Thionitrite and Perthionitrite in NO Signaling at Zinc

Article abstract of DOI:10.1002/anie.202104906

NO and H₂S serve as signaling molecules in biology with intertwined reactivity. HSNO and HSSNO with their conjugate bases ^?SNO and ^?SSNO form in the reaction of H₂S with NO as well as S-nitrosothiols (RSNO) and nitrite (NO₂^?) that serve as NO reservoirs. While HSNO and HSSNO are elusive, their conjugate bases form isolable zinc complexes ^Ph,MeTpZn(SNO) and ^Ph,MeTpZn(SSNO) supported by tris(pyrazolyl)borate ligands. Reaction of Na(15-C-5)SSNO with ^Ph,MeTpZn(ClO₄) provides ^Ph,MeTpZn(SSNO) that undergoes S-atom removal by PEt₃ to give ^Ph,MeTpZn(SNO) and S=PEt₃. Unexpectedly stable at room temperature, these Zn-SNO and Zn-SSNO complexes release NO upon heating. ^Ph,MeTpZn(SNO) and ^Ph,MeTpZn(SSNO) quickly react with acidic thiols such as C₆F₅SH to form N₂O and NO, respectively. Increasing the thiol basicity in p-substituted aromatic thiols ^4?XArSH in the reaction with ^Ph,MeTpZn(SNO) turns on competing S-nitrosation to form ^Ph,MeTpZn-SH and RSNO, the latter a known precursor for NO.

Full text of DOI:10.1002/anie.202104906

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Accepted Article
Title: Thionitrite and Perthionitrite in NO Signaling at Zinc
Authors: Valiallah Hosseininasab, Jeffery A. Bertke, and Timothy H.
Warren
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10.1002/anie.202104906
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COMMUNICATION
Thionitriite and Perthionitrite in NO Signaling at Zinc
Valiallah Hoosseininasab, Jeffery A. Bertke, and Timothy H. Warren**
Abstract: NO and H2S serve as signaling molecules in biology with
intertwined reactivity. HSNO and HSSNO with their conjugate bases
-
-SNO and SSNO form in the reaction of H2S with NO as well as
S-
-
nitrosothiols (RSNNO) and nitrite (NO2 ) that serve as NO reservoirs.
While the elusivee nature of HSNO and HSSNO renders their study
challenging, their conjugate bases form isolable zinc complexes
Ph,,
MeTpZn(SNO)
and
Ph,MeTpZn(SSNO)
supported
by
tris(pyrazolyl)borate ligands. Reaction of Na(15-C-5)SSNO with
Ph,,
MeTpZn(ClO4) provides Ph,MeTpZn(SSNO) that undergoes S-atom
removal by PEt3 to give Ph,MeTpZn(SNO) and S=PEt3. Unexpectedly
stable at room ttemperature, these Zn-SNO and Zn-SSNO com-
plexes release NO upon heating. Ph,MeTpZn(SNO) and
Ph,,
MeTpZn(SSNO)) quickly react with acidic thiols such as C6F5SH to
form N2O and NO, respectively. Increasing the thiol basicity in p-
substituted aromatic thiols 4-XArSH in the reaction with
Ph,,
MeTpZn(SNO) tturns on competing
S
-nitrosation to form Ph,MeTpZn-
SH and RSNO, thhe latter a known precursor for NO.
Nitric oxide (NO) serves as a key signaling molecule in
biology that iss involved functions including vasodilation,
Figure 1. (a) Formation and reactivity of HSNO/SNO-. (b) Syn-
and anti-isomers for RNSOs and HSNO. (c, d) Transition metal
neurotransmisssion and cytoprotection.[1] Intriguingly, H2S
functions as a separate gasotransmitter that exhibits similar
physiological efffects as NO.[2] Endogenously produced H2S
functions as a relaxant of smooth muscle cells and as a
vasodilator.[3] Sttrong cellular communication involving NO and
H2S suggests a mutually dependent mechanism of action
between these two gasotransmitters.[4] The chemical basis for
this crosstalk may be related to the reaction between H2S and
complexes of HSNO/SNO- detected via mass spectrometry. (e)
-
Reaction of NO2
annd thiols at TpZn sites to form RSNOs. (f)
Transnitrosation reactions at TpZn-SR’ complexes with RSNOs.
