Synthesis and antioxidant capacity of novel stable 5-tellurofuranose derivatives

Article abstract of DOI:10.1039/c8cc00565f

Novel stable tellurium-containing carbohydrate derivatives are prepared from hexitols and pentitols through a double nucleophilic substitution with NaHTe in PEG-400. These tellurosugars react at very high rates with two-electron oxidants, including hypochlorous and peroxynitrous acid, formed at sites of inflammation, and show considerable promise as protective agents against oxidative damage.

Full text of DOI:10.1039/c8cc00565f

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Synthesis and Antioxidant Capacity of Novel Stable 5-
Tellurofuranose Derivatives
Elton L. Borges,a,b,c Marta T. Ignasiak,a Yuliia Velichenko,b Gelson Perin,c Craig A. Hutton,b Michael
J. Davies*a,d and Carl H. Schiesser*d
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Novel stable tellurium-containing carbohydrate derivatives are and related structures, affording highly-water soluble
prepared from hexitols and pentitols through
double species.7-10 These materials are scavengers of a wide range of
a
nucleophilic substitution with NaHTe in PEG-400. These biological oxidants including those generated by the
tellurosugars react at very high rates with two-electron oxidants, inflammatory enzyme myeloperoxidase (hypochlorous acid,
including hypochlorous and peroxynitrous acid, formed at sites of HOCl; hypobromous acid, HOBr; hypothiocyanous acid,
inflammation, and show considerable promise as protective HOSCN), peroxynitrous acid (ONOOH), peroxides (H2O2, ROOH)
agents against oxidative damage.
and singlet oxygen (1O2), with second order rate constants, k2,
10–100 fold higher than their sulfur analogues.7,8,11
Furthermore, these materials protect human plasma proteins
against oxidative damage,11 and strongly promote healing of
gastric ulcers and skin wounds in animal models.12, 13
Previous studies have shown that selenocysteine plays a
fundamental role as a component in the the active site of a
number of important protective enzymes in mammalian cells,
including glutathione peroxidases (GPx), thioredoxin
reductases (TrxR) and some methionine sulfoxide reductases
(MSRs).1, 2 GPx, together with its co-factor glutathione (GSH),
catalyzes the reduction of potentially damaging H2O2 and
hydroperoxides.3 TxrR and its protein partner, thioredoxin, are
key components of cellular reducing systems that maintain
protein thiols in a reduced active form.2, 4 The family of MSRs,
together with thioredoxin as a source of reducing equivalents,
reduce methionine sulfoxide residues formed on peptides and
proteins, back to native methionine (Met) residues, thereby
protecting proteins against irreversible damage and loss of
activity.5 In light of these data, a considerable number of low-
molecular-mass selenium species have been synthesized and
tested as GPx mimetics and direct antioxidants, with Ebselen
being the most widely studied.6 Many of the selenium species
examined, including mono- and di-selenides, have low
aqueous solubilities that hinder their biological use, although
we (and others) have recently established synthetic routes
that allow the incorporation of selenium in to carbohydrates
Figure 1. Te-carbohydrates.
Organotellurides have been shown to react two-to-three
orders of magnitude more rapidly with free radicals than their
selenium counterparts,14, 15 and water-soluble organotellurides
exhibit glutathione and thiol peroxidase activities,16 however
their reactivities with oxidants such as HOCl and ONOOH are
unknown. In the light of the potential potent biological
activities of tellurium-containing carbohydrates, such as
1
(Figure 1), we expected these tellurium species to exhibit
superior oxidant scavenging activities than their selenium
counterparts. Indeed, isolated reports on the reactivities of
diaryl tellurides toward oxidants lends support to this
hypothesis, with some previously synthesised materials
exhibiting potent GPx activity,17-19 effects on mitochondria,20
21
redox sensitivity,20, rapid reaction with ONOOH and other
oxidants (though absolute kinetic data were not
established),23-26 and are potent inhibitory agents against lipid
peroxidation.27, 28 These compounds are generally poorly water
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soluble, limiting their use in aqueous systems. Water-soluble in 65% yield after 1 h, suggesting that PEG-400 is important for
cyclodextrin species bearing tellurium substituents have been this transformation.‡ The cyclic telluride 12 was deprotected
reported, with these showing potent GPx activities, as well as a by treatment with catalytic trifluoroacetic acid (TFA) and H2O
capacity to inhibit thioredoxin reductase activity at nanomolar in CH2Cl2 at room temperature for 1 h, followed by purification
concentrations, and cancer cell growth, with IC50 values in the by silica-gel flash chromatography to afford 1,4-dideoxy-
low micromolar range.29 Despite these positive data, and the tellurotalitol (
) as a yellow solid in 53% isolated yield (Scheme
potent biological activity of the corresponding selenium- 1). The synthetic pathway described above was extended to
species, there are no reports to date on the synthesis of stable other carbohydrates. 1,4-Dideoxy- -tellurotalitol ), the
(ring) tellurium-modified carbohydrates, or their oxidant enantiomer of , was obtained in 55% yield, from L-mannose
scavenging activities; however, benzyl-protected (Scheme 1) however , which was obtained in 53% crude yield
) have been reported, from D-gulonic acid-1,4-lactone, proved to be unstable and
D-
1
L
(2
1
3
telluropyranose derivatives (e.g.,
8
although these could not be deprotected.30
unsuitable for further evaluation.
