Model studies of the (6-4) photoproduct photoreactivation: Synthesis and photosensitized splitting of uracil oxetane adducts

Article abstract of DOI:10.1016/S0045-2068(03)00082-8

Uracil oxetane adducts, which are model compounds for the oxetane intermediates generated during the formation of (6-4) photoproducts or in their photoenzymatic repair, have been synthesized using 1,3-dimethyluracil with carbonyl compounds. On the basis of fluorescence measurements and photolysis experiments, it is demonstrated that the oxetane adducts can be split into the nucleotide base and carbonyl compounds via an electron transfer reaction from photosensitizer. The reaction is more efficient for a stronger electron donor.

Full text of DOI:10.1016/S0045-2068(03)00082-8

BIOORGANIC
CHEMISTRY
Bioorganic Chemistry 31 (2003) 357–366
www.elsevier.com/locate/bioorg
Model studies of the (6-4)
photoproduct photoreactivation: synthesis and
photosensitized splitting of uracil oxetane adducts
*
Qinhua H. Song, Xiaoming Hei, Zhixiu Xu, Xiang Zhang,
and Qingxiang Guo
Department of Chemistry, University of Science and Technology of China, Hefei 230026, PR China
Received 14 January 2003
Abstract
Uracil oxetane adducts, which are model compounds for the oxetane intermediates gener-
ated during the formation of (6-4) photoproducts or in their photoenzymatic repair, have been
synthesized using 1,3-dimethyluracil with carbonyl compounds. On the basis of fluorescence
measurements and photolysis experiments, it is demonstrated that the oxetane adducts can
be split into the nucleotide base and carbonyl compounds via an electron transfer reaction
from photosensitizer. The reaction is more efficient for a stronger electron donor.
Ó 2003 Elsevier Science (USA). All rights reserved.
Keywords: (6-4) Photoproducts; Oxetane intermediate; DNA photorepair; Electron transfer
1
. Introduction
DNA is damaged by ultraviolet component from sunlight to give a variety of po-
tentially mutagenic photoproducts [1–4]. The pyrimidine cyclobutane dimers are the
most abundant photoproducts among the major three types of photoinduced DNA
damage. For this reason, most studies of chemical and biochemical aspects of DNA
photodamage have focused on this class of photoproducts. However, more recent
*
Corresponding author. Fax: +86-551-360-1592.
E-mail address: qhsong@ustc.edu.cn (Q.H. Song).
0
045-2068/$ - see front matter Ó 2003 Elsevier Science (USA). All rights reserved.
doi:10.1016/S0045-2068(03)00082-8

358
Q.H. Song et al. / Bioorganic Chemistry 31 (2003) 357–366
Scheme 1.
work has suggested that some of the less abundant UV photoproducts might actually
be more effective at causing damaging mutations [5,6].
The pyrimidine(6-4)pyrimidone adducts, simply termed (6-4) photoproducts, con-
stitute a second class of stable photoproducts in DNA and also play a role in UV-
induced cytotoxic damage [1,7–11]. Formation of a (6-4) product from T* + T
in DNA and U* + U in RNA via an initial Paterno-B u€ chi cycloaddition to form
an oxetane intermediate is depicted in Scheme 1. Clivio et al. [12] have reported
the isolation of a thietane intermediate generated during the formation of a (6-4)
photoproduct involving 4-thiothymidine. The work is one of the few pieces of exper-
imental evidence supporting the proposed mechanism for the formation of a (6-4)
photoproducts. In 1993, Todo et al. [13] reported the discovery of an enzyme from
Drosophila melanogaster cell extracts, which can mediate the reversal of (6-4) photo-
products under UVA and blue light. The (6-4) photolyase enzymes with similar func-
tion and sequence were subsequently discovered in other species [14–16]. Sancar and
co-workers [17–19] suggested an electron transfer (ET) repair mechanism for the
(
(
6-4) photolyase, which is analogous to that of cyclobutane pyrimidine dimer
1
CPD) photolyase enzyme [20–23]. DNA (6-4) photoproduct photolyase can specif-
ically bind to damaged sites containing a pyrimidine(6-4)pyrimidone and cause it to
revert back to the oxetane or azetidine (in the case of cytosine) intermediate. This is
followed by the absorption of a UV-A or visible light photon, resulting in an electron
transfer from reduced flavin to the intermediate. The radical anion of the oxetane or
azetidine fragment rapidly and back electron transfer restores the two pyrimidine ba-
ses and the functional form of flavin ready for a new cycle of catalysis (Scheme 1)
[
17–19,24].
Rapid fragmentation of the oxetane radical anion is a key premise of this mech-
anism. At the time of the original proposal there was no definitive evidence suggest-
1
Abbreviations used: CPD, cyclobutane pyrimidine dimer; DMA, N,N-dimethylaniline; DMT, 1,3-
dimethylthymine; DMU, 1,3-dimethyluracil; DMT, 1,3-dimethylthymine; ET, electron transfer; MHA,
10-methyl-9,10-dihydroacridine.

