Novel Water-Soluble Diorganyl Tellurides with Thiol Peroxidase and Antioxidant Activity

Article abstract of DOI:10.1021/jo990842k

Novel water-soluble diaryl tellurides, alkyl aryl tellurides, and dialkyl tellurides carrying sulfopropyl groups were prepared and found to possess potent peroxide decomposing and chain-breaking antioxidative capacity. The dilithium, disodium, dipotassium, and bis-tetramethylammonium salts of bis(4-hydroxyphenyl) telluride (4) were treated with 2.3 equiv of 1,3-propanesultone in aqueous tert-butyl alcohol to give the corresponding salts 5 of bis-O-sulfopropylated diaryl telluride. A variety of diaryl ditellurides were reduced with sodium borohydride in ethanol. Upon addition of propanesultone to the resulting sodium arenetellurolates, the corresponding 3-aryltellurenylpropanesulfonic acid sodium salts 8 were precipitated. Diphenyl diselenide and dibutyl ditelluride reacted similarly to afford the sodium salts of 3-benzeneselenenylpropanesulfonic acid (9) and 4-telluraoctanesulfonic acid (10), respectively. The glutathione peroxidase-like activity of the water-soluble compounds was assessed at pH = 7.4 by using the coupled GSSG reductase assay. Dialkyl telluride 10 turned out to be the most efficient catalyst. Several alkyl aryl tellurides 8 were also more efficient than any of the previously tested organotellurium compounds in this model. Bulky and electron-withdrawing aryl substituents seemed to reduce activity, whereas electron-donating groups enhanced it. Alkyl aryl selenide 9 was void of any catalytic activity. The novel compounds were also assessed by ¹H NMR spectroscopy for their capacity to catalyze the hydrogen peroxide oxidation of N-acetylcysteine in D₂O under acidic conditions. In the presence of 0.01 mol % of the organotellurium catalyst, the thiol concentration was reduced to 50% within 12 min for the most active catalyst (compound 5b). Although many of the compounds showed high catalytic activity, it was not possible to rationalize their relative efficiency. The capacity of the novel organotellurium compounds to act as a scavengers of 1,1-diphenyl-2-picrylhydrazyl (DPPH) was also investigated. The organotelluriums seem to act primarily as electron donors in their reaction with DPPH. Compounds 8d, 10, and 8b were the most effective scavengers. Bulky or electron-withdrawing aryl substituents caused a reduction in activity, whereas electron-donating ones enhanced it. None of the compounds could match vitamin E in their scavanging capacity.

Full text of DOI:10.1021/jo990842k

J . Org. Chem. 1999, 64, 8161-8169
8161
Novel Wa ter -Solu ble Dior ga n yl Tellu r id es w ith Th iol P er oxid a se
a n d An tioxid a n t Activity
Takahiro Kanda,† Lars Engman,*,† Ian A. Cotgreave,‡ and Garth Powis§
Uppsala University, Institute of Chemistry, Department of Organic Chemistry, Box 531,
S-751 21 Uppsala, Sweden, Division of Biochemical Toxicology, Institute of Environmental Medicine,
Karolinska Institute, Box 210, S-171 77 Stockholm, Sweden, and Arizona Cancer Center,
University of Arizona, Tucson, Arizona 85724-5024
Received May 24, 1999
Novel water-soluble diaryl tellurides, alkyl aryl tellurides, and dialkyl tellurides carrying sulfopropyl
groups were prepared and found to possess potent peroxide decomposing and chain-breaking
antioxidative capacity. The dilithium, disodium, dipotassium, and bis-tetramethylammonium salts
of bis(4-hydroxyphenyl) telluride (4) were treated with 2.3 equiv of 1,3-propanesultone in aqueous
tert-butyl alcohol to give the corresponding salts 5 of bis-O-sulfopropylated diaryl telluride. A variety
of diaryl ditellurides were reduced with sodium borohydride in ethanol. Upon addition of
propanesultone to the resulting sodium arenetellurolates, the corresponding 3-aryltellurenylpro-
panesulfonic acid sodium salts 8 were precipitated. Diphenyl diselenide and dibutyl ditelluride
reacted similarly to afford the sodium salts of 3-benzeneselenenylpropanesulfonic acid (9) and
4-telluraoctanesulfonic acid (10), respectively. The glutathione peroxidase-like activity of the water-
soluble compounds was assessed at pH ) 7.4 by using the coupled GSSG reductase assay. Dialkyl
telluride 10 turned out to be the most efficient catalyst. Several alkyl aryl tellurides 8 were also
more efficient than any of the previously tested organotellurium compounds in this model. Bulky
and electron-withdrawing aryl substituents seemed to reduce activity, whereas electron-donating
groups enhanced it. Alkyl aryl selenide 9 was void of any catalytic activity. The novel compounds
1
were also assessed by H NMR spectroscopy for their capacity to catalyze the hydrogen peroxide
oxidation of N-acetylcysteine in D2O under acidic conditions. In the presence of 0.01 mol % of the
organotellurium catalyst, the thiol concentration was reduced to 50% within 12 min for the most
active catalyst (compound 5b). Although many of the compounds showed high catalytic activity, it
was not possible to rationalize their relative efficiency. The capacity of the novel organotellurium
compounds to act as a scavengers of 1,1-diphenyl-2-picrylhydrazyl (DPPH) was also investigated.
The organotelluriums seem to act primarily as electron donors in their reaction with DPPH.
Compounds 8d , 10, and 8b were the most effective scavengers. Bulky or electron-withdrawing aryl
substituents caused a reduction in activity, whereas electron-donating ones enhanced it. None of
the compounds could match vitamin E in their scavanging capacity.
In tr od u ction
free radicals and their destruction. However, under
certain conditions the antioxidant system becomes over-
whelmed. The term “oxidative stress” has been intro-
duced by biochemists to describe this situation of elevated
cellular concentrations of oxygen-derived species,2 and
“antioxidant pharmacotherapy”3,4 has emerged as a
potential remedy for pathological conditions character-
ized by oxidative stress. For example, excessive radical
production has been implicated in chronic inflammatory
disorders, adult respiratory distress syndrome, athero-
sclerosis, ischemia/reperfusion injury, shock, and cata-
ract.
Despite numerous reports on the activities and proper-
ties of the different antioxidant enzymes (catalase, su-
peroxide dismutase, and glutathione peroxidases), their
relative importance in the cell and their cooperation are
still a subject of controversy. A recent study, focusing on
cell survival against oxidative stress, concluded that all
three enzymes are necessary for survival in normal
conditions. It was observed, though, that the glutathione
It is now well established that oxidants, many of which
are free radicals, are present in biological systems under
normal physiological conditions. For example, the activa-
tion of polymorphonuclear leukocytes in response to
inflammatory stimuli is known to result in the production
of superoxide.1 This species can dismutate to form
hydrogen peroxide and, via the enzyme myeloperoxidase,
be further converted to hypochlorous acid. In the presence
of suitable transition-metal reductants, Fenton chemistry
serves to further reduce hydrogen peroxide into the
highly reactive hydroxyl radical. To prevent undesired
radical-induced damage, the organism is equipped with
several lines of antioxidant defense. These act either by
interception of free radicals (superoxide dismutases,
vitamin E, ascorbate, glutathione, and uric acid) or by
destruction of precursors to free radicals (catalase and
glutathione peroxidases). Under normal conditions, there
is a balance between the production of oxygen-derived
† Uppsala University, Institute of Chemistry.
(2) Cadenas, E. In Oxidative Stress; Sies, H., Ed.; Academic Press:
London, 1985, pp 311-330.
‡ Institute of Environmental Medicine, Karolinska Institute.
§ Arizona Cancer Center, University of Arizona.
(3) Rice-Evans, C. A.; Diplock, A. T. Free Radical Biol. Med. 1993,
15, 77-96.
(1) Halliwell, B.; Gutteridge, J . M. C. Free Radicals in Biology and
Medicine; Oxford University Press: Oxford, 1989; pp 372-390.
(4) Bast, A. Drug. News Persp. 1994, 7, 465-472.
10.1021/jo990842k CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/29/1999

8162 J . Org. Chem., Vol. 64, No. 22, 1999
Kanda et al.
Sch em e 1
peroxidases were substantially more efficient on a molar
basis than the other two enzymes.5 The selenium-
containing glutathione peroxidases6 are selenoproteins,
a class of enzymes of which less than a dozen repesen-
tatives are known with respect to structure and function
in mammals.7 These enzymes catalyze the reduction of
hydrogen peroxide, fatty-acid hydroperoxides, and phos-
pholipid and cholesterol hydroperoxides using glu-
tathione (GSH) and other thiols as stoichiometric reduc-
ing agents. The four varieties of the enzyme presently
known serve their protective function in cells (GSH-Px-
1),8 plasma (GSH-Px-P),9 membranes (PHGPX),10 and the
gastrointestinal tract (GSHPx-GI).11 Considerable efforts
have been made to find compounds that could mimic the
properties of the glutathione peroxidase enzymes. Eb-
selen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) (1) was
taining enzymes,18 antibodies,19 and cyclodextrins20 have
all been demonstrated to catalyze the reduction of
peroxides in the presence of thiols. Some time ago, we
found that diorganyl ditellurides could also mimic the
glutathione peroxidase enzymes.21 The catalytic mecha-
nism probably resembles that postulated for diselenides.
