Synthesis of ω-hydroxy-α-alkyl/aryl-γ-organo-selenium and γ-organo-tellurium: a new class of organochalcogen compounds with antinociceptive activity

Article abstract of DOI:10.1016/j.tetlet.2008.03.088

We present here the results on the synthesis of alkynylselenoalcohols and alkynyltelluroalcohols using the reaction of lithium-alkynylchalcogenolates, generated via the reaction of alkynyllithium with elemental Se or Te, with bromo-alcohols. The reaction proceeded cleanly under mild reaction conditions, and alkynylchalcogenoalcohols were formed in good to excellent yields. The obtained compounds 2o and 2v were screened for antinociceptive activity using the acetic acid-induced writhing reaction in mice. Compound 2o administered by oral route at 5-50 mg/kg produced a significant inhibition of the acetic acid-induced abdominal constriction in mice.

Full text of DOI:10.1016/j.tetlet.2008.03.088

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3252–3256
Synthesis of x-hydroxy-a-alkyl/aryl-c-organo-selenium and
c-organo-tellurium: a new class of organochalcogen compounds
with antinociceptive activity
b
a
a
´
Afamefuna E. Okoronkwo , Alisson R. Rosario , Diego Alves ,
Lucielli Savegnago a, Cristina W. Nogueira a, Gilson Zeni a,*
a
ˆ
Laborato´rio de Sı´ntese, Reatividade, Avaliaßca˜o Farmacolo´gica e Toxicolo´gica de Organocalcogenios, CCNE, UFSM,
Santa Maria, Rio Grande do Sul, CEP 97105-900, Brazil
b Department of Chemistry, Federal University of Technology, P.M.B. 704 Akure, Ondo State, Nigeria
Received 12 February 2008; revised 10 March 2008; accepted 18 March 2008
Available online 23 March 2008
Abstract
We present here the results on the synthesis of alkynylselenoalcohols and alkynyltelluroalcohols using the reaction of lithium-
alkynylchalcogenolates, generated via the reaction of alkynyllithium with elemental Se or Te, with bromo-alcohols. The reaction
proceeded cleanly under mild reaction conditions, and alkynylchalcogenoalcohols were formed in good to excellent yields. The obtained
compounds 2o and 2v were screened for antinociceptive activity using the acetic acid-induced writhing reaction in mice. Compound 2o
administered by oral route at 5–50 mg/kg produced a significant inhibition of the acetic acid-induced abdominal constriction in mice.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Selenium; Tellurium; Pharmacological activity
1. Pharmacology
reversible catalytically effective biological antioxidants.1
After that a variety of organoselenium compounds with
potential pharmacological activity including ebselen ana-
logues, benzoselenazolinones, diaryl diselenides, selena-
mide, and related derivatives have been reported.4
Organoselenium compounds such as selenocystine and a
variety of diorganoyl diselenides can react with thiols such
as cysteine, dithiothreitol, and reduced glutathione to pro-
duce selenocysteine, selenols, and disulfides.1 In line with
these findings, Gunther2 showed that dithiothreitol, a com-
¨
2. Chemistry
pound with extremely low redox potential, reduced a vari-
ety of diorganoyl diselenides, forming selenols and trans-
4,5-dihydroxy-1,2-dithiane, the oxidation product of dithio-
threitol. Some decades ago, the reduction of diorganoyl
diselenides to selenol derivatives by reaction with thiols
was considered to be of physiological significance.3 Indeed,
Walter and co-workers hypothesized that selenoamino
acids, particularly methylselenocysteine, could act as
Organoselenium chemistry is a very broad and exciting
field, with many opportunities for research and develop-
ment of applications. Organoselenium compounds have
become attractive synthetic targets because of their
chemo-, regio-, and stereo-selective reactions, and their
useful biological activities.5 Furthermore, organoselenium
compounds can usually be used in a wide variety of func-
tional groups, thus avoiding protection group chemistry.6
Most organoselenium methodologies proceed stereo- and
regio-selectively in excellent yields. Although, the first
*
Corresponding author. Tel.: +55 55 220 8140; fax: +55 55 220 8031.
