Oxidative halogenation of cisplatin and carboplatin: Synthesis, spectroscopy, and crystal and molecular structures of Pt(iv) prodrugs

Article abstract of DOI:10.1039/c4dt02627f

A series of Pt(iv) prodrugs has been obtained by oxidative halogenation of either cisplatin or carboplatin. Iodobenzene dichloride is a general reagent that cleanly provides prodrugs bearing axial chlorides without the need to prepare intervening Pt(iv) intermediates or handle chlorine gas. Elemental bromine and iodine afford Pt(iv) compounds as well, although in the case of the iodine-mediated oxidation of carboplatin, an amido-bridged Pt(iv) side product also formed. A detailed analysis of the changes in spectroscopic and structural parameters induced by varying the axial halide is presented. A number of recurring motifs are observed in the solid state structures of these compounds. This journal is

Full text of DOI:10.1039/c4dt02627f

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Oxidative halogenation of cisplatin and
carboplatin: synthesis, spectroscopy, and crystal
Cite this: Dalton Trans., 2015, 44, 119
and molecular structures of Pt(IV) prodrugs†
Timothy C. Johnstone, Sarah M. Alexander, Justin J. Wilson and Stephen J. Lippard*
A series of Pt(IV) prodrugs has been obtained by oxidative halogenation of either cisplatin or carboplatin.
Iodobenzene dichloride is a general reagent that cleanly provides prodrugs bearing axial chlorides
without the need to prepare intervening Pt(IV) intermediates or handle chlorine gas. Elemental bromine
and iodine afford Pt(IV) compounds as well, although in the case of the iodine-mediated oxidation
of carboplatin, an amido-bridged Pt(IV) side product also formed. A detailed analysis of the changes in
spectroscopic and structural parameters induced by varying the axial halide is presented. A number of
recurring motifs are observed in the solid state structures of these compounds.
Received 28th August 2014,
Accepted 18th October 2014
DOI: 10.1039/c4dt02627f
www.rsc.org/dalton
platinum(II) almost invariably adopts, long dominated the
landscape of platinum drug development. Despite the mono-
Introduction
Platinum complexes play a significant role in the clinical treat- poly that Pt(II) holds over the market for platinum-based
ment of cancer, with cisplatin, carboplatin, and oxaliplatin drugs, platinum(IV) complexes also have biological activity,
(Chart 1) comprising one of the most widely prescribed classes as revealed in some of the earliest experiments.2 Pt(IV)
of antineoplastic drugs.1 These three coordination complexes compounds were extensively pursued in preclinical and clini-
feature platinum in the 2+ oxidation state. Indeed, this oxi- cal settings early in the history of this class of drugs (Chart 1).3
dation state, and the square-planar coordination geometry that The status of satraplatin (Chart 1) was closely monitored as it
progressed through clinical trials, although it ultimately failed
to achieve the desired increased lifespan when used in combi-
nation with prednisone for treatment of hormone-refractory
prostate cancer.4
Pt(IV) compounds as a class act as prodrugs that undergo
intracellular reduction to yield active Pt(II) species, which can
proceed to bind nuclear DNA and initiate a cellular response
that eventually triggers cell death pathways.5 Pt(IV) prodrugs
typically contain the four ligands of a Pt(II) precursor of known
anticancer activity arranged in a square-planar geometry
with two additional ligands, disposed trans to one another,
completing the octahedral coordination sphere.6 Although it is
widely stated that reduction of Pt(IV) prodrugs proceeds with
loss of these two additional, so-called “axial” ligands, recent
studies reveal that other reduction products are possible.7,8
The nature of the ligands bound to the Pt(IV) center signifi-
cantly influences the mechanism and kinetics of reduction.9,10
Most Pt(IV) prodrugs bear axial chloride, hydroxide, or carb-
oxylate ligands because of the synthetic ease with which they
can be installed.11 Oxidation of a Pt(II) complex with hydrogen
peroxide in water typically affords the Pt(IV) derivative with two
trans hydroxide ligands in which the relative geometry of the
ligands bound originally to the metal center remains un-
disturbed. The metal-bound hydroxide ligands are sufficiently
Chart 1 Selection of Pt(II) (top) and Pt(IV) complexes (bottom) investi-
gated in a clinical setting.