The observed glutathione peroxidase-like properties of
diaryl tellurides 222,23 and other organotelluriums24 rely
on a distinctly different mechanism, the redox cycling of
the heteroatom between the oxidation states II and IV
(Scheme 1). Recent studies showed that compounds of
this type could also inhibit azo-initiated peroxidation of
linoleic acid in a two-phase system containing a thiol in
the aqueous phase.25 The thiol peroxidase activity cer-
tainly contributes to the antioxidative protection offered
by these compounds.
the first compound found to have this capacity.12 In the
presence of glutathione, Ebselen is readily ring-opened
to give a selenosulfide. This species, the corresponding
selenol and selenenic acid are then thought to be involved
in the catalytic cycle responsible for the glutathione
peroxidase-like properties of the compound.13 Thus,
compounds that could serve as precursors to any of these
species could also be expected to have thiol peroxidase
activity. Ebselen homologues,14 selenenamides,15 dis-
elenides,16 R-phenylselenoketones,17 and selenium-con-
To also probe the catalytic concept of antioxidant
protection in nonlipid environments, access to water-
soluble diorganyl tellurides would be required. However,
by examining the many thousands of known organotel-
lurium compounds,26 one finds only a very small fraction
of water-soluble materials. In the following, we describe
the preparation of novel water-soluble diaryl tellurides,
aryl alkyl tellurides, and dialkyl tellurides with potent
thiol peroxidase and antioxidant activity.
(5) Michiels, C.; Raes, M.; Toussaint, O.; Remacle, J . Free Radical
Biol. Med. 1994, 17, 235-248.
(6) Spallholz, J . E.; Boylan, L. M. In Peroxidases in Chemistry and
Biology; Everse, J ., Everse, K. E., Grisham, M. B., Eds.; CRC Press:
Boca Raton, 1991; Vol. 1, Chapter 12.
(7) Sunde, R. A. In Handbook of Nutritionally Essential Mineral
Elements; O’Dell, B. L., Sunde, R. A., Eds.; Marcel Dekker: New York,
1997; Chapter 18.
(8) Rotruck, J . T.; Pope, A. L.; Ganther, H. E.; Swanson, A. B.;
Hafeman, D. G.; Hoekstra, W. G. Science 1973, 179, 588-590.
(9) Takahashi, K.; Avissar, N.; Whitin, J .; Cohen, H. Arch. Biochem.
Biophys. 1987, 256, 677-686.
Resu lts
Water solubility of organic compounds is frequently
required for evaluation in biological systems and for
applications in other hydrophilic environments. One
commonly used method for enhancing the hydrophilicity
involves introduction of sulfopropyl groups. Propane-
sulfonates of amines, alcohols, and phenols are conve-
niently prepared in the laboratory by ring-opening of 1,3-
(10) Ursini, F.; Maiorino, M.; Gregolin, C. Biochim. Biophys. Acta
1985, 839, 62-70.
(11) Chu, F.-F., Doroshow, J . H.; Esworthy, R. S. J . Biol. Chem.
1993, 268, 2571-2576.
(12) Mu¨ller, A.; Cadenas, E.; Graf, P.; Sies, H. Biochem. Pharmacol.
1984, 33, 3235-3239. Sies, H. Free Radical Biol. Med. 1993, 14, 313-
323. Schewe, T. Gen. Pharmacol. 1995, 26, 1153-1169. Sies, H.;
Masumoto, H. Adv. Pharmacol. 1997, 38, 229-246.
(13) Cotgreave, I. A.; Morgenstern, R.; Engman, L.; Ahokas, J .
Chem.-Biol. Interactions 1992, 84, 69-76. Morgenstern, R.; Cotgreave,
I. A.; Engman, L. Chem.-Biol. Interactions 1992, 84, 77-84.
(14) J acquemin, P. V.; Christiaens, L. E.; Renson, M. J . Tetrahedron
Lett. 1992, 33, 3863-3866.
(15) Reich, H. J .; J asperse, C. P. J . Am. Chem. Soc. 1987, 109, 5549-
5551. Back, T. G.; Dyck, B. P. J . Am. Chem. Soc. 1997, 119, 2079-
2083. Moutet, M.; D’Alessio, P.; Malette, P.; Devaux, V.; Chaudiere, J .
Free Radical Biol. Med. 1998, 25, 270-281. Erdelmeier, I.; Tailhan-
Lomont, C.; Moutet, M.; Chaudiere, J .; Yadan, J .-C. PCT Int. Appl.
WO 98/29417, 1998.
(16) Wilson, S. R.; Zucker, P. A.; Huang, R.-R. C.; Spector, A. J .
Am. Chem. Soc. 1989, 111, 5936-5939. Iwaoka, M.; Tomoda, S. J . Am.
Chem. Soc. 1994, 116, 2557-2561. Galet, V.; Bernier, J .-L.; He´nichart,
J .-P.; Lesieur, D.; Abadie, C.; Rochette, L.; Lindenbaum, A.; Chalas,
J .; Renaud de la Faverie, J .-F.; Pfeiffer, B.; Renard, P. J . Med. Chem.
1994, 37, 2903-2911. Wirth, T. Molecules 1998, 3, 164-166. Mugesh,
G.; Panda, A.; Singh, H. B.; Punekar, N. S.; Butcher, R. J . J . Chem.
Soc., Chem. Commun. 1998, 2227-2228. Tailhan-Lomont, C.; Er-
delmeier, I.; Moutet, M.; Chaudiere, J .; Yadan, J .-C. Eur. Pat. Appl.
EP 850, 924. 1998.
(18) Wu, Z.-P.; Hilvert, D. J . Am. Chem. Soc. 1990, 112, 5647-5648.
House, K. L.; Dunlap, R. B.; Odom, J . D.; Wu, Z.-P.; Hilvert, D. J . Am.
Chem. Soc. 1992, 114, 8573-8579. Liu, J .-Q.; J iang, M.-S.; Luo, G.-
M.; Yan, G.-L.; Shen, J - C. Biotech. Lett. 1998, 20, 693-696.
(19) Ding, L.; Liu, Z.; Zhu, Z.; Luo, G.; Zhao, D.; Ni, J . Biochem. J .
1998, 332, 251-255.
(20) Liu, J .-Q.; Gao, S.-J .; Luo, G.-M.; Yan, G.-L.; Shen, J .-C.
Biochem. Biophys. Res. Commun. 1998, 247, 397-400.
(21) Engman, L.; Stern, D.; Cotgreave, I. A.; Andersson, C.-M. J .
Am. Chem. Soc. 1992, 114, 9737-9743.
(22) Andersson, C.-M.; Hallberg, A.; Brattsand, R.; Cotgreave, I. A.;
Engman, L.; Persson, J . Bioorg. Med. Chem. Lett. 1993, 3, 2553-2558.
(23) Engman, L.; Stern, D.; Pelcman, M.; Andersson, C.-M. J . Org.
Chem. 1994, 59, 1973-1979.
(24) Detty, M. R.; Friedman, A. E.; Oseroff, A. R. J . Org. Chem. 1994,
59, 8245-8250.
(25) Vessman, K.; Ekstro¨m, M.; Berglund, M.; Andersson, C.-M.;
Engman L. J . Org. Chem. 1995, 60, 4461-4467.
(26) Irgolic, K. J . In Houben-Weyl. Methods of Organic Chemistry.
Organotellurium Compounds; Klamann, D., Ed.; Thieme: Stuttgart,
1990; Vol. E 12b.
(17) Engman, L.; Andersson, C.; Morgenstern, R.; Cotgreave, I. A.;
Andersson, C- M.; Hallberg, A. Tetrahedron 1994, 50, 2929-2938.

Novel Water-Soluble Diorganyl Tellurides
J . Org. Chem., Vol. 64, No. 22, 1999 8163
propanesultone (3).27 Unlike the corresponding γ-lactone,
conditions, a separable 7/1 mixture of compounds 6a and
6b was isolated in 56% yield. Sulfopropylation of com-
which behaves as an acylating agent in the reactions with
nucleophilic agents, 1,3-propanesultone undergoes alkyl-O
bond cleavage and behaves as a sulfoalkylating agent.