E-mail address: gzeni@quimica.ufsm.br (G. Zeni).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.088

A. E. Okoronkwo et al. / Tetrahedron Letters 49 (2008) 3252–3256
3253
Table 1
1) n-BuLi/THF(-78 ºC)
Reaction conditions optimizationa
OH
R
H
R
Y
2) Y0 (0 ºC or 70 ºC)
OH
n
1) BuLi/THF (-78 ºC), 1 h
Br
OH
3)
( )n
H
Se
2) Se0, 0
ºC
1a
2a
R= alkyl, aryl; Y= Se, Te; n= 2,3,6
OH
, r.t.
3) Br
Scheme 1.
No.
Solvent
n-BuLi (equiv)
Yield (%)
1
2
3
4
5
6
a
Hexane
Diethyl ether
THF
THF
THF
2
2
2
1
1.5
2.5
22
35
82
39
61
81
organoselenium compound has been prepared by Wo¨hler
in 1847,7 only in the early 1970s did the chemistry of orga-
noselenium become a versatile tool in organic chemistry.8
The organoselenium chemistry developed rapidly, mainly
in the area of selenocarbohydrates, selenoaminoacids,
and selenopeptides. The selenium group can be introduced
in an organic substrate via both nucleophilic and electro-
philic reagents. After being introduced in an organic sub-
strate, the organoselenium group can easily be removed
by selenoxide syn elimination,9 and [2,3] sigmatropic rear-
rangement.10 In addition, carbon–selenium bond can also
be replaced by a carbon–hydrogen,11 carbon–halogen,12
carbon–lithium,13 or carbon–carbon bonds.14
THF
Reactions performed in the presence of 1a (2 mmol), Se0 (2 mmol), and
2-bromoethanol (1 mmol).
2). It is relevant to note that when the amount of n-BuLi
is reduced from 2 to 1 equiv, a notable decrease in the
yields was observed (Table 1, entries 4 and 5). The use of
2.5 equiv of n-BuLi did not improve the yield (Table 1,
entry 6).
Thus, the careful analysis of the optimized reaction
revealed that the optimum condition for this protocol
was the addition of n-butyllithium (2 mmol) to a solution
of phenylacetylene (2 mmol) and THF (6 mL), at À78 °C.
The resulting solution was stirred for 30 min at this temper-
ature. After this the reaction was warmed to 0 °C and
elemental selenium was added. The reaction was allowed
to stir at room temperature until all Se0 has been consumed
(yellow solution), and then bromoalcohol (1 mmol) was
added. To demonstrate the efficiency of this reaction, we
explored the generality of our method, extending the con-
ditions to other alkynes and different bromoalcohols and
the results are summarized in Table 2.18
Inspection of Table 2 shows that the reaction worked
well for a variety of bromoalcohols and alkynes. Both
hindered and non-hindered alkyl and aryl alkynes gave
the desired alkynylselenoalcohols. A closer inspection of
the results revealed that the reaction is not sensitive to
the distance of hydroxyl group from bromine in the
bromoalcohol.
Alkynylchalcogen compounds are highly valuable inter-
mediates in organic synthesis due to their potential for
transformation into substituted olefins.15 Consequently, a
number of methodologies havef been developed for the
synthesis of these compounds.16 Most of the syntheses
described involve the use of diorganoyl diselenides as start-
ing materials, which are volatile, unstable, and have an
unpleasant odor. Additionally, to the best of our knowl-
edge the preparation of alkynylchalcogenoalcohols, having
a free hydroxyl group in the chemical structure, has been
scarcely reported.17 In view of these limitations, there is
still a need for the development of clean procedures for
the synthesis of these useful organochalcogen compounds.
In this Letter, we present our contribution to the field by
developing a mild protocol for the alkynylchalcogenoalco-
hols synthesis via the reaction of lithium-alkynylchalco-
genolates with bromo-alcohols, avoiding the previous
preparation of diorganoyl diselenides or selenols
(Scheme 1).
In an attempt to broaden the scope of our methodology,
the possibility of performing the reaction with tellurium
instead of selenium was also investigated. Thus, the stan-
dard reaction condition applied to prepare the
alkynylselenoalcohols was also tested for the alkynyltell-
uroalcohol derivatives. Unfortunately, this condition was
not effective and products were obtained in poor yields.