Department of Chemistry, Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, USA. E-mail: lippard@mit.edu
†Electronic supplementary information (ESI) available: NMR spectra, crystallo-
graphic parameters, and Cartesian coordinates of calculated structures. CCDC
1022055–1022064. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4dt02627f
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room temperature. Resonant absorptions are reported as
chemical shifts (δ) in ppm with respect to tetramethylsilane
(1H and 13C), NH4Cl (14N), or Na2PtCl6 195Pt). NMR spectra
(
were referenced to residual solvent signals (1H and 13C), an
external solution of NH4Cl in 0.1 M HCl (14N δ = 0 ppm), or
an external solution of K2PtCl4 in D2O (195Pt δ = −1628 ppm).
14N NMR spectra were acquired for 1 and 2 but not 3–6.18
Elemental analyses for the previously unreported compounds
Chart 2 The target Pt(IV) prodrugs of cisplatin, 1–3, and carboplatin, 4–6 were provided by a commercial laboratory. Combustion
4–6.
analyses were not carried out for the known compounds 1–3.
nucleophilic to attack carboxylic acid anhydrides to yield Pt(IV)
Syntheses
carboxylates.11 Similar nucleophilic attack of other substrates
Synthesis of iodobenzene dichloride. The synthesis is a
can afford Pt(IV) carbonates and carbamates.12,13 Treatment
modification of that previously reported.19 Iodobenzene
with hydrochloric acid results in substitution of the hydroxide
(250 mg, 1.22 mmol) was suspended in household bleach
ligands for chloride, presumably through an intermediate
(10 mL, 5.25% NaClO). Concentrated hydrochloric acid was
bearing aqua ligands.14 Pt(IV) prodrugs with chloride axial
added in a dropwise manner until gas evolution ceased (ca.
ligands can also be obtained by direct oxidation with chlorine
2 mL). The resulting yellow precipitate was collected by fil-
gas.15
tration, washed with water (3 × 10 mL), air dried, and washed
In the course of exploring the chemistry of Pt(IV) prodrugs,
with hexanes (3 × 10 mL). The solid was dissolved in a minimal
the oxidative halogenation of cisplatin and carboplatin was
amount of hot chloroform and cooled to room temperature. The
investigated with the aim of expanding the range of commonly
solution was allowed to stand at −40 °C overnight. Yellow
needles formed and were collected by filtration, washed with
encountered axial ligands and the synthetic methodologies for
accessing them (Chart 2). We found iodobenzene dichloride to
be a suitable replacement for chlorine gas in the preparation
of prodrugs with axial chloride ligands. Bromine and iodine
hexanes, and dried in vacuo for 2 h. Yield 240 mg, 72%. Spectro-
scopic characterization matches that previously reported.19
Synthesis of cis-[Pt(NH3)2Cl4] (1). Cisplatin (100 mg,
are more suitable than chlorine for laboratory handling and
0.33 mmol) was suspended in DMF (2 mL). A solution of iodo-
provided ready access to prodrugs having axial bromide
benzene dichloride (92 mg, 0.33 mmol) in DMF (1 mL) was
and iodide ligands, respectively. An unexpected dimerization
added to the cisplatin suspension. The color of the suspension
occurred as a side reaction upon treatment of carboplatin with
briefly turned deep orange, but quickly lightened to a bright
I2. Here we report details of the synthesis and characterization
yellow and all of the solids dissolved. The mixture was stirred
of these compounds and anticipate that these reactions will be
at room temperature for 10 min followed by addition of diethyl
readily applicable to the preparation of Pt(IV) prodrugs from
ether (30 mL) to precipitate a yellow solid. The solid was col-
other biologically active Pt(II) complexes. The crystal structures
lected by filtration, washed with diethyl ether, and dried
of several of these prodrugs, as well as those of related plati-
num complexes, were determined, salient features of which
are discussed.
