Oxidation and reduction of the 5-(2-Deoxyuridinyl)methyl radical

Article abstract of DOI:10.1002/anie.201209454

Sleeping beauty: The 5-(2-Deoxyuridinyl)methyl radical 1 is a key intermediate in the thymine oxidative reaction mediated by reactive oxygen species. Evidence is presented that 1 is prone to both oxidation and reduction reactions at the absence of O₂. These results question the current paradigm and suggest that the redox chemistry of 1, which has been largely overlooked in the past, may play a major role in determining the fate of 1. Copyright

Full text of DOI:10.1002/anie.201209454

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DOI: 10.1002/anie.201209454
Biological Radicals
Oxidation and Reduction of the 5-(2’-Deoxyuridinyl)methyl Radical**
Gengjie Lin and Lei Li*
Thymine is susceptible toward ionizing radiation, a typical
source of reactive oxygen species (ROS). The 5-(2’-deoxyur-
idinyl)methyl radical (1) is a key intermediate of thymine
radical reactions involving either a hydroxyl radical-mediated
H atom abstraction at the methyl moiety[1] or a one-electron
oxidation followed by deprotonation process.[2] Species 1 was
implied to possess neither reducing nor oxidizing properties.[3]
It can add to atom C8 of a vicinal guanine or adenine under
anaerobic conditions.[4] A similar 5-(2’-deoxycytidinyl)methyl
radical gave rise to an intrastrand cross-link lesion in
dinucleotides d(mCpG) and d(GpmC).[5] Further studies of
1 by Greenberg et al. found that it also reacts with the
opposing 2’-deoxyadenosine in duplex DNA to yield a cross-
linked TpA dimer with the thymine methyl group added to
the adenine N6.[6] Such a lesion is readily detected in g-
irradiated DNA and accounts for at least 25% of the DNA
interstrand cross-links.[6b]
linking product remains the same under degassed or aerobic
conditions.[6a] The fact that the presence of O2 did not further
lower the reaction yield implies that other routes may also be
involved in the quenching process of 1.
We thus re-examined the reactivity of 1 generated by
À
photolytic cleavage of the C S bond in 5-(phenylthiomethyl)-
2’-deoxyuridine (PhSmdU, Scheme 1). The PhSmdU was
These cross-linked base dimers are suggested to block
replication and transcription and are quite toxic to cells. It is
thus of great significance to understand the reactivity of 1. O2
reacts with 1, forming a peroxyl radical intermediate, which
then decomposes to yield 5-(hydroxymethyl)-2’-deoxyuridine
(HmdU),
5-(hydroperoxy
methyl)-2’-deoxyuridine
(HpmdU), and 5-formyl-2’-deoxyuridine (fdU).[1e,7] Specifi-
cally, the formation of HpmdU requires one electron to
reduce the peroxyl radical precursor, which may be provided
by a superoxide radical (O2CÀ)[8] or a thiol compound.[7a] The
reaction between 1 and O2 is reversible;[9] however, it is still
two orders of magnitude faster than its reaction with thiol (H
abstraction),[7a] suggesting that O2 may prevent the nucleo-
base cross-linking reaction. However, a recent study revealed
that after complete consumption of the radical precursor, only
25% of the generated 1 were involved in the crosslinking
reaction with adjacent nucleobases. The yield of the cross-
À
Scheme 1. Generation of 1 by photolytic cleavage of the C S bond in
5-(phenylthiomethyl)-2’-deoxyuridine (PhSmdU) as well as thiol addi-
tion products in the dinucleotide context.
linked to another thymidine by phosphoramidite chemistry
to yield the dinucleotide TpPhSmdU (2).[10] The photoreac-
tion of 2 was allowed to proceed for 5 min under 254 nm UV
light in the presence or absence of O2 (Figure 1), which
usually consumed about 15% of 2. The reaction was then
analyzed by HPLC; the yields for the major products in the
anaerobic reactions are shown in Table 1. Our results suggest
that 1 can undergo both oxidative and reductive reactions in
the absence of O2; the resulting anion and cation are
quenched by the general acid and base in solution respec-
tively. Under an oxidizing environment, the anion formation
is inhibited. Under a reducing environment, the cation
formation is suppressed.