Thus, a variety of conditions were investigated, including
temperature, solvent, stoichiometry, and time. It was grat-
ifying to discover that simply changing the temperature
from 0 °C to reflux, just after the tellurium addition, gave
the alkynyltelluroalcohols generally in reasonable to good
yields (68–94%) but in some cases (Table 3, entries 1, 4, 5
and 7) low yields (40%, 12%, 30%, and 23%) occurred.
Thus, the careful analysis of the optimized reaction condi-
tions revealed that the general synthetic procedure for the
reaction is as follows: n-butyllithium (2 mmol) is added
3. Results and discussion
Since our initial studies have focused on the develop-
ment of an optimum set of reaction conditions, we have ini-
tially chosen phenylacetylene and 2-bromoethanol as
standard substrate. In this way, n-butyllithium (2 mmol)
was added at À78 °C to a solution of phenylacetylene
(2 mmol) and THF (6 mL), after 1 h, elemental selenium
was added at 0 °C, and subsequent addition of 2-bromo
ethanol (1 mmol) gave the alkynylselenoalcohol corres-
ponding in 82% yield.
Regarding the influence of the solvent, better results
were achieved using THF, which furnished the desired
product 2a in 82% yield (Table 1, entry 3). We observed
that hexane and diethyl ether were less effective since prod-
uct 2a was obtained in poor yields (Table 1, entries 1 and

3254
A. E. Okoronkwo et al. / Tetrahedron Letters 49 (2008) 3252–3256
Table 2
Table 2 (continued)
Synthesis of alkynylselenoalcohols
No.
Bromo-alcohol
R
Producta (yield/%)
1) BuLi/THF (-78˚C), 1 h
OH
Se
(H3C)3C
OH
( )3
R
H
R
Se
2) Se0, 0 ºC
OH
n
1
2
16
1d
(CH3)3C
Br
3)
, r.t.
( )n
2p (96)
No.
1
Bromo-alcohol
R
Producta (yield/%)
Se
OH
6
OH
Br
( )6
1e
17
18
19
20
21
22
1e
n-C3H7
n-C4H9
n-C5H11
n-C6H13
n-C8H17
Ph
Se
OH
n-C3H7
n-C4H9
n-C5H11
n-C6H13
n-C8H17
Ph
OH
Br
( )2
2
2q (70)
n-C3H7
n-C4H9
n-C5H11
n-C6H13
n-C3H7
n-C4H9
n-C5H11
n-C6H13
1c
2b (50)
Se
OH
6
1e
1e
1e
1e
1e
1e
Se
OH
2
2r (67)
2
3
4
1c
1c
1c
2c (54)
Se
OH
6
Se
OH
2
2s (94)
Se
OH
6
2d (71)
Se
OH
2
2t (76)
Se
OH
6
2e (81)
Se
2u (72)
OH
2
5
6
7
8
1c
1c
1c
n-C8H17
n-C8H17
Se
2v (70)
OH
6
2f (76)
Se
OH
2
Se
OH
( )6
23
(H3C)3C
(H3C)3C
2g (19)
2w (60)
Se
OH
a
Yields of 2a–w are given for isolated products.
2
Ph
Ph
2a (82)
Se
to a solution of alkyne (2 mmol) and THF (6 mL), at
À78 °C. The resulting solution is stirred for 30 min at this
temperature. The temperature was warmed to room tem-
perature and tellurium powdered was added. This mixture
was then heated at reflux for 5 h and bromoalcohol
(1 mmol) was added at room temperature. Next, we
extended our studies on the scope of this reaction to differ-
ent alkynes and bromoalcohols and the results are summa-
rized in Table 3.19 Our investigations focused on the
influence of alkyl and aryl groups at terminal alkynes.
Satisfactorily, all alkynes were found to be effective,
although lesser yields were observed to alkylalkynes. Our
experiments also showed that performing n-BuLi and tellu-
rium addition at 0 °C and room temperature, respectively,
gave the product in an unsatisfactory yield.
