Turning pyridoxine into a catalytic chain-breaking and hydroperoxide- decomposing antioxidant

Article abstract of DOI:10.1021/jo3024297

Vitamin B6 is involved in a variety of enzymatic transformations. Some recent findings also indicate an antioxidant role of the vitamin in biological systems. We set out to turn pyridoxine (1a) into a catalytic chain-breaking and hydroperoxide-decomposing antioxidant by replacing the 2-methyl substituent with an alkyltelluro group. Target molecules 12 and derivatives 14, 17, 18, and 20 thereof were accessed by subjecting suitably substituted 2-halopyridin-3-ols to aromatic substitution using sodium alkanetellurolates as nucleophiles and then LAH-reduction of ester groups. The novel pyridoxine compounds were found to inhibit azo-initiated peroxidation of linoleic acid an order of magnitude more efficiently than α-tocopherol in a water/chlorobenzene two-phase system containing N-acetylcysteine as a reducing agent in the aqueous phase. The most lipid-soluble pyridoxine derivative 20c was regenerable and could inhibit peroxidation for substantially longer time (>410 min) than α-tocopherol (87 min). The chalcogen-containing pyridoxines could also mimic the action of the glutathione peroxidase enzymes. Thus, compound 20a catalyzed reduction of hydrogen peroxide three times more efficiently than Ebselen in the presence of glutathione as a stoichiometric reducing agent.

Full text of DOI:10.1021/jo3024297

Article
pubs.acs.org/joc
Turning Pyridoxine into a Catalytic Chain-Breaking and
Hydroperoxide-Decomposing Antioxidant
Vijay P. Singh, Jia-fei Poon, and Lars Engman*
Department of Chemistry−BMC, Uppsala University, Box 576, SE-751 23 Uppsala, Sweden
S
* Supporting Information
ABSTRACT: Vitamin B6 is involved in a variety of enzymatic
transformations. Some recent findings also indicate an antioxidant role
of the vitamin in biological systems. We set out to turn pyridoxine (1a)
into a catalytic chain-breaking and hydroperoxide-decomposing antioxidant
by replacing the 2-methyl substituent with an alkyltelluro group. Target
molecules 12 and derivatives 14, 17, 18, and 20 thereof were accessed by
subjecting suitably substituted 2-halopyridin-3-ols to aromatic substitution
using sodium alkanetellurolates as nucleophiles and then LAH-reduction of ester groups. The novel pyridoxine compounds were found to
inhibit azo-initiated peroxidation of linoleic acid an order of magnitude more efficiently than α-tocopherol in a water/chlorobenzene two-
phase system containing N-acetylcysteine as a reducing agent in the aqueous phase. The most lipid-soluble pyridoxine derivative 20c was
regenerable and could inhibit peroxidation for substantially longer time (>410 min) than α-tocopherol (87 min). The chalcogen-
containing pyridoxines could also mimic the action of the glutathione peroxidase enzymes. Thus, compound 20a catalyzed reduction of
hydrogen peroxide three times more efficiently than Ebselen in the presence of glutathione as a stoichiometric reducing agent.
in studies of their reactions with singlet oxygen.14 Thus,
INTRODUCTION
■
compounds 1a, 1b, 2a, and 3a quench 1O2 with bimolecular rate
The water-soluble vitamin B6 has an important role in living
systems. As a cofactor, it is involved in more than one hundred
enzymatic transformations.1 Vitamin B6 is the generic name for six
interconvertible forms of the vitamin (vitamers) with similar
structure. They include pyridoxine (1a), pyridoxal (2a), pyridox-
amine (3a), and their respective 5′-phosphate esters 1b, 2b, and 3b.
Phosphate esters of pyridoxine and pyridoxamine are both oxidized
in tissue to the biologically active pyridoxal-5′-phosphate (2b, PLP).
Essentially all enzymes that rely on PLP as a cofactor act upon amino
acids. Whereas the aldehyde condenses with the amine to form an
imine, the pyridine moiety serves as an electron sink in subsequent
transformations.2−4 Various transamination-, deamination-, race-
mization-, decarboxylation-, and β-elimination reactions are brought
about by these enzymes.5
constants ranging from 5.5 to 7.5 × 107 M−1 s−1.15
3-Pyridinols carrying strongly electron-donating substituents
have been known for some time to be excellent chain-breaking
antioxidants with reactivities toward peroxyl radicals matching or
exceeding those recorded for α-tocopherol.16 However, neither
pyridoxine itself (vide infra) nor any of the other vitamin B6 vitamers
are expected to possess any appreciable chain-breaking antioxidant
capacity. In an effort to improve the radical trapping activity,
Culbertson17 some time ago introduced a strongly electron-donating
dimethylamino group into the 3-pyridinol scaffolds of pyridoxine and
pyridoxamine. Although the chain-breaking antioxidant capacity of
these materials (4a and 4b, respectively) was not well documented,18
it is clear that 4b reduced the formation of advanced glycation end
products (AGE) more efficiently than the parent 3a and nearly as
efficiently as Trolox in model systems.
We have recently described another strategy for improving
chain-breaking antioxidative capacity. Introduction of an
alkyltelluro group into the ortho-position of phenols (for example
5a and 5b19) and 3-pyridinols (for example 6a and 6b20) was
found to dramatically increase reactivity toward peroxyl radicals.
In contrast to the parent phenols and pyridinols, the alkyltelluro-
modified antioxidants were readily regenerable by N-acetylcys-
teine when assayed for their capacity to inhibit azo-initiated
peroxidation of linoleic acid in a water/chlorbenzene two-phase
system. In view of the antioxidant role of pyridoxine in biological
systems we thought it would be interesting to modify the
structure in such a way that the compound could also act in a
The vitamin B6 family of 3-pyridinol compounds has been the
subject of numerous structural modifications. Some of them were
made with the purpose to produce artificial enzymes,6,7 others
with the intention to modify/change the activity of the cofactor.8
Since the turn of the millennium it has been speculated that
vitamin B6 compounds could also have a role as antioxidants and
scavengers of reactive oxygen species in biological systems.9−11
Evidence for their quenching of superoxide12 and hydroxyl
radicals13 has been presented. However, the most convincing
results when it comes to antioxidative capacity have been obtained
Received: November 23, 2012
Published: January 14, 2013
© 2013 American Chemical Society
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of water and tetrahydrofuran for 4 h. (48% isolated yield of
compound 9b). Increasing the reaction time in order to improve
the conversion of starting material resulted in formation of
diiodinated product.
catalytic chain-breaking as well as hydroperoxide-decomposing
fashion. It is our hope that the modified compounds would still
be recognized in biological systems and that they would be
suitable for treatment of disorders caused by or involving
oxidative stress (such as atherosclerosis, stroke, rheumatoid
́
arthritis, and Parkinsons and Alzheimer’s diseases). In the
following we describe our attempts to install an alkyltelluro
group in place of the 2-methyl group of pyridoxine (1a). The
ability of newly prepared pyridoxine analogues to act as catalytic
chain-breaking and hydroperoxide-decomposing antioxidants in
model systems is also reported.
Iodopyridinol 9b was found to undergo aromatic nucleophilic
substitution at ambient temperature when treated with sodium
alkanetellurolates generated by sodium borohydride reduction of
the corresponding dialkyl ditellurides in ethanol. As shown in eq
2, the substitution products 11a−c were isolated in only modest
yields. The following reduction of ester groups to give target
molecules 12a−c was performed using lithium aluminum
hydride in dry ether following literature methods.24 Obviously,
reductive cleavage of the weak carbon−tellurium bond was not a
big problem in these reactions. When subjected to the same
reaction conditions as 9b, dibromo compound 8 afforded
tellurides 13a−c, and after reduction, brominated pyridoxine
analogues 14a−c. Surprisingly, the bromine in position 6 of the
dibromopyridinol resisted substitution even at forcing conditions
(refluxing ethanol and excess of tellurolate).
RESULTS
■
Synthesis. Introduction of alkyltelluro groups was envisioned
taking advantage of an old approach to pyridinols21 involving the
decarboxylative Diels−Alder reaction of 5-ethoxyoxazole-2-
carboxylic acid with diethyl maleate22 (eq 1) under solvent-free
conditions. It was hoped that regioselective halogenation in
position 2 of pyridinol 7, followed by substitution with highly
nucleophilic alkanetellurolate reagents and reduction of ester
groups, would provide the desired target molecules.
