Cleavage of the Pt-S bond of thiolated terpyridine-platinum(II) complexes by copper(II) and zinc(II) ions in phosphate buffer

Article abstract of DOI:10.1039/a708152i

Using the chelation of a triamine moiety and an S-bridged heterodinuclear unit, cleavage of the Pt-S bond in the thiolate-platinum complexes, [Pt(terpy)(BAT)]⁴⁺ and [Pt(terpy)(AET)]⁺ is induced by adding transition metals such as Cu²⁺ or Zn²⁺ in phosphate buffer (pH 7-8) at room temp.

Full text of DOI:10.1039/a708152i

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Cleavage of the Pt–S bond of thiolated terpyridine–platinum(ii) complexes by
copper(ii) and zinc(ii) ions in phosphate buffer
Chien-Chung Cheng* and Yen-Lin Lu
Institute of Chemistry, Academia Sinica, Taipei, Taiwan 11529, Republic of China
Using the chelation of a triamine moiety and an S-bridged
heterodinuclear unit, cleavage of the Pt–S bond in the
(BAT)]4+ in D
the UV–VIS spectrum displayed the absorbances at 486 nm
(e = 698 dm mol cm ), 342 (12959), 329 (12397) and 311
(11903) in phosphate buffer (pH 8.0), which agreed with the
characteristic features for establishing the formation of thiolate–
platinum bonds in the previous report.11 In addition, the
integration ratio of protons of terpyridine and the triamine
2
O showed a new downfield peak at d 8.82 and
4+
3
21
21
thiolate–platinum complexes, [Pt(terpy)(BAT)] and [Pt-
+
(
terpy)(AET)] is induced by adding transition metals such
2+
2+
as Cu or Zn in phosphate buffer (pH 7–8) at room
temp.
Many efforts in the development of platinum complexes as
anticancer drugs have been contemplated in order to reduce the
cytotoxicity and to improve the platin drug-resistance. Since
moiety in NMR spectra (D
suggesting no S-bridged diplatinum complex was generated.
In the presence of CuCl ·6H O (42 mm), the solution of
2
O) was approximately 0.93,
1
4
1
2
2
[Pt(terpy)(BAT)]4 (40 mm) exhibited a decreasing UV–VIS
absorption at 342 nm accompanied by an increasing absorption
at 329 nm in phosphate buffer (10 mm, pH 8.0). An isosbestic
point was observed at 337 nm in the spectrum, suggesting no
intermediate had been generated in the reaction with metal ions.
Also, no significant alteration was observed in the absence of
+
sulfur-containing compounds such as glutathione and metallo-
thioneins are rich in cells, the formation of the S–Pt bond is
generally believed to be one of the major mechanisms in the
resistance to cis-platin drugs in biological processes.2 In
contrast, recent NMR studies by Sadler and coworkers reveal
II
that S-bound l-methionine on Pt acts as a reversible binding
II
4+
ligand and is capable of undergoing intermolecular replacement
Cu . The cleavage of the Pt–S bond of [Pt(terpy)(BAT)] (40
3
II
by 5A-GMP in phosphate buffer (pH 7.2). In fact, the
mm) in the titration with Cu (10–84 mm) was found to require
II
concentration of glutathione (GSH) in intracellular cells is
commonly high ( > 1 mm). Therefore, in the reaction with platin
drugs, the formation of thiolate–platinum adducts is inevitable.4
The thiolate ion is capable of providing a stronger binding
1 equiv. of Cu to complete the reaction in 120 min. This
4
+
dissociation of the Pt–S bond of [Pt(terpy)(BAT)] was
revealed to be a pH dependent process in the range pH 4.8–10.0.
