Total Synthesis and Functional Characterization of Selenoneine

Article abstract of DOI:10.1002/anie.201908967

The N-α-trimethyl 2-selenohistidine selenoneine is the selenium isolog of the natural antioxidant ergothioneine. Sulfur-to-selenium substitutions are known to endow proteins and nucleic acids with special activities. In contrast, secondary metabolites tha

Full text of DOI:10.1002/anie.201908967

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Accepted Article
Title: Total synthesis and functional characterization of Selenoneine
Authors: David Lim, Dirk Gründemann, and Florian P. Seebeck
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10.1002/anie.201908967
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Total synthesis and functional characterization of Selenoneine
David Lim[a], Dirk Gründemann[b] and Florian P. Seebeck[a]*
Abstract: The N-a-trimethyl 2-selenohistidine selenoneine is the
selenium isolog of the natural antioxidant ergothioneine. Sulfur-to-
selenium substitutions are known to endow proteins and nucleic acids
with special activities. In contrast, secondary metabolites that exploit
selenium-specific chemistry are rare. Selenoneine therefore provides
a unique opportunity to study how natural organoselenides interact
with cellular processes. In this report we describe the chemical
synthesis of selenoneine and other 2-selenoimidazoles. With
synthetic selenoneine at hand we discovered a set of reactivities that
distinguish selenoneine from ergothioneine, showing that the two
compounds can fill distinct functional niches. Synthetic access to 2-
selenoimidazoles should pave the way to explore the pharmaceutical
potential and physiological function of this heretofore inaccessible
class of compounds.
Figure 1. a) Chemical structures of ebselen, selenoneine and ergothioneine. b)
Synthesis of 2-imidazole diselenide 3. Reaction conditions: a) 1) Imidazole, NaI,
K2CO3, DMF, 16 h; 2) Se, K2CO3, DMF, 80 °C, 16 h; 53 % yield; b) 1.7 M tBuLi
in hexane; THF, -78 °C, 30 mins, 94 %. Synthesis of 8-11 were performed using
Selenium is a critical micronutrient for humans. Too little or too
much of it can cause disease, including depression, dementia,
immune deficiency, hair loss or cardiovascular disease.[1]
Because selenium atoms have the same valency,
electronegativity and almost the same size as sulfur atoms, many
biosynthetic enzymes cannot efficiently distinguish between the
two elements.[1b] As a result, most known selenium metabolites
are isologs of the corresponding sulfur compounds including
similar procedures. Overall yields over three steps: 8: 41 %; 9: 42 %; 10: 55 %;
11: 5 %
weaker bonds with period 2 elements, allowing selenium
compounds to engage more readily in making and breaking
covalent bonds. Because of this versatility selenium has also
been included in the design of artificial enzymes,[8] enzyme
models,[9] protein ligation strategies, protein folding studies, [10] [7]
or molecular probes.[11] Furthermore, the observation that ebselen
(Figure 1a) and other synthetic organoselenides can catalyse
peroxide reduction and form covalent bonds to specific proteins
highlighted the therapeutic potential of such compounds.[11c, 12]
Indeed, a number of recent studies indicate that ebselen may be
used in the treatment of a wide range of health problems.[13]
Surprisingly, there are very few examples of natural
secondary metabolites that depends on selenium-specific
chemistry for function. From such molecules one could learn how
and where organoselenides – optimized by evolution – would
interfere with cellular processes.[14] One of these rare examples is
selenoneine (Figure 1a).[15] This selenium isolog of ergothioneine
(Figure 1a) was first isolated from the muscle tissue of marine
fish.[15-16] Selenoneine also accumulates in humans with a
seafood-rich diet which raises questions about potential health
risks or benefits emanating from this unusual selenium source.[16-
17] However, aside of intriguing indications that selenoneine may
provide protection against mercury poisoning, [16, 18] little is known
about the chemistry of such compounds.[19]
selenomethionine,
selenocysteine,
Se-adenosyl
seleno-
methionine or selenobiotin.[1b, Their cellular concentration is
largely dependent on the selenium content in the environment and