In this way, a variety of compounds, including dyes,28
lipids,29 surfactants,27,30 nucleosides,31 and proteins,32
were functionalized.
P r ep a r a tion of Wa ter -Solu ble Or ga n otellu r iu m
Com p ou n d s. Bis(4-hydroxyphenyl) telluride (4) (eq 1)
is a readily available diaryl telluride with excellent
antioxidative properties. To make it water-soluble, we
pound 6a , employing sodium hydroxide as the base,
proceeded in excellent yield (98%) under the above
conditions to give telluride 7. Unfortunately, successful
hydrolysis of the THP ether under a variety of acidic
conditions was always accompanied by decomposition/
precipitation of elemental tellurium.
Ring opening of 1,3-propanesultone with highly nu-
cleophilic arenetellurolate ion was considered for the
preparation of water-soluble aryl alkyl tellurides. A
variety of lithium arenetellurolates are readily available
by insertion of elemental tellurium into the carbon-
lithium bond of aryllithiums. The former are easily
prepared from aryl bromides by lithium bromine ex-
change, employing 2 equiv of tert-butyllithium. Although
in situ generated lithium arenetellurolates formed in this
way in tetrahydrofuran were found to readily ring open
1,3-propanesultone, the poor crystallinity and propensity
to hydrate formation of the resulting alkanesulfonic acid
lithium salts made purification practically impossible. As
observed already with the different bis-(propanesulfonate)
salts 5, the lithium salt is more difficult to purify than
the sodium, potassium, and tetramethylammonium salts.
Therefore, arenetellurolate sodium salts were prepared
in ethanol by sodium borohydride reduction of the cor-
responding diaryl ditellurides (eq 2). Addition of pro-
tried to attach sulfopropyl groups to one or both of the
phenolic oxygens. Treatment of telluride 4 with 1 equiv
of base (LiOH, NaOH, or KOH) in 2-propanol or tert-butyl
alcohol at 80 °C, followed by addition of a stoichiometric
amount of propanesultone and continued heating, caused
the precipitation of a mixture of mono- and bis-O-
sulfopropylated telluride. Repeated recrystallization of
this material failed to give a pure product. By increasing
the amount of propanesultone and changing the solvent
to aqueous tert-butyl alcohol, an 86% yield of essentially
pure dilithium salt 5a was isolated. Disodium salt 5b,
dipotassium salt 5c,and bis(tetramethylammonium) salt
5d were similarly isolated in 58%, 40%, and 49% yields,
respectively. Attempts were also made to introduce
sulfopropyl groups into bis(4-aminophenyl) telluride.
However, under conditions similar to those used above,
a dark red solid precipitate, insoluble in polar and
nonpolar solvents, was formed.
In another attempt to mono-O-sulfopropylate telluride
4, one of the phenolic groups was protected as a THP
ether. Heating of telluride 4 with dihydropyran in me-
thylene chloride in the presence of a catalytic amount of
p-toluenesulfonic acid resulted in the formation of mix-
tures of mono- and dialkylated materials. Under the best
panesultone and heating at 60 °C caused precipitation
of the analytically pure aryl alkyl tellurides 8 in yields
ranging from 68% to 94% (eq 2). Attempts to remove the
THP protective group of compound 8d under various
acidic conditions failed to produce the desired phenolic
compound. Again, decomposition and precipitation of
elemental tellurium was observed. The chemistry de-
scribed in eq 2 could also be extended to the preparation
of aryl alkyl selenides. Thus, reduction of diphenyl
diselenide with sodium borohydride in ethanol, followed
by addition of 1,3-propanesultone, afforded the analyti-
cally pure alkanesulfonic acid sodium salt 9 in 94%
(27) A radical-based method, avoiding handling of the carcinogenic
propanesultone, has also been used for the introduction of the
sulfopropyl group. Ikenoue, Y.; Saida, Y.; Kira, M.; Tomozawa, H.;
Yashima, H.; Kobayashi, M. J . Chem. Soc., Chem. Commun. 1990,
1694-1695. Schmitt, K. D. J . Org. Chem. 1995, 60, 5474-5479.
(28) Flanagan, J . H., J r.; Khan, S. H.; Menchen, S.; Soper, S. A.;
Hammer, R. P. Bioconjugate Chem. 1997, 8, 751-756. Adamczyk, M.;
Chen, Y.-Y.; Mattingly, P. G.; Pan, Y.; Rege, S. J . Org. Chem. 1998,
63, 5636-5639.
(29) Suga, K.; Miyashige, T.; Takada, K.; Watanabe, S.; Moriyama,
M. Aust. J . Chem. 1968, 21, 2333-2339.
(30) Gautun, O. R.; Carlsen, P. H. J .; Maldal, T.; Vikane, O.; Gilje,
E. Acta Chem. Scand. 1996, 50, 170-177.
(31) Carrea, G.; Ottolina, G.; Riva, S.; Danieli, B.; Lesma, G.;
Palmisano, G. Helv. Chim. Acta 1988, 71, 762-772.
isolated yield. Attempts were also made to prepare water-
soluble dialkyl tellurides. Readily available di-n-butyl
ditelluride gave, after sodium borohydride reduction in
(32) Ru¨egg, U. T.; Rudinger, J . Int. J . Protein Res. 1974, 6, 447-
456. Ru¨egg, U. T.; Rudinger, J . Methods Enzymol. 1977, 47, 116-122.

8164 J . Org. Chem., Vol. 64, No. 22, 1999
Kanda et al.
ethanol and addition of 1,3-propanesultone, an 84% yield
of the crystalline sodium salt of 4-telluraoctanesulfonic
acid (10).
assay, thiols are oxidized to the corresponding disulfides
in CD3OD/D2O in the presence of hydrogen peroxide and
the catalyst (0.3 mol %) to be evaluated. Catalyst ef-
ficiency was conveniently expressed as t50 values, the
time required to reduce the thiol concentration by 50%.
In this work, the novel organotellurium compounds were
assessed for their ability to catalyze hydrogen peroxide
oxidation of N-acetyl cysteine in unbuffered D2O (eq 4).
The presence of ammonium groups is known to confer
water solubility to organic compounds. In an effort to
make diaryl tellurides carrying this functional group,
THP-protected diaryltelluride 6a was treated with Es-
chenmoser’s salt [N,N-dimethylmethyleneammonium io-
dide (11)]. This compound is known to introduce dime-
thylaminomethyl groups into various phenolic com-
pounds.33 Prolonged heating of telluride 6a with Eschen-
moser’s reagent in methylene chloride containing potas-
sium carbonate, introduced a dimethylaminomethyl group
ortho to the phenolic hydroxyl group (30% yield). Sub-
sequent treatment of the oily telluride with an ether
solution of HCl caused separation of the corresponding
ammonium chloride 12.
(4)
To be able to conveniently monitor the progress of
reaction by 1H NMR spectroscopy, the amount of catalyst
was reduced to 0.01 mol %. The results are shown in
Table 1. Again, many of the tested compounds turned
out to be more active than any of the previously tested
diorganyl tellurides in this model.23 Thus, catalysts 5,
8a -e, and 12 all showed t50 values shorter than that of
compound 4, the previously most active compund in this
system.
The stable radical 1,1-diphenyl-2-picrylhydrazyl, DPPH
(13), has been previously used for assessment of antioxi-
dant capacity.35,36 This densely colored radical is reduced
by hydrogen atom/electron donors to a weakly absorbing
hydrazine (eq 5). Thus, its interaction with reducing
The solubility in water was determined for some of the
newly prepared compounds. The solubility of compound
7, the least soluble material, was 0.016 M at 20 °C. Some
other compounds were significantly more soluble in
water: compounds 5c, 8a , and 10 showed solubilities
exceeding 0.031, 0.14, and 1.3 M, respectively.
Th iol P er oxid a se Activity. Thiol peroxidase activity
can be assessed by several means.34 The direct methods
rely on monitoring the consumption of thiol or hydrogen
peroxide with time in the presence of a catalyst. Glu-
tathione peroxidase activity may also be indirectly as-
sessed by performing the reaction in the presence of
glutathione reductase and NADPH (eq 3). The progress
agents is conveniently monitored by spectrophotometry.