1
in vacuo. Yield: 121 mg, 99%. M.p. 220–230 °C (dec). H NMR
(500 MHz, DMF-d7) δ 5.87 (1JH–N = 55 Hz, JH–Pt = 50 Hz).
2
1H NMR (400 MHz, DMSO-d6) δ 5.83 (1JH–N = 52 Hz, JH–Pt
=
2
56 Hz). 14N NMR (28.9 MHz, DMSO-d6) δ −33.7 (1JN–H = 53 Hz,
1JN–Pt = 177 Hz). 195Pt NMR (108 MHz, DMF-d7) δ −257.
195Pt NMR (86 MHz, DMSO-d6) δ −127.
Experimental
Synthesis of cis,cis,trans-[Pt(NH3)2Cl2Br2] (2). Cisplatin
(100 mg, 0.33 mmol) was suspended in DMF (2 mL). A solu-
tion of bromine (53 mg, 0.33 mmol) in DMF (1 mL) was added
to the cisplatin suspension. The mixture was stirred at room
temperature for 10 min. Addition of diethyl ether (15 mL)
resulted in precipitation of an orange solid. The solid was
collected by filtration, washed with diethyl ether, and dried
General considerations
Unless otherwise specified, reactions were conducted in a
fume hood with protection from light. Reactions leading to
the formation of the Pt(IV) iodide complexes were particularly
prone to photodecomposition. All reagents were used as
received from commercial vendors without further purifi-
cation. Carboplatin was prepared as previously described.16
cis,trans-[Pt(CBDCA)(NH3)2(OH)2], where CBDCA is 1,1-cyclo-
butane-dicarboxylate, was prepared as previously reported.17
1
in vacuo. Yield: 121 mg, 80%. M.p. 200–220 °C (dec). H NMR
2
(400 MHz, DMSO-d6) δ 5.77 (1JH–N = 52 Hz, JH–Pt = 52 Hz).
14N{1H} NMR (28.9 MHz, DMSO-d6) δ −40.9 (1JN–Pt = 175 Hz).
195Pt NMR (86 MHz, DMSO-d6) δ −732 (1JPt–N = 175 Hz, 2JPt–H
=
Physical measurements
1H, 13C, 14N, or 195Pt NMR spectra were acquired on either a
50 Hz).
Synthesis of cis,cis,trans-[Pt(NH3)2Cl2I2] (3). Cisplatin
Varian Inova-500 or a Bruker DPX-400 spectrometer in the MIT (100 mg, 0.33 mmol) was suspended in DMF (2 mL). A solu-
Department of Chemistry Instrumentation Facility (DCIF) at tion of iodine (84 mg, 0.33 mmol) in DMF (2 mL) was added to
120 | Dalton Trans., 2015, 44, 119–129
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the cisplatin suspension. The mixture was stirred at room consistent with its formulation as 6. Yield: 108 mg, 64%.
temperature for 10 min. Addition of diethyl ether (25 mL) M.p. 164–180 °C (dec). 1H NMR (500 MHz, DMF-d7) δ 6.25 (6H,
1
2
3
resulted in precipitation of a red-purple solid. The solid was m, JH–N = 52 Hz, JH–Pt = 50 Hz), 2.67 (4H, t, JH–H = 7.5 Hz),
collected by filtration, washed with diethyl ether, and dried 1.90 (2H, p, JH–H = 7.5 Hz). 13C NMR (125 MHz, DMF-d7)
3
in vacuo. Yield: 133 mg, 73%. M.p. 205–218 °C (dec). H NMR δ 178.3, 58.1, 33.1, 16.6. 195Pt NMR (108 MHz, DMF-d7) δ −856.