The coordina
ion chemistry of HSNO/SNO- with biologically
relevant metal ce
ters is complex and not well understood.[10]
t
t
n
n
Nitrite reduction at an iron(II) porphyrin results in the formation of
an [FeIII]-NO species that undergoes reaction with HS- proposed
to give [FeII](HSNO) observed via high resolution cryospray ESI-
NO and its counterparts S-nitrosothiols (RSNOs) and nitrite
]
TOF (Figure 1c).[11 Addition of NO+ to a copper(I) hydrosulfide
-
(NO2 ) to form HSNO, the smallest
S
-nitrosothiol (Figure 1a).[5]
[CuI]-SH generates N2O and S8, thought to proceed via an
HSNO is an incredibly reactive species whose instabilty
poses challengges in understanding its biochemistry and
mechanisms off action.[6] Its reactivity may derive from the
elongated S-N bond of 1.852 Å in trans-HSNO,[7] the longest
among regular RRSNOs with typical S-N distances of 1.70 - 1.80
Å (Figure 1b).[[7] Contrary to typical RSNOs, HSNO easily
diffuses through cell membranes and acts as a nitrosating agent
for large proteiins.[5c] HSNO may serve as a precursor for
multiple downstream products connecting to NO signaling that
includes HNO aand SSNO-.[6] Moreover, SSNO- also particpates
in NO signalingg and thiol trafficking pathways, formed in the
reaction of RSNOs and H2S via unstable HSNO.[5a, 6]
unstable {[CuI](H NO)}+ adduct.[12] Additionally, the disulfido
SS
complex[(edta)RuIII-S-S-RuIII(edta)]4- reacts with NO to give
−
−
[(edta)RuIII(SNO)]2 characterized by mass spectrometry (Figure
1d).[13]
H2S and
N
O
species play important roles in zinc
biochemistry. Whe
n
n exposed to H2S, some zinc finger proteins
undergo persulfidation (-SCys to -SSCys)[14] that releases
structural Zn2+ ion
the zinc sites ar
ss, but only under aerobic conditions and when
ee exposed and not enshrouded by RNA
binding.[15] Carbonic anhydrase can convert carbonyl sulfide
(COS) to H2S,[16] inhibiting CO2 hydration. Inspired by the
-
generation of NO from NO2 at carbonic anhydrase,[17] TpZn
Owing to ttheir high acidity, HSNO and HSSNO likely exist
as thionitrite (SNO-) and perthionitrite (SSNO-) under
models of its His3Zn2+ active site reveal that thiols RSH react
with zinc-bound nitrite to generate NO via thermally sensitive
nitrosothiols RSN (Figure 1e). Emulating the activation of
His3Zn2+ via the cl avage of the Zn-SCys linkage,[18] TpZn-SR’
S-
physiological coonditions (calculated pKa’s
= 3.5 and 0.2,
respectively for syn-isomers).[8] Charge balance by non-
O
ee
O
interacting cations enables isolation and X-ray characterization
complexes undergo reversible transnitrosation with
S-
of
[PPN][SNNO]
and
[PPN][SSNO]
(PPN
=
nitrosothiols (RSNO) (Figure 1f).[19] Employing similar TpZn
models, we examine the interaction of SNO- and SSNO- at Zn to
explore their reactivity patterns that can inform the biochemistry
bis(triphenylphosphine)iminium). [PPN][SSNO] forms in the
reaction of [PPPN][NO2] with elemental sulfur and undergoes
desulfurization by triphenylphosphine to give [PPN][SNO].[9]
of these species thaat result from NO / H2S crosstalk.
V. Hosseininnasab, Dr. J. A. Bertke, Prof. Dr. T. H. Warren
Department of Chemistry, Georgetown University
Box 5712277, Washington, DC 20057-1227 (USA)
E-mail: thw@georgetown.edu (T.H.W.)
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10.1002/anie.202104906
Angewandte Chemie International Edition
COMMUNICATION
Comparison of IR spectra of Ph,MeTpZn(SSNO) (3) and its
15N-isotopologue Ph,MeTpZn(SS15NO) (3-15N) allowed assignment
of S-N and N-O stretches at 686 and 1330 cm-1 for 3.