their physiological purpose is unclear.[3]
2]
In contrast, elaborate enzymatic machineries have evolved
to enable targeted incorporation of selenium in the form of
selenocysteine and 2-selenouridine into specific proteins and
nucleic acids.[1b, 4] Specific sulfur-to-selenium substitutions can be
advantageous because of the two elements show distinctly
different reactivities.[1c] For example, selenols are more acidic and
more reducing that thiols (pKa,SeH: ~ 5; pKa,SH: ~ 9).[5] Selenols
can efficiently react with triplet oxygen (3O2) whereas autoxidation
of thiols usually depends on catalysis by transition metals.[6]
Although diselenide bonds are more stable than disulfide bonds,[7]
selenium generally forms
[a]
[b]
Dr. D. Lim and Prof. Dr. F.P. Seebeck*
Department for Chemistry
University of Basel
Mattenstrasse 24a, 4002, Basel, Switzerland
E-mail: florian.seebeck@unibas.ch
Prof. Dr. Dirk Gründemann
Department of Pharmacology, University of Cologne, Faculty of
Medicine and University Hospital Cologne, Gleueler Straße 24,
50931, Cologne, Germany
In the quest of learning more, we developed the first chemical
synthesis of unprotected 2-selenoimidazoles. Based on this
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201908967
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Se
-
Se
N
Ph
CO2
2
N
N
a)
b)
c)
N
N
HN
HN
Me3N
HN
NH
Ph
H2N
CO2Me
BocHN
CO2Me
13
N
MeO2C
NHBoc
15
BocHN
CO2Me
14
12
Se
d)
O
O
Se
OEt
OEt
NH
Se
Se
Se
Se
N
g)
f)
2
2
e)
N
N
O
N
O
N
NH
NH
N
N
NMe3
EtO
EtO
-O2C
-O2C
NMe3
19
MeO2C
NMe2
16
Me2N
CO2Me
Me3N
CO2Me
20
18
17
Scheme 1. Total synthesis of selenoneine. Reaction conditions: a) 1) (Boc)2O, trimethylamine, MeOH; 2) K2CO3, MeOH, reflux, 2 h, 76 %; b) 1) phenylallyl bromide,
K2CO3, NaI, DMF; 2) Se, K2CO3, 80 °C, 81 %; c) 1.7 M t-BuLi in hexane, THF, -78 °C, 30 mins, 100 %; d) 1) trifluoroacetic acid, triisopropylsilane, DCM; 2) CH2O,
NaCNBH3, MeOH, 1 h, 53 % over two steps; e) 1) NaCNBH3, DCM, 30 mins; 2) triethylamine, ethylchloroformate, 10 °C, 1 h, 31 %; f) MeI, THF, 16 h, 21 %; g)
LiOH.H2O, H2O, 1 h, 100 %. Synthesis protocols and characterization of compounds are described in the supporting information.
methodology we synthesized selenoneine and characterized
its properties in comparison with ergothioneine (Figure 1a).
selone 14. Deprotection of 14 gave the diselenide 15 in
racemic form, as inferred by polarimetry. Removal of the Boc-
protecting group under acidic conditions, followed by reductive
amination with formaldehyde gave dimethylamine 16 in 53 %
yield over two steps. 16 was reduced and then reacted with
ethyl chloroformate to give 17. Methylation with methyl iodide
gave 18. Treatment of this compound with LiOH.H2O produced
selenoneine, which was isolated as diselenide 19 in 2 % yield
(120 mg) over 11 steps.
In a next step we started to characterize the properties of
synthetic selenoneine. As noted before selenoneine readily
oxidizes to a stable diselenide.[27] In contrast, ergothioneine is
largely resistant towards autooxidation and the symmetric
disulfide slowly decomposes by hydrolysis at neutral pH.[28]
The proton NMR spectra recorded of selenoneine and
ergothioneine in buffered solutions at pH between 6 and 13
show that both molecules are characterized by a single
deprotonation event at alkaline pH (pKa,sel = 10.1, pKa,erg = 10.6,
published pKa,erg = 10.8)[29], suggesting that both molecules are
neutral under physiological conditions (Figure S1). This finding
establishes that the higher propensity of selenoneine for
oxidative dimerization is not due to higher acidity.
Presently, the only available selenoimidazole derivative
is L-selenoneine that is isolated either from marine fish or from
fermented Schizosaccharomyces pombe.[20] These sources
are limited by low yields and restricted to the naturally
occurring
compound.
Protocols
to
synthesize
2-
mercaptoimidazoles, including ergothioneine are well
established,[21] but these procedures invariably fail in the
synthesis of 2-selenoimidazoles. A suggested synthesis of
selenoneine proved irreproducible in our hands and others.[20b,
22] Approaches that were devised to make N-monosubstituted
or N,N’-disubstituted 2-selenoimidazoles are comparatively
inefficient [9, 23] and impose narrow restrictions on the range of
permissible N-substituents.
