Synthesis of telluroamino acid derivatives with remarkable GPx like activity

Article abstract of DOI:10.1039/b814990a

A series of modular telluroamino acid derivatives with remarkable GPx-like behavior was prepared in an efficient and short two-step synthesis.

Full text of DOI:10.1039/b814990a

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of telluroamino acid derivatives with remarkable GPx like activity†
Antonio L. Braga,* Eduardo E. Alberto, Letie´re C. Soares, Joa˜o B. T. Rocha, Je´ssie H. Sudati and
Daniel H. Roos
Received 28th August 2008, Accepted 3rd November 2008
First published as an Advance Article on the web 13th November 2008
DOI: 10.1039/b814990a
A series of modular telluroamino acid derivatives with re-
markable GPx-like behavior was prepared in an efficient and
short two-step synthesis.
and studied the antioxidant properties of compounds 314 and
4.15 A noteworthy characteristic of these compounds is the much
improved antioxidant activity of tellurides, when compared with
their selenium and sulfur analogues.
Amino groups that are capable of interacting with selenium,
through Se–N nonbonded interactions, are known to play a
significant role in modulating the redox proprieties of seleno-
based antioxidants.16 However, to the best of our knowledge,
there are just a few reports concerning the synthesis and GPx like
evaluations of aminoacid derivatives containing selenium17 and
none about tellurium. As part of our growing interest in aminoacid
derivatives containing chalcogen,3c,18 we report herein the synthesis
of novel telluroaminoacid derivatives, easily obtained in a simple,
modular and efficient two-step synthesis. We envisioned that this
modular characteristic would allow us to investigate the structure–
activity relationship of these compounds. Their GPx like activity
was evaluated, and we promoted the variation of aminoacid
residues, the chain length between the chalcogen atom and the
aminoacid moiety in order to find a more efficient catalyst.
GPx mimics 7a–g were prepared in two steps, in 51–78 overall
yield, from readily available L-aminoesters and the appropriate
bromo-carboxylic acid, as shown in Scheme 1.
Glutathione peroxidase enzymes (GPx) are excellent catalysts
for antioxidant reactions. They protect our body against the
potentially damaging effects of reactive oxygen species (ROS),
such as hydrogen peroxide and some organic hydroperoxides,
formed during aerobic metabolism. Several neurodegenerative
diseases, including Alzheimer’s and Parkinson’s disease are linked
to ROS activity.1 Since the discovery that selenium plays a pivotal
role in GPx enzymes, catalyzing the reduction of hydroperoxides
at the expense of glutathione (GSH),2 synthetic developments
and design of new chalcogen-based catalytic antioxidants have
attracted considerable attention.3 Synthetic organoselenium and
organotellurium compounds have emerged as excellent candidates
to act as GPx mimics, due their well-known ability to undergo two-
electron redox cycle between chalcogen (II) and (IV) species.4
The cyclic selenenamide ebselen 1 (Fig. 1), was the first synthetic
compound suggested for hydrogen peroxide inactivating therapy
in the presence of glutathione.5
Fig. 1 Representative examples of GPx mimics.
Based on the recognized GPx like activity of ebselen, several
papers have appeared describing simple synthetic organosele-
nium compounds with this property (e.g., benzoselenazinones,6
benzoselenazolinones,7 camphor-derived selenenamide,8 diaryl
diselenides9 and dendrimers with a diselenide core10).
Scheme 1 Synthetic strategy to prepare compounds 7a–g. Reagents:
i) bromo-carboxylic acid, NMM, ethyl chloroformate, CHCl3; ii) PhTe)2,
NaBH4, THF, EtOH.
On the other hand, the first organotellurium compound 2,
described as a GPx mimic, was reported by Detty.11 After that,
a series of diaryl ditellurides12 and diaryl tellurides13 have been
reported. Engman and collaborators have developed the synthesis
The catalytic activity of tellurides 7a–g, as a GPx model
enzyme, was evaluated according to the Tomoda method15 using
benzenethiol as a glutathione alternative. The reduction of H2O2
was monitored through the UV absorption increase at 305 nm,
due to diphenyl disulfide formation.
