Oxidation of 8-thioguanosine gives redox-responsive hydrogels and reveals intermediates in a desulfurization pathway

Article abstract of DOI:10.1039/d0cc02926b

A disulfide made by oxidation of 8-thioguanosine is a supergelator. The hydrogels are redox-responsive, as they disassemble upon either reduction or oxidation of the S-S bond. We also identified this disulfide, and 2 other compounds, as intermediates in oxidative desulfurization of 8-thioG to guanosine. This journal is

Full text of DOI:10.1039/d0cc02926b

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Oxidation of 8-Thioguanosine Gives Redox-Responsive Hydrogels
and Reveals Intermediates in a Desulfurization Pathway
Songjun Xiao,* Wes Lee, Fu Chen, Peter Zavalij, Osvaldo Gutierrez* and Jeffery T. Davis*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A disulfide made by oxidation of 8-thioguanosine is a supergelator. glycosidic bond (Fig. 2a). Because the base’s “sugar” edge is
The hydrogels are redox-responsive, as they disassemble upon blocked in the syn conformation (Fig. 2c), H-bonded ribbon
either reduction or oxidation of the S-S bond. We also identified motifs that compete with the G-quartet are inhibited (Fig. S2-
this disulfide, and 2 other compounds, as intermediates in oxidative S3). Sessler found that templating cations were not needed to
desulfurization of 8-thioG to guanosine.
form G-quartets from a syn C8-aryl G.8 In the realm of soft
materials, 8-aryl G analogs form nanogels,9 and 8-BrG, 8-OMeG
and 8-NH2G,10,11,5a all analogs that favor a syn conformation,
assemble into G-quartet hydrogels. In designing hydrogelators
we were drawn to 8-thioG disulfide 1 because: 1) its large C8-
substituent should ensure a syn conformer; 2) its two G units
should enable a cross-linked network, as do other G dimers;12
and 3) it should be redox-active and respond to reductive or
oxidative cleavage of S-S bonds. While redox-responsive
hydrogels made from polymers are relatively well-known,13
there are fewer examples of low molecular weight gelators that
give redox-responsive hydrogels.14 Recently, we used redox
chemistry to write, read and erase images on G-quartet
hydrogels.15 Now, we describe another unique and redox-
From seabird guano, to GMP nucleotides, to G-quadruplex DNA,
guanine’s “G” is iconic. We focus here on 8-thioguanosine
disulfide 1, a new compound in the literature, but one that likely
exists in Nature. We want to make 2 points in this paper. First,
the supergelator disulfide 1 forms redox-responsive hydrogels
at low mM concentrations and ambient temperature. Quantum
mechanical calculations reveal that disulfide 1 favors a
conformation that facilitates formation of a G-quartet mesh.
Second, disulfide 1 is likely an intermediate on a natural
“desulfurization” pathway that leads from the oxidative
metabolite 8-thioG 2 to guanosine 3 (Fig. 1).
Supramolecular hydrogels are soft materials, made mostly
of water, that typically respond to external stimuli.1 These gels,
held together by non-covalent interactions, are prepared from
low-molecular weight gelators, either synthetic compounds or
natural products like sugars, peptides and nucleosides.2
Although hydrogels made from guanosine analogs have long
been known,3 we have witnessed a resurgence in the synthesis
of “G”-gels because of their many biomedical, environmental
and materials applications.2,4-6 These “G” gels are often built up
responsive “G” gelator, 8-thioG disulfide 1.
O
O
O
N
H
N
NH
NH2
N
S
HN
H2N
HN
H2N
8
S
S
N
H2O
rt
N
I2
N
N
9
N
N
O
O
O
1ʹ
OH
HO
TCEP
HO
OH
OH
HO
OH
HO
G-Quartet
Hydrogel
OH
8-ThioG 2
8-disulfideG 1
Previous Work
H2O2
AcOH
H2O2
or
1O2
loss of
“S” atom
from the G-quartet,7
a H-bonded macrocycle typically
O
O
templated by cations. The planar G-quartets stack to form G-
quadruplex nanofibers that stick to each other to create a
matrix that traps water, giving a self-standing gel (Fig. S1).