1
(500 MHz, DMF-d7) δ 5.77 (1JH–N = 53 Hz). 195Pt NMR Anal. calcd for C12H26I2N4O6Pt: C 18.69, H 3.40, N 7.26; found:
(108 MHz, DMF-d7) δ −1866.
C 18.75, H 3.18, N 7.20.
Synthesis of cis,trans-[Pt(CBDCA)(NH3)2Cl2] (4). Carboplatin
(100 mg, 0.27 mmol) was suspended in DMF (6 mL). A solu-
tion of iodobenzene dichloride (83 mg, 0.30 mmol) in DMF
(2 mL) was added to the carboplatin suspension. The mixture
was stirred at 75 °C for 30 min after which time the solid was
consumed producing a yellow solution. The solution was con-
centrated under vacuum to a volume of approximately 5 mL.
Methanol (1 mL) was added and the solution was filtered
through Celite. Addition of diethyl ether (15 mL) resulted in
precipitation of a yellow solid. The solid was collected by fil-
tration, washed with diethyl ether, and dried in vacuo. Yield:
X-ray crystallography
Crystals of 1, 3, 4, and 5 were obtained by allowing diethyl
ether vapor to diffuse into a DMF solution of the compound.
The DMF-diethyl ether solvate of 1 was obtained in a similar
manner, whereas the DMSO solvate of 1 was obtained by layer-
ing toluene onto a DMSO solution of the compound. Crystalli-
zation vials containing spectroscopically pure 1 and 3 were left
to stand at room temperature for more than two months
and afforded crystals of the decomposition products fac-
[Pt(NH3)3Cl3]Cl and fac-[Pt(NH3)3Br3]Br. Crystals of 7 were
obtained directly from the reaction mixture and those of cis,
trans-[Pt(CBDCA)(NH3)2(OH)2] were formed by recrystallization
from hot water. Samples suitable for X-ray diffraction were
selected microscopically under crossed polarizers, mounted
on a nylon loop in Paratone oil, and cooled to 100 K under
a stream of nitrogen. Diffraction was carried out on a Bruker
APEX CCD X-ray diffractometer controlled by the APEX2 soft-
ware using Mo Kα radiation (λ = 0.71073 Å).20 The data were
integrated with SAINT21 and absorption, Lorentz, and polariz-
ation corrections were calculated by SADABS.22 Space group
determination was carried out by analyzing the Laue symmetry
and the systematically absent reflections with XPREP.23 Struc-
tures were solved by direct or heavy atom methods and refine-
ment was performed with the SHELX-97 program suite.24
Refinement was carried out against F2 using standard pro-
cedures.25 Non-hydrogen atoms were located in difference
Fourier maps and refined anisotropically. Hydrogen atoms
were placed at calculated positions and refined using a riding
model unless otherwise specified in the corresponding
CIF (see ESI†). For coordinated NH3 and terminal CH3 groups,
1
97 mg, 85%. M.p. 167–173 (dec). H NMR (500 MHz, DMF-d7)
1
2
δ 6.10 (6H, m, JH–N = 50 Hz, JH–Pt = 45 Hz), 2.59 (4H,
t, 3JH–H = 8 Hz), 1.88 (2H, p, 3JH–H = 8 Hz). 13C NMR (125 MHz,
DMSO-d6) δ 176.5, 55.8, 31.8, 15.6. 195Pt NMR (108 MHz,
DMF-d7) δ 761. Anal. calcd for C12H26Cl2N4O6Pt: C 24.50,
H 4.45, N 9.52; found: C 24.07, H 4.13, N 9.66.
Synthesis of cis,trans-[Pt(CBDCA)(NH3)2Br2] (5). Carboplatin
(150 mg, 0.40 mmol) was suspended in DMF (2 mL) and a
solution of bromine (65 mg, 0.40 mmol) in DMF (1 mL) was
added. The mixture was stirred at room temperature for
30 min and then at 50 °C for an additional 10 min, after which
time the solid was consumed producing an orange solution.