In the present study, t1/2, the half-life of the 517 nm
absorption of DPPH, was recorded in the presence of 0.5
molar equiv of the novel water-soluble organotellurium
compounds. As indicated by the short t1/2 values in Table
1, most of the water-soluble organotelluriums acted as
scavengers of DPPH. The nonphenolic alkyl aryl telluride
8d (t1/2 ) 4.5 min) and phenolic diaryl telluride 12 (t1/2
)
5.5 min) were the most efficient quenchers. These com-
pounds were significantly more reactive than the bisphe-
nolic diaryl telluride 4 (t1/2 ) 14 min), suggesting that a
phenolic group is not essential for quenching. However,
none of the compounds tested could match the activity
of vitamin E (t1/2 ) 0.5 min).
of reaction may then be conveniently followed spectro-
photometrically by observing the fall in absorbance at
340 nm (NADPH). Poor catalyst water solubilty has
previously been a problem in this coupled reductase
assay. Usually, substantial amounts of dimethyl sulfoxide
were added to the buffered aqueous medium to obtain a
homogeneous system. The novel water-soluble organo-
tellurium compounds prepared in this work could be
evaluated in an aqueous phosphate buffer at physiologi-
cal pH (7.4). The results are shown in Table 1. Catalyst
activity (% catalysis) was determined as the initial rate
increase (as compared with the uncatalyzed process) in
the reaction between GSH and hydrogen peroxide. Some
of the catalysts tested (compounds 8b-d and 10) turned
out to be more active than any of the previously tested
diorganyl tellurides in this system.22
Discu ssion
1,3-Propanesultone is known to be ring-opened by a
variety of heteroatom nucleophiles. It is therefore not
surprising that bisphenolic diaryl telluride 4 and highly
nucleophilic arene- and alkanetellurolates and seleno-
lates are readily alkylated by this substance. Purification
of water-soluble sulfopropylated products is troublesome.
Often, one has to rely on reversed-phase preparative
HPLC or ion-exchange chromatography/lyophilization to
obtains products of sufficient purity. Fortunately, bis-O-
1
Some time ago, we introduced a H NMR method for
(35) Blois, M. S. Nature 1958, 181, 1199-1200. Noguchi, N.;
Yoshida, Y.; Kaneda, H.; Yamamoto, Y.; Niki, E. Biochem. Pharmacol.
1992, 44, 39-44. Fraisse, L.; Verlhac, J .-B.; Roche, B.; Rascle, M. C.;
Rabion, A.; Seris, J .-L.; J . Med. Chem. 1993, 36, 1465-1473. Valgimigli,
L.; Banks, J . T.; Ingold, K. U.; Lusztyk, J . J . Am. Chem. Soc. 1995,
117, 9966-9971.
the assessment of thiol peroxidase activity.21,23 In this
(33) Pochini, A.; Puglia, G.; Ungaro, R. Synthesis 1983, 906-907.
Tramontini, M. Synthesis 1973, 703-775.
(34) Cotgreave, I. A.; Molde´us, P.; Brattsand, R.; Hallberg, A.;
Andersson, C.-M.; Engman, L. Biochem. Pharmacol. 1992, 43, 793-
802.
(36) Engman, L.; Persson, J .; Vessman, K.; Ekstro¨m, M.; Berglund,
M.; Andersson, C-M. Free Radical Biol. Med. 1995, 19, 441-452.

Novel Water-Soluble Diorganyl Tellurides
J . Org. Chem., Vol. 64, No. 22, 1999 8165
Ta ble 1. Glu ta th ion e P er oxid a se, Th iol P er oxid a se, a n d An tioxid a n t Activity of Wa ter -Solu ble Or ga n otellu r iu m
Com p ou n d s
alkylated compounds 5 were found to crystallize as
formed when the reaction was performed in aqueous tert-
butyl alcohol containing excess 1,3-propanesultone and
an alkali metal or tetramethylammonium hydroxide. In
stoichiometric reactions, mono-O-sulfopropylated prod-
ucts could not be freed from bis-alkylated material. The
purification of sodium propanesulfonates 8 was also very
simple as the materials crystallized as formed when
sodium arene- and alkanetellurolates and -selenolates
were treated with 1,3-propanesultone in ethanol. Con-
sidering the ready availability of aliphatic and aromatic
ditellurides and diselenides, this reaction would be useful
for the preparation of a variety of water-soluble alkyl aryl
tellurides and selenides.
telluride 4 (1400% catalysis) causes only a modest
increase in glutathione peroxidase-like activity (1325-
1696%). Also, the effect of the sulfonate counterion (Li,
Na, K, and Me4N) is minimal. Because hydroxy and
alkoxy groups have similar electron-donating capacities
and the sulfopropyl groups are well separated from the
phenolic oxygen, the electron density at tellurium is not
expected to vary much among compounds 4 and 5. Little
mechanistic information is available concerning the
oxidation and reduction steps of the catalytic cycle shown
in Scheme 1. However, it seems reasonable to assume
that oxidation involves nucleophilic attack of tellurium
on hydrogen peroxide. The observed catalytic activity of
sulfonate 7 (1325%) and ammonium compound 12 (1721%)
are also in accord with the above analysis. Essentially,
the different kinds of derivatization of compound 4 confer
water solubility but retain glutathione peroxidase-like
activity. J udging from the activities of compounds 8a -
d , alkyl aryl tellurides are intrinsicly better catalysts
Because glutathione is used as the stoichiometric
reducing agent and the assay can be performed at pH
7.4, the coupled reductase method for assessment of thiol
peroxidase activity mimics physiological conditions well.
As seen from Table 1, bis-O-sulfopropylation of diaryl

8166 J . Org. Chem., Vol. 64, No. 22, 1999
Kanda et al.
than diaryl tellurides. This could be due to less steric
hindrance around the heteroatom. Also, there is a
tendency that electron-releasing para-substituents in the
aryl moiety (OMe, OTHP, and NMe2) enhance activity,
whereas electron-withdrawing ones reduce it (CF3). Steric
hindrance in the aryl also causes a reduction in catalytic
activity (compound 8f). It is notewothy that catalyst 8h ,
containing a 3-thienyl group bonded to tellurium, is
significantly better than the 2-thienyl analogue 8g.
Maybe the sulfur lone pair is excerting some repulsive
action toward hydrogen peroxide if positioned too close
to the tellurium. The corresponding symmetrical diaryl
telluride, bis(2-thienyl) telluride, has previously been
found to possess low catalytic activity.23 Compound 9, the
selenium analogue of compound 8a , turned out to be
inactive as a catalyst. Probably, its reaction with hydro-
gen peroxide is too slow for it to act in a catalytic fashion
analogously to what is shown in Scheme 1. The water-
soluble dialkyl telluride 10 turned out to be by far the
most active catalyst in the coupled reductase system. This
could again be due to steric factors.
The thiol peroxidase activity of the new compounds was
also assessed by 1H NMR monitoring of N-acetylcysteine
consumption in D2O in the presence of hydrogen peroxide
(Table 1). Although the thiol peroxidase capacities of the
water-soluble catalysts were superior to those of the
lipophilic diorganyl ditellurides21 and diorganyl tel-
lurides23 previously tested, their relative activity could
not be easily rationalized. As expected, selenide 8 was
inactive. However, the bis-O-sulfopropylated sodium,
potassium, and tetramethylammonium compounds 5b-d
were significantly more active than the closely related
lithium salt 5a . Also, it is notable that dialkyl telluride
10 is one of the poorest performing compounds in this
assay. Among aryl alkyl tellurides 8, there appears to
be no clear-cut substituent and steric dependence on
activity. In fact, similar difficulties in rationalizing
relative catalyst efficiencies in this system were previ-
ously encountered.23 At this point, it seems premature
to do extensive speculation as to the reasons for the
inconsistency between the results obtained from the
coupled reductase assay and the 1H NMR method. Suffice
to say that the thiols are different, the pH is different
(7.4 as compared to ca. 2), and different steps in the
proposed catalytic cycle (Scheme 1) could be rate-
determining.
Chain-breaking, donating antioxidants act by donating
a hydrogen atom or an electron to peroxyl radicals, thus
eliminating these species from the catalytic cycle respon-
sible for autoxidation. Thus, the ability of antioxidants
to reduce the stable radical DPPH could serve as a simple
measure of their chain-breaking antioxidant capacity.
Because bis-O-alkylated derivatives of phenolic com-
pound 4 (compounds 5 and 7) show essentially the same
activity as the parent compound, quenching seems to
occur primarily by electron transfer. The poor quenching
ability of electron-deficient compound 8e and sterically
hindered compound 8f emphasize the importance of
electronic and steric factors. With some exceptions, the
glutathione peroxidase-like activity as assessed by the
coupled reductase assay parallells the antioxidant activ-
ity as determined by the capacity to quench DPPH. The
absorbance/time traces recorded for determination of t1/2
values not only reflect the kinetics of the reaction but
also give a hint as to the value of the stoichimetric factor
n, the number of radicals that each antioxidant molecule
can quench. Vitamin E is known to quench two molecules
of DPPH. Because the same final absoption was arrived
at (although more slowly) using diorganyl tellurides as
quenchers, we conclude that the value of n for tellurides
is also two. Probably, the organotellurium compounds are
oxidized to the corresponding tellurium(IV)-dimethoxides
in the reaction.
