Oxidation of 9-β-d-ribofuranosyl uric acid by one-electron oxidants versus singlet oxygen and its implications for the oxidation of 8-oxo-7,8-dihydroguanosine

Article abstract of DOI:10.1016/j.tetlet.2010.11.123

Uric acid, a cellular antioxidant, undergoes oxidation in the presence of one-electron oxidants as well as singlet oxygen. In the present work, the oxidation pathways and products formed from oxidation of the uric acid nucleoside are compared to the more commonly studied uric acid free base. A wider distribution of products, including allantoin, urea, caffolide, and 5-carboxamido-5-hydroxyhydantoin nucleosides, are formed when the N9 position of uric acid is glycosylated. The oxidation pathways share some features in common with the oxidation of 8-oxo-7,8-dihydroguanosine, but the additional spectrum of products implies that the combination of oxidative and deaminative damage to guanosine may lead to a more complex set of DNA lesions than originally described.

Full text of DOI:10.1016/j.tetlet.2010.11.123

Tetrahedron Letters 52 (2011) 2176–2180
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Oxidation of 9-b-D-ribofuranosyl uric acid by one-electron oxidants
versus singlet oxygen and its implications for the oxidation
of 8-oxo-7,8-dihydroguanosine
⇑
Khiem V. Nguyen, James G. Muller, Cynthia J. Burrows
Department of Chemistry, University of Utah, 315 S. 1400 East, Salt Lake City, UT 84112-0850, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 27 November 2010
Uric acid, a cellular antioxidant, undergoes oxidation in the presence of one-electron oxidants as well as
singlet oxygen. In the present work, the oxidation pathways and products formed from oxidation of the
uric acid nucleoside are compared to the more commonly studied uric acid free base. A wider distribution
of products, including allantoin, urea, caffolide, and 5-carboxamido-5-hydroxyhydantoin nucleosides, are
formed when the N9 position of uric acid is glycosylated. The oxidation pathways share some features in
common with the oxidation of 8-oxo-7,8-dihydroguanosine, but the additional spectrum of products
implies that the combination of oxidative and deaminative damage to guanosine may lead to a more
complex set of DNA lesions than originally described.
Ó 2010 Elsevier Ltd. All rights reserved.
8-Oxo-7,8-dihydro-20-deoxyguanosine (OG) is an abundant
product of oxidative damage in DNA.1,2 OG is also characterized
by its high susceptibility to further oxidation and its secondary
oxidation products have been characterized under various condi-
tions.3,4 In addition to oxidation, the exocyclic primary amino
group of guanosine is known to be reactive with nitrogen electro-
philes,5 such as nitric oxide,6 to form xanthosine and oxanosine as
the major products both in vitro6,7 and in vivo.8–11 However, the
same reaction in the case of OG to form uric acid nucleoside has
not been studied. One possible reason is that the deamination reac-
tion of OG leading to uric acid nucleoside is even more sensitive to
oxidation than OG, undergoing subsequent oxidation more rapidly
than it can be detected. Thus, it was of interest to characterize the
further oxidation products of uric acid nucleoside in order to gain
more insight to the pathways and products of OG under conditions
involving oxidation and deamination with the potential benefit of
shedding light on additional products formed in peroxynitrite-
mediated damage to DNA, a common outcome of inflammation.12
Moreover, the one-electron oxidation of uric acid nucleoside is also
of interest in terms of its mechanistic aspects, because of parallels
between the oxidation of uric acid (UA) alone and the hydantoin
products derived from OG nucleoside oxidation.13,14 Although the
sugar moiety is known to have an influence on the redox properties
of oxidized purines,15,16 no direct comparisons have been made be-
tween oxidations of OG nucleoside and UA nucleoside (termed ‘RU’
in this work).
