A Chemical Photo-Oxidation of 5-Methyl Cytidines

Article abstract of DOI:10.1002/adsc.201900811

A new approach for the oxidation of 5-methyl cytidine modification in nucleic acids to 5-formyl cytidine is reported. This method displays excellent chemo-/bio- selectivity, from which the methyl group in cytidine nucleosides could be selectively oxidized to biologically important formyl functionality without interfering with other cellular biomolecules. (Figure presented.).

Full text of DOI:10.1002/adsc.201900811

Title: A chemical photo-oxidation of 5-methyl cytidines
Authors: Xiao-Yang Jin, Rui-Li Wang, Li-Jun Xie, De-Long Kong, Li Liu,
and Liang Cheng
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900811
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10.1002/adsc.201900811
Very Important Publication - VIP
FULL PAPER
DOI: 10.1002/adsc.201900811
A chemical photo-oxidation of 5-methyl cytidines
a,b
a,b
a,b
a
a,b
Xiao-Yang Jin, Rui-Li Wang, Li-Jun Xie, De-Long Kong, Li Liu, and Liang
a,b,
Cheng *
a
Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Molecular Recognition and
Function, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese
Academy of Sciences, Beijing 100190, China. E-mail: chengl@iccas.ac.cn
University of Chinese Academy of Sciences, Beijing 100049, China.
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A new approach for the oxidation of 5-methyl
cytidine modification in nucleic acids to 5-formyl cytidine is Keywords: 5-methylcytidine; 5-formylcytidine;
reported. This method displays excellent chemo-/bio- photochemical oxidation; artificial enzymes; epigenetic
selectivity, from which the methyl group in cytidine modifications
nucleosides could be selectively oxidized to biologically
important formyl functionality without interfering with other
cellular biomolecules.
an essential role through its ability to pair with G and
Introduction
A in the third position of the codon, thus furnishing
the decoding of non-universal AUA codon as Met.10
Previous reports have suggested that the oxidative
step from 5-methylcytidine to 5-formylcytidines is
Oxidation phenomenon is involved in various
biochemical pathways and plays a crucial role in
numerous pathological events and clinical situations.
1
11
catalyzed by TET and ABH1 enzymes (Scheme 1A).
The precise oxidation states in biological
macromolecules (nucleic acids, proteins, etc.)
accurately controls cellular signaling pathways and
has been recognized as a major target for potential
Owing to the inertness of the methyl substituent and
fragility of glyosidic bond, the oxidation of the C-H
bond in 5-methylcytidine is always difficult to
1
2
achieve with external chemical reagents. An early
attempt was made by Itahara et al., who treated 5-
methylcytidine with peroxosulfate ions at high
pharmaceutical intervention.2
Consequently, the
precise chemical regulation of these redox change
under the assistance of small organic molecules
o
temperature (75 C) to produce 5-formylcytidine in
1
3
(
SOM) have attracted increased attention in recent
23% yield.
Recently Cadet and Nishimoto et al.
3
years. These chemical motifs or artificial enzymes
with the capacity of mimicking redox pathways could
potentially be utilized as biological probes or
pharmaceutical candidates that regulate cellular fate
and differentiation by controlling the redox state
within the cells.
applied a photochemical reaction into the oxidation of
5-formylcytidine. 5-Formyl-2’-deoxycytidine was
obtained under the irradiation of UV light (312 nm)
with Menadione in a low yield (13%), which
unfortunately limited the method only to the
1
3
mechanistic study. Recently we demonstrated that
6
the demethylation process of N -methyladenosine
4
6
5
-Methylcytidine and its oxidation intermediates (5-
(m A) in live cells could be achieved by a
5
6
hydroxymethylcytidine, 5-formylcytidine and 5-
bioorthogonal
photo-oxidation
with
Flavin
7
14
carboxylcytidine )
are
important
epigenetic
mononucleotide.