Our prime concern in the evaluation of these compounds as
GPx mimics was the influence of the chain length between the
tellurium atom and aminoacid moiety. It should be noted that
compounds 7a (n = 2) and 7b (n = 3) derived from L-Valine
Departamento de Qu´ımica, Universidade Federal de Santa Maria, 97.105–
900, Santa Maria, RS, Brazil. E-mail: albraga@quimica.ufsm.br
† Electronic supplementary information (ESI) available: General pro-
cedures, 1H and 13C NMR spectra of selected compounds. See DOI:
10.1039/b814990a
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 43–45 | 43
©

View Article Online
showed the same activity. Linear increases in absorbance (Fig. 2)
were observed by mixing MeOH, catalyst 7a–d (2.6 mol%), PhSH
and H2O2. Taking advantage of the modular characteristic of our
synthetic route, we explored the influence of the aminoacid residue
in the reduction of hydrogen peroxide in the presence of an excess
of thiol. Compounds 7c (n = 2) and 7d (n = 3) derived from
L-Phenylalanine were tested in the same conditions. Compound 7c,
with a shorter chain length, showed the same catalytic activity
that compounds 7a and 7b. However, 7d was less effective in the
reduction of hydrogen peroxide.
7g derived from L-aspartic acid (Entry 7) was the best catalyst,
promoting the reduction of H2O2 concentration to a half in
8.15 min. On the other hand, a seleno derivative 7h (Entry 8)
was not able to promote the reduction of H2O2 in an appreciable
rate (T50 = 1543 min). Diphenyl ditelluride was also employed
as reducing agent, and it was found that it is less effective than
compounds 7a–g, (T50 = 16.73 ( 0.26) min). We also investigated
if the tellurium moiety remains intact after reaction with H2O2.
To address this issue we performed a GC analysis of telluride 7g,
and another one with the reaction of GPx using 7g as catalyst (see
supporting information). To our delight, compound 7g was also
present after its application in the standard reaction. Apart from
the main product, diphenyldisulfide, some minor side products are
formed which may originate in some decomposition of the catalyst
or of other components involved.
Encouraged by these results, we next explored the effects
of substituents in the aryl group attached to tellurium in 7g
derivatives. A new series of telluroaminoacids were prepared with
electron donating 7i–k, electron withdrawing 7l and 7m, as well as
with steric hindrance substituents 7n and 7o (Fig. 3).
Fig. 2 GPx like behavior of compounds 7a-d.
The time required to reduce the thiol concentration to a half
(T50) is shown in Table 1. Compounds 7a (n = 2) and 7b (n = 3),
derived from L-valine and 7c (n = 2) from L-phenylalanine showed
almost the same T50, near to 13 min (Entries 1–3). For compound
7d (n = 3) derived from L-phenylalanine it was 21.61 min (Entry 4).
On the basis of these initial observations, we used tel-
luroaminoacids with n = 2 as standard catalysts, and promoted the
variation of amino acid moiety to enhance their ability to mimic
the glutathione peroxidase enzyme. L-Alanine 7e (Entry 5) and
L-leucine 7f (Entry 6) derivatives showed T50 of 10.41 and
12.75 min. respectively, and to our delight we found that telluride
Fig. 3
A new set of experiments to screen the GPx activity of these
new catalysts was performed with 7i–o (2 mol%), in a more
concentrated solution (Table 2). It was found that the GPx
behavior is strongly influenced by steric effects. The T50 of para
substituted compounds were lower when compared with the ortho
analogues (Entries 2 and 3, 5 and 6). The changing of electronic
environment at the tellurium atom did not produce a pronounced
change to the thiol peroxidase activity of these compounds. The
T50 of 7g (Ar = Ph, Entry 1), 7i (Ar = p-tolyl, Entry 2), 7k (Ar = 4-
MeOC6H4, Entry 4), and 7l (Ar = 4-ClC6H4, Entry 5) was between
2.11 and 2.98 min.