Uric acid is known to be a scavenger for reactive oxygen species
(ROS) in vivo.17,18 While photophysical and biological aspects of
the photosensitized oxidation of uric acid derivatives have been
extensively studied,19–24 mechanistic aspects for the transforma-
tion to oxidation products still require more work. There are argu-
ments, for example, in differentiating between type I and type II
photooxidation25,26 or in formation and decomposition of reaction
intermediates.24–26 In this study, some mechanistic aspects of the
photosensitized oxidation of uric acid nucleoside will be presented
and compared to the well-characterized photooxidation process of
its analogous structure 8-oxo-7,8-dihydroguanosine.27–29
The ribose form of uric acid nucleoside (9-ribofuranosyl-b-D-
uric acid, RU) was chosen as the substrate to be oxidized due to
its more convenient preparation compared with the 20-deoxyribose
form; in addition, the 20-hydroxyl group should stabilize the
glycosidic bond with respect to hydrolytic cleavage. The 20, 30
and 50-hydroxyl groups of RU were acylated (Ac3RU) to facilitate
the separation of oxidation products by reversed phase HPLC and
to better mimic the chemistry in a DNA strand in which no free
hydroxyls are present.27 Metal complexes (Na2IrCl6 or K3Fe(CN)6)
were used as one-electron oxidants. Riboflavin was used as a ‘Type
I’ photosensitizer to undergo electron transfer chemistry, while
rose bengal or methylene blue were used as ‘Type II’ photosensitiz-
ers that predominantly generate singlet oxygen.30,31
Oxidation of a 0.3 mM solution of Ac3RU in aqueous phosphate
buffer at pH 7 by Na2IrCl6 (0.6 mM) led to the formation of five sta-
ble products32 (1–5) that were characterized by RP-HPLC (Fig. 1).
An identical result was obtained from the oxidation with
K3Fe(CN)6. Products were identified on the basis of their masses
from LC–ESI-MS studies and compared with known products of
⇑
Corresponding author. Tel.: +1 801 585 7290; fax: +1 801 585 0024.
E-mail address: burrows@chem.utah.edu (C.J. Burrows).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.123

K. V. Nguyen et al. / Tetrahedron Letters 52 (2011) 2176–2180
2177
precursor to allantoin, and TP2 and TP3 as precursors of urea, caffo-
lide, and HICA amide. The LC–ESI-MS analysis showed the masses of
TP2 and TP3 were the same at 460 amu (M+34) and yielded a frag-
ment at 442 amu corresponding to the loss of a neutral water mole-
cule. The identical mass spectra and very close retention in RP-HPLC
time suggested that TP2 and TP3 were diastereoisomers. Experi-
ments carried out in H218O led to a gain of 4 amu for both TP2 and
TP3, corresponding to incorporation of two 18O atoms from water.
These data are consistent with the structure of 4,5-OH–RU, analo-
gous to the precursors of HICA in OG oxidation by peroxynitrite36
and of caffolide in the caffolide degradation pathway of uric acid.37
TP1 was very unstable at pH 7 but its stability was increased
when the pH was lowered. The LC–ESI-MS analysis of TP1 could
only be performed at pH 3.2, and it too indicated mass of
460 amu, although it did not behave like TP2 and TP3 in yielding
a 442 amu product due to dehydration. Therefore, we propose
TP1 is the 5,6-dihydroxylated structure 5,6-OH–RU, a precursor
to allantoin, by analogy to the enzymatic oxidation of uric acid38
and to the mechanism of formation of guanidinohydantoin (Gh)
from OG oxidation.13,39 When experiments were conducted in
H218O, the allantoin mass increased by 2 amu while a gain of
4 amu was observed for caffolide. In the case of HICA amide, the re-
sults showed that two or three 18O were incorporated, suggesting
some solvent exchangeability occurred at one more carbonyl
group. These observations help support the mechanism in Scheme
1 for the structural rearrangements occurring from precursors to
products.
Figure 1. HPLC traces of (A) the starting material (B) the oxidation products of
Ac3RU by Ir(IV), monitored at 220 nm.
uric acid derivatives.16,25,26,33–35 From that, 1 was assigned as
ribosylurea, 2 and 3 as two diastereoisomers of allantoin ribonu-
cleoside, 4 as two diastereomers of 5-carboxamido-5-hydroxyhyd-
antoin ribonucleoside (HICA amide), and
ribonucleoside (Scheme 1).