The aerobic reaction generated TpHmdU, TpHpmdU,
and TpfdU (Figure 1A), in agreement with the previous
reports that 1 is prone to O2 oxidation.[1e,7a] Surprisingly, an
unknown product X was also generated. In contrast, the
anaerobic reaction yields TpT and X as the major products
and TpHmdU as the minor product. The TpT formation is
puzzling as it was suggested to be formed by an H-abstraction
mechanism, with thiols such as glutathione or thiophenol
serving as the H-donor.[1e,7a] However, no thiol was added to
our reaction. One possibility is that the PhS· generated may
[*] Dr. G. Lin, Prof. L. Li
Department of Chemistry and Chemical Biology
Indiana University-Purdue University Indianapolis (IUPUI)
402 N. Blackford St., Indianapolis, IN 46202 (USA)
E-mail: lilei@iupui.edu
Prof. L. Li
Department of Biochemistry and Molecular Biology
Indiana University School of Medicine
635 Barnhill Drive, Indianapolis, IN 46202 (USA)
[**] We thank all of the referees for their insightful suggestions and
comments. We thank Professor Steven Rokita at the Johns Hopkins
University for helpful discussions on the TpT radical reduction. We
thank the National Institutes of Health (R00ES017177) as well as
the IUPUI startup fund for financial support. The NMR and MS
facilities are supported by the National Science Foundation MRI
grants CHE-0619254 and DBI-0821661.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209454.
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Table 1: Product yields in photoreactions of 2 at the absence of O2.
Reactions
Yield [%][a]
Mass
balance
Anion
TpT
Cation
Adduct X Other thiol
adduct
none
Na2S2O4
PhSH
44.5Æ2.3 43.2Æ4.1
–
–
–
89.2Æ5.9[b]
91.3Æ4.3[c]
87.3Æ7.0
86.2Æ3.0
77.5Æ3.4
85.4Æ5.7
39.0Æ2.5
–
–
–
4-
46.6Æ1.9
OHC6H4SH
DTT
(1 mm)
DTT
(10 mm)
DTT
(40 mm)
48.5Æ2.1 37.4Æ3.9 5.1Æ0.7
44.0Æ1.9 26.1Æ1.5 20.7Æ1.4
36.3Æ4.0 13.8Æ1.9 33.8Æ3.3
88.7Æ5.4
89.1Æ4.2
86.5Æ7.5
[a] The yields were based upon the amount of 2 reacted and were
calculated by HPLC peak integrations (See the Supporting Information).
[b] The yield of TpHmdU was about 2.5%. [c] The yield of TpmdUSO2H
was 12.1Æ2.8%.
Figure 1. HPLC chromatograph of TpPhSmdU (2, 200 mm) photoreac-
tion under 254 nm UV light. A) In H2O in air; B) in degassed H2O in
a Coy anaerobic chamber; C) in degassed H2O in a Coy anaerobic
chamber and supplemented by 1 mm sodium dithionite.
be reduced to PhSH and subsequently donates an H atom to
1 to yield TpT. To exclude this possibility, 1 mm PhSH was
added to the solution before 2 was irradiated. Such a large
excess of PhSH only improved the TpT yield by about 20%
(Figure 3B), proving that PhSH can serve as the H donor;
however, such an H donation process is not the major reaction
pathway to quench 1.