The reactivity of the Pt–S bond cleavage was reduced with a
decreasing pH and ceased at pH < 6, implying that the
participation of the amino group plays a vital role in the
5
affinity owing to its better s-donating ability. Such a Pt–S bond
is considered relatively inert, which may cause the inhibition of
the anticancer activity of platin drugs. Thus, the great challenge
is to break the Pt–S bond in the thiolate–platinum adducts.
To approach this goal, thiolated derivatives of terpy–
platinum(ii) complexes are used as a source to study the Pt–S
bond owing to their characteristic electronic absorption and
cleavage. In fact, when a hydroxylthiol derivative of [Pt(ter-
+
py)(SCH
2
CH
2
OH)] , was used instead of an amino derivative,
under the same conditions, no cleavage of the Pt–S bond was
observed.
The isolation of the cleavage product was performed in
6–8
NMR spectra. Here, we report that transition metals such as
MeOH in order to simplify the product analysis. After the
II
II
4+
Cu or Zn are capable of inducing cleavage of the Pt–S bond
2 2
addition of CuCl ·6H O, a red solution of [Pt(terpy)(BAT)]
of thiolated terpyridine platinum(ii) complexes, [Pt(terpy)-
turned into a blue-green suspension containing orange solid.
This orange solid was isolated in a yield of 75–80% with
electronic absorptions at 382, 332 and 320 nm in phosphate
+
4+
(
AET)] (AET = 2-aminoethanethiol) and [Pt(terpy)(BAT)]
[BAT = N,NA-bis(aminoethyl)aminoethanethiol], particularly
in phosphate buffer as shown in Fig. 1. The introduction of a
triamine moiety to the complex structure increases the dissocia-
tion rate and the selectivity of the Pt–S bond cleavage in
thiolate–platinum complexes. To our knowledge, this is the first
reported example of Pt–S bond cleavage among thiolate–
platinum(ii) complexes in phosphate buffer.
2
buffer (pH 8) and NMR peaks in D O at d 7.8 (m), 7.5 (m) and
7.2 (t), suggesting it lacked the Pt–S bond linkage. Furthermore,
FAB mass and isotope abundance simulation studies disclosed
that the molecular ion at 464 contained a chloride ion,
+
suggesting that [Pt(terpy)Cl] was one of the cleavage products.
+
11
[
Pt(terpy)(AET)] was prepared by published methods. The
i, ii
4
+
HSCH2CH2NH2HCl
Ph3CSCH2CH2NH2
synthesis of a triamine derivative, [Pt(terpy)(BAT)] , was
+
2
achieved by the coupling reaction of [Pt(terpy)Cl] with the
modified multistep synthesis1
2–15
of triaminothiol, 1, in water as
iii–v
HOCH2CH2NH2
vi
NBoc
illustrated in Scheme 1. The NMR spectrum of [Pt(terpy)-
3
2
+ 3
Ph3CSCH2CH2N(CH2CH2NHBoc)2
4
vii
N
Pt
N
N
Cu2 or Zn2+
viii
[Pt(terpy)(BAT)]4+
N
SR
N
Pt
N
X
+
M
SR
HSCH2CH2N(CH2CH2NH2)2
1, BAT
Scheme 1 Reagents and conditions: i, triphenylmethanol, neat TFA, 25 °C,
0 min, 89%; ii, NaOH(aq), 92%; iii, conc. H SO ; vacuum (0.1 mmHg) at
80 °C, overnight, 62%; iv, KOH(aq), distillation; v, (Boc) O, dioxane–H O,
0 °C, warming to room temp. overnight; vi, MeCN, reflux, 3 days, 75–80%;
vii, TFA, triethylsilane 84%; viii, deionized H O, [Pt(terpy)Cl]Cl, N , 25
°C, 5 h; recrystallization with MeOH–MeCN, 40%.
phosphate buffer
(pH 7-8), room temp.
3
2
4
R = CH2CH2NH2, AET
R = CH2CH2N(CH2CH2NH2)2, BAT
X = Cl or OH2 M = Cu2+, Zn2+
2
2
2
2
Fig. 1 General equation representing the cleavage of the Pt–S bond
Chem. Commun., 1998
253