Coordination to Zn results in a strengthening of both the S-N and
N-O bonds relative to Na(15-C-5)SSNO (2) which appear at 677
and 1313 cm-1, respectively. The UV-vis spectrum of 3 in
dichloromethane shows a band centered at λmax = 402 nm (1800
M−1cm−1), shifted towards lower wavelengths relative to 2 (λmax
=
427 nm (5330 M-1cm-1)). The 15N NMR spectrum of 3 in MeCN
exhibits a resonance at 641.3 ppm compared to 706.7 ppm for
Na(15-C-5)SSNO (2).
Figure 2. Synthesis and X-ray structure of Na(15-C-5)SSNO (2).
A synthetically versatile source of the SSNO- anion results
Addition of an equimolar amount of triethylphosphine to
Ph,MeTpZn(SSNO) (
3
) in dichloromethane leads to a color change
from light orange to reddish-green that affords light pink
Ph,MeTpZn(SNO) (
) in 52% crystallized yield (Figure 3). X-ray
from crown ether complexation of its sodium salt. Addition of 1
t
equiv. BuONO to Na(15-C-5)SH (
1
) (obtained from addition of
4
15-C-5 to NaSH in MeOH) in fluorobenzene leads to rapid
development of dark red color. Crystallization from
fluorobenzene yields Na(15-C-5)SSNO ( ) as red crystals in
analysis reveals both syn and anti conformers that exhibit
positional disorder. The anti conformer is the major species
(75%) with κ1-S binding (Zn-S 2.250(3)Å, Zn-S-N = 94.7(4)°)
while the syn conformer (25%) exhibits κ2-S,O binding of the
thionitrite group (Zn-S 2.254(8), Zn-O, 2.302(3) Å, Zn-S-N =
112.2(8)°). Notably, the Zn-S bond in each conformer of 4 is
shorter than that of the corresponding perthionitrite 3. The S-N
and N-O bond lengths in the anti (1.748(10), 1.206(10) Å) and
syn (1.741(12), 1.211(12) Å) conformers of 4 are both shorter
(S-N) and longer (N-O) than in organic derivatives such as the
a
2
42% yield (Figure 2). X-ray diffraction analysis shows κ2-S,O
binding of the SSNO- anion to sodium with Na-S and Na-O
distances of 2.889(4) and 2.378(7) Å (Figures 2 and S25). The
S-S, S-N, and N-O bond distances of 1.982(3), 1.655(5), and
1.269(6) Å are in agreement with the reported values for the free
SSNO- anion in [PPN][SSNO] (S-S 1.9750(9), S-N 1.696(3), N-O
1.246(3) Å)[9] as well as the potassium salt K(18-C-6)[SSNO] (S-
S 1.9526(9), S-N 1.669(2), N-O 1.247(2) Å) isolated upon NO
addition to a nickel-sulfide [NiII]-S-K(18-C-6).[20]
S
-nitrosothiol Ph3CSNO (S-N, 1.792(5) Å, N-O, 1.177 Å).[22] The
IR spectrum of
shows a S-N stretch at 717 cm-1, higher than
4
Addition of Na(15-C-5)SSNO
(
2)
to
a
solution of
650 cm-1 reported for Ph3CSNO. Moreover, the NO stretch for 4
at 1436 cm-1 appears at lower energy than in Ph3CSNO (1514
cm-1). The UV-vis absorption spectrum of 4 in CH2Cl2 shows a
sharp band centered at 340 nm (4440 M-1cm-1) as well as a low
intensity broad band feature at 578 nm (8 M-1cm-1). Such a low
Ph,MeTpZn(ClO4)[21] in dichloromethane leads to a rapid color
change from dark red to light orange. Crystallization from THF
affords Ph,MeTpZn(SSNO) (
structure of
3
) in 51% yield (Figure 3). The X-ray
3
reveals κ2-S,O binding of the SSNO- anion to the
zinc center with Zn-S and Zn-O distances of 2.3132(9) and
2.302(3) Å. Such symmetric κ2-S,O binding of the perthionitrite
energy feature typically occurs in
S-nitrosothiols such as
Ph3CSNO (600 nm (39 M-1cm-1) in CH2Cl2).[22]
anion at zinc as compared to the sodium salt
much greater thiophilicity of zinc. On the other hand, the S-S, S-
2 likely reflects the
1
The H NMR spectrum of Ph,MeTpZn(SNO) (4) in MeCN-d3
confirms the presence of two isomers in an 85 / 15 ratio in
solution at room temperature. Two sets of resonances appear
for the pyrazole C-H (6.37 and 6.33 ppm) and pyrazole-Me (2.61
N and N-O bond lengths for
3 of 1.9826(15), 1.666(4) and
1.232(4) Å, respectively, are quite similar to those in free SSNO-.