OH
( )2
1c
(CH3)3C
(H3C)C
2h (75)
Se
OH
3
OH
Br
( )3
9
n-C5H11
n-C6H13
n-C4H9
n-C3H7
n-C5H11
n-C6H13
n-C4H9
n-C3H7
1d
2i (89)
Se
OH
3
10
11
12
1d
1d
1d
2j (87)
Se
OH
3
2k (97)
Se
OH
3
2l (67)
4. Pharmacology
Se
OH
3
13
14
15
1d
1d
1d
n-C8H17
n-C8H17
Based on the previous screening for antioxidant activity
of alkynylselenoalcohol compounds, 2o and 2v were chosen
for evaluating antinociceptive activity of this class of
organochalcogens. The obtained compounds 2o and 2v
were screened for antinociceptive activity using the acetic
acid-induced writhing reaction in mice. The acetic acid-
induced writhing reaction in mice is described as a model
for visceral pain. This methodology has long been used
2m (86)
Se
OH
3
2n (50)
Se
OH
3
Ph
Ph
2o (80)

A. E. Okoronkwo et al. / Tetrahedron Letters 49 (2008) 3252–3256
3255
Table 3
40
Synthesis of alkynyltelluroalcoholsa
30
20
10
0
1) BuLi/THF (-78 ºC), 1 h
OH
R
H
R
Te
2) Te0, 70 ºC
OH
n
***
1
4
***
***
Br
3)
( )n
No.
1
Bromo-alcohol
R
Producta (yield/%)
Te
OH
2
OH
Br
( )2
n-C4H9
n-C4H9
C
1
5
10
50
3a (40)
1c
Compound 2O (mg/kg)
Te
OH
2
40
30
20
10
0
2
1c
1c
1c
Ph
Ph
3b (68)
Te
OH
2
3
(CH3)3C
(H3C)3C
3c (45)
Te
OH
2
4b
5c
6
Ph
Ph
C
1
5
10
50
3b (12)
Compound 2V (mg/kg)
Te
OH
2
1c
Ph
Fig. 1. Effect of compounds 2o and 2v administered orally against acetic
acid-induced writhing movements in mice. Each column represents the
mean with SEM. for 6–12 mice in each group. Control (C) indicates the
animal injected with canola oil. Asterisks denote the significance levels,
when compared to the control group (one-way ANOVA followed by
Ph
3b (NR)
Te
OH
OH
Br
3
( )3
n-C5H11
n-C6H13
Ph
n-C5H11
22
***
Duncan’s test) P < 0.001.
1d
3d (30)
Te
OH
test). Conversely, compound 2v (1–50 mg/kg) did not cause
significant inhibition of the nociceptive response induced
by acetic acid. All alkynylchacogenoalcohols are currently
under study on acetic acid-induced abdominal constriction
and will be reported in due course.
3
7
1d
n-C6H13
3e (23)
Te
OH
3
8
1d
Ph
3f (94)
In summary, the procedure described herein provides an
interesting protocol for the synthesis of alkynyl-
chalcogenoalcohols. We have shown that the anion
lithium-alkynylchalcogenolate readily reacts with bromo-
alcohols in THF to give the corresponding alkynyl-
chalcogenoalcohols in good yields. Additionally, by our
method the preparation of diorganoyl diselenides or selenol
is avoided. The synthesized compounds have promising
antinociceptive activity and should be pharmacologically
interesting. We expect that these findings would be useful
in choosing a method for the synthesis of x-hydroxy-c-
organo-selenium and c-organo-tellurium alkynes. This
reaction associated with the nickel-catalyzed cross-
coupling of selenides14 or palladium cross-coupling of
tellurides21 can contribute to an interesting alternative
route to the preparation of more functionalized alkynes.
Te
OH
( )6
OH
Br
( )6
1e
9
n-C5H11
(CH3)3C
Ph
n-C5H11
3g (34)
Te
OH
6
10
1e
1e
C(H3C)3
3j (67)
Te
OH
6
11
Ph
3k (92)
a
Yields of 3a–i are given for isolated products.
n-BuLi was added at room temperature.
Te0 was added at room temperature.
b
c
as a screening tool for the assessment of antinociceptive
property of new agents.20 The results of antinociceptive
effect induced by compounds 2o and 2v on acetic acid-
induced abdominal constriction response in mice are pre-
sented in Figure 1. The best result was obtained using com-
pound 2o. In fact, compound 2o administered by oral route
at 5–50 mg/kg produced a significant inhibition of the ace-
tic acid-induced abdominal constriction in mice when com-
pared to the control group (p < 0.05 by Newman–Keuls’
1
Analysis of the H and 13C NMR spectra showed that all
the obtained products presented data in full agreement
with their assigned structures.
