Thermal degradation of platinum(IV) precursors to antitumor drugs

Article abstract of DOI:10.1007/s10973-010-0933-3

Organoplatinum antitumor agents are very effective, broad-spectrum drugs used for the treatment of a variety of cancerous conditions. The two most prominent of these, Cisplatin [cis-diamminodichloroplatinum(II)] and Carboplatin [diammino(1,1-cyclobutanedicarboxylato)platinum(II)], are large scale commercial successes. The third, Oxaliplatin [((trans-1,2-diamminocyclohexane) oxalato)platinum(II)], is now commercially available. The administration of all these drugs is accompanied by severe side effects. For Cisplatin, the most debilitating of these is kidney damage and extreme nausea. Several approaches to generate drug-release formulations that might mitigate toxic side effects have been explored. Now, platinum(IV) compounds which are more inert than platinum(II) compounds, and consequently less toxic, but which may be reduced to platinum(II) species within the cell are being evaluated for effectiveness in the treatment of cancer. The thermal stability of several precursors to compounds of this kind has been examined by thermogravimetry. In general, these materials lose ligands sequentially to generate a residue of platinum. This behavior may be generally useful for the characterization of such materials.

Full text of DOI:10.1007/s10973-010-0933-3

J Therm Anal Calorim (2010) 102:499–503
DOI 10.1007/s10973-010-0933-3
Thermal degradation of platinum(IV) precursors to antitumor
drugs
•
•
•
B. A. Howell P. Chhetri A. Dumitrascu
K. N. Stanton
NATAS2009 Special Issue
´
´
Ó Akademiai Kiado, Budapest, Hungary 2010
Abstract Organoplatinum antitumor agents are very
effective, broad-spectrum drugs used for the treatment
of a variety of cancerous conditions. The two most promi-
nent of these, Cisplatin [cis-diamminodichloroplatinum(II)]
and Carboplatin [diammino(1,1-cyclobutanedicarboxylato)
platinum(II)], are large scale commercial successes. The
third, Oxaliplatin [((trans-1,2-diamminocyclohexane)oxa-
lato)platinum(II)], is now commercially available. The
administration of all these drugs is accompanied by severe
side effects. For Cisplatin, the most debilitating of these is
kidney damage and extreme nausea. Several approaches to
generate drug-release formulations that might mitigate toxic
side effects have been explored. Now, platinum(IV) com-
pounds which are more inert than platinum(II) compounds,
and consequently less toxic, but which may be reduced to
platinum(II) species within the cell are being evaluated for
effectiveness in the treatment of cancer. The thermal sta-
bility of several precursors to compounds of this kind has
been examined by thermogravimetry. In general, these
materials lose ligands sequentially to generate a residue of
platinum. This behavior may be generally useful for the
characterization of such materials.
Introduction
Several developments have impacted the formulation
of effective, non-toxic, sustained action organoplatinum
antitumor drugs. The first was the serendipitous discovery of
the remarkable biological activity of cis-dichlorodiam-
mineplatinum(II) (Cisplatin) [1–8]. Cisplatin is a broad-
spectrum cancer drug effective against a wide range of
tumors. For many years, Cisplatin was the most widely used
anticancer drug. It is often used in combination with organic
antitumor compounds or with Carboplatin [diammino(1,1-
cyclobutanedicarboxylato)platinum(II)], the second plati-
num anticancer drug to gain widespread commercial use.
Carboplatin displays a somewhat different toxicity profile
than does Cisplatin, making it an attractive compliment to
Cisplatin [9–11]. All the compounds shown below reflect the
structure required for antitumor activity (two inert cis
ligands and two labile ligands; chlorine displays a near
optimum hydrolysis rate under physiological conditions:
half-life of about 1 h at 37 °C).
O
O
Cl
Cl
O
O
C
O
O
H3N
H3N
H3N
H3N
H2N
H2N
Pt
Pt
Pt
C
O
Keywords Platinum(IV) prodrugs Á Platinum(II)
oxidation Á Functionalized platinum drugs Á
Ligand lability Á Thermal stability
O
Cisplatin
Carboplatin
Oxaliplatin
The potential of these drugs has been limited because of
severe side effects which accompany their administration.
Among the most debilitating side effects induced by
organoplatinum drugs are severe kidney damage [12] and
extreme nausea (as a class, the platinum compounds are
among the most effective nausea producing agents known,
to the point that some patients refuse to complete the
treatment regimen) [13, 14]. In an attempt to identify active
B. A. Howell Á P. Chhetri Á A. Dumitrascu Á K. N. Stanton
Center for Applications in Polymer Science, Central Michigan
University, Mt. Pleasant, MI, USA
B. A. Howell (&) Á P. Chhetri Á A. Dumitrascu Á K. N. Stanton
Department of Chemistry, Central Michigan University,
Mt. Pleasant, MI 48859-0001, USA
e-mail: bob.a.howell@cmich.edu
123