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II
II
II
The chloride ion in the isolated product may be acquired from
the use of metal chloride salt as the starting material. In addition,
the residual Cu complex in the solution was determined to be a
symmetric dimer of copper–triaminothiol complex by NMR
and FAB MS analysis. The dimer adduct may be obtained by the
coupling reaction with monomer of copper–triaminothiol once
released from the platinum–thiolate complexes.
tetrahedral Zn , square-planar Cu and octahedral Ni in the
transition state may be attributed to the different reactivity and
selectivity of different metal ions in the Pt–S bond cleavage.
The detailed mechanism is under current investigation.
In summary, we have demonstrated that the cleavage of the
+
4+
Pt–S bond of [Pt(terpy)(AET)] and [Pt(terpy)(BAT)] can be
achieved by the addition of transition metal ions such as Zn or
Cu in either phosphate buffer or MeOH. Importantly [Pt(ter-
py)Cl] is isolated and identified as one of the major products in
II
II
Furthermore, a comparison of the reactivity using different
II
II
II
+
metals Ni , Cu and Zn in the Pt–S bond dissociation in
[
Pt(terpy)(BAT)]4+ in phosphate buffer is also examined.
the dissociation of the Pt–S bond of [Pt(terpy)(BAT)] in the
4+
Interestingly, the result shows that the dissociation induced by
presence of ZnCl
2
or CuCl
2
. In fact, the Cl ligand is very labile
O or
II
II
transition metals varied in a descending order: Zn > Cu
>
and readily replaced by other nucleophiles such as H
2
II
6
Ni , as illustrated in Fig. 2. The rate constant has been estimated
imidazole. Namely, in the biological system, the replacement
of the labile Cl ligand may be achieved by surrounding guanine
15
23
under the first-order condition to give a value of 7.9 3 10
2
1
II
24 21
II
24 21
2
s
for Zn , 5.3 3 10
s
for Cu and 1.9 3 10
s
for
residues resulting in the recovery of anticancer activity of
II
+
Ni . Moreover, the same cleavage product, [Pt(terpy)Cl] , also
platin drugs. Interestingly, the dissociation of the Pt–S bond and
the formation of a labile chloro species can also be detected
using [Pt(dien)(BAT)] , (dien = diethylenetriamine) in phos-
phate buffer in the presence of Zn or Cu ions. Therefore, these
results may provide an alternative pathway in the regeneration
of the active Pt complexes from the platinum–thiolate adduct,
which may relate to the restoration of the anticancer activity of
platin drugs in biological systems.
4+
can be obtained from [Pt(terpy)(BAT)] using ZnCl
phosphate buffer. Zn had the strongest preference for promot-
2
in
II
4+
II
II
ing Pt–S bond cleavage, and was about 15 times faster than
II
CuCl
2
. Besides, Zn also exhibited the highest selectivity in the
cleavage of the Pt–S bond of the triaminothiol species,
4
+
[
Pt(terpy)(BAT)] , but produced no reaction with the amino-
+
thiol species, [Pt(terpy)(AET)] .
In order to eliminate the possibility of the aggregation of
polyaromatic compounds,10 which may enhance the cleavage
by neighboring complexes, the dissociation process was also
examined at a low concentration (10–12 mm) of [Pt(terpy)-
C.-C. Cheng thanks Academia Sinica and the National
Science Council, Taiwan, ROC, for financial support.
4+
(
BAT)] . The result showed no significant difference in the
Footnote and References
dissociation rate of the Pt–S bond at either a low or high
concentration of polyaromatic compounds. Moreover, the
preliminary cleavage mechanism has been studied using Cu in
NMR. In phosphate buffer, one of the terpyridine peaks and all
of the aliphatic protons are shifted from d 8.88 and 2.2–2.7 to d
*
E-mail: cccheng@chem.sinica.edu.tw
II
1
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9
.06 and 2.7–3.1 respectively, indicating the S-bridged hetero-
II
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4
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0
200 400 600 800 1000 1200 1400 1600 1800
t / s
1
Fig. 2 Comparison of the reactivity in the cleavage of the Pt–S bond by
2
+
2+
2+
Zn , Cu and Ni ions. These data were collected at a fixed absorption
wavelength of 342 nm at intervals of 50 s per cycle at a concentration of
15 K. A. Connors, Chemical Kinetics: The study of Reaction Rates in
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4
+
[
Pt(terpy)(BAT)] (40 mm) and metal ion (40–42 mm) in 10 mm phosphate
buffer (pH 8.0) at room temp. (5) Zn , ( ~ ) Cu , (-) Ni
2+ 2+ 2+
.
Received in Cambridge, UK, 12th November 1997; 7/08152I
254
Chem. Commun., 1998