In conclusion, we have prepared a series of novel water-
soluble diorganyl tellurides with potent peroxide decom-
posing and antioxidant properties. We are presently
evaluating the protective/antioxidative properties of our
materials in biological systems37 and their stabilizing
capacity in various types of synthetic and man-made
polymeric materials.38
Exp er im en ta l Section
Melting points are uncorrected. 1H and 13C NMR spectra
were recorded at 300 and 75 MHz, respectively, using CDCl3,
CD3OD, or D2O as an internal reference. Tetrahydrofuran and
diethyl ether were refluxed over sodium turnings under
nitrogen atmosphere and then distilled prior to use. Dichlo-
romethane was refluxed over CaH2 under nitrogen atmosphere
and then distilled prior to use. HPLC-grade methanol, ethanol,
2-propanol, and 2-methylpropane-2-ol were used without
further purification. Diphenyl ditelluride,39 bis(4-methoxyphe-
nyl) ditelluride,39 bis[4-(dimethylamino)phenyl] ditelluride,39
bis(4-trifluoromethylphenyl) ditelluride,39 bis(2-thienyl) ditel-
luride,40 bis(3-thienyl) ditelluride,41 di-n-butyl ditelluride,42 and
4-(2-tetrahydropyranyloxy)phenyl bromide43 were synthesized
according to literature methods. Unless otherwise specified,
all reactions were performed under an atmosphere of dry
nitrogen. Elemental analyses were performed by Analytical
Laboratories, Lindlar, Germany. Reduced glutathione, glu-
tathione reductase (grade 1 from yeast), and NADPH were
obtained from Sigma. Ca u tion : propanesultone is a carcino-
gen. It should be handled in a well-ventilated hood, and any
contact with it should be avoided.44
Bis(2,6-d im eth ylp h en yl) Ditellu r id e. To a solution of 2,6-
dimethylbromobenzene (3.0 g, 16.2 mmol) in tetrahydrofuran
(45 mL) was added tert-butyllithium (19.1 mL 1.7 M; 32.5
mmol) in pentane at -78 °C. After 1 h, the cooling bath was
removed, and finely ground elemental tellurium (2.07 g, 16.2
mmol) was added. When only traces of tellurium remained (ca.
0.5 h), the mixture was poured into a separatory funnel
containing K3Fe(CN)6 (5.35 g, 16.2 mmol) in water. The
ditelluride formed was extracted into methylene chloride.
Drying and evaporation of solvent afforded a crude product,
which was recrystallized from ethanol to give 3.05 g (80%) of
the title compound as reddish orange needles, mp 151-153
°C: 1H NMR (CDCl3, 300 MHz) δ 2.38 (s, 6 H), 7.01-7.09
(several peaks, 3 H); 13C NMR (CDCl3) δ 30.2, 115.8, 125.9,
129.5, 146.2. Anal. Calcd for C16H18Te2: C, 41.28; H, 3.91.
Found: C, 41.11; H, 3.78.
Bis[4-(2-tetr a h yd r op yr a n yloxy)p h en yl] Ditellu r id e. To
a solution of 4-(2-tetrahydropyranyloxy)phenyl bromide (1.250
g, 4.9 mmol) in tetrahydrofuran (30 mL) was added tert-
butyllithium (7.6 mL 1.33 M, 10.1 mmol) in pentane at -78
°C. After 30 min, the cooling bath was removed, and finely
(37) Wieslander, E.; Engman, L.; Svensjo¨, E.; Erlansson, M.; J o-
hansson, U.; Linden M.; Andersson, C.-M.; Brattsand, R. Biochem.
Pharmacol. 1998, 55, 573-584.
(38) Malmstro¨m, J .; Engman, L.; Bellander, M.; J acobsson, K.;
Stenberg, B.; Lo¨nnberg, V. J . Appl. Polym. Sci. 1998, 70, 449-556.
(39) Engman, L.; Persson, J . J . Organomet. Chem. 1990, 388, 71-
74.
(40) Engman., L.; Cava, M. P. Organometallics 1982, 1, 470-473.
(41) Dereu, N.; Renson, M. J . Organomet. Chem. 1983, 258, 163-
169.
(42) Engman, L.; Cava, M. P. Synth. Commun. 1982, 12, 163-165.
(43) Parham, W. E.; Anderson, E. L. J . Am. Chem. Soc. 1948, 70,
4187-4189.
(44) Lenga, R. E. The Sigma-Aldrich Library of Chemical Safety
Data, 1st ed.; 1985, p 1541.

Novel Water-Soluble Diorganyl Tellurides
J . Org. Chem., Vol. 64, No. 22, 1999 8167
ground elemental tellurium (0.638 g, 5.0 mmol) was added.
When only traces of tellurium remained (ca. 1 h) the solution
was poured into a separatory funnel containing K3Fe(CN)6
(1.70 g, 5.2 mmol) in water. The ditelluride formed was
extracted into methylene chloride. Drying and evaporation of
solvent afforded an oil, which was subjected to chromato-
graphic purification (CH2Cl2) to afford 0.479 g (32%) of the title
compound as dark red needles, mp 110-111 °C (dec): 1H NMR
(CDCl3) δ 1.55-1.70 (several peaks, 3 H), 1.82-2.02 (several
peaks, 3 H), 3.56-3.62 (several peaks, 1 H), 3.87 (dt, J ) 10.3,
3.0 Hz, 2 H), 5.41 (t, J ) 3.0 Hz, 1 H), 6.88 (d, J ) 8.7 Hz, 2
H), 7.68 (d, J ) 8.7 Hz, 2 H); 13C NMR (CDCl3) δ 18.7, 25.2,
30.3, 62.1, 96.3, 98.6, 117.5, 140.1, 157.7. Anal. Calcd for
dure for compound 5b (tetrabutylammonium hydroxide was
used instead of sodium hydroxide): yield 49%; mp 267-268
°C (dec); 1H NMR (CD3OD) δ 2.13 (quint, J ) 7.0 Hz, 2H),
2.87 (t, J ) 7.0 Hz, 2 H), 3.09 (s, 12 H), 4.00 (t, J ) 7.0 Hz, 2
H)), 6.71 (d, J ) 8.8 Hz, 2 H), 7.50 (d, J ) 8.8 Hz, 2 H); 13C
NMR (CD3OD) δ 26.3, 49.4, 55.8, 67.6, 105.3, 117.0, 140.9,
160.5. Anal. Calcd for C26H44N2O8S2Te ‚ H2O: C, 43.22; H, 6.43.
Found: C, 43.37; H, 6.32.
4-Hyd r oxyp h en yl 4-(2-Tetr a h yd r op yr a n yloxy)p h en yl
Tellu r id e (6a ). Bis(4-hydroxyphenyl) telluride (1.254 g, 4.00
mmol), 3,4-dihydro-2H-pyrane (1.664 g, 1.480 mL, 16.00
mmol), p-TsOH‚H2O (0.022 g, 0.12 mmol), dichloromethane (50
mL), THF (10 mL), and a stirring bar were placed into a two-
necked round-bottom flask equipped with a reflux condenser.
After 16 h of refluxing and workup, involving washing with a
saturated NaHCO3 solution, drying over anhydrous Na2SO4,
and removal of the solvent, chromatographic purification (CH2-
Cl2) of the resulting orange oil first gave 0.135 g (7%) of bis-
[4-(2-tetrahydropyranyloxy)phenyl] telluride (6b) as pale yel-
low needles, mp 59-60 °C: 1H NMR (CDCl3) δ 1.56-2.01
(several peaks, 6 H), 3.54-3.60 (several peaks, 1 H), 3.82-
3.90 (several peaks, 1 H), 5.38 (t, J ) 3.4 Hz, 1 H), 6.89 (d, J
) 8.3 Hz, 2 H), 7.61 (d, J ) 8.3 Hz, 2 H); 13C NMR (CDCl3) δ
18.7, 25.2, 30.3, 62.1, 96.2, 105.4, 117.8, 139.6, 157.2. Anal.
Calcd for C22H26O4Te: C, 54.81; H, 5.45. Found: C, 54.81; H,
5.48. Continued elution gave 0.783 g (49%) of the title
compound as pale yellow needles, mp 100-101 °C: IR (KBr)
3274; 1H NMR (CDCl3) δ 1.54-2.05 (several peaks, 6 H), 3.56-
3.62 (several peaks, 1 H), 3.84-3.92 (several peaks, 1 H), 5.40
(t, J ) 3.4 Hz, 1 H), 5.53 (br s, 1 H), 6.65 (d, J ) 8.6 Hz, 2 H),
6.89 (d, J ) 8.8 Hz, 2 H), 7.57 (d, J ) 8.6 Hz, 2 H), 7.58 (d, J
) 8.8 Hz, 2 H); 13C NMR (CDCl3) δ 18.7, 25.1, 30.2, 62.2, 96.3,
104.0, 105.7, 116.9, 117.8, 139.4, 140.2, 155.8, 157.0. Anal.