One strategy to drive G-quartet assembly is to use
conformationally restricted monomers substituted at the C8
position, which favor syn vs. anti conformers about the C-N
O
N
O
S
O
N
SO2
O
NH
N
N
HN
H2N
N
H
N
S
HN
H2N
LiOH
NH2
N
N
O- Li+
N
AcOH
O
O
O
HO
HO
OH
HO
OH
HO
HO
OH
G 3
8-sulfinateG 5
8,5’-cyclosulfinateG 4
Fig. 1. This study focuses on the properties of 8-disulfideG 1 and its hydrogels.
The first part of this paper describes experimental and
computational studies on this new dinucleoside 1 and its redox-
responsive hydrogels. The second part of our story deals with
further oxidation of 8-disulfideG 1. Living organisms are
Department of Chemistry & Biochemistry, University of Maryland College Park, MD
20742, USA. E-mail: jdavis@umd.edu, sxiao@terpmail.umd.edu, ogs@umd.edu
Electronic Supplementary Information (ESI) available: DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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constantly bombarded by reactive oxygen species (ROS) that at m/z = 635.019 (M + Li+), 650.925 (M + Na+) and V6i6ew6A.9rt7ic4le O(Mnlin+e
damage DNA.16 Guanine, the easiest nucleobase to oxidize,17 K+), corresponding to adducts of 1 with alDkOalIi: c10a.t1i0o3n9s/.DD0CiaCg0n2o9s2t6iBc
reacts with ROS to give a variety of adducts. While 8-oxoguanine changes occurred in NMR spectra after oxidation of 1, especially
1
is the most well studied oxidation product, 8-thioG 2 is also of for NH7, N7 and C8. The H NMR spectrum of 8-thioG 2 in
biological importance. Thus, Akaike and colleagues discovered DMSO-d6 has signals for 2 amide protons, N7H and N1H at δ
that 3ʹ,5ʹ-cyclic guanosine monophosphate (cGMP) is oxidized 12.91 and 11.03 ppm. The N7H peak disappeared upon
by peroxynitrite to 8-nitro-cGMP, which reacts with oxidation of 8-thioG 2 to disulfide 1. Addition of reductant
-
endogenous HS to form 8-thio-cGMP, a signalling molecule that tris(2-carboxyethyl)phosphine (TCEP)22 to a solution of disulfide
protects against cardiac damage in mice. The 8-thio-cGMP is 1 regenerated 8-thioG 2 (Fig. S17), a welcome finding in our
subsequently converted back to cGMP via chemical oxidation.18 quest for a redox-responsive gelator. Based on an established
Chatgilialoglu also described photo-oxidation of 8-thioG 2 by correlation,23 the chemical shift of δ 4.99 ppm for H2ʹ indicates
singlet oxygen to give G 3 (Fig. 1).19 Although C8-disulfides were the syn conformer of 1 dominates (≥ 95%). Solid-state 15N NMR
mentioned as potential oxidation products in both processes, revealed a difference of >100 ppm for N7 in 8-thioG 2 (δ 142)
they were not identified and, until now, such species have been and disulfide 1 (δ 260). Lastly, 13C NMR showed a significant
elusive. During our studies on hydrogelation we have change in the C8 chemical shift (δ 165.7) upon oxidation of 8-
characterized disulfide 1 as a key intermediate in the oxidative thioG 2 to disulfide 1 (δ 139.4).
desulfurization of 8-thioG 2 to guanosine 3.
O
O
H
O
N
H
N
N
7
(a)
HN
1
N
N
HN
H2N
NH
NH2
conformers
S
SH
8
S
N
H2N
HO
N
O
OH
N
N
O
O
5ʹ
HO
1ʹ
OH
tautomers
HO
HO
(b)
HO
OH
OH
syn, thione
8-thioG 2
anti
thiol
H
(c)
k
o
c
o
i
r
g
s
C
t
-
e
e
n
O
N
n
o
s
H
t
a
Fig. 3: (a) Inverted vials of 8-disulfideG 1 in water at various concentrations (wt %) and
times after sonication. As shown in the lower left, hydrogelation by 8-disulfideG 1 at
ambient temperature occurs at concentrations as low as 0.1 wt % (1.6 mM). (b) Addition
of 1 eq of an aqueous solution of TCEP to a hydrogel made from 8-disulfideG 1 (0.5 wt%,
8 mM) destroys the gel within minutes, to give a suspension of 8-thioG 2.
W
H
N
N
N
S
H
N
Sugar Edge
H
O
OH
HO
OH
Disulfide 1 is a supergelator, as it forms hydrogels at
concentrations ≤ 0.1% (w/v).24 Sonication of 1.0 wt % of 8-
disulfideG 1 (16 mM) in water produced self-supporting
hydrogels within 2 minutes at ambient temperature (Fig. 3a).