500
B. A. Howell et al.
but less toxic drugs literally hundreds of platinum com-
pounds in which the structure of the amine ligand has been
varied have been synthesized and evaluated for antitumor
activity. In the main, this has been a fruitless undertaking.
While some ligands impart better solubility, activity, or
toxicity than similar properties associated with compounds
derived from simple ammonia ligands, no compounds with
clearly superior performance have been found. Of the
hundreds of compounds synthesized, fewer than thirty have
entered clinical trials as antitumor agents [15, 16].
Pt(IV)
Reduction
Pt(IV) ?
Pt(II)
Pt(II)
DNA
binding
Protein binding
(deactivation)
A second development has been the huge progress in
the utilization of polymeric carriers for a variety of drugs
[17–25]. The use of a polymer-drug conjugate may provide a
number of advantages over the drug alone. These may
include increased water solubility, sustained delivery of
drug, reduced toxicity, enhanced biodistribution, and pref-
erential penetration of abnormal tissue.
Scheme 1 Possible fate of organoplatinum(IV) compounds in cancer
chemotherapy
platinum(IV) species two additional coordination sites
become available for the introduction of functionality to
enhance uptake via drug targeting, to inhibit resistance, to
improve biodistribution, to modify lipophilicity, or to pro-
vide monomers for the generation of polymeric prodrugs. It
is thought that platinum(IV) compounds are reduced to
platinum(II) species in the cell which act as the effective
antitumor agent for interaction with DNA (Scheme 1).
A third development has been the discovery of dendritic
polymers [26, 27]. Dendrimers offer multiple modes of
drug incorporation. In particular, the poly(amidoamine)
[PAMAM] dendrimers are attractive as drug carriers. They
are water-soluble, multivalent, and in general, non-toxic
[28–30]. Dendrimers are highly branched macromolecules
with precisely controlled size, shape, and end-group func-
tionality. They represent unique core–shell structures con-
sisting of three basic architectural components: a core, an
interior of cells (generations) that have repeating branch-cell
units, and terminal functional groups (outer shell or periph-
ery). Each generation is built sequentially from a predecessor
to form a symmetrical, nearly monodisperse structure of
precise molecular mass and nanoscale dimensions [31]. For
PAMAM dendrimers half-generation structures are carboxyl-
terminated; full generations are amine-terminated. Both types
of functionality are useful for drug conjugation [32].
Experimental
General
In general, reactions were carried out in a dry (all glassware
was dried in an oven overnight at 120 °C and allowed to cool
under a stream of dry nitrogen prior to use) three-necked,
round-bottomed flask fitted with Liebig condenser bearing a
gas-inlet tube, a magnetic stirring bar (or Trubore stirrer),
and a pressure-equalizing dropping funnel (or syringe port).
Thermal decomposition temperatures were obtained using a
TA Instruments 2950 Hi-Res TGA instrument interfaced
with the Thermal Analyst 2100 control unit. Most generally,
a heating rate of 10 °C min-1 was used. TA Universal
Thermal Analysis software was used for data analysis.
Samples (5–10 mg) were contained in a platinum pan.
Extrapolated degradation onset temperatures were deter-
mined from the derivative plot of mass loss versus temper-
atures. The sample compartment was purged with dry
nitrogen at 50 cm3 min-1 during analysis. Nuclear magnetic
resonance (NMR) spectra were obtained using a 10–25%
solution in dimethyl sulfoxide-d6 and a Varian Mercury
300 MHz spectrometer. Proton and carbon chemical shifts
were reported in parts-per-million (d) with respect to tetra-
methylsilane (TMS) as internal reference (d = 0.00).
Infrared (IR) spectra were obtained using solid solutions
(1%) in anhydrous potassium bromide (as discs) using a
Nicolet MAGNA-IR 560 spectrometer. Absorptions were
recorded in wave numbers (cm-1).
A fourth development has been the discovery that func-
tionalized, water-soluble carbon nanotubes are able to tra-
verse the cell membrane by endocytosis to deliver a
chemotherapeutic agent [33–38]. This has been exploited for
the delivery of organoplatinum prodrugs [37, 38]. Approx-
imately 65 platinum(IV) units per nanotube may be loaded
[38]. This is comparable to the number of (diamminocy-
clohexane)platinum(II) units that may be attached to the
surface of a generation 4.5 poly(amidoamine) [PAMAM]
dendrimer [32]. Further, the multivalent prodrug may be
functionalized with a folate component to specifically target
folate receptor-enriched tumor cells [37].
Finally, a fifth development has been the recognition that
platinum(IV) compounds could act as prodrugs for delivery
of effective antitumor agents [37, 39–41]. With respect to
their platinum(II) counterparts, platinum(IV) compounds
possess a greater kinetic inertness. Thus, more of the plati-
num species may reach the targeted region prior to decom-
position. When platinum(II) compounds are oxidized to
123

