Chemistry Reference
In-Depth Information
radicals lead to the formation of the respective amine, as is the case with thiyl radicals,
26-28
or when the
oxoammonium cation is highly unstable as in the case of TEMPONE
22
and 4-amino-TEMPO (unpublished
results). The highly oxidizing oxoammonium cation can mediate selective oxidation of primary alcohols
in mono- and polysaccharides that are catalyzed by nitroxides.
9,31
The formation of the oxoammonium
cation could be also responsible for the pro-oxidative activity and potential adverse effects of nitroxides
that otherwise act as antioxidants.
32
Nitroxides also differ from common LMWA by their multifunctionality, that is, they operate through
diverse modes of action.
23,32,33
While this multifunctionality contributes toward the biological activity of
nitroxides, it greatly complicates the study and elucidation of the mechanisms underlying their effects.
In contrast to common LMWA, the catalytic nature of the chemistry of nitroxides allows their self-
replenishment. Such recycling plays an important role particularly, since the nitroxide administered into the
tissues is reduced to the respective hydroxylamine by cellular reducing equivalents. There is an equilibrium
between the nitroxide and the hydroxylamine, which is dependent on the oxygen status and redox status
of the tissue milieu.
34
While reduction of nitroxide to hydroxylamine can be reversed, such recycling is
achievable via different mechanisms. The elucidation of the mechanisms underlying nitroxides catalytic
activity requires characterization of their apparent self-replenishment as well as detailed kinetic studies of
the individual reaction steps. Here, the main mechanisms by which cyclic nitroxides detoxify biologically
deleterious radicals, which are key intermediates in many inflammatory and degenerative diseases, are
reviewed.
17.2 Mechanisms of nitroxide reactions with biologically relevant small radicals
The reactions of
•
NO
2
,CO
3
•
−
,HO
2
•
and RO
2
•
radicals (denoted as X
•
) with nitroxides lead to a
common intermediate, which can oxidize ferrocyanide, NADH and 2,2
-azino-bis(3-ethylbenzothiazoline-
6-sulfonate) (ABTS
2
−
).
15,19 - 22
In some cases the intermediate was identified spectrophotometrically as
the oxoammonium cation.
15,21,22
The kinetic results demonstrate that the formation of the oxoammonium
cation proceeds via an inner sphere electron transfer mechanism (Equations 17.1 and 17.2).
R
2
NO
•
X
•
+
R
2
NO
−
X
(17.1)
R
2
N
+
=
X
−
R
2
NO
−
X
O
+
(17.2)
This conclusion was derived using Marcus theory of oxidation - reduction reactions
35
for the formation of
the oxoammonium cation via Equation 17.3.
R
2
NO
•
X
•
R
2
N
+
=
O
X
−
+
+
(17.3)
Assuming that Equation 17.3 takes place via an outer sphere electron transfer mechanism,
k
3
can be
calculated using the Marcus equation,
k
3
=
1
/
2
.Here
k
3
is the electron transfer rate constant for
the cross reaction,
k
aa
and
k
bb
are the self-exchange rate constants for the reactants,
K
3
is the cross reaction
equilibrium constant, and ln
f
3
=
(
k
aa
k
bb
K
3
f
3
)
2
/4ln(k
aa
k
bb
/
10
22
. Using the oxidation potentials for the redox
couples R
2
N
+
=
O/R
2
NO
•
and X
•
/X
−
(Table 17.1), it is possible to calculate
K
3
as
(ln
K
3
)
)
E
3
o
=
(RT/nF)ln
K
3
and
-
E
o
(R
2
N
+
=
O/R
2
NO
•
). The self-exchange rate constant for X
•
/X
−
is significantly
low,
36-39
and since that for R
2
N
+
=
O/R
2
NO
•
cannot exceed 1
E
3
o
E
o
(X
•
/X
−
)
=
10
10
M
−
1
s
−
1
, the calculated values of
k
3
are orders of magnitude lower than the experimental ones determined using pulse radiolysis.
15,19 - 22
Therefore, the reaction of R
2
NO
•
with X
•
must take place via an inner sphere electron transfer mechanism
(Equations 17.1 and 17.2). In the case of carbon-centered radicals, which are important in biological systems
×
Search WWH ::
Custom Search