Halogenation of pyridinol 7 turned out to be more
troublesome than expected. Bromination with an equivalent
amount of tetra-n-butylammonium tribromide in methylene
chloride at ambient temperature afforded only the dibrominated
pyridinol 8 along with unreacted starting material and none of
the desired monobromination product 9a. With a 2-fold excess of
tetra-n-butylammonium tribromide, compound 8 was isolated in
90% yield. At lower temperature (−80 °C) we observed selective
monobromination (9a:8 ratio = 10:1), but the overall conversion
of starting material was less than 20%. Attempts were also made to
introduce bromine prior to the cycloaddition step. Thus, 4-bromo-
5-ethoxyoxazole-2-carboxylic acid (10b) was prepared by bromi-
nation of 2-carboethoxy-5-ethoxyoxazole and alkaline hydrolysis of
the ester. Unfortunately, attempted reaction of compound 10a with
diethyl maleate produced a complex product mixture from which
the target molecule could not be isolated.
If the cycloaddition shown in eq 1 is carried out using the ethyl
ester of 5-ethoxyoxazole-2-carboxylic acid, decarboxylation is no
longer possible and the carboethoxy group will appear in position
6 of the pyridinol product 15a. This compound was also
subjected to bromination (15b; 72% yield using Bu4NBr3),
substitution with sodium alkanetellurolates (16a−c), and ester
reduction to afford pyridoxine derivatives 17a−c. The poor
isolated yields in the reduction this time is probably a
consequence of the higher water solubility of these materials.
In an effort to reduce the hydrophilicity of some of the newly
prepared pyridoxine derivatives, we decided to protect hydrox-
ymethyl groups as acetonides. Stirring of compounds 12a−c at
room temperature for 20 h with 2,2-dimethoxypropane in acetone
containing an equimolar amount of p-toluenesulphonic acid
afforded compounds 18a−c where the pyridinolic moiety was left
untouched. Interestingly, when compounds 14a−c were subjected
to the similar reaction conditions, products 19a−c, resulting from
ketalization between the pyridinolic and 4-hydroxymethyl groups,
were isolated. Workup of the reaction mixture after 2.5 h provided
ketals 20a−c as major products in addition to 19a, 19b, and 19c
(18%, 9%, and 15% isolated yields, respectively). Probably,
We next turned the attention to electrophilic iodination.
Iodine in the presence of sodium bicarbonate has previously been
used for the introduction of iodine into pyridinols.23 We were
pleased to find that pyridinol 7 was selectively monoiodinated in
position 2 when heated with this reagent at reflux in a 1:1 mixture
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whether NAC (1 mM) was present in the aqueous phase, inhibition
times and inhibited rates of peroxidation were essentially the same.
Thus, N-acetylcysteine in the aqueous phase cannot regenerate the α-
tocopheroxyl radical in the system before quenching of a second
peroxyl radical and conversion to other, nonradical products.
All new pyridoxine analogues containing an alkyltelluro group
in position 2 were evaluated for their chain-breaking capacity and
regenerability in the model lipid peroxidation system (Table 1).
In the absence of NAC in the aqueous phase, none of the
compounds showed any appreciable chain-breaking activity
(Rinh = 449−592 μM h−1). This is due to oxidation at tellurium by
residual amounts of linoleic acid hydroperoxide always contained
in commercial samples of linoleic acid. The resulting telluroxides are
known to act as poor retarders of lipid peroxidation rather than as
inhibitors. N-Acetylcysteine will reduce telluroxides formed and
keep catalyst tellurium in the active, divalent state. With few
exceptions (diesters 13 and triesters 16 with Rinh values in the range
of 84−140 and 86−124 μM h−1, respectively), newly prepared
pyridinolic antioxidants were as efficient (diesters 11 with Rinh
values in the range of 24−25 μM h−1) or significantly better
quenchers of peroxyl radicals than α-tocopherol. Reduction of ester
groups to the corresponding benzylic alcohols improved antioxidant
capacity significantly. Thus, pyridoxine-like compounds 12 (Rinh
values in the range of 0.8−2.8 μM h−1) were approximately an order
of magnitude more reactive than the corresponding esters 11.
Similarly, compounds 14 and 17 were more potent antioxidants
than their respective ester precursors 13 and 16.
compounds 20a−c are kinetically favored, whereas 19a−c are
thermodynamically more stable.
We anticipated already at the outset of this project that the high
water solubility of our target molecules could be a problem when
compounds were to be evaluated in the lipid peroxidation model. If
too much of the catalyst escapes from the chlorobenzene into the
aqueous layer, the duration of the antioxidant protection will be
reduced. Inspection of inhibition times (Table 1; Tinh) shows that
many catalysts tested inhibit peroxidation for only marginally longer
times than recorded for α-tocopherol (compounds 11−14, 16, 17).
However, there is a trend in each series of compounds that increasing
lipophilicity in the alkyltelluro moiety causes an increase in the
inhibition time (hexadecyltelluro > octyltelluro > butyltelluro). The
effect is never dramatic, though. In contrast, an almost 2-fold increase
in inhibition time was recorded for catalysts 12 and 14 when
hydroxymethyl groups were protected as acetonides (compounds 18
and 20). The most long-lasting antioxidant protection was offered by
catalyst 20c, which showed an inhibition time of more than 410 min.
This result lends further support to the idea that a certain lipophilicity
of the antioxidant is required in order to maintain a high enough
concentration in the chlorobenzene layer to allow regeneration by the
co-antioxidant contained in the aqueous phase. As we have seen
before,26 the limitation for the duration of the catalytic antioxidant
protection seems to be the amount of thiol present in the aqueous
phase. When all thiol is oxidized to the corresponding disulfide,
peroxidation is no longer inhibited.
A free pyridinolic group in the organotellurium compound seems
to be essential for good antioxidant performance. When acetonide
formation with compounds 14 occurred between phenolic and
neighboring hydroxymethyl groups (compounds 19), both
quenching capacity (Rinh = 46−79 μM h−1) and regenerability
(Tinh = 88−99 min) were drastically reduced.
For comparison, pyridoxine (1a) was also evaluated in the two-
phase model. As anticipated, the compound slightly retarded
peroxidation (Rinh = 457 μM h−1) but did not quench peroxyl
radicals. Peroxidation traces recorded with pyridoxine (1a), α-
tocopherol, and the most regenerable pyridoxine analogue 20c are
shown in Figure 1. It should be clear from this figure that
Inhibition Studies in a Two-Phase Lipid Peroxidation
Model System. Azo-initiated peroxidation of linoleic acid or
derivatives thereof has commonly been used for studying the chain-
breaking capacity of synthetic and natural antioxidants. Some time
ago, we modified this system to allow for regeneration of the lipid-
soluble antioxidant by co-antioxidants contained in an aqueous
phase.25 In the experimental setup for this two-phase system (eq 3),
linoleic acid (L-H) and a trace amount of the antioxidant in
chlorobenzenewere stirred with an aqueous phase containing N-
acetylcysteine (NAC) as a stoichiometric co-antioxidant. 2,2′-
Azobis(2,4-dimethylvaleronitrile AMVN) was added as an initiator,
and the progress of peroxidation was monitored by HPLC analysis of
the chlorbenzene layer (formation of conjugated diene hydro-
peroxide, L-OOH at 234 nm). When evaluated in this model, good
chain-breaking antioxidants show an inhibited phase of peroxidation
that can be clearly distinguished from the uninhibited phase that
follows when the antioxidant is all consumed (vide infra). The slower
the rate of LOOH formation during the inhibited phase (Rinh), the
more efficiently does the antioxidant quench peroxyl radicals. The
duration of the inhibited phase, Tinh, is another interesting parameter.