Thermal degradation of platinum(IV) precursors
Materials
501
at 70 °C. The mixture was allowed to cool and most of the
solvent was removed by rotary evaporation at reduced
pressure. The residue was treated with 75 cm3 of diethyl
ether to provide a suspension of a bright yellow solid. The
solid was collected by filtration at reduced pressure,
washed, successively, with cold ethanol and diethyl ether,
and dried over Drierite at reduced pressure to afford
0.397 g (66.2% yield) of the hydroxo/ethoxo compound.
Common solvents and reagents were obtained from Ther-
moFisher Scientific or the Aldrich Chemical Company.
Tetrahydrofuran (THF) was distilled from lithium alu-
minium hydride in a nitrogen atmosphere prior to use;
methylene chloride from calcium hydride. Potassium tet-
rachloroplatinate(II) and cis-dichloro(diammine) plati-
num(II) were obtained from Alfa Aesar and used as
received. Nitrogen dioxide (C99.5%) was from Aldrich.
Results and discussion
Synthesis
The observation that platinum(IV) compounds might act as
robust prodrugs for the delivery of effective platinum(II)
chemotherapeutic agents has opened a wide range of pos-
sibilities for the formulation of antitumor drugs. In general,
a platinum(II) compound is oxidized to a platinum(IV)
species which may add ligands to generate compounds
which display potential as antitumor agents or which pro-
vide reactive sites suitable for the attachment of a range of
functionality [37, 43]. In one approach, cis-dichloro(di-
ammine) platinum(II) is oxidized with dinitrogen tetroxide
in the presence of a suitable ligand (L) to produce a suit-
able platinum(IV) compound directly [43]. This is illus-
trated in Scheme 2.
cis-Dichloro-trans-dihydroxy-cis-diammineplatinum(IV)
[42, 43]
cis-Dichloro-diammineplatinum(II) (3.01 g, 0.01 mol) was
suspended in 75 cm3 of water and 114 cm3 of 30% aque-
ous hydrogen peroxide (0.10 mol; tenfold excess). The
mixture was stirred at 50 °C in a nitrogen atmosphere and
the absence of light for an hour at solvent reflux. The
mixture was allowed to cool and to stand at 5 °C overnight
for crystallization of the product. The bright yellow solid
which formed was collected by filtration at reduced pres-
sure and washed, successively, with cold water, ethanol,
and diethyl ether. The solid was dried over Drierite at
reduced pressure (15 Torr) to afford 2.57 g (77.3% yield)
of the dihydroxy compound.
This procedure seems to be unreliable and to lack gen-
erality for the convenient generation of useful platinum(IV)
compounds. In a second, more useful, approach the plati-
num(II) compound is oxidized to generate the corresponding
dihydroxy platinum(IV) compound. The hydroxyl groups
are sufficiently nucleophilic to react with good electrophiles,
most commonly succinic anhydride, to generate compounds
with functionality that may be used for the attachment of a
variety of groups [37] (Scheme 3).
cis-Dichloro-trans-disuccinato-cis-diamineplatinum(IV)
A solution of 0.27 g (2.67 mmol) of succinic anhydride and
0.21 g (0.67 mmol) of cis-dichloro-trans-dihydroxy-cis-di-
ammineplatinum(IV) in 5.0 cm3 of dimethylsulfoxide was
stirred in nitrogen in the absence of light at 70 °C for 24 h.
The solution was allowed to cool and the solvent was
removed by lyophilization. The residual solid was sus-
pended in dichloromethane to remove succinic anhydride.
The insoluble material was collected by filtration at reduced
pressure and washed with several portions of dichloro-
methane. Recrystallization from acetone (-23 °C) afforded
the disuccinato compound as yellow needles which were
collected by filtration at reduced pressure, washed with cold
acetone, and dried over Drierite at reduced pressure to pro-
vide 0.202 g (63.1% yield) of the expected product [37, 41].
The approach has been utilized for the attachment of both
a carbon nanotube carrier and a folate targeting moiety [37].
All the compounds have been characterized using infrared
spectroscopy and thermogravimetry. Infrared spectra are
displayed in Fig. 1. The depicted transformations are readily
apparent from these spectra. Conversion of Cisplatin to the
corresponding dihydroxo compound introduces a hydroxyl
absorption at 3459 cm-1 into the spectrum. Transformation
of the dihydroxo to the disuccinato compound generates a
spectrum lacking the hydroxyl absorption but containing an
ester carbonyl absorption.
L1
cis-Dichloro-trans-hydroxo/ethoxo-cis-
diamineplatinum(IV)
N2O4 (NO2)
H3N
H3N
H3N
H3N
Cl
Cl
Cl
Cl
Pt
Pt
0.1M aq. HCl or
H2O and ligand
L2
To a stirred suspension of 0.50 g (1.67 mmol) of cis-di-
chlorodiammine platinum(II) in 625 cm3 of ethanol main-
tained at 70 °C was added 2.1 cm3 of aqueous hydrogen
peroxide solution. The resulting mixture was stirred for 5 h
Cisplatin
Platinum(IV) derivative
Scheme 2 Generation of platinum(IV) compounds by oxidation with
dinitrogen tetroxide
123