The mixture was filtered through Celite and addition of the
filtrate to diethyl ether (150 mL) resulted in precipitation of an
orange solid. The solid was collected by filtration, washed with
diethyl ether, and dried in vacuo. Yield: 181 mg, 84%. M.p.
1
169–172 °C (dec). H NMR (500 MHz, DMF-d7) δ 6.01 (6H, m,
2
3
1JH–N = 52 Hz, JH–Pt = 45 Hz), 2.60 (4H, t, JH–H = 10 Hz), 1.89
(2H, p, JH–H = 10 Hz). 13C NMR (125 MHz, DMSO-d6) δ 176.6,
3
56.0, 31.8, 15.5. 195Pt NMR (108 MHz, DMF-d7) δ 229 (1JPt–N
=
150 Hz). Anal. calcd for C6H12Br2N2O4Pt·0.3DMF (supported
by NMR integration): C 14.99, H 2.57, N 5.83; found: C 15.32,
H 2.49, N 5.33.
hydrogen atom isotropic displacement parameters (Uiso
)
were set equal to 1.5 times the Uiso of the atom to which they
were attached. For other hydrogen atoms, Uiso = 1.2 Uiso of
the attached atom. The details of any restraints employed are
presented in the corresponding CIF (see ESI†). All structures
were checked for missed higher symmetry and twinning
with PLATON and were further validated using CheckCIF.26
Least-squares planes were fit using XP and visualized using
Mercury.24,27 Refinement details are presented in Table 1
and depictions of the molecular structures of the platinum
complexes from their respective crystal structures are shown
in Fig. 1.
Oxidation of carboplatin with I2. Carboplatin (100 mg,
0.27 mmol) was suspended in DMF (2 mL). A solution of
iodine (70 mg, 0.27 mmol) in DMF (3 mL) was added to the
carboplatin suspension. The mixture was stirred at room temp-
erature for 30 min, during which time a yellow solid began to
form. Addition of diethyl ether (5 mL) induced precipitation of
more yellow solid and the mixture was cooled at 4 °C for 1 h.
The yellow solid was collected by filtration and washed with
cold DMF (8 mL) and diethyl ether (15 mL). Spectroscopic and
crystallographic analysis revealed this substance to be the
amido-bridged dimer [Pt(CBDCA)I(NH3)(μ-NH2)]2 (7). The red-
purple filtrate was added to 100 mL of rapidly stirring diethyl
Computational details
ether to precipitate a red-brown solid. The solid was collected DFT calculations were executed with Gaussian 03.28 The
by filtration, washed with diethyl ether, and dried under PBE0 hybrid functional was employed.29 The valence electrons
vacuum. The spectroscopic properties of this complex are of the Pt, Br, and I atoms were treated using the LANL2DZ
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Table 1 Crystallographic parameters for 1·3DMF, 3·3DMF, 4·DMF, 5·DMF, and 7·3DMF·Et2O
1·3DMF
3·3DMF
4·DMF
5·DMF
7·3DMF·Et2O
Formula
FW
Space group
a (Å)
b (Å)
c (Å)
C9H27Cl4N5O3Pt
590.25
P21/c
10.0850(4)
12.9560(5)
16.0513(6)
C9H27Cl2I2N5O3Pt
773.15
P21/c
21.974(3)
12.4000(14)
17.573(2)
C9H19Cl2N3O5Pt
515.26
P1
C9H19Br2N5O5Pt
604.18
P1
C22H53I2N7O12Pt2
1287.72
P1
ˉ
ˉ
ˉ
8.0456(5)
10.2110(6)
10.2604(6)
98.438(1)
104.454(1)
106.933(1)
758.64(8)
2
8.1817(4)
9.5209(5)
11.4203(5)
108.009(1)
107.490(1)
95.406(1)
789.55(7)
2
13.0123(11)
13.2677(11)
13.388(2)
94.816(2)
100.174(2)
118.650(1)
1958.0(4)
2
α (°)
β (°)
104.918(1)
112.003(2)
γ (°)
V (Å3)
2026.59(14)
4
4439.6(9)
8
Z
T (K)
100(2)
7.466
2.05 to 28.33
40 197
5046
100(2)
9.358
1.92 to 28.97