This finding represents the first
8
modifications in nucleic acids, which plays pivotal
roles in accurate and efficient transcription and
translation of genetic information. In recent years, 5-
formylcytidine has attracted significant attention as a
distinctive oxidative derivative of 5-methylcytidine
demethylation. In DNA, 5-formylcytidine affects the
rate and specificity of RNA polymerase II (RNAPII)
and causes increased RNAPII backtracking, increased
pausing, and reduced fidelity in nucleotide
example of in vitro modulating RNA epigenetic
modification with SOMs.
1
5
Herein, we present a
facile opto-transformation under mild conditions to
produce 5-formylcytidine and its analogous from 5-
methylcytidine under the promotion of a small
organic molecular photosensitizer without disturbing
other vulnerable C-H bonds in other biomolecules
(Scheme 1B).
Such approach, without over-
expression or inhibiting corresponding enzymes,
9
incorporation. 5-Formylcytidine in RNA also plays
would be of great potential for in vivo/vitro studies of
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201900811
5
-formylcytidine and other epigenetic cytosine
hydroxymethylcytidine 4, the preliminary oxidative
product, was produced in trace levels and can only be
observed with HPLC (vida infra).
variants. On the other hand, it would also facilitate
5
the f C-containing nucleic acid oligo synthesis or
NTP
polymerization.
synthesis
for
enzymatic
catalyzed
Table 1. SAS-catalyzed photo-oxidation of 5-
[
a]
methylcytidine 1
Scheme 1. A) Enzymatic post-transcriptional modification
of cytidines. B) Chemical photo-oxidation of 5-
methylcytidine (this work).
Entry
1
Photosensitizer
Yield (%)
67
Results and Discussion
3a
3a
3a
None
3b
3c
In the journey to develop a bioorthogonal approach
2[b]
NR
NR
NR
34
5
on the conversion on 5-methylcytidine 1 (m C) to
5
3[c]
produce the 5-formyl functionality 2 (f C) without
interfering with other oxidation-labile components,
we were inspired by the biological enzymatic
4
1
6
5[d],[e]
6[d],[e]
7[d],[e]
8[d],[f]
9[e],[g]
oxidation mediated by quinone-type cofactors
Table 1). After screening diverse photocatalysts,
(
21
sodium 2-anthraquinone sulfonate (SAS, 3a), a
water-soluble anthraquinone derivative, was found to
be the optimal molecule for this oxidation (Table S1).
Upon the irradiation with near-UV light (365 nm)
3d
3e
trace
trace
10
under atmospheric O
2
at room temperature, the major
3f
5
oxidative product f C was isolated in 67% yield in an
aqueous solution at room temperature (entry 1, Table
0[d],[e]
1
3g
3h
3i
30
11[e],[g]
NR
NR
62
1
). To the best of our knowledge, this is the so far the
best result of converting the methylated cytosine
directly to the formyl product under physiological
conditions. The generation of 2 was not detectable
2[e],[g],[h]
1
1
1
3[i]
3a
without O
2
(entry 2), light (entry 3), or photocatalyst
4[j]
3a
64
(
entry 4), indicating that SOM-promoted irradiation
[a]
Unless otherwise specified, all reactions were carried out
using 1 (5-methylcytidine, 0.1 mmol, 25 mg) and 3a (SAS,
was crucial for activating the methyl group. No
improvement in yield was observed when using other
quinone-type photosensitizers 3b-g (entries 5-10). It
is worthy to note that Menadione 3f and its sulfonate
0
2
.05 mmol, 16 mg) in the solvent of DMSO and H
.5 mL total) at room temperature (37 C) for 11 hours
2
O (9/1,
o
under 1 atm of oxygen (balloon). Isolated yield was given.
NR: No reaction.
adduct 3g (Vitamin K
3
), the catalysts previously used
[b]
Oxidation conducted under N
2
instead
1
3
for oxidizing 5-methyl-2’-deoxycytidine, showed
inferior activity towards 1 (10% yield with 3f, entry 9
and 30% with 3g, entry 10), which was in consistence
[c]
[d]
of O
2
.
Oxidation conducted under dark.
DMSO-H O
2
[e]
[f]
(
1/1) was used.
Reaction time: 8 hrs.
