.57-1.87 (m, 2H, CH2), 2.0-2.33
6 | J. Name., 2012, 00, 1-3
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(m, 2H, CH2), 3.47 (m, 13H, CHOH + DMSO), 4.00 (m, 2H, 2CHOH) completely clear and the reaction presumably gave 2.43·10-4 mol of
ppm. 13C NMR (CD3OD): δ = 42.24, 44.10, 44.90, 45.94 (s, 2 signals the intermediate [Pt(salicylate-O,O')(Me2SO-S)2],
4, assuming
CH3, DMSO and 2 CH2), 68.95, 73.23, 78.20, 84.73, 193.13 (s, COO) complete conversion.
ppm. 195Pt NMR (CD3OD): δ = - 3265 ppm. S25°C (H2O): 48 g L-1. The A solution of PTA (76 mg, 4.86·10-4 mol, MW 157.0 g/mol, 2 eq) in
crystallographic structure of
MeOH (see Fig. 3).
3
was determined on crystals grown in acetone (5 mL) was then added under nitrogen to the previous
solution. Complex precipitated as a white solid. After 30 min, it
was filtered and washed with acetone (131 mg, 2.03·10-4 mol, MW
, using the 645.5 g/mol, yield 84%).
C19H28O3N6P2Pt (645.5): % found (% calc. for) C 34.99 (35.35), H:
7
Synthesis of [Pt(salicylate-O,O’)(Me2SO-S)2]
Complex was prepared in the same way as complex
following quantities:
(4).
4
3
[PtCO3(Me2SO-S)2], 100 mg (2.43·10-4 mol, MW 411.2 g/mol) in 10 4.34 (4.37), N: 12.95 (13.02). 1H NMR (D2O): δ = 4.20 (d, NCH2P, 2JHP
mL of H2O and 34 mg of salicylic acid (2.43·10-4 mol, MW 138.1 14 Hz), 4.40 and 4.42 (2s, NCH2N), 6.65 (m, 2H, Ph), 7.20 (m, 1H, Ph)
g/mol, 1eq) in 20 mL of H2O. A pale yellow solid (94 mg, 1.92·10-4 and 7.60 (m, 1H, Ph) ppm. H NMR (DMSO-d6): δ = 4.25 (d, NCH2P,
1
mol, MW 487.4 g/mol, 79%) was obtained in 2 hours.
2JHP 14 Hz), 4.50 (m, NCH2N), 6.5 (m, 1H, Ph), 6.6 (m, 1H, Ph), 7.12
C11H16O5S2Pt (487.4): % found (% calc. for) C 27.03 (27.10), H: 3.45 (m, 1H, Ph) and 7.65 (m, 1H, Ph) ppm. 31P NMR (D2O): δB = - 64.98
(3.31), S 13.07 (13.16).1H NMR (D2O): δ = 3.22-3.37 (m, 12H, (d, JPtPB 3182 Hz, PTAB), δA = - 63.55 (d, JPtPA 3393 Hz, PTAA) ppm,
1
1
DMSO), 6.70 (2H), 7.20 (1H), 7.63 (1H) (m, Ph) ppm. 1H NMR 2JPAPB 25.7 Hz. 31P NMR (DMSO): δB = - 64.55 (d, JPtPB 3156 Hz,
1
3
3
(acetone-d6): δ = 3.46 (s, JPtH 19 Hz, 6H, DMSO), 3.54 (s, JPtH 20.5 PTAB), δA = - 63.12 (d, 1JPtPA 3416 Hz, PTAA) ppm, 2JPAPB 25.5 Hz. S25°C
Hz, 3H, DMSO), 3.54 (s, 3JPtH 20.5 Hz, 3H, DMSO), 6.68 (m), 6.81 (d), (H2O) = 42 gL-1.
7.14 (m) (4H, Ph) ppm. 13C NMR (acetone-d6): δ = 41.23, 41.30 (s, 2
CH3, DMSO); 116.70, 120.20, 131.73 and 132.53 (Ph); 164.51(C-O), The above described intermediate
165.37 (s, COO) ppm. 195Pt NMR (acetone): δ = - 3118 ppm. S25°C quinic acid (47 mg, 2.43·10-4 mol, MW 192.2 g/mol, 1 eq) in 5 mL of
(H2O): 5.0 g L-1. The crystallographic structure of was determined CH3OH to a suspension of [PtCO3(Me2SO-S)2] (100 mg, 2.43·10-4
One-pot synthesis of [Pt(D(-)quinate-O,O’)(PTA)2] (8).
was formed by adding D(-)-
3
4
on crystals grown in acetone for two weeks (see Fig. 4).
mol, MW 411.2 g/mol) in 20 mL of CH3OH. The mixture was left
under vigorous stirring for one night. The intermediate complex
One-pot synthesis of [Pt(L(+)mandelate-O,O’)(dppe)] (5).