Table 1
Table 2
c,d
c,d
Entrya
Catalystb
Y
n
R
T50
Entrya
Catalystb
Ar
T50
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
Te
Te
Te
Te
Te
Te
Te
Se
2
3
2
3
2
2
2
2
i-Pr
i-Pr
Bn
Bn
Me
i-Bu
CH2COOMe
i-Pr
13.43 ( 0.15)
13.14 ( 0.27)
13.43 ( 0.31)
21.61 ( 1.10)
10.41 ( 0.52)
12.75 ( 1.03)
8.15 ( 0.61)
1543 ( 1.82)
1
2
3
4
5
6
7
8
7g
7i
phenyl
p-tolyl
o-tolyl
4-methoxyphenyl
4-chlorophenyl
2-chlorophenyl
2-naphthalene
1-naphthalene
2.98 ( 0.21)
2.78 ( 0.20)
4.78 ( 0.12)
2.11 ( 0.24)
2.94 ( 0.19)
8.14 ( 1.52)
3.65 ( 0.18)
4.27 ( 0.32)
7j
7k
7l
7m
7n
7o
7g
7h
a Under this condition addition of H2O2 in the absence of telluride did
not produce any significant oxidation of PhSH. b MeOH (1 mL); catalyst
a Under this condition addition of H2O2 in the absence of telluride did
not produce any significant oxidation of PhSH. b MeOH (1 mL); catalyst
c
c
[0.05 mmol L-1]; PhSH [1.9 mmol L-1]; H2O2 [8.8 mmol L-1]. T50 is the
[0.1 mmol L-1]; PhSH [5 mmol L-1]; H2O2 [5 mmol L-1]. T50 is the time
time required, in min, to reduce the thiol concentration with 50% after the
required, in min, to reduce the thiol concentration with 50% after the
addition of H2O2; d Data in parentheses: experimental error.
addition of H2O2. d Data in parentheses: experimental error.
44 | Org. Biomol. Chem., 2009, 7, 43–45
This journal is
The Royal Society of Chemistry 2009
©

View Article Online
Concerning mechanistic aspects, and in agreement with Detty’s
study,19 we believe that initially Te(II) compounds 7a-o react with
H2O2 to form the Te(IV) oxides 8a–o, and H2O (Scheme 2).
Addition of one equivalent of PhSH to these compounds generate
tellurenyl sulfides 9a–o which react with another equivalent of
PhSH to regenerate 7a–o to the catalytic cycle and produce
PhSSPh and H2O.
in Biology and Human Health, ed. R. F. Burk, Springer-Verlag, New
York, 1994.
3 (a) G. Mugesh and H. Singh, Chem. Soc. Rev., 2000, 29, 347; (b) G.
Mugesh, W. W. -du Mont and H. Sies, Chem. Rev., 2001, 101, 2125;
(c) C. W. Nogueira, G. Zeni and J. B. T. Rocha, Chem. Rev., 2004, 104,
6255; (d) B. K. Sarma and G. Mugesh, Org. Biomol. Chem., 2008, 6,
965.
4 (a) H. J. Reich, Acc. Chem. Res., 1979, 12, 22; (b) K. B. Sharpless,
K. M. Gordon, R. F. Lauer, D. W. Patrick, S. P. Singer and M. W.
Young, Chem. Scr., 1975, 8A, 9; (c) M. R. Detty, Organometallics,
1991, 10, 702; (d) M. R. Detty, P. B. Merkel and S. K. Powers, J. Am.
Chem. Soc., 1988, 110, 5920.
5 (a) A. Mu¨ller, E. Cadenas, P. Graf and H. Sies, Biochem. Pharmacol.,
1984, 33, 3235; (b) A. Wendel, M. Fausel, H. Safayhi, G. Tiegs and R.
Otter, Biochem. Pharmacol., 1984, 33, 3241; (c) M. J. Parnham and S.
Kindt, Biochem. Pharmacol., 1984, 33, 3247.
6 P. V. Jacquemin, L. E. Christiaens and M. J. Renson, Tetrahedron Lett.,
1992, 33, 3663.
7 V. Galet, J. L. Bernier, J. P. He´nichart, D. Lesieur, C. Abadie, L.
Rochette, A. Lindenbaum, J. Chalas, J. F. R. de la Faverie, B. Pfeiffer
and P. Renard, J. Med. Chem., 1994, 37, 2903.
8 T. G. Back and B. P. Dick, J. Am. Chem. Soc., 1997, 119, 2079.
9 (a) S. R. Wilson, P. A. Zucker, R. R. C. Huang and A. Spector, J. Am.