[9]
Figgure 3. Synthesis and X-ray structures of Ph,MeTpZn(SSNO) ( nti isomers of Ph,MeTpZn(SNO) (
3) and syn and aa 4).
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10.1002/anie.202104906
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COMMUNICATION
and 2.58 ppm) groups that exhibit only modest broadening upon
heating to 80 °C (Figure S12). This allows us to assign a barrier
of more than 18 kcal/mol for the interconversion of the syn and
anti-isomers of Ph,MeTpZn(SNO) (4) in solution. This is markedly
higher than the barrier for S-N bond rotation of 10.7 kcal/mol
from M-SSNO species, addition of 1 equiv. CF3COOH to sodium
salt Na(15-C-5)SSNO (2) leads to NO formation in 78% yield
also with observation of S8 (Supporting Information Section S11).
These reaction products are consistent with the decay of
unstable HSSNO.[6a, 9b, 24]
determined for the
S
-nitrosothiol Ph3CSNO,[22] consistent with
Reaction of Ph,MeTpZn(SNO) (4) with C6F5SH appears to
proceed by a similar acid-base mechanism with release of
HSNO since Ph,MeTpZn-SC6F5 (5) forms in near quantitative yield.
Headspace gas analysis reveals that the reaction generates N2O
estimated in 39% yield, assuming a reaction stoichiometry of
[Zn](HSNO) : 1/2 N2O (Figure 5b). S8 also forms as by-product.
These observations are consistent with the formation of HSNO
that leads to the transient generation of HNO which decays into
N2O.[5a, 6a, 9b, 24] Thus, protonation of the SSNO- and SNO- anions
in zinc complexes 3 and 4 by the acidic thiol C6F5SH leads to
different signaling outputs, generating NO and HNO,
respectively.
the stronger S-N bond in 4 revealed by IR spectroscopy. The 15
N
NMR spectrum of 4 in MeCN-d3 at RT reveals a single
resonance centered at 836.6 ppm for the major isomer, similar in
chemical shift for the anti conformer of Ph3CS15NO (δ 843.8
(anti) and 754.8 (syn) ppm).[22]
Zinc perthionitrite and thionitrite complexes 3 and 4 are
Reactions
involving
Ph,MeTpZn(SSNO)
(3)
and
Ph,MeTpZn(SNO) (4) with thiols are quite sensitive to the thiol
acidity. While the less acidic thiol 4-MeArSH does not react with
dithionitrite 3 in dichloromethane at RT, addition of 4-MeArSH to
Ph,MeTpZnSNO (4) results in a slow reaction. 1H NMR analysis
after 5 h reveals formation of both Ph,MeTpZn-SAr4-Me (75%) and
Ph,MeTpZn-SH[25] (21%) indicating two distinct pathways (Figures
5b and 6a). Suggesting HSNO formation, N2O gas forms (29%
based on 4) in addition to the disulfide 4-MeArS-SAr4-Me (21%
based on 4) that likely arises from decomposition of the
Figure 4. (a) Heating
(b) Enhanced S-N bond character in Zn-SNO species 4.
3 and 4 to 75 °C slowly releases NO.
quite thermally stable at room temperature. UV-vis studies in
fluorobenzene reveal that they degrade slowly upon heating to
75 °C with half-lives of ca. 5 and 7 h, respectively, dramatically
longer than the
S-nitrosothiol Ph3CSNO (t1/2 ≈ 10 min) under
similar conditions. Analysis of the headspace gas in the
thermolysis of 3 and 4 each reveal NO in 80 and 60% yield,
respectively (Figure 4a). Unfortunately, these transformations
did not follow well defined kinetics nor were we able to track the
fate of the zinc complexes following NO release. The high
thermal stability of the Zn-SNO complex 4 as compared to
corresponding
S
-nitrosothiol 4-MeArSNO[26] that forms along with
Ph,MeTpZn-SH. Following the reaction of Ph,MeTpZn(SNO) (4) with
4-FArSH by UV-vis spectroscopy confirms the initial formation of
organic
S-nitrosothiols RSNO may result from greater
stabilization of the resonance form with increased S-N π-bond
character due to the increased electropositive nature of Zn
(Figure 4b). Both IR (higher ѵ(SN)) and NMR (higher barrier for
S-N rotation) spectroscopy indicate strengthening of the
thionitrite S-N bond upon coordination to an electropositive
element such as zinc.