Reaction time:
[g]
[i]
[h]
1
0 hrs.
H
2
O was used.
Photoreceptor loading: 10
with previous work.
Traditional photoactive
mol%.
Na HPO
Oxidation conducted in DMSO-PBS Buffer
molecules, such as TCBN 3h and Methylene blue 3i,
[j]
(
2
4
-NaH
2
PO
4
, 40 mM, pH = 7.0).
Oxidation
were totally inactive under the standard conditions
conducted in DMSO-PBS Buffer (10 mM, pH = 7.0).
(
entries 11-12). It should be mentioned that due to
5
the solubility difficulty of m C in water, DMSO was
largely used as co-solvent. Nonetheless, DMSO-PBS
buffer mixture can also be utilized for this process
and comparable yields were obtained (entries 13-14),
indicating that this chemistry has the potential to be
applied to nucleic acid oligo modification. It’s also
worth to mention that in most cases 5-
17
Considering the low cellular toxicity of SAS and the
developed oxidation was proceeded smoothly in
aqueous conditions at room temperature and
physiological pH, we set out to explore the reactivity
and selectivity of this promising bioorthogonal
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201900811
reaction. Thus, the chemical photo-oxidation of other
epigenetic methylated nucleosides/bases was
investigated (Figure 1). As expected, 5-methyl-2’-
deoxycytidine furnished the corresponding 5-formyl-
We also observed
a
trace amount of 5-
hydroxymethylcytidine during the oxidative process
from HPLC analysis, whose existence was confirmed
with an authentic sample. Integration of the signals
showed that the generation of 5-formylcytidine
(ember line) was correlated with the decomposition
of 5-methylcytidine (gray line), while the amount of
5-hydroxymethylcytidine adopted a bell shaped curve
(blue line) (Figure 2B). It should be noted that the
reason for the late-stage decrease of 5-
hydroxymethylcytidine was still unclear. A control
experiment with 5-hydroxymethylcytidine as the
substrate under the standard oxidation condition
didn’t not yield 5-formylcytidine, suggesting that 5-
hydroxymethylcytidine could not undergo further
oxidation under this circumstances, but may
decompose to other products. In addition, another
2’-deoxycytidine with a comparable isolated yield
(
65%). In contrast, natural nucleosides rA, rU, rC, rG
6
and other epigenetic patterns, such as N-methyl m A
and O-methyl A /C , remained largely untouched
m
m
under the standard conditions according to thin-layer
chromatography and high performance liquid
chromatography analysis. However, due to the
purification difficulties encountered with some
nucleosides, reduced recovery yields were obtained in
some cases. To our delight, the C-methyl pyridine
nucleoside analogue, dT, was predominately
recovered after the process (80%), suggesting this
approach represents
a
particularly selective
recognition and activation of the C-methyl cytidines.
To explore the selectivity of this oxidation process,
the standard procedure was applied to various
endogenous and exogenous biomolecules, such as
alkaloid (Theophylline), natural and unnatural amino
intermediate
5-hydroperoxymethyl
was observed by LC-MS analysis
cytidine
5
13[c],18
(oxm C)
(Figure 2C), indicating that peroxyl radicals may be
involved in this process.
acids
(
L
-Tryptophan and N-Bz-Alanine), and
-Xylose and α- -galactopyranose).
oligosaccharides (
D
D
Most of these substrates largely remained intact under
the opto-oxidative condition, again demonstrating the
compatibility of this process. To further validate this
approach can be applied to biomacromolecules, we
subjected
two
nucleic
acid
and
oligo
(5’-
5’-
GGGUACAGAU-3’
ATTGTCAACAGCAGA-3’) to the standard reaction
conditions and no decomposition was observed
(
Supporting Information).
Figure 1. Recovery of nucleosides, alkaloids, amino acids
and carbohydrates upon the oxidative condition (Raw data
in Supporting Information).