Acknowledgments
We are grateful to FAPERGS, CAPES (SAUX/2007),
and CNPq for the financial support. CNPq is also

3256
A. E. Okoronkwo et al. / Tetrahedron Letters 49 (2008) 3252–3256
ethyl acetate (20 mL) and washed with aqueous NH4Cl (20 mL) and
water (3 Â 20 mL). The organic phase was separated, dried over
MgSO4, and concentrated under vacuum. The residue was purified by
flash chromatography on silica gel using ethyl acetate/hexane as the
eluent. Selected spectral for 2a. Yield: 0.185 g (82%). 1H NMR:
(400 MHz, CDCl3): d 7.42–7.38 (m, 2H), 7.30–7.27 (m, 3H), 4.02–3.99
(t, 2H, J = 5.8 Hz), 3.01 (t, 2H, J = 5.8 Hz), 2.55 (sl, 1H). 13C NMR:
(100 MHz, CDCl3): d 131.45, 128.21, 128.19, 123.08, 99.42, 68.91,
61.14, 32.26.
acknowledged for a fellowship [to GZ, C.W. Nogueira, and
Okoronkwo (CNPq/TWAS)].
References and notes
1. Walter, R.; Schwartz, I. L.; Roy, J. Ann. N.Y. Acad. Sci. 1972, 192,
175–180.
2. Gunther, W. H. H. J. Org. Chem. 1967, 32, 3931.
¨
19. General procedure for the alkynyltelluroalcohols synthesis: To a two-
neck round-bottomed flask, under argon, containing a solution of
appropriated alkyne (2 mmol) in THF (6 mL) at À78 °C was added to
n-BuLi (0.8 mL of a 2.5 M solution in hexane; 2 mmol). The reaction
mixture was stirred for 30 min. After this the reaction was warmed to
0 °C and elemental tellurium (0.256 g; 2 mmol) was added. The
reaction was allowed to stir at reflux for 5 h. After this time, the
reaction was cooled to room temperature and then the appropriated
bromoalcohol (1 mmol) was added. The reaction mixture was allowed
to stir at room temperature for additional 12 h. After this time, the
mixture was diluted with ethyl acetate (20 mL) and washed with
saturated aqueous NH4Cl (20 mL) and water (3 Â 20 mL). The
organic phase was separated, dried over MgSO4, and concentrated
under vacuum. The residue was purified by flash chromatography on
silica gel using ethyl acetate/hexane as the eluent. Selected spectral for
(3c). Yield: 0.114 g (45%). 1H NMR: (400 MHz, CDCl3): d 4.03 (t,
2H, J = 6.3 Hz), 2.98 (t, 2H, J = 6.3 Hz), 2.60 (sl, 1H), 1.24 (s, 9H).
13C NMR: (100 MHz, CDCl3): d 121.19, 62.93, 31.06, 29.43, 28.79,
13.08.
20. (a) Vinegar, R.; Truax, J. F.; Selph, J. L.; Jonhston, P. R. Antagonism
of pain and hyperalgesia. Anti-inflammatory drugs. In Handbook of
Experimental Pharmacology, 50/II; Vane, J. R., Ferreira, S. H., Eds.;
Springer: Berlin, 1979; (b) Tjolsen, A.; Hole, K. Animal models of
analgesia. In The Pharmacology of Pain; Dieckson, A., Besson, J.-M.,
Eds.; Springer: Berlin, 1997.
21. (a) Zeni, G.; Ludtke, D. S.; Panatieri, R. B.; Braga, A. L. Chem. Rev.
2006, 106, 1032–1076; (b) Zeni, G.; Braga, A. L.; Stefani, H. A. Acc.
Chem. Res. 2003, 36, 731–738.
3. Dickson, R. C.; Tappel, A. L. Arch. Biochem. Biophys. 1969, 130,
547–550.
4. Sies, H. Free Radical Biol. Med. 1993, 14, 313–323.
5. Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Chem. Rev. 2004, 104,
6255–6286.