Transparent and self-standing hydrogels formed, albeit slowly,
even at 0.1 wt% (1.6 mM). Importantly, this disulfide-based
Fig. 2. (a) Conformational and tautomeric isomers for 8-thioG 2; (b) crystal structure of
8-thioG 22H2O shows the N7H, C8 thione tautomer, with its C1ʹ-N9 glycosidic bond in
the syn conformation and a C2ʹ-endo sugar; (c) different hydrogen bonding edges on 8-
thioG 2. The “sugar edge” is blocked when 2 is in a syn conformation.
Understanding the structure of 8-thioG 2 is important for hydrogel is redox-responsive.Addition of 1 eq of reductant TCEP
unravelling its function in Nature. We used X-ray diffraction to destroyed the yellow hydrogel (0.5 wt%, 8 mM) within 5
determine that 2 exists as the thione tautomer, with a C=S bond minutes at ambient temperature to give a colorless suspension
of 1.69 Å (Fig. 2). Sulfur’s size enforces a syn conformation of 8-thioG 2 (Fig. 3b). This rapid response to TCEP indicates that
about the C1ʹ-N9 glycosidic bond and an intramolecular H-bond the gel network requires the covalent S-S bond and a H-bond
(dON= 2.90 Å) between the 5ʹ-OH group and N3 stabilizes this pattern that allows for G-quartet assembly.25
conformation. The syn conformation blocks the “sugar edge” of
Circular dichroism (CD) spectroscopy is used to probe
2 and orients the nucleobase so that its Watson-Crick and supramolecular chirality of G-quadruplexes made from DNA
Hoogsteen edges are available for molecular recognition (Fig. and “small-molecule” G-analogs.26 The CD spectra in Fig. 4 show
2c). Since N7 is protonated, 8-thioG 2 cannot form a G-quartet. that the self-assembled hydrogel made from 1 contains both G-
We expected that disulfide 1, with its imino N7 and C8 S-S bond, quadruplexes and axially-chiral disulfide bonds. The CD
should form G-quartets, especially if the C1ʹ-N9 conformation is spectrum is drastically different when disulfide 1 is incorporated
syn.
into the gel or when dissolved in DMSO. A solution of disulfide
Depending on the oxidant’s strength, thioureas can be 1 in DMSO (8.0 mM) showed a weak Cotton band (yellow line),
oxidized to disulfides and further to sulfenic (-SOH), sulfinic (- indicating little self-association in this solvent. The CD spectrum
SO2H) or sulfonic (-SO3H) acids.20 Although disulfide 1 was not of the hydrogel (0.5 wt %, 8.0 mM) showed 2 key features that
known until this study, a similar disulfide had been made by provide insight into the self-association of 1 in water. First, the
oxidation of 6-thioG with the mild oxidant iodine.21 Addition of strong exciton centered at 270 nm (peak at 258 nm and trough
I2 to a suspension of 8-thioG 2 in MeOH/CH3CN gave disulfide 1 at 282 nm) is diagnostic of a chirality axis running down the
in 88% yield. MALDI-TOF mass spectrometry showed 3 signals middle of a stack of G-quartets.26 Second, the large peak at 360
2 | J. Name., 2012, 00, 1-3
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nm indicates axial chirality about an anisotropic S-S bond in this a S-S torsion of  -64.3, much more typical for a disulfide bond
View Article Online
dinucleoside.27
(Fig. 5A; right).
DOI: 10.1039/D0CC02926B
The consequence of all these non-covalent forces is that the
GA and GB units in the low-energy conformation of 1 form a “C-
shaped” structure whose exposed H-bonding edges are
oriented anti-parallel orientation relative to each other (Fig.
5B). As depicted in Fig. 5C we hypothesize that this unique π-
stacked conformation enables self-assembly to give a dense
matrix of cross-linked G-quartets that can trap water to give this
redox-sensitive G4-hydrogel.
Fig. 4: Photographs of a hydrogel made from 8-disulfideG 1 (0.5 wt%, 8 mM) and a
solution of 8-disulfide G 1 (8 mM) in DMSO. The red curve shows CD spectrum of
hydrogel made from 8-disulfideG 1 (0.5 wt%, 8 mM) and the yellow curve shows a CD
spectrum of a solution of 1 (8 mM) in DMSO.