L(+)mandelic acid (37 mg, 2.43·10-4 mol, MW 152.1 g/mol, 1 eq) [Pt(D(-)quinate-O,O’)( Me2SO-S)2],
3
was obtained (2.43·10-4 mol,
solution of assuming total conversion) and left in solution. PTA (76 mg,
[PtCO3(Me2SO-S)2] (100 mg, 2.43·10-4 mol, MW 411.2 g/mol) in 10 4.86·10-4 mol, MW 157.1 g/mol, 2 eq), solubilized in 10 mL of
mL of water. The formation of the intermediate [Pt(L-mandelate- CH3OH, was then added under nitrogen. Complex precipitated as
gave 2.43·10-4 mol, assuming complete a white solid and then was filtered and washed with methanol (142
mg, 2.03·10-4 mol, MW 699.4 g/mol, yield 84%).
dissolved in
2 mL of water was added to a
8
O,O')(Me2SO-S)2],
2,
conversion.
After one hour, bis(diphenylphosphino)ethane (dppe, 96.7 mg, C19H34O6N6P2Pt (699.5): % found (% calc. for) C 32.52 (32.62), H:
1
2.43·10-4 mol, MW 398.4 g/mol, 1 eq), dissolved in 5 mL of 4.94 (4.90), N: 12.15 (12.01). H NMR (D2O): δ = 1.6 – 2.0 (m, 4H),
acetone, was added to the previous solution. Complex
5
3.38 (m, 1H), 3.85 (m, 2H) (cyclohexane), 4.2 (d, 12H, PTA), 4.45 (s,
precipitated immediately as a white solid (163 mg, 2.19·10-4 mol, 12H, PTA). 31P NMR (D2O): δB = - 60.81 (s, 1JPtPB 3083 Hz, PTAB), δA =
1
MW 743.5 g/mol, yield 90.1%).
- 60.81 (s, JPtPA 3479 Hz, PTAA) ppm. 31P NMR (DMSO): δB = - 63.33
1
1
C34H30O3P2Pt (743.6): % found (% calc. for) C 54.93 (54.92), H: 4.14 (d, JPtPB 2995 Hz, PTAB), δA = - 62.04 (d, JPtPA 3340 Hz, PTAA) ppm,
1
(4.07). H NMR (acetone-d6): δ = 2.65 (bs, PCH2CH2P, 4H), 5.35 (bs, 2JPAPB 24 Hz. 13C NMR (DMSO): ca 40 ppm, under solvent signal (CH2
CHCOO), 7.1-8.2 (m, 5H, Ph), ppm. 31P NMR (acetone): δA = 28.42 quinic acid); 49.51 and 49.91 (d, NCH2P, JCP = 24.5 and 24.2 Hz),
1
1
1
2
(d, JPtPA 3671 Hz, PA), δB = 33.30 (d, JPtPB 3113 Hz, PB), ppm, JPAPB 67.08 (s, 2 CHOH quinic acid), 71.61 and 71.68 (s, NCH2N), 77.03 (s,
10.7 Hz. S25°C (H2O) < 1 g L-1.
1 CHOH quinic acid), 80.50 (s, COHCOOH), 173.06 (s, COO). S25°C
Exchange of DMSO for PPh3 in [Pt(salicylate-O,O’)(Me2SO-S)2] (H2O) = 64 g L-1.
giving [Pt(salicylate-O,O’)(PPh3)2] Two-step synthesis of [Pt(L-carnitine-O,O’)(PTA)2]BF4
Two eq of PPh3 were added to a solution of in acetone. The Complex was obtained by a two-step synthesis, the first occurring
(6
)
.
(9).
4
9
observation of 31P NMR after a few minutes showed the formation in water and the second in acetone.
of complex
6
(by comparison with reported data).35
Step 1: formation of
D, as reported in ref 18.