In an effort to determine the intermediates on the
oxidation of 5-methylcytidine, we further studied the
time-course of the reaction by means of HPLC and
LC-MS (Figure 2 and Figure S3). The enzymatic
oxidation of 5-methylcytidine with TET/ABH1
afforded 5-formylcytidine as the major product, while
our chemical opto-oxidative transformation in Figure
2
A
also suggested that this SAS-mediated
photochemical oxidation proceeded in a similar
manner and predominately yielded 5-formylcytidine.
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201900811
Figure 2. Mechanistic studies. A) HPLC analysis of the
oxidative procedure at 0 hrs, 4 hrs and 11 hrs, respectively.
The new peaks were assigned as 5-hydroxymethylcytidine
and 5-formylcytidine. B) Kinetic measurement: 5-
methylcytidine (0.1 mmol, 25 mg), SAS (0.05 mmol, 16
mg), U (internal standard, 0.1 mmol, 24 mg) in
previously investigated by using different chemical
methods. However, those harsh reaction conditions
and extreme low conversions/yields significant
retarded their further application as effect
bioorthogonal approaches for potential in vivo or in
vitro post-modification of 5-methylcytidine. In this
work, we have reported that the 365 nm irradiation of
an aqueous solution of 5-methylcytidine in the
presence of a small organic molecule SAS led to the
formation of 5-formylcytidine as the main final
oxidized product. Moreover, the detection of the
DMSO/H
under O
2
O (2.5 mL), irradiated with UV light of 365 nm
at room temperature. (Raw date in Supporting
2
Information). C) Mass profile of the reaction mixtures at 4
hrs.
preliminary
hydroxymethylcytidine and the unstable intermediate
5-hydroperoxymethylcytidine provided further
oxidative
product
5-
Based on our previous work on selective recognition
1
9
of RNA and in view of the above-mentioned results,
it is concluded that the SAS-promoted oxidation of 5-
methylcytidine may be through a radical pathway
support for a peroxyl radical mechanism. We have
found that natural biomolecules, most importantly,
other epigenetic modifications did not undergo
oxidation and remained relatively stable under the
standard conditions, which unquestionably enables it
as a potential bioorthogonal modulation of 5-
methylcytidine in nucleic acids. In a future stage,
attempts will be made to study the in vivo and in vitro
post-modification of 5-methylcytidine at nucleic acid
and live cell levels. Such artificial modulation of
nucleic acid epigenetic variants and its application in
the regulation of important cellular signal pathways
will be reported in due courses.
(
Figure 3). The photosensitizer (PS) SAS was
excited by photo absorption to a singlet/triplet state,
followed by interacting with 5-methylcytidine to
generate the methyl-centered radical I. In the
subsequent step, the radical I reacted with oxygen
leading to the formation of peroxyl radical II, which
furnished peroxyl intermediate III. Dehydration of
III gave rise to the formation of 5-formylcytidine. It
should be mentioned that the formation of 5-
hydroxymethylcytidine can be explained through
decomposition of the unstable peroxyl radical II
20
through a Russell mechanism (path a) or from the
benzyl-type cation V followed by trapped with water
(
path b).
Experimental Section
Procedure for the chemical photo-oxidation: To a
5
solution of 5-methylcytosine (m C) (25 mg, 0.1 mmol) in a
mixture of dimethyl sulfoxide and water (2.5 mL, v/v 9/1)
was added sodium anthraquinone-2-sulfonate (16 mg, 0.05
mmol). The mixture was stirred for 11 hours under the
irradiation of 365 nm UV light under oxygen at room
temperature and then purified by reversed phase column
chromatography (C18 column, elute: methanol/water 20/80)
5
to afford 5-formylcytidine (f C) as a white solid (18 mg,
yield 67%).
Acknowledgements
This work was supported by the National Key R&D Program of
China (2017YFA0208100, 2016YFA0602900), National Natural
Science Foundation of China (91853124, 21778057 and
2
1420102003) and Chinese Academy of Sciences. This article is
dedicated to the memory of Prof. Ronald Breslow (1931-2017)
for his pioneering contributions to the field of
biomimetic/bioorganic chemistry.
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A Chemical Photo-oxidation of 5-Methyl Cytidines
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