Owing to their biological significance, we examined the
reactivity of Ph,MeTpZn(SSNO) (3) and Ph,MeTpZn(SNO) (4) with
thiols. We examined aromatic thiols ArS-H for the ability to
predictably modulate their acidity. Reaction of Ph,MeTpZn(SSNO)
(3) with the highly acidic thiol C6F5SH at room temperature leads
to a rapid color change from orange to light yellow. 1H NMR
analysis of the reaction confirms the formation of Ph,MeTpZn-
SC6F5 (5) in near quantitative yield (Figure 5a).
In the reaction between Ph,MeTpZn(SSNO) (3) and the
acidic thiol C6F5SH, we envision an acid-base exchange
mechanism that releases HSSNO that subsequently converts to
NO and S8, known products in the decomposition of HSSNO.[5a,
23] Moreover, NO forms in 82% yield and we observe S8 as well.
Further supporting HSSNO formation via acid-base exchange
Figure 6. (a) Mechanistic pathways considered for the reaction of
Ph,MeTpZnSNO (
4) and ArSH. (b) Hammett plot comparing [Zn]-SR
and [Zn]-SH products upon reaction of [Zn](SNO) (
4) with p-
substituted thiols 4-XArSH.
Figure 5. Reactivity of (a) Ph,MeTpZn(SSNO) ( ) and (b) Ph,MeTpZn(SNO) ( ) with C6F5SH and 4-MeArSH.
3 4
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10.1002/anie.202104906
Angewandte Chemie International Edition
COMMUNICATION
4-FArSNO (Figure S24).
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of Ph,MeTpZn(SNO) (4) with aromatic thiols ArSH (Figure 6a).
Acid-base exchange between Ph,MeTpZnSNO (4) and ArSH leads
to the formation of HNSO along with corresponding zinc thiolate
Ph,MeTpZn-SAr. HSNO released further decomposes to observed
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OMe) increasingly turns on thiol -nitrosation, better competing
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(from
-nitrosation) and Ph,MeTpZn-SAr4-X (from acid-base
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S
S
and Ph,MeTpZn(SNO) (4) enable the isolation, characterization
and reactivity study of the perthionitrite and thionitrite anions at
zinc. Unlike HSSNO and HSNO, these zinc complexes possess
high stability, decomposing with NO release only after heating to
75 °C. In particular, [Zn](SNO) species 4 is much more stable
[10]
[11]
than related
S-nitrosothiols such as Ph3CSNO, attributed to a
stronger S-N interaction in 4 supported by IR and NMR
spectroscopy.
Importantly,
Ph,MeTpZn(SSNO)
and
Ph,MeTpZn(SNO) each react with acidic thiols, releasing HSSNO
and HSNO that ultimately form NO and N2O, respectively.
Nonetheless, increasing thiol nucleophilicity RSH turns on
[12]
[13]
[14]
[15]
competing
to release
S
S
-nitrosation in reactions with [Zn](SNO) complex 4
-nitrosothiols RSNO. As -nitrosothiols serve as
S
mobile carriers for NO, this work illustrates subtle effects at play
that control the signaling output of perthionitrite and thionitrite at
zinc.
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Acknowledgements
T.H.W. thanks the National Institutes of Health (R01GM126205).
Conflict of interest
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The authors declare no conflict of interest.
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Keywords: Nitric oxide • S-nitrosothiol • Thionitrite • Zinc •
Bioinorganic
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10.1002/anie.202104906
Angewandte Chemie International Edition
COMMUNICATION
Entry for thhe Table of Contents (Please choose one layout)
Layout 1:
COMMUNNICATION
NO and H2S serve as
Valiallah Hosseininasab,
Jeffery A. Bertke, and
Timothy H. Warren*
signaling
molecules
in
biology with intertwined
reactivity through formation
of HSNO and HSSNO.
Zinc complexes of their
Page No. – Page No.
Thionitrite and
Perthionitrite in NO
Signaling at Zinc
conjugate
bases
and
Ph.MeTpZn(SNO)
Ph,MeTpZn(SSNO) result in
stabilization of these anions
at
a biologically relevant
metal site yet reveal
disparate signaling output
upon reaction with thiols.
This article is protected by copyright. All rights reserved.