If the co-antioxidant contained in the aqueous phase can continuously
regenerate the antioxidant in the chlorobenzene layer, the inhibition
time can be significantly extended.19,20,26 α-Tocopherol (α-TOC)
was used as a reference compound (see Table 1). Regardless of
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Table 1. Inhibited Rates of Linoleic Acid Peroxidation (Rinh) and Inhibition Times (Tinh) in the Presence and Absence of NAC
d
(1 mM) for Antioxidants Tested in the Two-Phase Model System
a
b
Rate of peroxidation during the inhibited phase (uninhibited rate ca. 650 μM h−1). Errors correspond to SD for triplicates. Duration of the
c
inhibited phase of peroxidation. Reactions were monitored for 410 min. Errors correspond to SD for triplicates. NADPH consumption for the
initial 10 s of reaction. Values were corrected for the spontaneous oxidation of GSH (22 3 μM min−1) and the maximal initial consumption of
NADPH that could be attributed to glutathione reductase reduction of telluroxide (Table S5 in the Supporting Information). Errors correspond to
d
SD for triplicates. Glutathione peroxidase-like activities of antioxidants as determined by initial rates of NADPH consumption (ν0) in the
presence of H2O2, glutathione, and glutathione reductase.
introduction of tellurium in place of the methyl group in the
2-position of pyridoxine dramatically improves antioxidant
quenching capacity as well as regenerability.
Glutathione Peroxidase-Like Antioxidant Activity. The
glutathione peroxidases (GPx) are a small family of selenoenzymes
that catalyze reduction of hydrogen peroxide and organic
hydroperoxides to water and alcohols, respectively, using
glutathione, GSH, as the stoichiometric reducing agent. The
reason Nature selected selenium for this important task is
probably that this element is easily redox-cycled. In the proposed
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2.5 mol % of this catalyst). Pyridoxine analogues 12a, 14a, 17a,
18a, and 20a, carrying a butyltelluro group in place of a methyl in
position 2, showed a GPx activity that was 2−3 times higher than
that recorded for Ebselen. However, in all series of compounds
the activity was reduced as the size of the alkyl group was
increased (butyl > octyl > hexadecyl) and the catalytic activity of
the hexadecyl derivatives could never match that recorded for
Ebselen. The reaction of hydrogen peroxide with the organo-
tellurium catalyst (eq 4) is likely to involve a nucleophilic attack of
tellurium on oxygen. The rate of this reaction would be affected by a
combination of electronic and steric effects. Electronically as well as
sterically, the pyridinol moieties of compounds 12, 14, 17, 18, and
20 would seem to have a rather similar influence. Thus, we conclude
that the varying GPx activities recorded largely reflect the steric
hindrance of the alkyl group attached to tellurium. The poor
performance of catalysts 19a−c in the GPx assay can probably also
be ascribed to steric hindrance around tellurium. Also, this is the
only organotellurium compound studied that does not have a
phenolic moiety in the ortho-position. The hydroxyl substituent
may in fact assist by hydrogen bonding in the reaction of tellurium
with hydrogen peroxide.
Figure 1. Peroxidation traces (linoleic acid hydroperoxide concen-
tration vs time) recorded using compounds 20c, α-TOC, and
pyridoxine (1a) (40 μM) as antioxidants in the chlorobenzene layer
in the presence of NAC (1 mM) in the aqueous phase.
mechanism for the action of active site selenocysteine, selenium
traverses the selenol, selenenic acid, and selenosulfide oxidation
states while hydrogen peroxide is reduced to water and two
molecules of glutathione are oxidized to the corresponding
disulfide, GSSG. Other types of chalcogen compounds also
undergo facile redox cycling and can be useful as mimics of the
glutathione peroxidase enzymes. This is especially true for
divalent organotellurium compounds, R2Te, which could be
oxidized to the corresponding telluroxides R2TeO.
The glutathione peroxidase-like activities of all new pyridoxine
analogues were assessed by using the coupled reductase assay.27
Telluroxide produced in the reaction of hydrogen peroxide with
catalyst (eq 4) is reduced by GSH to the divalent state with
Not unexpectedly, pyridoxine (1a) did not show any GPx-like
activity.
Catalytic Parameters and Consumption of Hydrogen
Peroxide. The two most active GPx mimics, compounds 17a
and 20a, were subjected to further kinetic studies. Maximum
velocities (Vmax) were obtained by recording initial rates of NADPH
consumption (v0) in the presence of increasing amounts of GSH. As
shown in Figure 2 for compound 17a, saturation kinetics was
Figure 2. Effect of thiol concentration on initial rates of NADPH
consumption for reduction of H2O2 (0.80 mM) by GSH (0.1−2.0 mM)
in the presence of catalyst 17a.
disulfide formation (eq 5). We have previously shown for other
telluride/thiol/hydrogen peroxide systems that oxidation of
telluride is much slower than reduction of telluroxide and that the
resting state of the catalyst is telluride.28 This is likely to be the
case also in this system. Oxidized glutathione (GSSG) is then
continuously reduced by GSSG-reductase with consumption of
NADPH (eq 6). GPx-activities are shown in Table 1 as initial
rates (v0) of NADPH-consumption (eq 7) recorded by UV
spectroscopy at 340 nm for the first 10 s of reaction. Values in
Table 1 are corrected for the uncatalyzed background reaction of
GSH with H2O2 and the slow initial consumption of NADPH
that was recorded for each catalyst (4−17 μM/min) in separate
experiments (normal assay conditions minus GSH). Obviously,
telluroxides can act as substrates for GSSG-reductase as shown in
eq 8. Ebselen (2-phenyl-1,2-benzisoselenazol-3-(2H)-one, a
well-known GPx mimic,29 was included as a reference compound
and bench-mark (v0 was 60 1 μM/min in the presence of
observed. From Lineweaver−Burk plots (Figures S1−S8 in
Supporting Information) where the concentration of hydrogen
peroxide was also varied, kinetic parameters such as the maximum
velocity (Vmax), Michaelis constant (KM), catalytic constant (kcat),
and catalytic efficiency (η) were determined as shown in Table 2. In
contrast to experiments where GSH was varied, saturation was not
observed with increasing amounts of H2O2.
The performance of the GPx mimics was in a few cases
followed for a much longer time (for the first 200 min of
reaction) than during the initial phase of conversion of starting
materials. As shown in Figure 3, essentially all hydrogen peroxide
was reduced within 200 min in the presence of 5 mol % of
catalysts 17a and 20a. The consumption of NADPH is mainly
due to the catalyzed reaction during the first 50% of conversion,
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reduction of telluroxide to telluride as well as a one-electron
reduction/protonation of a phenoxyl radical. We are presently
trying to find experimental evidence for this new antioxidant
mechanism.
Table 2. Catalytic Parameters (Vmax, KM, kcat, η) for
Compounds 17a and 20a
Vmax
KM
(mM)
kcat
η (mM−1
min−1
catalyst
(μM min−1
)
(min−1
)
)
The novel pyridoxine compounds are likely to serve as
excellent scavengers of reactive oxygen species. Since thiols can
serve as stoichiometric reducing agents both for scavenging
peroxyl radicals and hydroperoxides, the cellular environment
with glutathione present in millimolar concentrations may
provide the reducing capacity needed for catalysis. Although
little is known about the toxicity of organotellurium compounds
in biological systems,31 it is clear that the small amounts of the
element that we consume via the normal diet can be metabolized
and excreted.
17a
GSH (variable)
H2O2 (variable)
238.66
0.03
2.52
11.93
56.08
384.93
22.25
1121.70
20a
GSH (variable)
H2O2 (variable)
242.13
0.03
12.12
403.55
13.12
4179.02
15.92
208.95
EXPERIMENTAL SECTION
■
1H NMR spectra were recorded on 300 and 400 MHz spectrometers.
13C spectra were recorded at 100 and 75 MHz. NMR chemical shifts are
reported in ppm referenced to the solvent peak of CDCl3 (7.26 ppm for
1H and 77.20 ppm for 13C, respectively), CD3OD (3.31 ppm for 1H and
49.00 ppm for 13C, respectively), or DMSO-d6 (2.50 ppm for H and
1
39.52 ppm for 13C, respectively). Melting points are uncorrected. High
resolution mass spectra (HRMS) were obtained using a time-of-flight
instrument equipped with electrospray ionization. Diethyl ether for
LAH-reductions was dried over sodium/benzophenone. 5-Ethoxy-2-
carboethoxyoxazole was obtained as a yellow, viscous, liquid cyclo-
dehydration product by heating of ethyl N-ethoxalylglycinate (prepared
by heating ethyl glycinate hydrochloride with diethyl oxalate and
triethylamine in C2H5OH at 50−55 °C for 24 h22a) in refluxing
chloroform containing phosphorus oxychloride (POCl3) and triethyla-
mine.22b Hydrolysis of the ester occurred in a 20% aqueous sodium
hydroxide solution to provide the corresponding carboxylic acid.22b
Heating of 5-ethoxyoxazole-2-carboxylic acid and 5-ethoxy-2-carboe-
thoxyoxazole, respectively, with neat diethyl maleate at 100 °C afforded
pyridinol 7 (as a yellow solid) and 15a (as an oil).22b The compounds
were purified by column chromatography on silica gel using pentane/
ethyl acetate (80:20) as an eluent. Di-n-butyl ditelluride,32 di-n-octyl
ditelluride,33 and di-n-hexadecyl ditelluride34 were prepared according
to literature methods.