A)
1.82
1.82
1.80
1.80
To further characterize disulfide 1 and explore factors that
stabilize specific conformers, especially about the S-S bond, we
carried out computational analysis using dispersion-corrected
density functional theory. We initiated our studies by
performing an extensive conformational search on the C8-S-S-
C8 dihedral angles from 0, 90, 180, to -90 degrees (Fig. S34). We
MTID
1
MGD
3.5 Å
3.4 Å
performed
optimizations
using
B3LYP-D3/6-31G(d)-
θ (C-S-S-C) = -64.3o
θ (C8-S-S-C8) = -17.4o
CPCM(water)28,29 and carried out single point energy
calculations using a larger basis set B3LYP-D3/Def2SVP-
CPCM(water)30 to refine energetics. We found the lowest
energy conformer for disulfide 1 to be nearly eclipsed (
for C8-S-S-C8; Fig. 5A). All other conformers were > 7 kcal higher
in energy (Fig. S35). This eclipsed conformation is unusual for a
disulfide, as the C-S-S-C torsion is typically near ± 90o.31 We
reasoned that the nucleobase and sugar in disulfide 1 likely
influence conformational stability so as to overcome the
electronic destabilization that occurs in an eclipsed S-S bond.
Inspection of the lowest-energy conformation for 1 revealed
that the nucleobases (GA and GB in Fig. 5) stack one on the other
(d =3.5 Å between centroids), in an “anti-parallel” orientation.
Along with stabilization via dispersion forces, this “anti-parallel”
π-stacking seems favoured by electrostatic interactions
between the 6-membered rings, as atoms with positive atomic
polar tensor (APT) charges in one ring stack directly over atoms
with negative APT charges in the other 6-membered ring (Fig.
S38). Both GA and GB adopt syn conformations about their C1ʹ-
θ (C8-S-S-C8) = 5.5o
B)
GA
GA
GB
GB
C)
H
N
R
N
N
H
S
N
H
O N
N
O
N
H
S
H
N
R
N
N
H
G-Quartet 14
G4 Network 1n
Fig. 5: A) Lowest energy conformations for disulfides 1, N-methylguanine disulfide (MGD)
and N-methyl-imidazole disulfide (MTID). B) Top view and side view of lowest energy
conformation for 8-disulfide G 1. The purine rings stack directly one over the other in an
anti-parallel orientation. C) A cartoon showing how self-assembly of this C-shaped “anti-
parallel” conformer would lead to a 3D mesh made up of G-quartets.
…
N9 glycosidic bonds that are stabilized by 5ʹ-OH N3 H-bonds
Since 8-thioG 2 can be converted to G 3 in Nature,16,17 we
sought more information about that oxidative pathway. (Fig. 1).
We also reasoned that further oxidation to break S-S bonds
would disassemble hydrogels made from disulfide 1. Treatment
of 1 with 7 eq of H2O2 and acetic acid gave 8,5ʹ-cyclosulfinateG
4 as the only isolated product, with m/z = 330.07 (M + H+). The
1H NMR spectrum revealed features indicating cyclization: 1)
signals for diastereotopic H5ʹ, H5ʹʹ are shifted downfield to δ=
4.74 & 4.40 ppm (δ=3.66 & 3.54 ppm in 1), consistent with an
electron withdrawing substituent at C5ʹ; 2) H5ʹ and H5ʹʹ
resonances are 0.34 ppm apart, as these atoms are constrained
in unique environments by the 8,5ʹ-ring; 3) the 5ʹ-OH signal
disappears upon oxidation of 2. Presumably cyclic nucleoside 4
arises by intramolecular attack of the 5ʹ-oxygen on a protonated
C8 sulfinic acid intermediate.
(dHN= 1.80 Å). Moreover, a GA-GB H-bond (dHN= 1.82 Å) between
the 2ʹ-OH in one G subunit and N7 in the other subunit, and 1,4
CH-S interactions between H1ʹ and S8 , help rigidify the low-
energy structure.32
To gain more insight into the role of ribose and the 6-
membered ring in stabilizing the “π-stacked” conformation, we
conducted calculations on simpler model compounds, including
N9-methylguanine disulfide (MGD) and N-methylimidazole
disulfide (MTID) (Figs. S34-S38). For MGD, we found that the
low energy conformation adopted a C-S-S-C torsion of =-17.4o,
with similar π-π stacking as disulfide 1 (Fig. 5A; middle). The
importance of π-π stacking interactions in these guanine
systems (1 and MGD) is evident from calculations showing that
MTID, which lacks the purine 6-membered ring and sugar, has
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4
(a) V. Venkatesh et al. J. Am. Chem. Soc. 2017, 139, 5656. (b) A. Rotaru,
View Article Online
We found that cyclosulfinate 4 could be hydrolysed by base
to give 8-sulfinateG 5. Desulfurization of 5, with loss of SO2 to
give G 3, was slow at rt(14 d). Clean formation of G 3 from 8-
A. , G. Pricope, T. N. Plank, L. Clima, L. Ursu, D. Peptanariu, J. T. Davis
DOI: 10.1039/D0CC02926B
and M. Barboiu Chem. Commun. 2017, 53, 12668.