6. (a) Nicolaou, K. C.; Petasis, N. A. Selenium in Natural Products
Synthesis; CIS: Philadelphia, 1984; (b) Paulmier, C. Selenium
Reagents and Intermediates in Organic Synthesis; Pergamon: Oxford,
1986; (c) Wirth, T.; Organoselenium Chemistry—Modern Develop-
ments in Organic Synthesis, Top. Curr. Chem. 208, Springer:
Heidelberg, 2000; (d) Mugesh, G.; Singh, H. B. Acc. Chem. Res.
2002, 35, 226–236.
7. Wo¨hler, F.; Siemens, C. Ann. Chem. 1847, 61, 360–365.
8. Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc. 1973, 95, 2697–2699.
9. (a) Huguet, J. L. Adv. Chem. Ser. 1967, 345–348; (b) Sharpless, K. B.;
Young, M. W.; Lauer, R. F. Tetrahedron Lett. 1973, 22, 1979–1982.
10. (a) Reich, H. J. J. Org. Chem. 1975, 40, 2570–2572; (b) Sharpless, K.
B.; Lauer, R. F. J. Am. Chem. Soc. 1972, 94, 7154–7155.
11. Sevrin, M.; Vanende, D.; Krief, A. Tetrahedron Lett. 1976, 30, 2643–
2646.
12. Sevrin, M.; Dumont, W.; Hevesi, L. D.; Krief, A. Tetrahedron Lett.
1976, 30, 2647–2650.
13. (a) Seebach, D.; Peleties, N. Chem. Ber. 1972, 105, 511–515; (b)
Seebach, D.; Beck, A. K. Angew. Chem., Int. Ed. Engl. 1974, 13, 806–
807; (c) Reich, H. J.; Shah, S. K. J. Am. Chem. Soc. 1975, 97, 3250–
3252.
14. Silveira, C. C.; Braga, A. L.; Vieira, A. S.; Zeni, G. J. Org. Chem.
2003, 68, 662–665.
22. Bioassay: The abdominal constriction was induced according to
procedures described previously by Coˆrrea23 and modified by
Nogueira24 and resulted in the contraction of the abdominal muscle
together with a stretching of the hind limbs in response to an
intraperitoneal injection of acetic acid (1.6%) at the time of the test.
Mice were pre-treated with compounds 2o and 2v (1–50 mg/kg) by
oral route, 30 min before the irritant injection. Control animals
received a similar volume of vehicle (10 ml/kg, canola oil). After the
challenge, mice were individually placed in separate boxes and the
abdominal constrictions were counted cumulatively over a period of
20 min. Antinociceptive activity was expressed as the reduction in the
number of abdominal constrictions, that is, the difference between
control animals (mice pre-treated with vehicle) and animals
pre-treated with the drug.
15. (a) Sun, A. M.; Huang, X. Synthesis 2000, 775–777; (b) Zeni, G.;
Stracke, M. P.; Lissner, E.; Braga, A. L. Synlett 2003, 1880–1882; (c)
Comasseto, J. V.; Menezes, P. H.; Stefani, H. A.; Zeni, G.; Braga, A.
L. Tetrahedron 1996, 52, 9702–9787.
16. Comasseto, J. V.; Ling, L. W.; Petragnani, N.; Stefani, H. A.
Synthesis 1997, 373–413.
17. Ganjian, I.; Lalezari, I.; Herbert, H. J. Heterocycl. Chem. 1985, 22,
857–858.
18. General procedure for the alkynylselenoalcohols synthesis: To a two-
neck round-bottomed flask, under argon, containing a solution of
appropriated alkyne (2 mmol) in THF (6 mL) at À78 °C was added to
n-BuLi (0.8 mL of a 2.5 M solution in hexane; 2 mmol). The reaction
mixture was stirred for 30 min. After this the reaction was warmed to
0 °C and elemental selenium (0.158 g; 2 mmol) was added. The
reaction was allowed to stir at room temperature until all Se0 has been
consumed (yellow solution), and then the appropriated bromoalcohol
(1 mmol) was added. The reaction mixture was allowed to stir at room
temperature for 12 h. After this time, the mixture was diluted with
23. Correˆa, C. R.; Kyle, D. J.; Chakravarty, S.; Calixto, J. B. Br. J.
Pharmacol. 1996, 117, 552–558.
24. Nogueira, C. W.; Quinhones, E. B.; Jung, E. A. C.; Zeni, G.; Rocha,
J. B. T. Inflamm. Res. 2003, 52, 56–63.