2,6-Dibromo-4,5-bis(carboethoxy)-3-pyridinol (8). To a stirred
solution of compound 7 (2.0 g, 8.36 mmol) in CH2Cl2 (10 mL) at room
temperature was added dropwise tetrabutylammonium tribromide (8.06 g,
16.7 mmol) in CH2Cl2 (10 mL). After 1 h of stirring, water (2 mL) was
added, and stirring continued overnight. The organic layer was separated
and extracted with CHCl3. The combined organic phases were dried over
anhydrous Na2SO4 and evaporated in vacuo. Purification by column
chromatography using pentane/ethyl acetate (90:10) as eluent afforded the
title compound as a white solid. Yield: 3.00 g (90%). Mp 72−74 °C. 1H
NMR (300 MHz, CDCl3): δ 1.38−1.45 (several peaks, 6H), 4.39−4.50
(several peaks, 4H), 11.39 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 13.9,
14.1, 62.8, 64.4, 117.7, 125.6, 130.9, 133.1, 153.5, 164.8, 166.7. HRMS
(TOF MS ES+) m/z calcd for C11H11Br2NO5 [M + H]+: 395.9082; found
395.9076.
2-Bromo-4,5-bis(carboethoxy)-3-pyridinol (9a). If the above
reaction was carried out at −80 °C for 5−10 min only, compound 8
(1.3% yield) and the title compound 9a (11% yield) were isolated as a
light yellow oil along with unreacted starting material (82%). 1H NMR
(400 MHz, CDCl3): δ 1.36−1.41 (several peaks, 6H), 4.37 (q, J = 7.2
Hz, 2H), 4.46 (q, J = 7.2 Hz, 2H), 8.13 (s, 1H), 10.12 (br s, 1H). 13C
NMR (100 MHz, CDCl3): δ 13.9, 14.2, 62.5, 63.6, 119.2, 127.5, 135.6,
139.4, 151.8, 165.5, 166.9. HRMS (TOF MS ES+) m/z calcd for
C11H12BrNO5 [M + Na]+: 339.9797; found 339.9778.
2-Iodo-4,5-bis(carboethoxy)-3-pyridinol (9b). To a solution of
compound 7 (1.20 g, 5.0 mmol) in THF (4.5 mL) and H2O (4.5 mL)
were added iodine (1.53 g, 5.5 mmol) and NaHCO3 (0.506 g, 5.5 mmol)
in one portion at room temperature. The reaction mixture was then
stirred under reflux for 4 h. Residual iodine was quenched by the
addition of a 10% aqueous solution of Na2S2O3. The aqueous solution
Figure 3. Consumption of H2O2 (in percent as determined by NADPH
consumption) with time using (a) catalyst 17a and (b) catalyst 20a.
Assay conditions: phosphate buffer (100 mM), pH 7.5, with EDTA
(1 mM), GSH (0.25 mM), NADPH (0.2 mM), GR (1 unit/mL),
organotellurium catalyst (10 μM), and H2O2 (0.20 mM).
but mostly due to the spontaneous background reaction of
hydrogen peroxide with glutathione toward the end (for control
experiments see Figures S9 and S10 in the Supporting
Information).
DISCUSSION AND CONCLUDING REMARKS
■
Replacement of the 2-methyl group with alkyltelluro in the structure
of pyridoxine has a rather dramatic effect on the antioxidant profile
of the compound. Not only does the ortho-arrangement of 3-
pyridinol and alkyltelluro groups add value in the form of a chain-
breaking capacity exceeding that of α-tocopherol. The very presence
of the heavy chalcogen tellurium in the molecule also implies that it
could act as a preventive antioxidant and catalyze decomposition of
hydroperoxides using thiols as stoichiometric reducing agents. The
reasons for the latter, glutathione peroxidase-like activity of our
antioxidants, has been discussed above in some detail. However, the
mechanisms for quenching of peroxyl radicals and regeneration of
the antioxidant in the two-phase peroxidation model, accompanied
by thiol oxidation in the aqueous phase, are as yet not fully
understood. Evans−Polanij plots of log kinhibition versus BDE(O−H)
for phenols with similar steric crowding showed that introduction of
an ortho-alkyltelluro group increased the reactivity toward peroxyl
radicals with 2 orders of magnitude more than expected from
substituent effects considerations.19 This dramatic effect suggests
that another mechanism than direct H-atom transfer from O−H
could be operative with the chalcogen-containing antioxidants. We
hypothesize that peroxyl radicals could add to tellurium with O-
atom transfer30 and the resulting alkoxyl radical abstract a hydrogen
atom in a solvent cage from neighboring phenolic or pyridinolic
groups. The formation of a telluroxide would provide a large
thermodynamic driving force for the reaction. Catalyst regeneration
by thiol contained in the aqueous phase then has to involve the usual
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was extracted with CHCl3 (3 × 10 mL). The combined organic phases
were dried over anhydrous Na2SO4 and filtered, and the solvent was
evaporated under vacuum. The crude product was purified by column
chromatography using pentane/ethylacetate (85:15) as eluent to afford
the title compound as a yellow oil. Yield: 0.88 g (48%). Unreacted
22.8, 29.1, 29.3, 31.6, 31.9, 32.4, 61.9, 63.1, 112.3, 124.4, 141.2, 155.2,
166.9, 168.3. HRMS (TOF MS ES+) m/z calcd for C19H29NO5Te
[M + H]+: 482.1186; found 482.1177.
4,5-Bis(carboethoxy)-3-hydroxy-2-pyridyl Hexadecyl Tellur-
ide (11c). Yellow solid. Yield: 39%. Mp 49−51 °C. 1H NMR (400 MHz,
CDCl3): δ 0.88 (t, J = 7.0 Hz, 3H), 1.25−1.38 (several peaks, 32H), 1.87
(quintet, J = 7.4 Hz, 2H), 3.14 (t, J = 7.5 Hz, 2H), 4.35 (q, J = 7.2 Hz,
2H), 4.40 (q, J = 7.2 Hz, 2H), 8.23 (s, 1H), 10.58 (br s, 1H). 13C NMR
(100 MHz, CDCl3): δ 9.1, 13.9, 14.2, 14.3, 22.9, 29.2, 29.5, 29.7, 29.8,
29.9, 31.6, 32.1, 32.4, 61.9, 63.2, 112.4, 124.4, 141.2, 155.2, 166.9, 168.3.
HRMS (TOF MS ES+) m/z calcd for C27H45NO5Te [M + H]+:
594.2438; found 594.2446.
1
starting material could also be recovered from the column. H NMR
(400 MHz, CDCl3): δ 1.36−1.40 (several peaks, 6H), 4.37 (q, J = 7.1
Hz, 2H), 4.44 (q, J = 7.1 Hz, 2H), 8.11 (s, 1H), 10.57 (s, 1H). 13C NMR
(100 MHz, CDCl3): δ 13.9, 14.2, 62.4, 63.7, 114.8, 116.3, 127.8, 140.4,
154.4, 165.7, 167.2. HRMS (TOF MS ES+) m/z calcd for C11H12NIO5
[M + Na]+: 387.9658; found 387.9646.