1
31P NMR (acetone): δB = 13.4 (d, JPtPB 3560 Hz, Ph3PB) ppm, δA
=
Step 2: [Pt(L-carnitine-O,O’)(Me2SO-S)2]BF4, D
, (263 mg, 4.40·10-4
14.18 (d, 1JPtPA 3862 Hz, Ph3PA), 2JPAPB 27 Hz. S25°C (H2O) < 1 g L-1. The mol, MW 598.2 g/mol) was suspended in 20 mL of acetone, and
crystallographic structure was determined on crystals of
from an acetone solution (see Fig. 5).
6
grown PTA (138 mg, 8.79·10-4 mol, MW 157.1 g/mol, 2 eq in 20 mL of
acetone) was added under nitrogen. The mixture was kept under
One-pot synthesis of [Pt(salicylate-O,O’)(PTA)2] (7).
vigorous stirring for 12 hours. The pale yellow precipitate, 9, was
Salicylic acid (34 mg, 2.43·10-4 mol, MW 138.1 g/mol, 1 eq) then filtered and dried under vacuum over P2O5. (200 mg, 2.64·10-4
dissolved in 5 mL of acetone was added to a suspension of mol, MW 756.4 g/mol, yield 60%).
[PtCO3(Me2SO-S)2] (100 mg, 2.43·10-4 mol, MW 411.2 g/mol) in 5 C19H38BF4O3N7P2Pt (756.4): % found (% calc. for) C 30.12 (30.17), H:
mL of acetone. In the course of one hour, the mixture became 5.23 (5.06), N: 12.85 (12.96). 31P NMR (CH3OH): δB = - 61.88 (d, 1JPtPB
This journal is © The Royal Society of Chemistry 20xx
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3018 Hz, PTAB), δA = - 58.63 (d, 1JPtPA 3692 Hz, PTAA) ppm, 2JPAPB 24.3
Hz. 1H NMR (CD3OD): δ = 2.45 (m, 2H, CH2COO), 3.20 (s, 9H, NMe3),
3.42 (m, 2H, CH2N), 4.32 (d, 13H, PTA + CH), 4.60 (s, 12H, PTA).
S25°C (H2O) = 8.5 g L-1.
Conclusions
As a general final consideration about the quite extended group of
reactions of complex [PtCO3(Me2SO-S)2], , here reported, it is
1
possible to affirm that the substitution of carbonate with carboxylic
acids or hydroxycarboxylic acids through protonolysis was
successful in every case we tested, included the monocarboxylic
acid DCA (dichloroacetic acid), which does not benefit from the
stabilizing effect of a metal-chelate formation, and which will be
object of another paper.
X-Ray Crystallography
Single-crystal diffraction data for complexes
3, 4 and 6 were
collected on a Nonius Kappa diffractometer equipped with a CCD
detector with graphite-monochromatized MoKα radiation (λ =
0.71069 Å). Intensities were corrected for Lorentz, polarization and
absorption effects.50 The structures were solved by direct methods
with the SIR97 suite of programs51 and refinement were performed
on F2 by full-matrix least-squares methods with all non-hydrogen
atoms anisotropic. The absolute configuration of the quinic ligand
This reactivity can be exploited for preparing a variety of DMSO-Pt-
carboxylate complexes. The subsequent substitution of DMSO with
a phosphine, e.g. PPh3, dppe or PTA, occurs smoothly, opening an
access to a new group of potential Pt anticancer drugs.
in complex
3
was confirmed by the value of the Flack parameter
the electron density difference map
(0.007(6)). In complex
6
Conflict of interest
showed some rather large, broad peaks located among the
complexes. Attempts to identify the solvent molecules failed.
Instead, a new set of F2 (hkl) values with the contribution from
solvent molecules withdrawn was obtained by the SQUEEZE
procedure implemented in PLATON.52 The potential solvent volume
The authors declare no competing financial interest.
Acknowledgements
in the crystals was 176.4 Å3 per unit cell volume. In
3, hydrogen
We thank Dr T. Bernardi, Dr E. Bianchini and Dr P. Formaglio for
technical assistance and CIRCMSB (Consorzio Interuniversitario di
Ricerca in Chimica dei Metalli nei Sistemi Biologici) for support.
atoms of the hydroxyl groups were found in the difference Fourier
map and refined isotropically; all other hydrogens were included on
calculated positions, riding on their carrier atoms. All calculations
were performed using SHELXL-9753, implemented in the system of
programs WINGX.54 Crystal data are given in Supporting Material.
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