Calcd for C17H18O3Te: C, 51.31; H, 4.57. Found: C, 51.50; H,
4.59.
4-(Su lfop r op yloxy)p h en yl 4-(2-Tet r a h yd r op yr a n yl-
oxy)p h en yl Tellu r id e Sod iu m Sa lt (7). 4-Hydroxyphenyl
4-(2-tetrahydropyranyloxy)phenyl telluride (0.576 g, 1.45 mmol),
sodium hydroxide (0.058 g, 1.46 mmol), 2-propanol (20 mL),
water (0.1 mL). and a stirring bar were placed in a two-necked
round-bottom flask (50 mL) and then stirred at 80 °C for 0.5
h. Into this solution was added 1,3-propanesultone (0.185 g,
1.52 mmol). After the mixture was heated at the same
temperature for 4 h, filtration gave 0.652 g (98%) of the title
compound as colorless microfine needles, mp 213-214 °C
(dec): 1H NMR (CD3OD) δ 1.45-1.93 (several peaks, 6 H), 2.14
(quint, J ) 7.0 Hz, 2 H), 2.89 (t, J ) 7.0 Hz, 2 H), 3.46-3.52
(several peaks, 1 H), 3.72-3.80 (several peaks, 1 H), 4.00 (t, J
) 7.0 Hz, 2 H), 5.32 (t, J ) 3.4 Hz, 1 H), 6.72 (d, J ) 8.4 Hz,
2 H), 6.81 (d, J ) 8.4 Hz, 2 H), 7.47 (d, J ) 8.4 Hz, 2 H), 7.52
(d, J ) 8.4 Hz, 2 H); 13C NMR (CD3OD) δ 19.9, 26.3, 26.3, 31.4,
49.1, 63.2, 67.6, 97.6, 105.1, 106.7, 117.0, 118.8, 140.4, 141.1,
158.5, 160.6. Anal. Calcd for C20H23NaO6STe‚H2O: C, 42.88;
H, 4.15. Found: C, 42.52; H, 4.35. Water solubility (20 °C)
0.016 M.
C
22H26O4Te2: C, 43.34; H, 4.31. Found: C, 43.07; H, 4.18.
Bis(4-h yd r oxyp h en yl) Tellu r id e (4). Into a three-necked
round-bottomed flask equipped with a reflux condenser were
placed TeCl4 (27.2 g, 0.1 mol), phenol (25.4 g, 0.14 mol), CCl4
(80 mL), and a stirring bar. After refluxing for 3 h, the
resulting precipitate was filtered and then washed with CH2-
Cl2 (60 mL × 5) until the filtrate was colorless. Drying of the
resulting yellow powder in vacuo for 3 h gave 4-hydroxyphe-
nyltellurium trichloride in a quantitative yield. This material
was dissolved into EtOAc (100 mL) in a three-necked round-
bottom flask equipped with a dropping funnel. Into this
solution was added sodium ascorbate (67 g, 0.33 mol) in water
(116 mL) dropwise at 20 °C during 1 h (the color of the solution
gradually changed to reddish black). The mixture was further
stirred for 6 h, the organic phase was decantated, and the
residual black aqueous phase was washed and extracted with
EtOAc (60 mL × 3). The combined wine-red extracts were then
heated at reflux with freshly prepared copper powder (38 g,
0.6 mol) until the solution had turned pale yellow (6-12 h).
After filtration from black insoluble material (Cu and CuTe),
the solution was passed through Celite (Φ 40 mm × 100 mm),
and the residue was evaporated to give 13.5 g (86%) of the
title compound as an orange solid. The physical and spectro-
scopic properties of the material were identical to those
previously reported by us.45
Typ ica l P r oced u r e. Bis[4-(su lfop r op yloxy)p h en yl] Tel-
lu r id e Disod iu m Sa lt (5b). Bis(4-hydroxyphenyl) telluride
(0.628 g, 2.00 mmol) and sodium hydroxide (0.160 g, 4.00
mmol) were mixed in t-BuOH/H2O (10/1, 17 mL) at 80 °C and
stirred for 30 min. Into this solution was added 1,3-propane-
sultone (0.529 g, 4.50 mmol). After the mixture stirred at 80
°C for 16 h, 0.701 g (58%) of colorless crystals, mp > 300 °C,
of the title compound were filtered off: 1H NMR (D2O) δ 1.91
(quint, J ) 7.0 Hz, 2 H), 2.77 (t, J ) 7.0 Hz, 2 H), 3.72 (t, J )
7.0 Hz, 2 H), 6.49 (d, J ) 8.5 Hz, 2 H), 7.35 (d, J ) 8.5 Hz, 2
H); 13C NMR (D2O) δ 25.9, 49.5, 68.2, 106.6, 117.9, 141.5, 160.1.
Anal. Calcd for C18H20Na2O8S2Te‚H2O: C, 34.86; H, 3.58.
Found: C, 34.99; H, 3.42.
Bis[4-(su lfop r op yloxy)p h en yl] tellu r id e d ilith iu m sa lt
(5a ) was prepared using the procedure for compound 5b
(lithium hydroxide was used instead of sodium hydroxide):
yield 86%; mp > 300 °C; 1H NMR (D2O) δ 1.95 (quint, J ) 7.0
Hz, 2 H), 2.82 (t, J ) 7.0 Hz, 2 H), 3.85 (t, J ) 7.0 Hz, 2 H),
6.59 (d, J ) 8.8 Hz, 2 H), 7.41 (d, J ) 8.8 Hz, 2 H); 13C NMR
(D2O) δ 26.0, 49.6, 68.2, 106.7, 117.8, 141.5, 160.1. Anal. Calcd
for C18H20Li2O8S2Te‚H2O: C, 36.77; H, 3.78. Found: C, 36.88;
H, 3.58.
Bis[4-(su lfop r op yloxy)p h en yl] tellu r id e d ip ota ssiu m
sa lt (5c) was prepared using the procedure for compound 5b
(potassium hydroxide was used instead of sodium hydroxide):
yield 40%; mp > 300 °C; 1H NMR (D2O) δ 1.97 (quint, J ) 7.8
Hz, 2 H), 2.85 (t, J ) 7.8 Hz, 2 H), 3.88 (t, J ) 7.8 Hz, 2 H),
6.62 (d, J ) 8.3 Hz, 2 H), 7.44 (d, J ) 8.3 Hz, 2 H); 13C NMR
(D2O) δ 26.0, 49.6, 68.4, 118.1, 127.3, 141.7, 160.2. Anal. Calcd
for C18H20K2O8S2Te‚0.5H2O: C, 33.60; H, 3.29. Found: C,
33.42; H, 3.05. Water solubility (20 °C) > 0.031 M.
3-(Ben zen etellu r en yl)p r op a n esu lfon ic Acid Sod iu m
Sa lt (8a ). Typ ica l P r oced u r e. Into a suspension of diphenyl
ditelluride (0.819 g, 2.00 mmol) in ethanol (20 mL) in a two-
necked round-bottomed flask equipped with a reflux condensor
was added sodium borohydride (0.200 g, 5.30 mmol) in small
portions at 20 °C. After a further 30 min of stirring under the
same conditions, 1,3-propanesultone (0.513 g, 4.20 mmol, 1.05
equiv) was added. The reaction mixture was then heated to
60 °C and stirred for 0.5 h. After this solution cooled to ambient
temperature, 1.309 g (94%) of milky white crystals, mp 223-
225 °C (dec), of the title compound was filtered off: 1H NMR
(CD3OD) δ 2.15 (quint, J ) 7.8 Hz, 2 H), 2.81 (t, J ) 7.8 Hz,
2
2 H), 2.92 (t, J ) 7.8 Hz, J Te-H ) 29 Hz, 2 H), 7.08-7.21
(several peaks, 3 H), 7.64 (dd, J ) 8.1, 1.5 Hz, 2 H); 13C NMR
(CD3OD) δ 7.3 (1J C-Te ) 145 Hz), 28.5, 54.3, 112.5, 128.6, 130.2,
139.4. Anal. Calcd for C9H11NaO3STe: C, 30.90; H, 3.18.
Found: C, 30.89; H, 3.09. Water solubility (20 °C) > 0.143 M.
3-(4-Met h oxyben zen et ellu r en yl)p r op a n su lfon ic a cid
sod iu m sa lt (8b) was prepared according to the procedure
for compound 8a [bis(4-methoxyphenyl) ditelluride was used
Bis[4-(su lfop r op yloxy)p h en yl] tellu r id e bis(tetr a m -
eth yla m m on iu m ) sa lt (5d ) was prepared using the proce-
(45) Engman, L.; Persson, J .; Andersson, C.-M.; Berglund, M. J .
Chem. Soc., Perkin Trans. 2 1992, 1309-1313.