502
B. A. Howell et al.
O
Scheme 3 Synthesis of cis-
dichloro-trans-dihydroxo-cis-
diammineplatinum(IV) and cis-
dichloro-trans-disuccinato-cis-
diammineplatinum(IV)
O
CH2CH2C OH
O
C
OH
Pt
O
O
H2O2/H2O
H3N
H3N
H3N
H3N
H3N
H3N
Cl
Cl
Cl
Cl
Cl
Cl
O
Pt
Pt
OH
O
C
CH2CH2C OH
O
O
cis-dichloro-trans-dihydroxo-
cis-diammineplatinum(IV)
cis-dichloro-trans-disuccinato-
cis-diammineplatinum(IV)
Cisplatin
Table 1 Thermal decomposition of cis-dichloro-trans-dihydroxo-
cis-diammineplatinum(IV)
C
90
80
70
60
50
Mass loss Onset
temperature/ °C
Loss/% of initial mass
Observed Calculated
Fragments
I
125
10.1
11.9
10.18
10.18
Hydroxyl
ligands
B
40
30
20
II
233
Ammine
ligands
A
10
III
321
400
23
55
21.26
58.38
Chloride
ligands
0
–10
Residue
4000
3500
3000
2500
2000
1500
1000
500
Wavenumbers/cm–1
of the chloride ligands (321 °C) to leave a residue of
platinum. This is summarized in Table 1.
Fig. 1 Infrared spectra for a cis-dichloro(diammine)platinum(II),
b cis-dichloro-trans-dihydroxo-cis-diammineplatinum(IV), and c cis-
dichloro-trans-disuccinato-cis-diammineplatinum(IV)
Conclusions
110
The thermal decomposition of several Pt(IV) precursors to
antitumor drugs has been examined using thermogravi-
metry. In general, decomposition is well behaved and
reflects sequential loss of ligands to generate a residue of
platinum. Initial decomposition for cis-dichloro-trans-
dihydroxy-cis-diamminoplatinum(IV) occurs at relatively
low temperature (125 °C) and reflects the loss of hydroxyl
ligands. Conversion of the hydroxyl groups to succinate
esters lead to a thermally more stable compound with ini-
tial decomposition corresponding to loss of the succinato
ligands at 233 °C. The thermal decomposition of these
compounds is very well behaved and may form the basis
for a general method of analysis [ligand present; elemental
composition (% Pt)] for material of this kind.
a
100
90
80
70
c
b
60
50
40
30
50
100
150
200
250
300
350
400
450
500
Temperature/°C
Fig. 2 Thermal decomposition of a cis-dichloro(diammine)plati-
num(II), b cis-dichloro-trans-dihydroxo-cis-diammineplatinum(IV),
and c cis-dichloro-trans-disuccinato-cis-diammineplatinum(IV)
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