4-Bromo-5-ethoxyoxazole-2-carboxylic Acid (10b). To a
solution of 5-ethoxy-2-carboethoxyoxazole (0.54 g, 2.90 mmol) in
CH2Cl2 (10 mL) was added tetrabutylammonium tribromide (1.40 g,
2.90 mmol) as described for preparation of compound 8. After the usual
workup and purification by column chromaography using pentane/ethyl
acetate (96:4) as eluent a white crystalline bromination product 10a was
obtained as a solid (0.25 g, 32%). Mp 70−72 °C. 1H NMR (300 MHz,
CDCl3): δ 1.39−1.55 (several peaks, 6H), 4.39−4.50 (several peaks,
4H). 13C NMR (75 MHz, CDCl3): δ 14.3, 15.1, 62.8, 70.9, 93.4, 142.5,
154.7, 156.5. HRMS (TOF MS ES+) m/z calcd for C8H10BrNO4 [M +
Na]+: 285.9691; found 285.9690. Hydrolysis of the material (0.18 g,
0.68 mmol) with 20% aqueous NaOH solution and acidic workup
afforded the title compound, 0.095 g (59%). Mp 92−94 °C. 1H NMR
(300 MHz, DMSO-d6): δ 1.35 (t, J = 7.0 Hz, 3H), 4.42 (q, J = 7.2 Hz,
2H). 13C NMR (75 MHz, DMSO-d6): δ 14.8, 70.8, 92.3, 143.2, 155.4,
155.6. HRMS (TOF MS ES+) m/z calcd for C6H6BrNO4 [M − H +
2Na]+: 279.9197; found 279.9182.
4,5-Bis(carboethoxy)-6-bromo-3-hydroxy-2-pyridyl Butyl
1
Telluride (13a). Yellow solid. Yield: 56%. Mp 39−41 °C. H NMR
(400 MHz, CDCl3): δ 0.95 (t, J = 7.2 Hz, 3H), 1.36−1.47 (several peaks,
8H), 1.87 (quintet, J = 7.5 Hz, 2H), 3.13 (t, J = 7.5 Hz, 2H), 4.37−4.44
(several peaks, 4H), 11.19 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 9.6,
13.7, 13.9, 14.1, 25.4, 33.6, 62.4, 63.7, 112.7, 126.4, 128.9, 140.2, 155.9,
165.8, 167.4. HRMS (TOF MS ES+) m/z calcd for C15H20BrNO5Te [M
+ H]+: 503.9665; found 503.9651.
4,5-Bis(carboethoxy)-6-bromo-3-hydroxy-2-pyridyl Octyl
1
Telluride (13b). Yellow solid. Yield: 48%. Mp 45−47 °C. H NMR
(400 MHz, CDCl3): δ 0.87 (t, J = 6.8 Hz, 3H), 1.26−1.43 (several peaks,
16H), 1.88 (quintet, J = 7.5 Hz, 2H), 3.12 (t, J = 7.5 Hz, 2H), 4.37−4.43
(several peaks, 4H), 11.19 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 9.9,
13.9, 14.1, 14.3, 22.8, 29.1, 29.4, 31.5, 32.0, 32.3, 62.4, 63.7, 112.7, 126.4,
128.9, 140.2, 155.9, 165.8, 167.4. HRMS (TOF MS ES+) m/z calcd for
C19H28BrNO5Te [M + H]+: 560.0291; found 560.0285.
4,5-Bis(carboethoxy)-6-bromo-3-hydroxy-2-pyridyl Hexa-
2-Bromo-4,5,6-tris(carboethoxy)-3-pyridinol (15b). Synthe-
sized from compound 15a (1.0 g, 3.21 mmol) in CH2Cl2 (3 mL) and
tetrabutylammonium tribromide (2.0 g, 4.17 mmol) according to the
procedure for preparation of compound 8. The title compound was
obtained as a white solid after purification by column chromatography
using pentane/ethyl acetate (90:10) as an eluent. Yield: 0.90 g (72%).
1
decyl Telluride (13c). Yellow solid. Yield: 44%. Mp 68−70 °C. H
NMR (400 MHz, CDCl3): δ 0.88 (t, J = 6.9 Hz, 3H), 1.26−1.43 (several
peaks, 32H), 1.88 (quintet, J = 7.5 Hz, 2H), 3.12 (t, J = 7.5 Hz, 2H),
4.37−4.45 (several peaks, 4H), 11.19 (br s, OH, 1H). 13C NMR (100
MHz, CDCl3): δ 9.9, 13.9, 14.1, 14.3, 22.9, 29.2, 29.5, 29.6, 29.7, 29.8,
29.9, 31.5, 31.6, 32.1, 32.3, 62.4, 63.7, 112.7, 126.4, 128.9, 140.3, 155.9,
165.8, 167.4. HRMS (TOF MS ES+) m/z calcd for C27H44BrNO5Te
[M + H]+: 672.1543; found 672.1524.
1
Mp 73−74 °C. H NMR (300 MHz, CDCl3): δ 1.37−1.45 (several
peaks, 9H), 4.39−4.53 (several peaks, 6H), 12.07 (s, 1H). 13C NMR (75
MHz, CDCl3): δ 13.8, 13.9, 14.3, 62.4, 62.6, 64.4, 116.2, 131.2, 133.9,
136.0, 156.5, 162.9, 165.3, 167.7. HRMS (TOF MS ES+) m/z calcd for
C14H16BrNO7 [M + Na]+: 412.0008; found 411.9994.
Butyl 3-Hydroxy-4,5,6-tris(carboethoxy)-2-pyridyl Telluride
1
(16a). Yellow solid. Yield: 35%. Mp 57−59 °C. H NMR (300 MHz,
CDCl3): δ 0.95 (t, J = 7.5 Hz, 3H), 1.25−1.51 (several peaks, 11H), 1.90
(quintet, J = 7.4 Hz, 2H), 3.20 (t, J = 7.5 Hz, 2H), 4.36−4.48 (several
peaks, 6H), 11.85 (br s, 1H). 13C NMR (75 MHz, CDCl3): δ 9.3, 13.7,
13.9, 14.0, 14.3, 25.6, 33.9, 61.9, 62.1, 63.8, 111.2, 127.9, 137.9, 139.4,
158.6, 164.2, 166.4, 168.4. HRMS (TOF MS ES+) m/z calcd for
C18H25NO7Te [M + H]+: 498.0772; found 498.0779.
Typical Procedure for Introduction of Alkyltelluro Groups by
Nucleophilic Aromatic Substitution. Butyl 4,5-Bis(carboethoxy)-
3-hydroxy-2-pyridyl Telluride (11a). To a solution of di-n-butyl
ditelluride (0.325 g, 0.88 mmol) in deoxygenated ethanol (5 mL) was
added NaBH4 (0.67 g, 1.76 mmol) under an inert atmosphere at 0 °C,
and the mixture was stirred at room temperature until colorless. Then,
compound 9b (0.320 g, 0.88 mmol) in ethanol (2 mL) was added
dropwise to the in situ prepared solution of n-BuTeNa at 0 °C.
Additionally, the mixture was stirred at room temperature for 4−5 h and
then heated at 60 °C for 2 h. The solvent was removed under reduced
pressure, and the residue was dissolved in CHCl3 and washed with
water. The organic layers and CHCl3 extracts from the aqueous layer
were combined and dried over anhydrous Na2SO4. After evaporation
and column chromatography using pentane/ethyl acetate (90:10) as
eluent, the pure title compound was isolated as an yellow liquid. Yield:
0.115 g (31%). 1H NMR (400 MHz, CDCl3): δ 0.93 (t, J = 7.3 Hz, 3H),
1.34−1.48 (several peaks, 8H), 1.86 (quintet, J = 7.5 Hz, 2H), 3.15 (t, J =
7.5 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H), 8.24
(s, 1H), 10.59 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ 8.7, 13.7,
13.9, 14.3, 25.4, 33.7, 61.9, 63.2, 112.4, 124.4, 141.1, 141.2, 155.2, 166.9,
168.3. HRMS (TOF MS ES+) m/z calcd for C15H21NO5Te [M + H]+:
426.0560; found 426.0568.
3-Hydroxy-4,5,6-tris(carboethoxy)-2-pyridyl Octyl Telluride
1
(16b). Yellow solid. Yield: 29%. Mp 43−45 °C. H NMR (300 MHz,
CDCl3): δ 0.87 (t, J = 7.0 Hz, 3H), 1.26−1.42 (several peaks, 19H), 1.91
(quintet, J = 7.7 Hz, 2H), 3.20 (t, J = 7.5 Hz, 2H), 4.34−4.48 (several
peaks, 6H), 11.86 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ 9.8, 13.9,
14.0, 14.2, 14.3, 22.8, 29.2, 29.5, 31.8, 32.0, 32.6, 61.9, 62.1, 63.8, 111.1,
127.9, 137.9, 139.4, 158.6, 164.1, 166.4, 168.4. HRMS (TOF MS ES+)
m/z calcd for C22H33NO7Te [M + H]+: 554.1398; found 554.1413.