We report here the synthesis and oxidant scavenging activity
O
O
of carbohydrate derivatives 1–7 that are also cyclic tellurides
OH OH
O
H
HO
OH
O
(Figure 1). These novel and stable§ compounds exhibit very
high oxidant scavenging capacities, with some of the highest
known rate constants for reaction with HOCl and ONOOH.
i
OH
HO
OH OH
OH
O
O
OH
13
O
O
(rac)
15 (18%)
O
O
14 (20%)
H
H
OH
O
O
O
HO
HO
OH
OH
ii
i
O
H
O
O
OH
HO
HO
HO
H
H
90%
O
85%
OMs
Te
OH
iii
iv
ii
O
O
O
Te
14
mannose
60%
53%
90%
O
O
O
OMs
O
HO
OH
rac-4
O
O
9
10
18
iii 82%
16
O
MsO
Te
O
O
Te
O
HO
HO
H
O
H
H
O
O
iii
ii
89%
iv
88%
OMs
Te
O
15
O
OH
OH
HO
Te
iv
60%
v
O
OMs
O
O
HO
53%
O
65%
O
OMs
O
19
5
HO
OH
O
17
1
12
11
Scheme 2. Reagents and conditions: (i) H2SO4, CuSO4, Me2CO; (ii) Et3N, MsCl, CH2Cl2; (iii)
Te, NaBH4, PEG-400; (iv) TFA, H2O, CH2Cl2.
HO
HO
H
H
HO
HO
Te
Te
In a complementary procedure, galactitol (13) underwent
reaction with acetone in the presence of anhydrous CuSO4
under acidic conditions to afford a mixture of racemic and
meso diols, 14 and 15, respectively, following a literature
procedure (Scheme 2);31 14 and 15 were separated by
fractional recrystallization and converted to the corresponding
HO
3 (53%)
HO
2 (55%)
OH
OH
Scheme 1. Reagents and conditions: (i) p-TSA, 2,2-dimethoxypropane, Me2CO; (ii)
NaBH4, MeOH; (iii) Et3N, MsCl, CH2Cl2; (iv) Te, NaBH4, PEG-400; (v) TFA, H2O, CH2Cl2.
Starting from commercially available carbohydrates, a number dimesylates 16 and 17 (90% and 89% yields respectively).
of tellurosugar analogues with varying stereochemistries and Dimesylates 16 and 17 were reacted with NaHTe (as above), to
functionalities were prepared. Accordingly, D-mannose afford the cyclic tellurides 18 and 19 in 60% yield.
underwent reaction with 2,2-dimethoxypropane in the Deprotection with TFA and H2O in CH2Cl2 and purification by
presence of catalytic p-toluenesulfonic acid and acetone under flash chromatography led to decomposition of rac-
anhydrous conditions to afford the protected D-mannose was obtained as a crystalline, hygroscopic orange solid.
(85% yield) (Scheme 1). The extracted product was
4, however
9
5
9
H
H
H
OH
O
O
HO
TBSO
recrystallized and reacted with sodium borohydride (NaBH4) in
methanol to give diol 10 (90% yield), which was converted into
the corresponding dimesylate 11 (82% yield), by reaction with
methanesulfonyl chloride (MsCl) in dichloromethane (CH2Cl2)
and triethylamine. Separately, the nucleophilic tellurium
species (NaHTe) was generated in situ by the reaction of
elemental tellurium with NaBH4 in EtOH, after which it was
added to dimesylate 11 with stirring for 1 h at 70 °C, however
the desired product 12 was not obtained. Decreasing the
reaction temperature to 55 °C, did however give 12 in 10%
yield after 2h. Repetition of this reaction in polyethylene glycol
(PEG-400) instead of EtOH under the same conditions, gave 12
TBSO
O
O
6
OH
O
O
O
O
O
O
20
Scheme 3. Preparation of 1,4-dideoxy-L-tellurolyxitol (6).