8168 J . Org. Chem., Vol. 64, No. 22, 1999
Kanda et al.
instead of diphenyl telluride]: yield 1.401 g (92%) of milky
white crystals; mp 222-223 °C (dec); 1H NMR (CD3OD) δ 2.09
(quint, J ) 7.6 Hz, 2 H), 2.79 (t, J ) 7.6 Hz, 2 H), 2.82 (t, J )
7.6 Hz, 2J Te-H ) 28 Hz, 2 H), 3.68 (s, 3 H), 6.69 (d, J ) 9.7 Hz,
2 H), 7.59 (d, J ) 9.7 Hz, 2 H); 13C NMR (CD3OD) δ 7.6 (1J C-Te
) 145 Hz), 28.4, 54.3, 55.6, 101.2, 116.2, 142.2, 161.4. Anal.
Calcd for C10H13NaO4STe: C, 31.51; H, 3.36. Found: C, 31.61;
H, 3.46.
(diphenyl diselenide was used instead of diphenyl telluride):
yield 94% of a slightly bluish white powder; mp > 250 °C (dec);
1H NMR (CD3OD) δ 2.06 (quint, J ) 7.5 Hz, 2 H), 2.84 (t, J )
2
7.5 Hz, 2 H), 2.96 (t, J ) 7.5 Hz, J Se-H ) 24 Hz, 2 H), 7.13-
7.21 (several peaks, 3 H), 7.43 (d, J ) 8.1 Hz, 2 H); 13C NMR
(CD3OD/D2O 1/1) δ 26.5 (1J C-Se ) 194 Hz), 27.0, 52.0, 128.0,
130.2, 133.5, 158.2. Anal. Calcd for C9H11NaO3SSe: C, 35.88;
H, 3.69. Found: C, 35.79; H, 3.62.
3-[4-(N ,N -D im e t h y la m in o )b e n ze n e t e llu r e n y l]p r o -
p a n su lfon ic a cid sod iu m sa lt (8c) was prepared according
to the procedure for compound 8a [bis(4-(N,N-dimethylamino)-
phenyl) ditelluride was used instead of diphenyl telluride]:
3-(n -Bu ta n etellu r en yl)p r op a n esu lfon ic a cid sod iu m
sa lt (10) was prepared according to the procedure for com-
pound 8a (di-n-butyl ditelluride was used instead of diphenyl
telluride): yield 84% of white crystals; mp 199-200 °C (dec);
1H NMR (CD3OD) δ 0.85 (t, J ) 7.5 Hz, 3 H), 1.33 (sext, J )
7.5 Hz, 2 H), 1.65 (quint, J ) 7.5 Hz, 2 H), 2.10 (quint, J ) 7.5
1
yield 89% of milky white crystals; mp 206-207 °C (dec); H
NMR (CD3OD) δ 2.09 (quint, J ) 7.5 Hz, 2 H), 2.75 (t, J ) 7.5
2
2
Hz, J Te-H ) 29 Hz, 2 H), 2.80 (t, J ) 7.5 Hz, 2 H), 2.82 (s,
Hz, 2 H), 2.60 (t, J ) 7.5 Hz, J Te-H ) 24 Hz, 2 H), 2.67 (t, J
6H), 6.53 (d, J ) 8.7 Hz, 2 H), 7.52 (d, J ) 8.7 Hz, 2 H); 13C
NMR (CD3OD) δ 7.4 (1J C-Te ) 154 Hz), 28.3, 40.5, 54.4, 95.9,
114.8, 142.3, 152.0. Anal. Calcd for C11H16NNaO3STe: C,
33.62; H, 4.11. Found: C, 33.46; H, 4.02.
) 7.5 Hz, J Te-H ) 25 Hz, 2 H), 2.81 (t, J ) 7.5 Hz, 2 H). 13C
2
NMR (CD3OD) δ 1.0 (1J C-Te ) 131 Hz), 2.6 (1J C-Te ) 149 Hz),
13.8, 26.1, 28.9, 35.6, 54.5. Anal. Calcd for C7H15NaO3STe: C,
25.49; H, 4.59. Found: C, 25.37; H, 4.58. Water solubility (20
°C) >1.3 M.
3-[4-(2-Te t r a h yd r op yr a n yloxy)b e n ze n e t e llu r e n yl]-
p r op a n esu lfon ic a cid sod iu m sa lt (8d ) was prepared ac-
cording to the procedure for compound 8a [bis(4-(2-tetrahy-
dropyranyloxy)phenyl) ditelluride was used instead of diphenyl
telluride]: yield 74% of white crystals; mp 206-207 °C (dec);
1H NMR (CD3OD) δ 1.48-1.95 (several peaks, 6 H), 2.11
(quint, J ) 7.5 Hz, 2 H), 2.80 (t, J ) 7.5 Hz, 2 H), 2.84 (t, J )
4-(2-Tetr a h yd r op yr a n yloxy)p h en yl 3-(Dim eth yla m i-
n om eth yl)-4-h yd r oxyp h en yl Tellu r id e Hyd r och lor id e
(12). 4-Hydroxyphenyl 4-(2-tetrahydropyranyloxy)phenyl tel-
luride (0.528 g, 1.33 mmol), N,N-dimethylmethyleneammo-
nium iodide (0.258 g, 1.40 mmol), anhydrous potassium
carbonate (0.276 g, 2.00 mmol), dichloromethane (20 mL), and
a stirring bar were heated at reflux for 16 h. After the mixture
was washed with a saturated NaHCO3 solution and dried over
anhydrous Na2SO4, removal of the solvent and chromato-
graphic purification of the resulting oil, eluting with Et2O and
then MeOH, gave 0.186 g (30%) of 4-(2-tetrahydropyranyloxy)-
phenyl 3-(dimethylaminomethyl)-4-hydroxyphenyl telluride as
a colorless oil: 1H NMR (CDCl3) δ 1.55-1.75 (several peaks,
3 H), 1.80-2.08 (several peaks, 3 H), 2.27 (s, 6 H), 3.53-3.63
(several peaks, 3 H), 3.86 (td, J ) 10.3, 3.0 Hz, 1 H), 5.38 (t,
J ) 3.0 Hz, 1 H), 6.68 (d, J ) 8.0 Hz, 1 H), 6.89 (d, J ) 8.8 Hz,
2 H), 7.37 (m, 1 H), 7.53 (d, J ) 8.0 Hz, 1 H), 7.56 (d, J ) 8.8
Hz, 2 H); 13C NMR (CDCl3) δ 18.7, 25.1, 30.3, 44.5, 62.1, 62.4,
96.2, 101.6, 105.8, 117.5, 117.7, 123.4, 138.9, 139.0, 139.7,
157.0, 158.6. 4-(2-Tetrahydropyranyloxy)phenyl 3-(dimethy-
laminomethyl)-4-hydroxyphenyl telluride (0.133 g, 0.286 mmol),
an ether solution of HCl (1.0 M, 0.30 mL, 0.300 mmol), and
ether (40 mL) were stirred at 20 °C for 16 h. Drying of the
resulting precipitate in vacuo at 80 °C gave 0.145 g (quantita-
tive yield) of the pure title compound as colorless microfine
2
7.5 Hz, J Te-H ) 29 Hz, 2 H), 3.50 (dt, J ) 11.5, 5.0 Hz, 1 H),
3.77 (ddd, J ) 11.5, 8.7, 3.1 Hz, 1 H), 5.33 (t, J ) 3.1 Hz, 1 H),
6.81 (d, J ) 8.6 Hz, 2 H), 7.58 (d, J ) 8.6 Hz, 2 H); 13C NMR
(CD3OD) δ 7.6 (1J C-Te ) 145 Hz), 19.9, 26.3, 28.4, 31.4, 54.3,
63.2, 97.6, 102.6, 118.7, 141.9, 158.7. Anal. Calcd for C14H19
-
NaO5STe‚0.5H2O: C, 36.63; H, 4.40. Found: C, 36.71; H, 4.12.
3-(4-T r iflu o r o m e t h y lb e n ze n e t e llu r e n y l)p r o p a n e -
su lfon ic a cid sod iu m sa lt (8e) was prepared according to
the procedure for compound 8a [bis(4-trifluoromethyl)phenyl)
ditelluride was used instead of diphenyl telluride]: yield 69%;
mp 219-224 °C (dec); 1H NMR (CD3OD) δ 2.20 (quint, J )
7.5 Hz, 2 H), 2.84 (t, J ) 7.5 Hz, 2 H), 3.04 (t, J ) 7.5 Hz,
2J Te-H ) 30 Hz, 2 H), 7.38 (d, J ) 8.4 Hz, 2 H), 7.78 (d, J ) 8.4
Hz, 2 H); 13C NMR (CD3OD) δ 7.7 (1J C-Te ) 154 Hz), 28.6, 40.5,
54.2, 119.4, 125.8 (1J C-F ) 269 Hz), 126.6 (3J C-F ) 4 Hz), 130.3
(2J C-F ) 32 Hz), 138.5. Anal. Calcd for C10H10F3NaO3STe: C,
28.74; H, 2.42. Found: C, 28.70; H, 2.28.