Hexadecyl 3-Hydroxy-4,5,6-tris(carboethoxy)-2-pyridyl Tel-
luride (16c). Yellow solid. Yield: 25%. Mp 56−57 °C. 1H NMR (400
MHz, CDCl3): δ 0.87 (t, J = 7.7 Hz, 3H), 1.25−1.41 (several peaks,
35H), 1.90 (quintet, J = 7.5 Hz, 2H), 3.18 (t, J = 7.5 Hz, 2H), 4.34−4.46
(several peaks, 6H), 11.85 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 9.8,
13.9, 14.0, 14.2, 14.3, 22.9, 29.3, 29.5, 29.7, 29.8, 29.9, 31.8, 32.1, 32.6,
61.8, 62.1, 63.7, 111.1, 127.9, 137.9, 139.4, 158.6, 164.1, 166.3, 168.4.
HRMS (TOF MS ES+) m/z calcd for C30H49NO7Te [M + H]+:
666.2649; found 666.2652.
The following compounds were analogously prepared starting from
2-halo-3-pyridinols 8, 9b, and 15 and the appropriate, in situ prepared,
sodium alkanetellurolates (n-butylTeNa, n-octylTeNa, or n-hexadecyl-
TeNa).
4,5-Bis(carboethoxy)-3-hydroxy-2-pyridyl Octyl Telluride (11b).
Yellow liquid. Yield: 33%. 1H NMR (300 MHz, CDCl3): δ 0.87 (t, J = 6.7
Hz, 3H), 1.26−1.41 (several peaks, 16H), 1.87 (quintet, J = 7.6 Hz, 2H),
3.14 (t, J = 7.5 Hz, 2H), 4.30−4.44 (several peaks, 4H), 8.23 (s, 1H),
10.59 (br s, 1H). 13C NMR (75 MHz, CDCl3): δ 9.1, 13.9, 14.2, 14.3,
Typical Procedure for LAH-Reduction of Carboethoxy Groups.
4,5-Bis(hydroxymethyl)-3-hydroxy-2-pyridyl Butyl Telluride (12a).
To a stirred suspension of LiAlH4 (0.094 g, 2.48 mmol) in dry ether
(6 mL) was added dropwise compound 11a (0.35 g, 0.83 mmol) in ether
(2 mL) at 0 °C under an inert atmosphere. The reaction mixture
was then stirred at room temperature for 1 h, and H2SO4 (10% aq) was
added to quench the excess LiAlH4. After 5 min the mixture was
neutralized with NaOH (5% aq), and the separated aqueous layer was
extracted several times with ethyl acetate. The combined organic
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extracts were dried over anhydrous Na2SO4 and evaporated. Purification
of the residue by column chromatography on silica gel using pentane/
ethyl acetate (50:50) as eluent afforded the title compound as a white
(20:80). Yield: 14%. Mp 96−98 °C. 1H NMR (400 MHz, CD3OD): δ
0.90 (t, J = 7.0 Hz, 3H), 1.24−1.43 (several peaks, 26H), 1.87 (quintet,
J = 7.6 Hz, 2H), 3.07 (t, J = 7.5 Hz, 2H), 4.65 (s 2H), 4.76 (s, 2H), 4.96
(s, 2H). 13C NMR (100 MHz, CD3OD): δ 7.4, 14.5, 23.8, 30.2, 30.5,
30.4, 30.80, 30.82, 33.1, 33.3, 33.5, 57.3, 59.8, 64.3, 129.9, 131.3, 132.5,
151.6, 154.4. Anal. Calcd for C24H43NO4Te: C, 53.7; H, 8.1; N, 2.6.
Found: C, 53.8; H, 8.1; N, 2.5.
1
solid. Yield: 0.175 g (63%). Mp 88−90 °C. H NMR (400 MHz,
CD3OD): δ 0.93 (t, J = 7.3 Hz, 3H), 1.44 (sextet, J = 7.9 Hz, 2H), 1.82
(quintet, J = 7.6 Hz, 2H), 3.05 (t, J = 7.5 Hz, 2H), 4.58 (s, 2H), 4.92
(s, 2H), 7.99 (s, 1H). 13C NMR (100 MHz, CD3OD): δ 6.9, 13.9, 26.3,
35.3, 59.7, 60.5, 130.1, 132.7, 134.2, 143.2, 154.9. Anal. Calcd for
C11H17NO3Te: C, 38.9; H, 5.1; N, 4.1. Found: C, 39.0; H, 5.0; N, 4.0.
The following compounds were analogously prepared starting from
appropriately substituted alkyl pyridyl tellurides.
Typical Procedure for Acetonide Formation. 8-Butyltelluro-
3,3-dimethyl[1,3]dioxepino[5,6-c]pyridin-9-ol (18a). To a stirred
solution of compound 12a (100 mg, 0.295 mmol) in acetone (4 mL)
were added 2,2-dimethoxypropane (0.5 mL) and p-toluenesulfonic acid
monohydrate (56 mg, 0.295 mmol), and stirring was continued for 20 h
at room temperature. During this period the solution turned yellowish.
After pouring into a saturated NaHCO3 solution, the aqueous layer was
extracted with CHCl3 and dried over anhydrous Na2SO4. Removal of
the solvent under vacuo and purification of the residue by silica gel
column chromatography using pentane/ethyl acetate (90:10) as eluent
afforded the title compound as a yellow solid. Yield: 70 mg (64%). Mp
84−87 °C. 1H NMR (400 MHz, CDCl3): δ 0.88 (t, J = 7.3 Hz, 3H), 1.37
(sextet, J = 7.1 Hz, 2H), 1.51 (s, 6H), 1.75 (quintet, J = 7.5 Hz, 2 H), 2.90
(t, J = 7.7 Hz, 2H), 4.83 (s, 2H), 4.93 (s, 2H), 6.21 (br s, 1H), 7.93 (s,
1H). 13C NMR (100 MHz, CDCl3): δ 10.7, 13.5, 23.9, 25.2, 34.1, 60.3,
61.5, 102.8, 128.1, 131.6, 135.9, 141.4, 151.3. HRMS (TOF MS ES+) m/
z calcd for C14H21NO3Te [M + H]+: 382.0662; found 382.0654.
The following compounds were analogously prepared starting from the
appropriately substituted alkyl pyridyl telluride.
4,5-Bis(hydroxymethyl)-3-hydroxy-2-pyridyl Octyl Telluride
1
(12b). White solid. Yield: 49%. Mp 92−94 °C. H NMR (400 MHz,
CD3OD): δ 0.90 (t, J = 7.0 Hz, 3H), 1.29−1.41 (several peaks, 10H),
1.83 (quintet, J = 7.3 Hz, 2H), 3.04 (t, J = 7.5 Hz, 2H), 4.57 (s, 2H), 4.92
(s, 2H), 7.99 (s, 1H). 13C NMR (100 MHz, CD3OD): δ 7.2, 14.5, 23.7,
30.1, 30.4, 33.0, 33.1, 33.3, 59.7, 60.5, 130.0, 132.7, 134.2, 143.2, 154.9.
Anal. Calcd for C15H25NO3Te: C, 45.6; H, 6.4; N, 3.5. Found: C, 45.5;
H, 6.4; N, 3.5.
4,5-Bis(hydroxymethyl)-3-hydroxy-2-pyridyl Hexadecylyl
1
Telluride (12c). White solid. Yield: 43%. Mp 99−102 °C. H NMR
(400 MHz, CD3OD): δ 0.90 (t, J = 7.0 Hz, 3H), 1.24−1.43 (several
peaks, 26H), 1.83 (quintet, J = 7.6 Hz, 2H), 3.04 (t, J = 7.5 Hz, 2H), 4.58
(s, 2H), 4.92 (s, 2H), 7.99 (s, 1H). 13C NMR (100 MHz, CD3OD): δ
7.2, 14.5, 23.8, 30.2, 30.5, 30.6, 30.7, 30.8, 30.9, 33.0, 33.1, 33.3, 59.7,
60.5, 130.0, 132.6, 134.3, 143.3, 154.9. Anal. Calcd for C23H41NO3Te: C,
54.5; H, 8.1; N, 2.8. Found: C, 54.6; H, 8.2; N, 2.7.