5
as caffolide
To obtain additional support for the structural assignments of the
oxidation products, we attempted to characterize reaction interme-
diates. For this purpose, 100-lL aliquots were taken from the reac-
tion mixture periodically, and the product composition was
monitored immediately by HPLC. Three transient peaks, TP1–TP3,
were identified with retention times at 17.1, 20.9, and 21.2 min,
respectively. TP1 was very unstable under these conditions, and to-
tally disappeared after 5 min while the two peaks corresponding to
allantoin diastereomers increased. TP2 and TP3 were more stable,
but completely decomposed after 2 h, and the peaks corresponding
to HICA amide, urea, and caffolide appeared and increased during
this period of time. It was, therefore, reasonable to assign TP1 as a
The dependence of the product distribution on pH was also
investigated because previous investigations indicated that OG oxi-
dation to form hydantoin products Sp and Gh, as well as uric acid
oxidation, are highly pH dependent. The oxidation of Ac3RU was
carried out at pH 5.4, 6.2, 7.0, 8.0, and 9.2. The results showed that
HICA amide was formed at pH values higher than 6.2, and the
amount was increased when increasing the pH. In contrast, both
allantoin and caffolide formation were favored at pH 5.4–7.0 and
decreased when increasing the pH.
O
O
OH
OH
O
H
H
N
O
OH
H
N
H
N
N
OH
NH
-2e-2H+
H2O
NH2
O
NH
N
N
H2O
NH
O
NH
O
O
O
O
N
R
N
R
N
H
O
N
H
N
N
O
N
R
N
O
N
O
R
R
Alla
M-10
5,6-OH-RU
M+34
RUox
5-OH-RU
H2O
Ac3RU
M
H
N
O
O
OH
H
N
H
O
NH2
NH
N
pH<8
pH<8
O
O
O
O
N
NH
R
N
H
O
N
R
R HO
O
Caffolide
4,5-OH-RU
M+34
Urea
M+17
M-108
pH>6.2
O
OH
H
N
NH2
R= 2',3',5'-tri-O-acetylribose
O
N
R
O
HICA amide
M-9
Scheme 1. Proposed mechanism for the one-electron oxidation of Ac3RU.

2178
K. V. Nguyen et al. / Tetrahedron Letters 52 (2011) 2176–2180
Our experimental observation of reaction intermediates pro-
pared to 5-OH–OG. Reasonably, the more reactive C4 was easier
to attack by solvent water in competition with an intramolecular
acyl shift. Thus, pathway I was not observed in the oxidation of
RU by one-electron oxidants.
vides insights into the reaction mechanism of RU oxidation by
one-electron oxidants (Scheme 1). A common intermediate, 5-
OH–RU may form first from the addition of water to C5 of a quino-
noid intermediate RUox. Two electrophilic centers, C4 or C6 of
5-OH–RU were further attacked by water and led to the formation
of two observable intermediates 4,5-OH–RU and 5,6-OH–RU. In
the case of 5,6-OH–RU, the C6–N1 bond was broken, followed by
decarboxylation leading to the formation of allantoin.
The decomposition pathways of the intermediate 4,5-OH–RU
are likely more complicated. The first-steps are probably the cleav-
age of either C4–N9 or C4–N3 bond with the assistance of the 5-OH
group. When the C4–N9 bond is broken, the final product is ribo-
sylurea after elimination of alloxan. When the C4–N3 bond is
cleaved, two subsequent pathways may occur. One pathway in-
volves hydrolysis of the amide linkage, C2–N1, which leads to HICA
amide. The fact that the amide linkage is more labile under basic
conditions explains the increasing amount of HICA amide when
the pH increases. Another pathway is an intramolecular process
in which 4-OH participates in formation of a carbonyl; a subse-
quent attack of the C5–OH at C2 and elimination of NH3 would
form caffolide. This process may occur more readily if the NH2
group could be protonated during elimination, consistent with caf-
folide formation being more favorable at low pH.
Our results show that the presence of the ribose moiety at the
N-9 position led to the formation of more oxidation products than
the uric acid heterocycle alone. The oxidation of uric acid by Ir(IV)
at pH 7 gave allantoin as the only detectable product (see Supple-
mentary data), while three more products (ribonucleosides of HICA
amide, caffolide, and urea) were obtained in the case of uric acid
nucleoside oxidation under the same conditions. The influence of
N-substitution on the redox property of uric acid heterocycle has
been investigated; however, the explanations were mainly based
on theoretical calculations.40 The present mechanistic studies pro-
vided more details on understanding the difference between one-
electron oxidation pathways of ribofuranosyl uric acid and the uric
acid heterocycle. It is clear that 5-OH–UA and the analogous 5-
OH–RU are the common intermediates of UA and RU oxidation,
respectively. At pH 7, the predominant form of 5-OH–UA is the
N9-deprotonated species,38 and the C4 is, therefore, unreactive
with nucleophiles due to the negative charge density (Scheme 2).