5
6
(a) T. N. Plank, L. P. Skala and J. T. Davis, Chem. Commun. 2017, 53,
6235. (b) S. Xiao and J. T. Davis, Chem. Commun. 2018, 54, 11300.
(a) Z. Li, L. E. Buerkle, M. R. Orseno, K. A. Streletzky, S. Seifert, A. M.
Jamieson and S. J. Rowan, Langmuir, 2010, 26, 10093. (b) R. Q. Zhong
et al. Adv. Mater. 2018, 30, 1706887. (c) F. Carducci, J. S. Yoneda, R.
Itri and P. Mariani, Soft. Matter, 2018, 14, 2938-2948.
o
sulfinateG 5 was accelerated, either by heating to 50 C or by
adding CH3COOH at rt (Fig. S32). This study shows that disulfide
1, 8,5ʹ-cyclosulfinateG 4 and 8-sulfinateG 5, new compounds to
the literature, are intermediates in oxidation of 8-thioG 1 to G
3. Importantly, hydrogels made from disulfide 1 respond to
oxidation. Thus, addition of disulfide 1 (8 mM, 0.5 wt %) to a
solution containing H2O2 (112 mM) and acetic acid (51 mM)
gave a hydrogel that contains the oxidant that causes its own
destruction. This gel disassembled over the course of 10 days at
rt, whereas a control without oxidant remained self-standing
(Fig. S33). So, hydrogels made from disulfide 1 can be
dismantled by either reduction or oxidation of S-S bonds. This
suggests that a biocompatible gel made from disulfide 1 might
well protect cells against cytotoxic ROS species such as H2O2.33
Oxidation of 8-thioG 2, a bioactive signalling molecule,16
with I2 provided 8-disulfideG 1, a compound we suggest is likely
naturally-occurring compound. Disulfide 1 is a supergelator as it
forms hydrogels at concentrations as low as 0.1 wt % at rt. This
propensity to gel is likely due to the 2 guanosines linked
together, since reductive cleavage of the S-S bond destroyed
the gel. We hypothesize, based on computations, that disulfide
1 adopts a C-shaped conformation that orients the guanosines
in an anti-parallel stacked conformation, which drives
formation of a G-quartet network that entrains water. Using
stronger oxidation conditions, with excess H2O2, we
demonstrated that both 8-thioG 2 and its disulfide 1 could be
converted to G 3 via oxidative desulfurization and we identified
C8-sulfinates that may be metabolic intermediates in this
biologically relevant pathway. These hydrogels made from
disulfide 1 are also responsive to oxidation by ROS species.
Currently, we are trying to control disassembly, under reducing
and oxidizing conditions, for release of molecular cargo from
this “G” gel.
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Acknowledgements
25 G-quartets are typically templated by alkali cations, although there are
examples of “empty” G-quartets. Here, the hydrogel formed by disulfide
1 does so without addition of metal salts. In fact, addition of salts caused
precipitation of 1 from solution without any gel formation (Fig. S30). An
alternative motif to the G-quartet that might drive gelation, one that we
haven’t ruled out, is the H-bonded ribbon I shown in Fig. S2.
26 S. Masiero, R. Trotta, S. Pieraccini, S. De Tito, R. Perone, A. Randazzo
and G. P. Spada, Org. Biomol. Chem. 2010, 8, 2683.
We thank the DOE (DE-FG02-98ER14888 to JD) and NSF
(CAREER, 1751568 to OG). We thank the NSF (NSF-1726058) for
funding a solid-state NMR spectrometer. We thank the
UMaryland computational resources (DeepThought2 and
MARCC/BlueCrab HPC clusters) and XSEDE (CHE160082 and
CHE160053). We thank Taylor Plank and Gretchen Peters for
helpful comments.
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