Besides TpT, species X is another major product, whose
nature needs to be revealed before the reactivity of 1 can be
understood. X exhibits a mass of 1199.26 in the positive-ion
mode, corresponding to a formula of [TpT+ 2-2H]. Such
a compound can be obtained either by TpTradical addition to
2 followed by elimination of an H atom or by TpT cation
addition followed by loss of a proton. 1H NMR
analysis suggests X to be a mixture of products with
the thymine methyl group added to the phenyl ring
of 2 (Figure 2A); however structural details cannot
be obtained for the compounds that comprise the
spectrum owing to signal overlap. This addition
pattern was further supported by the MS/MS
spectrum of X, in which three major fragments
were found (Figure 2B), with the corresponding
chemical structures shown in Figure 2A. To reveal
the structure of X, we examined the PhSmdU
photoreaction as a model system.[10] As expected,
the reaction produced thymidine and HmdU. More
importantly, two species X’1 and X’2 were formed
and separated by HPLC, both of which possess
a mass of [T+ PhSmdU-2H]. 1H NMR analyses
confirm that the thymine methyl moiety is added to
the para position of the phenyl ring in X’1 and to
the ortho position in X’2 (Scheme 2). The yield of
isolated X’2 is about 50% higher than that of X’1.
Scheme 2. Addition of the thymine methyl cation to the para position
of the phenyl ring in X’1 and to the ortho position in X’2.
Figure 2. A) Proposed structure of product X, suggesting that a TpT moiety is added
to the phenyl ring of -SPh. B) LC-MS/MS analysis of ion [X+H]+ at 1199.26. The
As the ring possesses two positions ortho and one
position para to the SR substituent, our data structures of the three fragmentation ions (f1, f2, and f3) are indicated in (a).
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suggest that the ortho positions are slightly less active toward
the addition reaction probably due to the steric hindrance of
the SR moiety.
producing 2, which escapes from the HPLC detection. To
test this hypothesis, we repeated the photoreaction in the
presence of 1 mm 4-hydroxythiophenol (4-OH-C6H4-SH). As
expected, formation of X was suppressed and a new species 5
was generated (Figure 3C). NMR and MS analyses confirm
that 5 is the addition product Tp(4-OH)C6H4SmdU formed
between the TpT cation and 4-OH-C6H4-SÀ (Scheme 1).[10]
Equal amounts of 5 and X were produced as shown in
Figure 3A and C, indicating that 5 is formed at the expense of
X (Table 1). The cation can also be trapped by other thiols,
such as DTT. Addition of 1–40 mm DTT did not markedly
increase the yield of TpT (Figure 3D–F), again suggesting
that H-abstraction is unlikely to play a major role. Under
1 mm DTT, formation of X decreased by only about 10%,
contrasting to the nearly complete quenching by 1 mm PhSH.
With 40 mm DTT, formation of X decreased by 50%. These
results are in line with the rationale that DTT is a better
reductant, but a much worse nucleophile than PhSH. The
reactions also yield the expected TpmdU-DTT adduct 6
(Scheme 1).[10] 6 exist as a pair of DL isomers, as indicated by
the doublet peak in HPLC chromatograph, which result from
the DL mixture of DTT used.