3,3-Dimethyl-8-octyltelluro[1,3]dioxepino[5,6-c]pyridin-9-ol
4,5-Bis(hydroxymethyl)-3-hydroxy-6-bromo-2-pyridyl Butyl
Telluride (14a). White solid. Yield: 48%. Mp 137−140 °C. 1H NMR
(400 MHz, CD3OD): δ 0.96 (t, J = 7.5 Hz, 3H), 1.44 (sextet, J = 7.1 Hz,
2H), 1.85 (quintet, J = 7.5 Hz, 2H), 3.05 (t, J = 7.3 Hz, 2H), 4.73
(s, 2H), 4.96 (s, 2H). 13C NMR (100 MHz, CD3OD): δ 7.9, 13.9, 26.3,
35.2, 60.3, 61.5, 131.1, 133.2, 134.8, 136.0, 154.9. Anal. Calcd for
C11H16BrNO3Te: C, 31.6; H, 3.9; N, 3.3. Found: C, 31.8; H, 3.9; N, 3.4.
4,5-Bis(hydroxymethyl)-3-hydroxy-6-bromo-2-pyridyl Octyl
Telluride (14b). White solid. Yield: 59%. Mp 128−131 °C. 1H NMR
(400 MHz, CD3OD): δ 0.90 (t, J = 6.4 Hz, 3H), 1.30−1.42 (several
peaks, 10H), 1.86 (quintet, J = 7.2 Hz, 2H), 3.04 (t, J = 7.4 Hz, 2H), 4.73
(s, 2H), 4.96 (s, 2H). 13C NMR (100 MHz, CD3OD): δ 8.3, 14.5, 23.7,
30.1, 30.4, 33.0, 33.3, 60.3, 60.5, 131.1, 133.2, 134.9, 136.0, 154.9. Anal.
Calcd for C15H24BrNO3Te: C, 38.0; H, 5.1; N, 2.9. Found: C, 38.1; H,
5.1; N, 3.0.
4,5-Bis(hydroxymethyl)-3-hydroxy-6-bromo-2-pyridyl Hexa-
decyl Telluride (14c). White solid. Yield: 45%. Mp 115−118 °C. 1H
NMR (400 MHz, CD3OD): δ 0.90 (t, J = 6.8 Hz, 3H), 1.24−1.42
(several peaks, 26H), 1.86 (quintet, J = 7.6 Hz, 2H), 3.04 (t, J = 7.5 Hz,
2H), 4.73 (s, 2H), 4.96 (s, 2H). 13C NMR (100 MHz, CD3OD): δ 8.3,
14.5, 23.8, 30.2, 30.5, 30.7, 30.78, 30.82, 30.85 33.0, 33.1, 33.3, 60.3, 60.6,
131.1, 133.2, 134.9, 136.9, 154.9. Anal. Calcd for C23H40BrNO3Te: C,
47.1; H, 6.9; N, 2.4. Found: C, 47.2; H, 6.9; N, 2.4.
1
(18b). Yellow solid. Yield: 63%. Mp 63−67 °C. H NMR (400 MHz,
CDCl3): δ 0.87 (t, J = 7.0 Hz, 3H), 1.23−1.34 (several peaks, 10H), 1.51
(s, 6H), 1.75 (quintet, J = 7.6 Hz, 2H), 2.88 (t, J = 7.4 Hz, 2H), 4.82
(s, 2H), 4.92 (s, 2H), 6.15 (br s, 1H), 7.92 (s, 1H). 13C NMR (100 MHz,
CDCl3): δ 11.0, 14.3, 22.8, 23.9, 28.9, 29.3, 31.9, 32.0, 32.2, 60.3,61.5,
102.8, 128.2, 131.6, 135.9, 141.4, 151.3. Anal. Calcd for C18H29NO3Te:
C, 49.7; H, 6.7; N, 3.2. Found: C, 49.4; H, 6.7; N, 3.3.
3,3-Dimethyl-8-hexadecyltelluro[1,3]dioxepino[5,6-c]-
pyridin-9-ol (18c). White solid. Yield: 54%. Mp 65−67 °C. 1H NMR
(400 MHz, CDCl3): δ 0.88 (t, J = 7.0 Hz, 3H), 1.23−1.25 (several peaks,
26H), 1.51 (s, 6H), 1.75 (quintet, J = 7.6 Hz, 2H), 2.88 (t, J = 7.4 Hz,
2H), 4.82 (s, 2H), 4.92 (s, 2H), 6.08 (br s, 1H), 7.93 (s, 1H). 13C NMR
(100 MHz, CDCl3): δ 11.2, 14.3, 22.9, 23.9, 29.0, 29.6, 29.7, 29.8, 29.9,
32.0, 32.1, 60.4, 61.6, 102.8, 127.8, 131.4, 136.1, 141.4, 151.3. Anal.
Calcd for C26H45NO3Te: C, 57.1; H, 8.3; N, 2.6. Found: C, 57.1; H, 8.3;
N, 2.5.
6-Bromo-8-butyltelluro-3,3-dimethyl[1,3]dioxepino[5,6-c]-
pyridin-9-ol (20a). Yellow solid. Yield: 48%. Mp 62−64 °C. 1H NMR
(300 MHz, CDCl3): δ 0.90 (t, J = 7.3 Hz, 3H), 1.37 (sextet, J = 7.2 Hz,
2H), 1.51 (s, H), 1.76 (quintet, J = 7.5 Hz, 2H), 2.93 (t, J = 7.5 Hz,
2H), 4.89 (s, 4H). 13C NMR (75 MHz, CDCl3): δ 11.7, 13.5, 23.8, 25.1,
33.9, 59.8, 63.8, 102.7, 126.3, 131.7, 134.7, 135.5, 151.5. Anal. Calcd for
C14H20BrNO3Te: C, 36.7; H, 4.4; N, 3.1. Found: C, 37.0; H, 4.5; N, 3.2.
6-Bromo-3,3-dimethyl-8-octyltelluro[1,3]dioxepino[5,6-c]-
Butyl 3-Hydroxy-4,5,6-tris(hydroxymethyl)-2-pyridyl Tellur-
ide (17a). The title compound was obtained as a yellow solid by column
chromatography on silica gel eluted with pentane/ethyl acetate (20:80).
1
pyridin-9-ol (20b). Orange semisolid. Yield: 65%. H NMR (300
1
MHz, CDCl3): δ 0.87 (t, J = 7.0 Hz, 3H), 1.24−1.40 (several peaks,
10H), 1.50 (s, 6H), 1.78 (quintet, J = 7.6 Hz, 2H), 2.93 (t, J = 7.6 Hz,
2 H), 4.90 (s, 4H). 13C NMR (75 MHz, CDCl3): δ 12.0, 14.3, 22.8, 23.8,
28.9, 29.3, 31.90, 31.96, 31.99, 59.8, 63.8, 102.6, 126.4, 131.7, 134.7,
135.5, 151.6. Anal. Calcd for C18H28BrNO3Te: C, 42.1; H, 5.5; N, 2.7.
Found: 42.3; H, 5.6; N, 2.8.
Yield: 18%. Mp 106−109 °C. H NMR (300 MHz, CD3OD): δ 0.95
(t, J = 7.3 Hz, 3H), 1.45 (sextet, J = 7.2 Hz, 2H), 1.86 (quintet, J = 7.4 Hz,
2H), 3.08 (t, J = 7.6 Hz, 2H), 4.66 (s, 2H), 4.75 (s, 2H), 4.96 (s, 2H). 13C
NMR (75 MHz, CD3OD): δ 7.1, 13.9, 26.4, 35.4, 57.3, 59.7, 64.2, 129.9,
131.4, 132.4, 151.6, 154.4. Anal. Calcd for C12H19NO4Te: C, 39.1; H,
5.2; N, 3.8. Found: C, 39.5; H, 5.2; N, 3.7.