A key challenge in the synthesis of unprotected 2-
selenoimidazoles stems from the vulnerability of the carbon-
selenium (C-Se) bond towards harsh reductive and oxidative
conditions. Hence, while alkylation of both nitrogen atoms is
essential for attaching selenium to the imidazole ring,[23a]
conditions for the subsequent deprotection are not compatible
in the presence of the selone function. As a solution to this
problem, we used 2-phenylallyl groups for N-protection.[24] As
a first model synthesis imidazole was bis-alkylated with
phenylallyl bromide 1 (Figure 1b). The resulting N,N-alkyl
imidazolium was reacted with a weak base and elemental
selenium to produce selone 2 in 53 % yield. Treatment of 2
with tert-butyl lithium allowed efficient removal of the
phenylallyl groups to produce selenoimidazole which oxidized
to the symmetric diselenide 3 (94 % yield). Similar procedures
were used to synthesize the diselenides 8 - 11, including the
isologs of lactoperoxidase and thyroid peroxidase (10),[23c, 23d,
The structural and electrostatic similarity of selenoneine
and ergothioneine suggest that selenoneine could be an
efficient substrate for the human ergothioneine transporter
(ETTh).[30] To test this idea, the ETTh was expressed and
assayed in human embryonic kidney 293 cells as established
previously (Supporting information).[31] Briefly, adherent cells
were incubated shortly with selenoneine at 37 °C in a
chemically defined buffer. After washing and cell lysis, the
selenoneine
content
was
determined
by
Liquid
Chromatography–Mass Spectrometry (LC-MS/MS). Uptake of
selenoneine was saturable (Figure S2), with a KM of 27 (95%
confidence interval, 16–46) μmol/L. Similar KM values were
reported previously for ergothioneine and the ETT transporters
from human (21 (16–28) µM),[30] pig (22 (12–39) μmol/L), and
chicken (11 (8–17) μmol/L).[32] In the particular experiment
shown, with a Vmax of 560 (standard error, ± 32) pmol min-1 mg
protein-1, the clearance (Vmax/KM, a measure of transport
25]
and known mercaptoimidazole-based inhibitors of
lipoxygenase (11).[26]
The synthesis of selenoneine was started with protection
of the primary amine of L-histidine methyl ester 12 with tert-
butyloxycarbonyl to give 13 (Scheme 1).
Using the
aforementioned phenylallyl protection, 13 was converted to
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10.1002/anie.201908967
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efficiency) was 21 µL min-1 mg protein-1, somewhat lower than
typically measured (i.e. 50-100 µL min-1 mg protein-1) for
ergothioneine and ETTh in our expression system.
Nevertheless these data support the idea that selenoneine is
efficiently distributed in the human body even at low
concentrations.[17a, 19]
as hydrogen peroxide and superoxide was shown to convert
ergothioneine to TMH (21, Scheme 2, Figure S3) or
ergothioneine sulfonic acid (22). Both metabolites have been
isolated from biological samples, indicating that oxidative
degradation of ergothioneine is a physiologically relevant
process.[34d] The intermediate oxidation products ergothioneine
disulphide (23) and ergothioneine sulfinic acid (24) are less
stable and do not accumulate.[28a] Selenoneine shows a very
different behaviour. Conditions that completely desulfurize
ergothioneine, convert selenoneine to the stable seleninic acid
(25, Figure S4). The same product emerges from a reaction of
hydrogen peroxide with selenoneine diselenide, suggesting
that the diselenide is an intermediate in the formation of
seleninic acid. Deselenation of the seleninic acid was observed
as a slow and hydrogen peroxide dependent reaction (rate: [3
± 1] x 10-3 min-1), suggesting that further oxidation to the
unstable selenonic acid (26) is a prerequisite for C-Se bond
cleavage.