21
22
We also explored the effect of the length of the side-chain
attached to C-4 of the cyclic telluride by preparing 1,4-dideoxy-
L-tellurolyxitol
(6), which was prepared from 2,3-
isopropylidene-D-ribonic acid 1,4-lactone (20) as the starting
carbohydrate (Scheme 3). The free alcohol was first protected
with tert-butyldimethylsilyl chloride (TBSCl) to afford the silane
2 | J. Name., 2012, 00, 1-3
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21 in almost quantitative yield. The protected lactone 21 was potent oxidant scavengers. The simplest structures
reduced to diol 22 with NaBH4 (82% yield), after which it was exhibit the fastest rate constants for reaction with HOCl, with
converted into tellurolyxitol using similar procedures to values comparable to those determined previously for the free
those described above;
was isolated as a yellow solid in 45% amino acid Cys (k2 ~ 3.2 x 108 M-1s-1) and other thiols,33 and of
7 and 6
6
6
yield; further details are found in the ESI.
the same magnitude as the analogous selenosugars,8 but
faster, in general, than those of thioethers (e.g. Met; k2 ~ 3.4 x
107 M-1s-1 33). As expected the two stereoisomeric Te-sugars
gave values that were not statistically different from each
other. The rate constants determined for HOBr are faster than
those determined for HOCl which is in contrast to the data
reported for the selenium analogues,8 but in line with the
enhanced reactivity of some amino acid side chains with HOBr
compared to HOCl (cf. previously reported data34-36).
HO
O
O
NaHTe
H2O
Te
HO
23
7
Scheme 4. Preparation of D,L-trans-3,4-dihydroxy-1-tellurolane.
For comparison purposes, racemic D,L-trans-3,4-dihydroxy-1-
tellurolane (7) was synthesized by the addition of an aqueous
solution of NaHTe to 1,3-butadiene bisepoxide (23), as a
yellow solid in 98% yield after 1 h (Scheme 4). To the best of
Table 1. Second order rate constants, k2, at 22° C and pH 7.4 (in 10 mM
phosphate buffer for HOCl and HOBr, 100 mM phosphate buffer for ONOOH) for
reaction of the oxidants HOCl, HOBr, and ONOOH with the Te sugars. For further
details, see the ESI.
our knowledge, trans-dihydroxytellurolane
7 appears to be
novel, and there are no literature reports on the use of this
protocol. Indeed, Klayman reported that NaHTe reacts very
slowly in water and affords no product.32 To overcome this
potential problem, we directly added an excess of NaBH4 to
the reaction mixture, which resulted in an increase in reactivity
Compound
k2 HOCl, M-1s-1
(2.0±0.4) x 108
(5.2±0.6) x 107
(6.0±0.7) x 107
(2.6±0.1) x 107
(1.5±0.1) x 108
k2 HOBr, M-1s-1
(1.1±0.3) x 108
(4.7±0.7) x 108
(2.5±0.7) x 108
(5.4±1.3) x 108
(2.6±0.2) x 109
k2 ONOOH, M-1s-1
(1.6±0.3) x 105
-
7
1
2
5
6
and product yield. It should be noted that
analogue of DHSred, a known biological antioxidant.12, It is
interesting to note that 1,4-dideoxy-L-tellurolyxitol ( ) and the
1,4-dideoxytellurotalitol isomers ( ) were inert, isolable
solids, while and were more labile. We are unable to
provide an explanation for these observations. The telluropane
, on the other hand, is stabilised through the larger ring that
7 is the tellurium
29
(1.5±0.3) x 104
(5.3±0.4) x 103
(4.1±0.2) x 104
6
1, 2
3
4
5
can better accommodate the longer C-Te bond distances.
Scheme 5. Proposed mechanism of reaction of oxidants with Te-sugars. Initial
fast reaction with the oxidant (with second order rate constant, k2) is followed by
reaction with H2O to give the corresponding telluroxide.
