H. Wei et al. / Inorganic Chemistry Communications 7 (2004) 792–794
793
Fig. 2. The negative ion ESMS full scan for the reaction of
PtM2 with GSH recorded after 50 min (molar ratio 1: 1, pH 2.36,
310 K).
Fig. 1. The HPLC chromatogram for the reaction of PtM2 with GSH
(molar ratio 1:1, pH 2.23, 310 K): (a) trans-PtM2; (b) cis-PtM2; (c) L-
MetH; (d–f) Pt–GS complexes.
also confirmed the fast release of L-MetH from PtM2.
With the increase of reaction time, the spectrum be-
comes less resolved, suggesting the formation of poly-
meric species [10].
Based on the above results, the proposed reaction
pathway is summarised in Scheme 1. The GSH reacts
with cis-isomer (faster) and trans-isomer (slower) of
PtM2 to give ring-opened species, followed by the re-
4.2 min (c) can be assigned to free
increased significantly 2 min after the addition of
GSH to solution, indicating the release of -MetH
L-MetH. Peak c
L
from PtM2. After 30 min of reaction, the ratio of cis-
and trans-isomer changed from 83.6:16.4 to 53.5:46.5,
suggesting the cis-isomer is more reactive to GSH
than the trans-isomer. New peaks (d)–(f) appeared
after 30 min and increased in intensity with time until
2 h. The chromatograms of the reaction remain ba-
sically unchanged afterwards. After 24 h, however, the
unreacted PtM2 regained its original equilibrium with
the cis- to trans-isomer ratio being 87:13.
lease of
olate bridged polynuclear Pt(II)–GS species.
The reaction of PtM2 with -Cys was also studied
L-Met from platinum(II) and formation of thi-
L
using the same technologies as stated above. The ra-
pid decrease in intensity of the peak for PtM2 in
HPLC chromatograms suggested that the reaction rate
was faster than that with GSH. Only binuclear species
was detected by the ESMS method. The 1H NMR
spectral changes were similar to those observed for
GSH. It is notable that the reaction solutions of PtM2
The reaction of PtM2 with GSH under the same re-
2
action condition was also studied by ESMS. Corre-
sponding to the HPLC results, the positive ion peak for
free
L
-MetH and negative one for [Pt(Met-S,N)(Met-
and
L-Cys started to turn turbid after 30 min
S)(GS-S)] (m=z ¼ 797:7) were observed in the ESMS
spectra immediately after mixing the two reactants,
suggesting that the ring-opening and subsequent release
with precipitation after 5 h, which suggests that
Pt(II)–Cys adducts may be less soluble than those of
Pt(II)–GS.
of S,N-chelated
L-Met in PtM2is rapid. Formation of
The reactions of PtM2 with GSH and L-Cys at dif-
polynuclear Pt(II)–GS species has been observed
(Fig. 2), the assignment of the major species is listed in
Table 1. Other peaks with m=z values of 526.5 and
1016.5 were previously observed and assigned to
{[Pt(Met-S,N)2] + Clꢁ}ꢁ and {2[Pt(Met-S,N)2] + Clꢁ}ꢁ,
respectively [14].
ferent pH values were conducted. It is evident that the
peak of cis-PtM2 diminished more rapidly at high pH
(8.09) than at low pH (2.23) as shown by HPLC chro-
matograms. This indicates that thiols are more com-
petitive towards Pt(II) at higher pH. At pH 8.54, only
di- and tri-nuclear platinum complexes were observed,
which suggested that the increase of pH reduced the
extent of polymerization or lowered the solubility of the
polynuclear species.
3
1
The H NMR data for the reaction of PtM2 with
GSH showed the appearance of S–CH3 signal of free
MetH at 2.06 ppm after 6 min its commencement, which
L
-
In conclusion, the biological thiols (GSH or
L-Cys)
can readily displace the S,N-chelated -Met from PtM2.
L
The HPLC data showed that the cis-isomer of PtM2 is
more reactive than the trans-isomer. The biological rel-
evance of these observations is not clear, but it is in-
teresting to note that the extra-cellular metabolite of
cisplatin can react fast with GSH in vitro. We are
2
Electrospray mass spectra were recorded by an LCQ electrospray
mass spectrometer (ESMS, Finnigan). The isotopic distribution of the
polymeric complexes was simulated with Isopro 3.0.
3
The 1H NMR data were acquired on a 500 MHz Bruker DMX
Spectrometer using standard pulse sequences.
Wei, Haiying