Chem. Soc., 1989, 111, 5936; (b) T. Wirth, Molecules, 1998, 3, 164;
(c) G. Mugesh, A. Panda, H. B. Singh, N. S. Punekar and R. Butcher,
J. Chem. Commun., 1998, 2227; (d) G. Mugesh, A. Panda, H. B. Singh,
N. S. Punekar and R. J. Butcher, J. Am. Chem. Soc., 2001, 123, 839.
10 X. Zhang, H. Xu, Z. Dong, Y. Wang, J. Liu and J. Shen, J. Am. Chem.
Soc., 2004, 124, 10556.
11 M. R. Detty and S. L. Gibson, Organometallics, 1992, 11, 2147.
12 L. Engman, D. Stern, I. A. Cotgreave and C. M. Andersson, J. Am.
Chem. Soc., 1992, 114, 9737.
13 (a) L. Engman, D. Stern, M. Pelcman and C. M. Andersson, J. Org.
Chem., 1994, 59, 1973; (b) K. Vessman, K. Ekstro¨m, M. Berglund,
C. M. Andersson and L. Engman, J. Org. Chem., 1995, 60, 4461.
14 L. Engman, D. Stern, H. Frisell, K. Vessman, M. Berglund, B. Ek and
C. M. Andersson, Bioorg. Med. Chem., 1995, 3, 1255.
Scheme 2
In conclusion, we have prepared a series of telluroamino acid
derivatives, in a short, modular and efficient synthetic route. These
compounds were tested as GPx mimics, catalyzing the reduction
of H2O2 to water at expense of thiophenol using a very low
amount of catalyst. We found that the time required to reduce
the concentration of the PhSH to a half, T50, is strongly influenced
by the aminoacid residue, as well as by steric effects. New studies
to investigate the influence of amino acid residues of telluroamino
acid derivatives have been performed in our lab using glutathione
as reducing agent.
15 (a) L. Engman, M. Laws, J. Malmstro¨m, C. H. Schiesser and L. M.
Zugaro, J. Org. Chem., 1999, 64, 6764; (b) J. Malmstro¨m, M. Jonsson,
I. A. Cotgreave, L. Hammarstro¨m, M. Sjo¨din and L. Engman, J. Am.
Chem. Soc., 2001, 123, 3434.
Acknowledgements
16 M. Iwaoka and S. Tomoda, J. Am. Chem. Soc., 1994, 116, 2557.
17 (a) P. P. Phadnis and G. Mugesh, Org. Biomol. Chem., 2005, 3, 2476;
(b) K. P. Bhabak and G. Mugesh, Chem. Eur. J., 2007, 13, 4594.
18 (a) A. L. Braga, J. A. Sehnem, F. Vargas and R. C. Braga, J. Org. Chem.,
2005, 70, 9021; (b) A. L. Braga, D. S. Lu¨dtke, M. W. Paixa˜o, E. E.
Alberto, H. A. Stefani and L. Juliano, Eur. J. Org. Chem., 2005, 4260;
The authors thank CNPq, CAPES, and FAPERGS for financial
support.
Notes and references
1 Free Radicals in Biology, ed. L. Flohe and W. A. Pryor, Academic Press,
New York, 1982.
2 (a) J. T. Rotruck, A. L. Pope, H. E. Ganther, A. B. Swanson, D. G.
Hafeman, W. G. Hoekstra, Science 1973, 179, 588; (b) L. Flohe´, E. A.
Gu¨nzler and H. H. Schock, FEBS Lett., 1973, 32, 132; (c) Selenium
(c) A. L. Braga, L. Wessjohann, M. W. Paixa˜o, O. E. D. Rodrigues, A.
Schneider and H. R. Appelt, Tetrahedron Lett., 2006, 47, 1019; (d) A. L.
Braga, D. P. Bottega, M. W. Paix
a˜o, A. M. Deobald, C. Peppe and P. H.
Schneider, J. Org. Chem., 2006, 71, 4305.
19 Y. You, K. Ahsan and M. R. Detty, J. Am. Chem. Soc., 2003, 125, 4918.
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 43–45 | 45
©