Scavenging of the biologically important oxidants HOCl and
HOBr by the Te-compounds (Scheme 5), was investigated using
a competition kinetics approach in which oxidation of Fmoc-
methionine (FmocMet) to Fmoc-methionine sulfoxide
(FmocMetSO) was used as a reference reaction, with the
second order rate constant for this reference reaction, k2
taken as 1.5 x 108 M-1 s-1.33 Representative scavenger plots (for
further details see the ESI) are shown in Figure 2A, and the
resulting k2 values are collected in Table 1. Rate constants for
reaction of ONOOH with the Te-compounds were determined
by stopped-flow spectroscopy, by monitoring the decay of
ONOOH at 302 nm in the absence and presence of added Te
compound as described previously,11 with the resulting
pseudo-first-order rate constants (kobs) subsequently plotted
against the Te-sugar concentration, to give k2 (Figure 2B, Table
1).
Figure 2. Kinetic analysis of: (A) the reaction of HOCl with Te-compounds determined
by competition kinetics with FmocMet with UPLC analysis, and (B) for reaction with
ONOOH as determined from direct kinetic determination of kobs by fitting of
exponential decay curves to the experimental data for ONOOH decay at 302 nm in the
absence and presence of the added Te compounds.
The k2 values obtained indicate that these novel Te-sugars are
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7
8
9
C. Storkey, M. J. Davies, J. M. White and C. H. Schiesser,
Chem Commun, 2011, 47, 9693.
C. Storkey, D. I. Pattison, J. M. White, C. H. Schiesser and M.
J. Davies, Chem Res Toxicol, 2012, 25, 2589.
M. Iwaoka, N. Sano, Y. Y. Lin, A. Katakura, M. Noguchi, K.
Takahashi, F. Kumakura, K. Arai, B. G. Singh, A. Kunwar and
K. I. Priyadarsini, Chembiochem, 2015, 16, 1226.
In the case of peroxynitrous acid (ONOOH),
7
was the most
exhibiting
efficient scavenger, with the seven-membered ring
5
the slowest rate constant among the Te-sugars examined. The
variation between the highest and lowest values for these Te-
sugars is approximately 30-fold. The reasons for this much
larger variation compared to the data for HOCl and HOBr, is
unclear at present, and warrants further investigation. These
rate constants for reactions of the Te sugars with ONOOH are
significantly higher than those for reaction with the sulfur-
containing amino acids Cys and Met, which have k2 values in
the 102–103 M-1s-1 range, and other protein side-chains (e.g.,
Trp11 and references therein), and also significantly greater
than for the corresponding seleno sugars which have k2 values
of ~2.5 x 103 M-1s-1.11 These data therefore indicate that some
10 1F. Kumakura, B. Mishra, K. I. Priyadarsini and M. Iwaoka,
Eur J Org Chem, 2010, 440.
11 C. Storkey, D. I. Pattison, M. T. Ignasiak, C. H. Schiesser and
M. J. Davies, Free Radic Biol Med, 2015, 89, 1049.
12 S. Chakraborty, S. K. Yadav, M. Subramanian, K. I.
Priyadarsini, M. Iwaoka and S. Chattopadhyay, Free Radic
Res, 2012, 46, 1378.
13 C. H. Schiesser, C. Storkey and M. J. Davies, Int. Patent Appl.
WO 2016/054671.
14 C. H. Schiesser and L. M. Wild, Tetrahedron, 1996, 52, 13265.
15 S. H. Kyne and C. H. Schiesser, in Encyclopedia of Radicals in
Chemistry, Biology and Materials, eds. C. Chatgilialoglu and
A. Studer, John Wiley and Sons, Chichester, UK, 2012, pp.
629.
of these Te sugars (e.g., 7) are efficient scavengers of ONOOH,
and should be effective protective agents against damage
induced by this oxidant.
16 T. Kanda, L. Engman, I. A. Cotgreave and G. Prowls, J Org
Chem, 1999, 64, 8161.
17 X. Lu, G. Mestres, V. P. Singh, P. Effati, J. F. Poon, L. Engman
and M. Karlsson Ott, Antioxidants, 2017, 6, 13.
18 Z. B. Chen, J. W. Lv, F. Q. Chen and L. D. Lin, J Mol Catal B-
Enzym, 2008, 55, 99.
In summary, we herein report the synthesis and potent
oxidant scavenging activity of a family of novel, stable, water
soluble tellurium-containing sugars. These materials show very
high reactivities toward biologically important two-electron
oxidants, with the overall order of oxidant reactivity being
HOBr > HOCl > ONOOH.