It is reasonable that pathway III (Scheme 3) is the only degradation
pathway of 5-OH–UA that leads to the formation of allantoin. In
contrast, 5-OH–RU is neutral, and C4 can, therefore, be readily at-
tacked by water to form the 4,5-dihydroxyl intermediate that then
decomposes to give urea, HICA amide, and caffolide (Scheme 1).
In the oxidation of RU by Ir(IV), the formation of a spirocyclic
product (pathway I, Scheme 3), that was observed in OG oxida-
tion13 as well as UA oxidation under more basic conditions,41
was not detected. Because 5-OH–OG and 5-OH–RU appear to be
the initial and common intermediates in oxidation of both nucleo-
sides, the difference in products must derive from degradation
pathways of these analogous intermediates. Pathways I and II both
involve nucleophilic addition to C4; however, one is an intramolec-
ular process (I) and the other is an intermolecular one (II). The
presence of a C2-carbonyl group in the case of 5-OH–RU leads to
an increase in C4 reactivity toward external nucleophiles com-
Nevertheless, we found that the distribution of products occur-
ring at C4 and C6 in RU oxidation shares some similarity with that
of OG oxidation. In the case of OG, pathway I was known to be
dominant over pathway III at high pH and high temperature.13
When the oxidation of RU was carried out at pH >7 or at 65 °C,
the amount of HICA amide was significantly increased, and the
amount of allantoin decreased (see Supplementary data). This indi-
cates that the C4 pathway is also more favorable at high pH and
high temperature in RU oxidation. Interestingly, the competition
between pathways I and III is also influenced by the nature of
nucleophiles used to trap the quinonoid intermediate. When lysine
was used as a nucleophile to compete with water to attack at C5 of
RUox generating a 5-Lys-RU intermediate, the allantoin-Lys adduct
was the only detectable product, whereas pathway I dominated for
the reaction of OG nucleoside under these conditions. Thus, the
replacement of an oxygen atom at C5 by nitrogen in the common
intermediate drove its decomposition toward pathway III.
In the work described above, the oxidation reactions likely pro-
ceed by two sequential one-electron oxidation steps with concom-
itant deprotonation. In order to compare the outcome of a potential
4-electron oxidant, singlet oxygen, the reactions were repeated
using two different Type II photosensitizers generating 1O2, rose
bengal (RB) and methylene blue (MB). For comparison, the Type
I photooxidant riboflavin (Rf) was also used. The excited state of
riboflavin is a powerful one-electron oxidant, but its subsequent
ꢀꢁ
radical anion reacts with O2 to further yield superoxide, O2
.
The HPLC traces of photooxidation of Ac3RU mediated by Rf,
MB, and RB at pH 7 are shown in Figure 2. Interestingly, Type I
(Rf) and Type II (MB, RB) photosensitized oxidation of Ac3RU gave
the same products with only a small difference in yield. On the ba-
sis of mass and by analogy to products from manganese porphy-
rin-mediated oxidation to guanosine,42–44 product
6
was
tentatively assigned as oxidized allantoin Allaox and product 7
was assigned as oxaluric acid OA. Indeed, OA was also the product
of riboflavin-mediated oxidation of OG,27 derived from the decom-
position of the unstable intermediate Ghox—an analogous structure
to Allaox. Thus, we wondered whether OA found in this experiment
was also formed from decomposition of Allaox. As previously de-
scribed, Ghox was relatively unstable at pH 7 and converted to
OA after 3 h.45 In the present case, Allaox was found to be stable
at pH 7 and did not significantly decompose after two days at room
temperature. This was not surprising because the Allaox nucleo-
base can be independently synthesized, although it decomposes
in very strong acidic or basic conditions.46 However, we found that
Allaox was unstable at high temperature. When heated up to 65 °C
for 2 h, Allaox was gradually converted to OA at pH 7. Thus, the
small amount of OA detected in the photosensitized oxidation of
Ac3RU may be evidence for the decomposition of the major prod-
uct Allaox when the reaction mixture was heated somewhat by the
irradiation lamp.