Such a reaction pattern suggests that X is formed by
a cation addition mechanism. If a radical addition is involved,
three products, with the thymine methyl group added
randomly to any of the five positions at the phenyl ring, are
expected. The thymine cation is still formed in the presence of
O2, as indicated by the generation of X in Figure 1A. Its
formation may be explained by competitive elimination of the
À
superoxide radical (O2 ) from the peroxyl radical precursor,
similar to what was observed in the addition of O2 to 2’-
deoxyuridin-1’-yl radical.[11] Alternatively, the peroxyl radical
may undergo a reverse process,[9] resulting in 1 and O2 with
1 being subsequently oxidized to the cation. Although HmdU
is typically formed by O2 oxidation to 1,[1e,7a,12] the TpHmdU
formed in the absence of O2 likely results from the H2O
addition to the cation followed by loss of a proton. After
diluting 2 by tenfold, the TpHmdU yield is improved at the
expense of X,[10] further supporting this mechanism. More-
over, if the reaction is conducted in methanol, the corre-
sponding methoxy adduct TpMeOmdU is produced.[10]
The presence of thiol compounds barely enhances the
TpT formation, contrasting with the fourfold enhancement
induced by 1 mm sodium dithionite in Figure 1C. Photo-
reaction of 2 in the presence of 1 mm PhSH results in the
disappearance of X (Figure 3B). As PhSH is an excellent
nucleophile, it likely quenches the thymine cation, re-
Formation of thymine cation from 1 is a one-electron
oxidation process. As no obvious electron acceptor can be
identified in the anaerobic reaction, it is intriguing to suggest
that another molecule of 1 accepts the electron to yield
a methyl anion, which then obtains a proton from water,
yielding TpT. This hypothesis is supported by the reaction in
À
D2O. The bond dissociation energy (BDE) for the O H bond
in water is 119 kcalmolÀ1,[14] which is about 30 kcalmolÀ1
[15]
À
higher than the C H bond in the thymine CH3 group. It
is highly unlikely that 1 would abstract a deuterium atom from
D2O. However, more than 95% of the TpTs formed contain
one deuterium, which is located on the methyl group, as
shown by 1H NMR spectroscopy.[10] When 2 was irradiated in
[D1]methanol (CH3OD), more than 95% of the TpTs are
[D1]TpTs as well,[10] showing that the stronger O D bond in
À
CH3OD is involved in TpT formation. As 2-deoxyribose is
prone for H-abstraction reactions,[16] these labeling studies
also allow us to exclude the possible involvement of the 2-
deoxyribose. Collectively, our data discriminate against the
H-abstraction mechanism, but support the anion reaction.
The formed anion takes a deuteron from solvent to yield
[D1]TpT.
Should 1 be reduced by another thymine radical, it would
be reduced by a stronger reductant. We thus examined the
reactivity of 1 in the presence of 1 mm sodium dithionite. As
expected, the reducing environment totally abolished the
cation-related products; the radical reduction product TpT
was increased about fourfold (Figure 1C), confirming that the
presence of a strong reductant facilitates the thymine anion
À
formation. The reaction also produced TpmdUSO2 as
a minor product (Figure 1C),[17] with its yield roughly 1/6 of
that for TpT. TpmdUSO2 is likely formed by a radical
Figure 3. HPLC chromatograph of anaerobic TpPhSmdU (2, 200 mm)
photoreaction under 254 nm UV light. A) In H2O; B) with 1 mm PhSH;
C) with 1 mm 4-OH-C6H4SH; D) with 1 mm DTT; E) with 10 mm DTT;
and F) with 40 mm DTT. As the DTT utilized was a DL mixture, the
resulting adducts 6 were a mixture as well, as indicated by the doublet
peak in the HPLC chromatograph. The two peaks marked by *
correspond to DTT and DTT disulfide, respectively, which already exist
in the DTT used.[13]
À
recombination mechanism. The dithionite dianion has a dis-
sociation constant Kd ꢀ 10À6 mm in water,[18] which results in
À
À
the formation of CSO2 . UV irradiation may promote the S S
bond cleavage in dithionite dianion, making the concentra-
tion of CSO2À even higher. It should be fairly favorable for 1 to
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recombine with CSO2À, yielding TpmdUSO2À. Although the
TpmdUSO2À formation rate cannot be obtained owing to the
difficulty to determine the exact concentrations of 1 and
The mechanistic discussions above only involve the
carbon-based radical 1. Considering the similar electronega-
tivity between C (2.544) and S (2.589),[21] the PhSC generated
À
CSO2À, the lower yield of TpmdUSO2 indicates that the
after the C S bond cleavage in 2 is likely involved in the redox
À
radical reduction reaction to produce TpT likely occurs with
a rate that is at least comparable to that of the radical
recombination reaction.
