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Kinetics and mechanism of reactions of the drug tiopronin with platinum(IV) complexes.
[cystinuria]
Tiopronin
,
a
synthetic
thiol-containing
drug
being
used
in
treatments
of
cystinuria
and
certain
types
of
rare
arthritis
,
is
also
a
hepatoprotective
and
a
detoxifying
agent
.
Many
analytical
methods
have
been
developed
based
on
its
redox
chemistry
with
metal
ions
/
complexes
,
but
the
kinetic
and
mechanistic
aspects
are
poorly
understood
.
In
this
work
,
the
oxidation
of
tiopronin
by
cisplatin
prodrug
and
a
model
compound
,
cis-
[
Pt
(
NH
3
)
2
Cl
4
]
and
trans-
[
PtCl
2
(
CN
)
4
]
(
2
-
)
,
was
investigated
.
The
oxidation
kinetics
was
followed
by
a
stopped-flow
spectrophotometer
over
a
wide
pH
range
under
the
pseudo
first
-order
conditions
of
[
Tiopronin
]
≫
[
Pt
(
IV
)
]
.
Time-resolved
spectra
were
also
recorded
for
both
Pt
(
IV
)
complexes
,
enabling
to
establish
an
overall
second
-order
rate
law
:
-
d
[
Pt
(
IV
)
]
/
dt
=
k
'
[
Tiopronin
]
[
Pt
(
IV
)
]
,
where
k
'
pertains
to
observed
second
-order
rate
constants
.
Under
the
kinetic
conditions
,
tiopronin
was
oxidized
to
form
the
tiopronin-disulfide
exclusively
as
identified
by
mass
spectrometry
.
A
reaction
mechanism
was
proposed
,
involving
parallel
reductions
of
the
Pt
(
IV
)
complexes
by
the
three
protolytic
tiopronin
species
as
rate-determining
steps
.
The
rate
constants
for
the
rate-determining
steps
were
derived
.
The
fully
deprotonated
tiopronin
is
about
4
×
10
(
4
)
more
reactive
than
its
corresponding
thiol
form
for
both
Pt
(
IV
)
complexes
;
the
huge
reactivity
difference
orchestrates
closely
with
the
fact
that
the
nucleophilicity
of
thiolate
is
much
higher
than
the
corresponding
thiol
.
Hence
,
the
attack
of
the
sulfur
atom
in
thiol
/
thiolate
of
tiopronin
on
the
axially-coordinated
chloride
in
the
Pt
(
IV
)
complexes
is
nucleophilic
in
nature
in
the
rate-determining
steps
,
resulting
in
a
bridge
formation
and
a
subsequent
bridged
electron-transfer
.
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symptom
cystinuria
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