Riboflavin-mediated oxidation involves electron transfer from
the purine to Rf, and the formation of O2ꢀꢁ, superoxide anion.47
In the case of OG, the reactive intermediates (cation radical OG+Å
or neutral radical OGÅ) then can be trapped by either a water mol-
ꢀꢁ
ecule or O2 that lead to the formation of two sets of oxidation
products.27 In the present study, the oxidation product Allaox
was believed to be formed via the superoxide adducted intermedi-
ate 5-OOH–RU (Fig. 2). Interestingly, water-derived products48
were not observed under the experimental conditions, which is
opposite to the case of OG where the water-derived product Sp
was found to be dominant at pH 7.27 As described for OG, the prod-
uct distribution was strongly dependent on pH. The radical cation
HO
H
O
N
HO
H
O
N
-H+
N
N
NH
NH
O
O
N
N
H
O
O
(-)
Scheme 2. N9-deprotonation of 5-OH–UA.

K. V. Nguyen et al. / Tetrahedron Letters 52 (2011) 2176–2180
2179
O
OH
H
N
NH
O
N
R
N
X
RU
X=O,
X=NH, OG
III
I
II
O
O
OH
H
O
O
HN
N
X
HN
NH
O
O
NH
O
NH2
N
R
N
N
N
H
X
N
R
X=O,
HN
H
HO
R
X
4,5-OH-RU
X=O,
X=NH
Alla
Sp
(X=O, NH)
R= H or 2',3',5'-tri-O-acetylribose
Scheme 3. Degradation pathways of the common 5-hydroxy intermediate.
, 4,5-OH-OG
Gh
X=NH,
OG+Å is much more reactive toward superoxide anion than the
deprotonated form OGÅ, and, therefore, O2ꢀꢁ-derived products were
found to be dominant at low pH. At pH 7, RU with a pKa of 5.4,49
mostly exists as the anion RUꢁ, so that the excited state after inter-
action with Rf must be the neutral radical RUÅ. Unlike OGÅ, this spe-
cies was exclusively trapped by anion O2ꢀꢁ, not by a water
molecule, and lead to the formation of 5-OOH–RU that decom-
posed to give Allaox. A possible explanation is that the presence
of an oxo function at C2 of RUÅ instead of an NH2 group, as in the
case of OGÅ, makes C5 more electropositive due to the charge
ꢀꢁ
delocalization. Thus, the affinity for anion O2 was reasonably
increased from OGÅ to RUÅ and O2ꢀꢁ was preferable while competing
with water to react with RUÅ.
Photooxidation mediated by RB or MB is known to generate sin-
glet oxygen as the reactive intermediate.47 Interestingly, the Type
II photosensitized oxidation of RU gave the same products as Type
I oxidation. This suggests that the 5-OOH–RU intermediate must
be formed at some stage. As for OG oxidation,28 singlet oxygen
most likely adds to the C4–C5 double bond of RU to form the
Figure 2. HPLC traces of starting material Ac3RU (A) and the oxidation reactions
with riboflavin (B), methylene blue (C), rose bengal (D), monitored at 220 nm.
OH
O
O
N
OH
O
O
O
N
OH
OH
NH
H
N
H
N
-H+
H
N
H
N
NH
NH
Type I
H2O
NH
O
O
O
O
N
R
N
R
O
N
H
O
N
R
N
R
O
N
O
5-OOH-RU
1O2
Ac3RU
Type II
O
N
H
N
OH
O
O
NH
H
O
O
H
O
N
N
NH2
O
O
O
R
N
N
O
R
H
N
O
NH2
COOH
NH2
O
O
N
R
N
O
N
O
R
Allaox
OA
Scheme 4. Proposed mechanisms for the photosensitized oxidation of Ac3RU.

2180
K. V. Nguyen et al. / Tetrahedron Letters 52 (2011) 2176–2180
dioxetane intermediate. At pH 7, RU exists as the anion RUꢁ and
the negative charge at on O2 may force the dioxetane to decom-
pose via C4–O bond breakage to form the superoxide intermediate
5-OOH–RU (Scheme 4). This is totally different from OG oxidation
where the analogous dioxetane was preferably decomposed via the
O–O and the C4–C5 bonds breakdown to generate the nine-mem-
ber ring intermediate.28
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Dedicated to Prof. Harry H. Wasserman on the occasion of his
90th birthday. This research was supported by a grant from the
National Science Foundation (0809483). The authors thank Aaron
Fleming (University of Utah) for helpful discussions and the
Vietnam Education Foundation for a fellowship to K.V.N.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.123.
44. Vialas, C.; Pratviel, G.; Claporols, C.; Meunier, B. J. Am. Chem. Soc. 1998, 120,
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