3-(2,6-Dim eth ylben zen etellu r en yl)pr opan esu lfon ic acid
sod iu m sa lt (8f) was prepared according to the procedure for
compound 8a [bis(2,6-dimethylphenyl) ditelluride was used
instead of diphenyl telluride]: yield 94% of of white crystals;
mp 182-185 °C (dec); 1H NMR (CD3OD) δ 2.01 (quint, J )
1
crystals: mp 77-79 °C (dec); IR (KBr) 3379; H NMR (CD3-
OD) δ 1.45-1.95 (several peaks, 6 H), 2.72 (s, 6 H), 3.45 (dt,
J ) 10.3, 3.0 Hz, 1 H), 3.73 (td, J ) 10.5, 3.0 Hz, 1 H), 5.31 (t,
J ) 3.0 Hz, 1 H), 6.73 (d, J ) 8.3 Hz, 1 H), 6.81 (d, J ) 8.7 Hz,
2 H), 7.51 (d, J ) 8.7 Hz, 2 H), 7.56-7.62 (several peaks, 2
H); 13C NMR (CD3OD) δ 19.9, 26.3, 31.4, 43.2, 57.8, 63.2, 97.6,
104.4, 117.4, 117.8, 118.9, 119.3, 140.8, 143.4, 143.6, 158.0,
158.7. Anal. Calcd for C20H26ClNO3Te‚H2O: C, 47.14; H, 5.55.
Found: C, 46.92; H, 5.40.
7.5 Hz, 2 H), 2.68-2.80 (several peaks, 4 H), 7.01 (s, 3 H); 13
C
NMR (CD3OD) δ 6.7 (1J C-Te ) 165 Hz), 28.7, 30.4, 54.8, 120.4,
127.2, 130.0, 146.5. Anal. Calcd for C11H15NaO3STe ‚ H2O: C,
33.37; H, 4.34. Found: C, 33.56; H, 4.15.
3-(2-Th iop h en et ellu r en yl)p r op a n esu lfon ic a cid so-
d iu m sa lt (8g) was prepared according to the procedure for
compound 8a [bis(2-thienyl) ditelluride was used instead of
diphenyl telluride]: yield 68% of milky white crystals; mp
173-175 °C (dec); 1H NMR (CD3OD) δ 2.12 (quint, J ) 7.5
Wa ter Solu bility. A weighed amount (ca. 0.090 g) of the
compound was stirred in a beaker at 20 °C, and water was
added by syringe in 0.5 mL portions until all of the crystals
had completely dissolved.
2
Hz, 2 H), 2.78 (t, J ) 7.5 Hz, J Te-H ) 34 Hz, 2 H), 2.80 (t, J
) 7.5 Hz, 2 H), 6.85 (dd, J ) 5.1, 3.6 Hz, 1 H), 7.30 (dd, J )
3.6, 1.2 Hz, 1 H), 7.42 (dd, J ) 5.1, 1.2 Hz, 1 H); 13C NMR
(CD3OD) δ 10.5 (1J C-Te ) 154 Hz), 28.2, 54.0, 98.4, 129.9, 135.4,
142.7. Anal. Calcd for C7H9NaO3S2Te: C, 23.62; H, 2.55.
Found: C, 23.43; H, 2.47.
Cou p led Red u cta se Assa y. The glutathione peroxidase-
like activity of the compounds under study was assessed by
their ability to catalyze the reaction between hydrogen per-
oxide and glutathione in an aqueous buffer at physiological
pH. The oxidation of GSH to GSSG was measured indirectly
by spectrophotometrically assessing the stimulated oxidation
of NADPH in the presence of glutathione reductase. Incuba-
tions were conducted at room temperature in an Aminco
Bowman Model 940 scanning double beam spectrophotometer
recording at 340 nm with air as a reference. They were
constructed in the following manner. Incubations in quartz
cuvettes were with 50 mM potassium phosphate buffer pH 7.4
(1 mL). Additions and measurements were made in the order
(all final concentrations): NADPH (250 µM), GSH (1 mM), test
substance (50 µM), record baseline, GSSG reductase (1 unit),
record, hydrogen peroxide (1 mM), record the decline in
absorbance. Rate assessments were performed when the
3-(3-Th iop h en et ellu r en yl)p r op a n esu lfon ic a cid so-
d iu m sa lt (8h ) was prepared according to the procedure for
compound 8a [bis(3-thienyl) ditelluride was used instead of
diphenyl telluride]: yield 84% of milky white crystals; mp
218-220 °C (dec); 1H NMR (CD3OD) δ 2.11 (quint, J ) 7.5
2
Hz, 2 H), 2.80 (t, J ) 7.5 Hz, J Te-H ) 30 Hz, 2 H), 2.81 (t, J
) 7.5 Hz, 2 H), 7.15 (dd, J ) 4.8, 1.0 Hz, 1 H), 7.27 (dd, J )
4.8, 3.0 Hz, 1 H), 7.51 (dd, J ) 3.0, 1.0 Hz, 1 H); 13C NMR
(CD3OD) δ 7.7 (1J C-Te ) 148 Hz), 28.5, 54.2, 102.3, 127.8, 134.5,
138.0. Anal. Calcd for C7H9NaO3S2Te: C, 23.62; H, 2.55.
3-(Ben zen eselen en yl)pr opan esu lfon ic acid sodiu m salt
(9) was prepared according to the procedure for compound 8a

Novel Water-Soluble Diorganyl Tellurides
J . Org. Chem., Vol. 64, No. 22, 1999 8169
decline in absorbance was constant for at least 20 s. The
consumption of NADPH in the absence of test substance
(control) was 28.0 ( 2 (n ) 6) µM NADPH/min. In the
catalyzed reactions, the following NADPH consumptions were
recorded: compound no. [NADPH consumption (µM/min ( SD,
n ) 3], 5a [450 ( 21], 5b [475 ( 13), 5c [389 ( 20], 5d [449 (
22], 7 [371 ( 25], 8a [552 ( 39], 8b [986 ( 52], 8c [840 ( 29],
8d [793 ( 53], 8e [317 ( 24], 8f [116 ( 10], 8g [288 ( 11], 8h
[589 ( 38], 9 [31 ( 2], 10 [2086 ( 85], 12 [482 ( 30]. Control
experiments revealed that the observed catalytic action of the
compounds was not influenced by increasing amounts of GSSG
reductase (0.5, 1.0, and 2.0 units) in the incubation. Controls
also showed that none of the compounds directly interacted
with the reduction of GSSG (250 and 500 µM) by the reductase.
Th iol P er oxid a se Activity. To a solution of N-acetylcys-
teine (0.050 g, 0.31 mmol) and hydrogen peroxide (30%, 15.7
µL, 0.15 mmol) in D2O (0.5900 mL) in an NMR tube (Φ 5 mm)
was added an aqueous solution of the catalyst (10 µL 3.00 mM;
0.00003 mmol, 0.01 mol % based on thiol), and the 1H NMR
spectrum of the solution was recorded at intervals during ca.
1 h at 21 ( 0.5 °C. The conversion of thiol to disulfide [as
determined by integration of the N-acetylcysteine methine and
N-acetylcystine methylene peaks at δ 4.40 (t) and 3.08 (dd),
respectively] was plotted against time to determine t50 values,
the time required to obtain 50% conversion of thiol to disulfide.
Values of t50 reported in Table 1 were based on duplicate
determinations. Values usually varied (15% between different
experiments. In the absence of catalyst, the half-life of N-
acetylcysteine was >30 h under the above conditions.
An tioxid a n t Activity. A Hewlett-Packard 8453 UV-
visible spectrophotometer (514 nm), equipped with a LAUDA
compact low-temperature thermostat RC6 CP, was used for
the spectrophotometric measurements. Into 3.0 mL of a 50 µM
methanolic solution of 2,2’-diphenyl-1-picrylhydrazyl in a 10
mm × 10 mm cuvette was added 100 µL of a 0.75 mM
methanolic solution of the antioxidant by syringe, and the fall
in absorbance, referenced to methanol, was recorded with time
at 25.0 ( 0.2 °C. Values for t1/2, the time required to reduce
the 517 nm absorption by 50% (Table 1), were based on
duplicate determinations.
Ack n ow led gm en t. Financial support by Cancer-
fonden, the Swedish Research Council for Engineering
Sciences, the Swedish Natural Science Research Coun-
cil, and the NIH (grants CA48725 and CA77204) is
gratefully acknowledged.
J O990842K