These experiments clearly indicate that 1 can undergo
both oxidation and reduction reactions (Scheme 3A); it
disproportionates in the absence of stronger redox reagents.
reactions as well. We thus carefully quantified all of the PhSC
related redox products under varying pH. The photoreaction
produces two minor products 3 and 4 (Figure 1A,B and
Supporting Information), both of which exhibit a mass of
761.14 at the negative-ion mode,[10] corresponding to a formula
of [PhSC + 2-H]. Limited by the low yields, we were unable to
isolate enough compound for NMR spectroscopy
characterization. However, 3 and 4 are likely to be
formed either by PhS+ addition to a double bond in 2
followed by loss of a H+, similar to the generation of
X, or by PhSC addition to 2 followed by loss of a HC
(e + H+). The released HC can combine with PhSC or
1, resulting in the reducing products PhSH and TpT,
respectively. Both routes indicate that 3 or 4 can be
treated as a cation product of PhSC (Scheme 3B).
Furthermore, the formed PhSH, the anion (reduc-
ing) product of PhSC, was extracted with hexane and
quantified by GC-MS spectroscopy (Table 2).
Excellent mass balance was obtained for the
redox process in all of the reactions in Table 2. When
pH ꢁ 7, the amounts of cationic and anionic prod-
ucts of 1 are roughly equal. Assuming PhSC and 1 do
not interact with each other, disproportionation of
1 becomes a simple interpretation for our data. In
contrast, under basic pH where [H+] is low, the
thymine anion formation is unfavored. Species 1 is
still oxidized to a cation; however, the preferred
electron acceptor becomes PhSC, yielding PhSÀ.
Formation of PhSÀ was implied by a 5,6-dihydro-5-
hydroxythymidin-6-yl radical study.[22] Furthermore,
we observed the dimer of 1 in our reaction, the
formation of which was suggested in previous
studies.[3,16b,19b,c] The dimer yield is very low under neutral or
acidic pH, which is consistent with the low yield obtained in
Scheme 3. Oxidation and reduction reactions of 1 and PhSC.
Pyrimidine radicals were known to disproportionate under
anaerobic conditions.[3,19] However, the reaction of 1 is differ-
ent as the disproportionations of previous pyrimidine radicals
and traditional alkyl radicals require an H atom b to the
radical center and the reactions proceed by a radical mediated
H-abstraction mechanism.[20] We tentatively ascribe the
difference to the polar solvents used here, which stabilize
the charged reaction intermediates by electrostatic interac-
tions. Moreover, although 1 can be reduced, a direct one-
electron reduction followed by protonation to yield thymine
is unfavorable owing to the poor stability of the thymine
methyl anion intermediate. Compound 1 is likely to be
À
TpmdUSO2 formation. These results re-confirm that the
radical recombination pathway is unfavorable; dimer forma-
tion increases only when the disproportionation reaction
slows down at pH 11. As PhSC is the electron acceptor in this
case, this result also indicates the electron transfer between
1 and PhSC to be slightly slower than that between two
molecules of 1, which likely rationalizes why disproportiona-
tion of 1 is favored in most of our reactions.
It is worth pointing out that the electron transfer process
between two 1 molecules (radical disproportionation reac-
tion) is unlikely to happen in vivo as it is implausible to have
two thymine radicals close to each other in duplex DNA. Our
=
protonated at the C4 O bond to a radical cation before the
reduction occurs (Scheme 3A).
Table 2: Products isolated [nmol] in photoreactions of 2 [40 nmol].
Anion products
Cation products
Dimer of 1
pH
TpT
PhSH
TpTOH
X
3+4
3–7
9
11
2.73Æ0.22
2.88Æ0.10
0.38Æ0.05
0.78Æ0.05
0.94Æ0.06
2.59Æ0.12
0.25Æ0.03
0.29Æ0.02
0.85Æ0.07
2.50Æ0.20
2.83Æ0.17
2.18Æ0.14
0.55Æ0.03
0.66Æ0.07
0.20Æ0.05
<0.02
0.05Æ0.01
0.39Æ0.04
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