On the other hand, 25 reacts rapidly and quantitatively
with GSH or DTT to reform selenoneine (Figure S4).[36] This
reactivity suggest that in a cellular context reductive recycling
of 25 is much more efficient than deselenation. Consequently,
selenoneine is more resistant towards irreversible oxidative
degradation than ergothioneine. Indeed, resistance towards
oxidative deselenation has been suggested as the main
evolutionary incentive for replacement of specific sulfur atoms
with selenium in proteins, nucleic acids and - as exemplified by
selenoneine - in secondary metabolites.[37]
An earlier study examined selenoneine uptake using the
diselenide form, and quantified uptake indirectly by Inductively
Coupled Plasma Mass Spectrometry (ICP-MS), using total
selenium content as a proxy.[17a] This experiment raised the
possibility that the diselenide instead of or in addition to the
reduced form might be a substrate for the ETTh. To test this
possibility, we prepared
a
redox-stable analogue of
selenoneine diselenide by linking two selones with a single
methylene group (20, Scheme 1). Accumulation of this
compound (incubation time 1 min, 1 µM and 10 µM) in ETT-
expressing cells was not higher than in control cells (not
shown). By contrast, uptake of ergothioneine (1 min, 10 µM)
measured in paired dishes was 30-fold higher in ETT-
expressing cells than in control cells. Thus, we conclude that
ETTh cannot efficiently transport 20. This finding underscores
the strict substrate specificity of ETTh and establishes that
selenoneine is transported in reduced form.[31] Most likely, the
complex cell culture medium used in the previous uptake
experiments contained sufficient free thiols (> 30 µM) to reduce
all or a fraction of the diselenide. Similarly, the extracellular
plasma contains a considerable pool of free thiols (~0.4–0.6
mM, mostly Cys34 on human serum albumin) that may account
for the efficient uptake of selenoneine in the human body.[33]
Under aerobic conditions and in the absence of reducing
equivalents the most stable form of selenoneine is the
diselenide 19.[16, 20b] Based on the report that selenenyl sulfides
and seleninic acids react with electron-rich arenes via
electrophilic aromatic substitution,[38] we wondered as to
whether selenoneine diselenide would react in a similar way.
Indeed, incubation of selenoneine diselenide with resorcinol in
a buffered aqueous solution at 37 °C for 24 h readily produced
a selenoneine adduct of resorcinol (27, Figure S5). Although
resorcinol is not itself
a known natural product, 1,3-
benzenediol motifs are common among phenylpropanoids,
terpenoids, polyketides and nonribosomal peptides. Therefore,
it is possible that a broad range of selenoneine adducts of
natural products may have yet to be discovered from natural
sources. To provide a few explicit examples we reacted the
phenylpropanoid resveratrol, the nonribosomal peptide
Scheme 2. Reactions of ergothioneine (a) and selenoneine (b) with H2O2
A final set of experiments were designed to compare the
redox reactivity of selenoneine and ergothioneine. The
consensus opinion in the literature posits that ergothioneine
protects cells from oxidative stress.[34] One way to decipher the
mechanisms of ergothioneine-based cytoprotection is to study
the redox reactivity of ergothioneine and its oxidation
products.[28a, 35] Treatment with reactive oxygen species such
vancomycin and polyketide proansamitocin[39]
with
selenoneine diselenide to produce the corresponding adducts
(28 - 30, Figure 2).
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Figure 2. Reactivity of selenoneine diselenide with C-nucleophiles. Reaction conditions: Selenoneine diselenide (0.2-1 mM), arene (4-10 mM), 0.1 M Tris (pH 8),
H2O or H2O/EtOH (9:1), 37 °C, 24 h. Products were identified by HR-ESI-MS. Yields were determined by HPLC peak integration (27: 89 %; 28: 86 %; 29: 87 %; 30:
5 %).
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selenoneine is imported by human cells with similar efficiency
as ergothioneine. Selenoneine was shown to engage in
reversible oxidation and reduction reaction under conditions
that irreversibly degrade ergothioneine. These findings
suggest that selenoneine is a more robust antioxidant than
ergothioneine. Selenoneine diselenide was shown to react with
complex natural products via electrophilic aromatic substitution
to form selenoneine adducts. These reactions occur under
physiological conditions raising the possibility that adduct
formation may be part of selenoneines functional portfolio. The
different reactivities of selenoneine and ergothioneine support
the idea that the two compounds fill distinct functional niches
in biology.
Acknowledgements
We thank Friederike Schäkel and Andreas Kirschning for
providing
a
sample of proansamitocin and Samira
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Boussettaoui and Simone Kalis for skilful technical assistance.
This project was supported by a starting grant from the
European Research Council (ERC-2013- StG 336559), the
NCCR for Molecular Systems Engineering and by the
“Professur für Molekulare Bionik”.
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Keywords: 2-selenoimidazole • antioxidant • organoselenide
• natural product • ergothioneine
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David Lim, Dirk Gründemann and
Florian P. Seebeck*
Page No. – Page No.
Total synthesis and characterization
of Selenoneine
Se
NH
HN
N
O
N
Ph
Ph
N
BocHN
O
OH
O
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