6-Bromo-3,3-dimethyl-8-hexadecyltelluro[1,3]dioxepino-
[5,6-c]pyridin-9-ol (20c). White solid. Yield: 47%. Mp 68−70 °C. 1H
NMR (400 MHz, CDCl3): δ 0.89 (t, J = 7.0 Hz, 3H), 1.25−1.30 (several
peaks, 26H), 1.50 (s, 6H), 1.78 (quintet, J = 7.7 Hz, 2H), 2.93 (t, J = 7.5
Hz, 2H), 4.89 (s, 4H), 5.98 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ
12.1, 14.3, 22.9, 23.8, 29.0, 29.5, 29.6, 29.7, 29.8, 29.9, 31.9, 32.0, 32.1,
59.8, 63.8, 102.6, 126.3, 131.7, 134.6, 135.6, 151.5. Anal. Calcd for
C26H44BrNO3Te: C, 49.9; H, 7.1; N, 2.2. Found: C, 50.1; H, 7.2; N, 2.3.
6-Bromo-8-butyltelluro-5-hydroxymethyl-4H-1,3-dioxino-
Octyl 3-Hydroxy-4,5,6-tris(hydroxymethyl)-2-pyridyl Tellur-
ide (17b). The title compound was obtained as a yellow solid by column
chromatography on silica gel eluted with pentane/ethyl acetate (20:80).
Yield: 22%. Mp 84−86 °C. 1H NMR (300 MHz, CD3OD): δ 0.90 (t, J =
7.0 Hz, 3H), 1.30−1.42 (several peaks, 10H), 1.87 (quintet, J = 7.2 Hz, 2
H), 3.08 (t, J = 7.3 Hz, 2H), 4.66 (s, 2H), 4.76 (s, 2H), 4.96 (s, 2H). 13C
NMR (100 MHz, DMSO-d6): δ 6.4, 13.5, 21.6, 27.9, 28.2, 30.8, 30.9,
31.3, 55.3, 56.3, 62.7, 129.8, 129.9, 130.7, 151.2, 151.3. Anal. Calcd for
C16H27NO4Te: C, 45.2; H, 6.4; N, 3.3. Found: C, 45.4; H, 6.4; N, 3.3.
Hexadecyl 3-Hydroxy-4,5,6-tris(hydroxymethyl)-2-pyridyl
Telluride (17c). The title compound was obtained as a white solid by
column chromatography on silica gel eluted with pentane/ethyl acetate
1
[4,5-c]pyridine (19a). Yellow semisolid. Yield: 52%. H NMR (400
MHz, CDCl3): δ 0.95 (t, J = 7.4 Hz, 3H), 1.44 (sextet, J = 7.1 Hz, 2H),
1.54 (s, 6H), 1.87 (quintet, J = 7.3 Hz, 2H), 3.12 (t, J = 7.5 Hz, 2H), 4.65
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(d, J = 3.1 Hz, 2H), 4.92 (s, 2H). 13C NMR (100 MHz, CDCl3): δ 8.5,
13.7, 24.7, 25.4, 33.9, 59.1, 61.2, 101.3, 126.4, 127.5, 133.8, 134.7, 149.3.
Anal. Calcd for C14H20BrNO3Te: C, 36.7; H, 4.4; N, 3.1. Found: C, 37.0;
H, 4.5; N, 3.1.
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6-Bromo-5-hydroxymethyl-8-octyltelluro-4H-1,3-dioxino-
1
[4,5-c]pyridine (19b). Yellow solid. Yield: 58%. Mp 58−60 °C. H
NMR (400 MHz, CDCl3): δ 0.87 (t, J = 6.9 Hz, 3H), 1.27−1.43 (several
peaks, 10H), 1.54 (s, 6H), 1.88 (quintet, J = 7.5 Hz, 2H), 3.10 (t, J = 7.6
Hz, 2H), 4.64 (s, 2H), 4.91 (s, 2H). 13C NMR (100 MHz, CDCl3): δ 8.9,
14.3, 22.8, 24.7, 29.1, 29.4, 31.7, 32.0, 32.4, 59.1, 61.1, 101.2, 126.4,
127.5, 133.8, 134.7, 149.3. Anal. Calcd for C18H28BrNO3Te: C, 42.1; H,
5.5; N, 2.7. Found: 42.3; H, 5.5; N, 2.7.
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6-Bromo-8-hexadecyltelluro-5-hydroxymethyl-4H-1,3-
dioxino[4,5-c]pyridine (19c). Light yellow solid. Yield: 15%. Mp 68−
70 °C. 1H NMR (400 MHz, CDCl3): δ 0.88 (t, J = 7.0 Hz, 3H), 1.26−
1.43 (several peaks, 26H), 1.55 (s, 6H), 1.88 (quintet, J = 7.5 Hz, 2H),
3.11 (t, J = 7.5 Hz, 2H), 4.65 (d, J = 3.1 Hz, 2H), 4.92 (s, 2H). 13C NMR
(100 MHz, CDCl3): δ 8.9, 14.3, 22.9, 24.8, 29.2, 29.6, 29.7, 29.8, 29.9,
31.8, 32.1, 32.4, 59.1, 61.2, 101.3, 126.4, 127.5, 133.8, 134.7, 149.3.
HRMS (TOF MS ES+) m/z calcd for C26H44BrNO3Te [M + H]+:
628.1645; found 628.1647.
HPLC Peroxidation Assay. The experimental setup for recording
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azo-initiated peroxidation of linoleic acid in a two-phase system was
recently described.35 Values reported in Table 1 for reactions performed
in the presence of NAC are means SD based on triplicates.
Coupled Reductase Assay. The GPx-like activities of novel
organotellurium compounds prepared were determined by UV
spectroscopy following the protocol by Wilson27 with slight
modifications. The test mixture contained GSH (1 mM), ethylene
diamine tetra acetate (EDTA, 1 mM), glutathione reductase (GR)
(1 unit/mL), and β-nicotinamide adenine dinucleotide phosphate
(NADPH, 0.2 mM) in potassium phosphate buffer (100 mM), pH 7.5.
Catalysts (20 μM) were added to the test mixture at 21 °C, and the
reaction was initiated by addition of H2O2 (0.8 mM). Initial reaction
rates were based on the consumption of NADPH as assessed by UV
spectroscopy at 340 nm. The initial reduction rate was determined at
least 3−4 times and calculated from the first 10 s of reaction by using
6.22 mM−1 cm−1 as the extinction coefficient for NADPH. GPx data
reported in Table 1 are means SD.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR data for all new compounds prepared. Results
from kinetic studies of compounds prepared (maximum velocities,
Lineweaver −Burk plots, control experiments, consumption of
hydrogen peroxide in long-lime experiments). This material is
available free of charge via the Internet at http://pubs.acs.org.
(17) (a) Culbertson, S. M.; Enright, G. D.; Ingold, K. I. Org. Lett. 2003,
5, 2659−2662. (b) Culbertson, S. M.; Vassilenko, E. I.; Morrison, L. D.;
Ingold, K. I. J. Biol. Chem. 2003, 278, 38384−38394.
(18) Compounds 4a and 4b were found to retard allophycocyanin
(APC) fluorescence as efficiently as Trolox in the presence of peroxyl
radicals.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: Lars.Engman@kemi.uu.se.
(19) (a) Amorati, R.; Pedulli, G. F.; Valgimigli, L.; Johansson, H.;
Engman, L. Org. Lett. 2010, 12, 2326−2329. (b) Johansson, H.; Shanks,
D.; Engman, L.; Amorati, R.; Pedulli, G. F.; Valgimigli, L. J. Org. Chem.
2010, 75, 7535−7541.
Notes
The authors declare no competing financial interest.
(20) (a) Kumar, S.; Johansson, H.; Kanda, T.; Engman, L.; Muller, T.;
̈
ACKNOWLEDGMENTS
■
Jonsson, M.; Pedulli, G. F.; Petrucci, S.; Valgimigli, L. Org. Lett. 2008, 10,
4895−4898. (b) Kumar, S.; Johansson, H.; Kanda, T.; Engman, L.;
The Swedish Research Council and Stiftelsen Olle Engkvist
Byggmastare are gratefully acknowledged for financial support.
̈
Muller, T.; Bergenudd, H.; Jonsson, M.; Pedulli, G. F.; Amorat, R.;
̈
Valgimigli, L. J. Org. Chem. 2010, 75, 716−725.
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