19 L. Engman, D. Stern, M. Pelcman and C. M. Andersson, J Org
Chem, 1994, 59, 1973.
20 R. L. Puntel, D. S. Avila, D. H. Roos and S. Pinton, Curr Org
Chem, 2016, 20, 198.
21 L. Wang, F. Q. Fan, W. Cao and H. P. Xu, Acs Appl Mater Inter,
We thank the Australian Research Council through the Centres
of Excellence Scheme, the University of Melbourne through
the International Research and Research Training fund (IRRTF),
the Novo Nordisk Foundation (grants: NNF13OC0004294 and
NNF15OC0018300) for financial support, and CNPq (Brazil) for
scholarships and research fellowships granted to ELB and GP.
2015, 7, 16054.
22 Z. R. Lou, P. Li and K. L. Han, Acc Chem Res, 2015, 48, 1358.
23 K. Briviba, R. Tamler, L. O. Klotz, L. Engman, I. A. Cotgreave
and H. Sies, Biochem Pharmacol, 1998, 55, 817.
24 L. Orian and S. Toppo, Free Radic Biol Med, 2014, 66, 65.
25 A. C. G. Souza, C. Luchese, L. S. S. Neto and C. W. Nogueira,
Life Sci, 2009, 84, 351.
26 X. J. Ren, Y. Xue, K. Zhang, J. Q. Liu, G. M. Luo, J. Zheng, Y. Mu
and J. C. Shen, FEBS Lett, 2001, 507, 377.
Conflicts of interest
27 C. M. Andersson, R. Brattsand, A. Hallberg, L. Engman, J.
Persson, P. Moldeus and I. Cotgreave, Free Radic Res, 1994,
20, 401.
There are no conflicts to declare.
28 J. Malmstrom, M. Jonsson, I. A. Cotgreave, L. Hammarstrom,
M. Sjodin and L. Engman, J Am Chem Soc, 2001, 123, 3434.
29 M. McNaughton, L. Engman, A. Birmingham, G. Powis and I.
A. Cotgreave, J Med Chem, 2004, 47, 233.
30 O. T. K. Nguyen and C. H. Schiesser, Tetrahedron Lett., 2002,
43, 2799.
31 R. M. Hann, W. D. Maclay and C. S. Hudson, J Am Chem Soc,
1939, 61, 2432.
32 D. L. Klayman and T. S. Griffin, J Am Chem Soc, 1973, 95, 197.
33 C. Storkey, M. J. Davies and D. I. Pattison, Free Radic Biol
Med, 2014, 73, 60.
Notes and references
‡
In our experience, NaHTe is very sensitive to trace amounts
of O2, much more so than NaHSe. PEG-400 generally affords
higher yields than EtOH/THF, which we ascribe to the lower
solubility of adventitious O2.
§
decompose above 80 °C. However,
Melting points for
1
–
7
could not be determined as they
are stable solids
1, 2, 5–7
that were shipped from Melbourne to Copenhagen without
special precautions. The compounds were stored at -20 °C with
minimal exposure to light, and were unchanged over one year.
34 D. I. Pattison and M. J. Davies, Chem. Res. Toxicol., 2001, 14
,
1453.
35 D. I. Pattison and M. J. Davies, Biochemistry, 2004, 43, 4799.
1
2
3
T. C. Stadtman, Annu Rev Biochem, 1996, 65, 83.
J. Lu and A. Holmgren, J Biol Chem, 2009, 284, 723.
L. Flohe, S. Toppo, G. Cozza and F. Ursini, Antioxid Redox
Signal, 2011, 15, 763.
36 D. I. Pattison and M. J. Davies, Curr. Med. Chem., 2006, 13
3271
,
4
S. Gromer, L. Johansson, H. Bauer, L. D. Arscott, S. Rauch, D.
P. Ballou, C. H. Williams, Jr., R. H. Schirmer and E. S. Arner,
Proc Natl Acad Sci U S A, 2003, 100, 12618.
B. C. Lee, A. Dikiy, H. Y. Kim and V. N. Gladyshev, Biochim
Biophys Acta, 2009, 1790, 1471.
5
6
H. Sies, Free Radic Biol Med, 1993, 14, 313.
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TOC entry
Novel stable tellurium-containing carbohydrates are prepared; these react very rapidly with two-
electron oxidants and show promise as protective agents.