88 414
11 675
413
100(2)
9.621
2.11 to 28.28
14 758
3744
100(2)
13.967
2.00 to 28.70
15 848
4040
100(2)
8.775
1.58 to 28.37
38 217
9716
μ(Mo Kα) (mm−1
θ range (°)
Total data
Unique data
Parameters
)
207
185
185
453
Completeness (%)
99.9
1.30
3.01
1.086
99.3
2.63
6.52
1.077
99.2
1.27
3.10
1.064
99.3
1.88
5.12
1.134
99.2
2.27
4.52
1.031
R1 a (%)
wR2 b (%)
GoFc
a R1 = ∑||Fo| − |Fc||/∑|Fo|. b wR2 = {∑[w(Fo2 − Fc2)2]/∑[w(Fo2)2]}1/2
.
c GoF = {∑[w(Fo2 − Fc2)2]/(n − p)}1/2
.
surface of the molecule. Comparison of the optimized
gas-phase structures to the crystallographically determined
molecular structures was performed using Mercury.27 Cartesian
coordinates for all optimized structures are provided in the
ESI.†
Results and discussion
Oxidative halogenation of cisplatin
The oxidation of an aqueous suspension of cisplatin with
chlorine to form 1 has been previously reported,15 as has oxi-
dation of cisplatin with bromine water to afford 2,34 but to the
best of our knowledge the oxidation of cisplatin using iodine
to yield 3 has not been described. We report here a general
procedure to obtain Pt(IV) trans dihalide complexes by treating
DMF solutions of the parent platinum(II) compounds with stoi-
chiometric amounts of oxidant, followed by precipitation with
diethyl ether.
Fig. 1 Molecular structures of platinum complexes from the crystal
structures of (a) 1, (b) 3, (c) 4, (d) 5, and (e) 7. Thermal ellipsoids are
shown at the 50% probability level and hydrogen atoms are shown as
spheres of arbitrary radius. Color code: Purple Pt, blue N, red O, grey C,
magenta I, orange Br. For (b) and (e) only one of the two crystallographi-
cally independent molecules present in the asymmetric unit is shown.
The methods most widely employed in the literature to
prepare Pt(IV) prodrugs bearing axial chlorides involve oxi-
dation of the Pt(II) precursor with Cl2 or with hydrogen per-
oxide in water to afford the dihydroxide complex followed by
treatment with hydrochloric acid.11 An alternative reaction that
in one step both oxidizes and chlorinates the platinum center
is treatment with PCl5. Phosphorus pentachloride was used to
convert [Pt(en)I2] to cis,trans-[Pt(en)I2Cl2].35 The use of the
mono-chlorinating oxidant N-chlorosuccinimide in the prepa-
ration of prodrugs bearing one axial chloride has very recently
been described.36 In only a few reports have we and others
used iodobenzene dichloride in the preparation of platinum
anticancer agents bearing axial trans chlorides.11,37–40
basis set and relativistic effects were taken into consideration
by employing the corresponding LANL2DZ effective core
potentials.30,31 The Pople-type 6-31++g(d,p) basis set was used
for all other atoms.32,33 Geometry optimizations were carried
out for 4, 5, and 6 in the gas phase followed by analytical fre-
quency calculations. The lack of imaginary frequencies in
the latter was used as confirmation that the converged-upon
geometry is indeed a minimum on the potential energy
Iodobenzene dichloride is readily prepared in a robust reac-
tion using iodobenzene, household bleach, and hydrochloric
122 | Dalton Trans., 2015, 44, 119–129
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