times as fast as R-tocopherol (kinh ) 3.2 × 106 M-1s-1). It
has been hypothesized that this rate enhancement is due to
polar effects in the transition state of the atom-transfer
reaction.6 Incorporation of an electron-donating amino sub-
stituent para to the hydroxyl group in the 3-pyridinol scaffold
in the form of a fused five-membered ring (compound 3)
resulted in the most effective phenolic chain-breaking
antioxidant reported to date. Its ionization potential is 7.0
kcal/mol lower than calculated for R-tocopherol, and therfore,
it is slowly decomposing when exposed to atmospheric
oxygen. Due to the 2.8 kcal/mol weaker O-H BDE of
compound 3 than R-tocopherol, the reactivity toward peroxyl
radicals is an impressive 88-fold higher (kinh ) 280 × 106
M-1s-1).7,8 The synthesis and antioxidative properties of
more Vitamin E-like derivatives of this kind,9 such as the
naphthyridinol 4, have recently been described.10
by one-electron (hydrogen atom) and two-electron (e.g., as
a cofactor for the glutathione peroxidase enzymes) chemistry.
However, early studies by Barclay15 showed that GSH is
incapable of regenerating R-tocopherol from the R-toco-
pheroxyl radical in simple model systems. In our search for
other chain-breaking antioxidants which could perform in a
catalytic fashion in the presence of thiols, we recently found
that 2,3-dihydrobenzo[b]selenophene-5-ols 516 as well as
ethoxyquins 617 were regenerable by N-acetylcysteine when
assayed for their capacity to inhibit azo-initiated peroxidation
of linoleic acid in a two-phase system. Considering that none
of these antioxidants quenched peroxyl radicals as efficiently
as R-tocopherol, we thought it would be interesting to modify
the efficient pyridinol antioxidants in such a way that they
could also act in a catalytic fashion in the presence of
stoichiometric amounts of a thiol reducing agent. Initially,
3-pyridinols 7a-c (Table 1) substituted in the 6-position with
octyltelluro-, octylseleno-, and octylthio groups, respectively,
and the corresponding 2-substituted derivatives 8a-c were
prepared starting from readily available 6-bromo- and
2-bromo-3-pyridinol. The capacity of these antioxidants to
inhibit 2,2′-azobis(2,4-dimethylvaleronitrile) (AMVN)-initi-
ated peroxidation of linoleic acid (L-H) to the corresponding
hydroperoxide (L-OOH) in a biphasic chlorobenzene/water
system was very dependent on the experimental conditions
(eq 2 and Table 1). In the absence of N-acetylcysteine in
the aqueous phase, the two organotelluriums 7a and 8a did
not inhibit peroxidation at all. However, in the presence of
the thiol reducing agent, the rate of linoleic acid hydroper-
oxide formation in the chlorobenzene layer, Rinh, was only
slightly higher (32 and 27 µM/h, respectively) than recorded
using R-tocopherol
R-Tocopherol, the most reactive component of Vitamin
E, is known to trap two peroxyl radicals before it is converted
into nonradical products. Nature has therefore arranged for
its regeneration to allow for a catalytic mode of action of
the antioxidant. In biological membranes, this process is
thought to occur by donation of a hydrogen atom from
ascorbate (AscOH) to the R-tocopheroxyl radical at the
lipid-aqueous interphase (eq 1).11-14
R-TO· + AscOH f R-TOH + AscO·
(1)
The tripeptide glutathione (GSH) is present in much higher
concentrations than ascorbate in human plasma. It is known
to act as a biological antioxidant and reducing agent both
(Rinh ) 24 µM/h) as an antioxidant under identical conditions.
R-Tocopherol is a nonregenerable antioxidant which inhibits
peroxidation for 90 min under the standard conditions of our
assay. Whereas the inhibition period for compound 7a was
70 min only, antioxidant 8a was clearly regenerable with an
inhibition time, Tinh, of 200 min. The selenium (7b, 8b) and
sulfur (7c, 8c) analogues were markedly poorer quenchers
of peroxyl radicals (115 < Rinh < 203 µM/h) than the
organotelluriums, and the addition of thiol to the aqueous
phase always caused an increase (17-100%) in Tinh
(Table 1).
Introduction of additional electron-releasing groups was
thought to further improve the chain-breaking capacity of our
antioxidants. Compounds 9a-c were therefore prepared from
commercially available 2-iodo-6-methyl-3-pyridinol and evalu-
ated together with the corresponding phenylchalcogeno com-
pounds 10a-c that we recently prepared.18 As noted above,
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