Q.H. Song et al. / Bioorganic Chemistry 31 (2003) 357–366
359
ing that any oxetane adduct of a pyrimidine would fragment following one-electron
transfer because the natural oxetane intermediates are not isolable, as they sponta-
neously undergo thermal ring-opening reaction to give the observed (6-4) photo-
products (see Scheme 1). Thymine oxetane adduct with benzophenone has been
obtained in early research [25]. Utilizing synthesized model thymine-based oxetane
adducts with aromatic carbonyl compounds, Falvey and co-workers [26,27] demon-
strated that both sensitized and direct irradiation of these model compounds resulted
in their splitting to give the base and the corresponding carbonyl compound. These
experiments provided evidence for the ET mechanism.
Gurzadyan and G o€ rner [28] demonstrated the formation of (6-4) photoproducts
0
0
in simple 5 -uracil- and 5 -cytosine-containing pyrimidine dinucleotides including
UpU, CpU, and CpT. In a more recent work, Douki and Cadet [29] found that
0
(
6-4) photoproducts can form at 5 -thymine–cytosine and cytosine–cytosine sites in
0
DNA by LC/MS analysis. Moreover, it is known that the 5 -cytosine residues in
the (6-4) photoproducts can be deaminated to form uracil-containing (6-4) photo-
products. Therefore, it would be of interest to synthesize uracil oxetane adducts
and examine whether these compounds show a similar ET repair mechanism. In this
work, we prepared oxetane adducts of 1,3-dimethyluracil (DMU) with benzophe-
none and benzaldehyde, and investigated their behavior under electron transfer con-
ditions by fluorescence measurements and photolysis experiments. In addition, we
carried out comparison of DMU and 1,3-dimethylthymine (DMT) from [2 + 2]
photocycloaddition with carboxyl compounds and the splitting reaction of their
formed oxetanes.
2
. Experimental details
2
.1. General methods
1
13
H, C NMR, and PS-NOESY spectra were measured on a Bruker AV 400 spec-
1
13
trometer operating at 400.13 MHz for H and 100 MHz for C. Mass spectra were
obtained on a Micromass GCF TOF mass spectrometer. UV–Vis spectra were mea-
sured on a Lambda Bio20 UV/VIS spectrometer using a 10 mm path length quartz
cell. Fluorescence emission spectra were measured on a 970CRT fluorescence spec-
trometer (Shanghai Analysis Instrument). The quenching constant (s
sitizer by DMU-base oxetanes was measured through Stern–Volmer analyses for
s q
k ) of the sen-
each oxetane/sensitizer.
Photolysis experiments were performed by a series of turntable experiments. In
these experiments, a group of samples are placed on a rotating turntable. The Hg
lamp is fixed in the center of the turntable. Using this procedure, the samples are
all irradiated under similar conditions. Each sample was prepared in 2 ml spectro-
3
scopic grade CH CN solution containing 2 mM sensitizer and 2 mM oxetane. The
solution was sealed in a Pyrex (>290 nm) tube, deaerated by high purity nitrogen
bubbling for 20 min, and irradiated for 10 min with a 300 W high pressure Hg lamp.
Deviations from the above mentioned conditions are indicated in the text. The

360
Q.H. Song et al. / Bioorganic Chemistry 31 (2003) 357–366
photolysis mixtures were analyzed using a high performance liquid chromatography
HPLC) instrument (HP Agilent 1100 series) with an UV/Vis absorption detector
(
and a C-8 reverse-phase column and methanol–water (60:40) as the eluent. The
flow rate in all cases was 1 ml/min and column temperature was 30 °C. The products
and reactants were identified by co-injections, separated, and their peak areas
quantified.
2
.2. Chemicals
Aniline, p-toluidine, N,N-dimethylaniline (DMA), 1-naphthylamine, and phenan-
threne are commercially available and were used as received after being recrystallized
or redistilled twice. Uracil, benzophenone, benzaldehyde, and acridine are also com-
mercially available. Acetonitrile (for HPLC) were used as received. 10-Methyl-9,10-
dihydroacridine (MHA) was prepared from 10-methylacridium iodide by reduction
with NaBH in methanol and purified by recrystallization from ethanol. 10-Methyl-
4
acridium iodide was prepared by the reaction of acridine (Merck, Darmstadt, FR
Germany) with methyl iodide in acetone [30].
2
3
.3. Preparation of Z-2,4-dimethyl-8,8-diphenyl-7-oxa-2,4-diazabicyclo[4.2.0]octane-
,5-dione
1,3-Dimethyluracil (DMU) was prepared by methylation of uracil with methyl
sulfate in alkaline aqueous solution [31] (Scheme 2). Benzophenone (2.6 g, 14 mmol)
was added to DMU (1.0 g, 7 mmol) in 70 ml CH CN. The solution was placed in a
3
2
pyrex reactor, bubbled with N to saturate, and irradiated with a 300 W high pres-
sure Hg lamp for 8 h. The solvent was removed by rotary evaporation. Elution of
the residue over silica with 4:1 petroleum ether/EtOAc gave 0.34 g of 1 as white crys-
1
tals, yield 14.8%, mp 134–135 °C; H NMR (DMSO, 400 MHz) d 2.81 (s, 3H), 2.92
1
3
(
(
1
(
s, 3H), 5.12 (d, J ¼ 8:8 Hz, 1H), 5.19 (d, J ¼ 8:8 Hz, 1H), 7.33 (m, 10H); C NMR
DMSO, 100 MHz) d 167.11, 151.22, 143.64, 139.62, 128.44, 128.06, 127.80, 125.44,
25.23, 95.27, 70.78, 59.28, 34.94, 26.75; IR 1717, 1682 cm ; TOFMS (EI) Calcd. for
þ
ꢀ
1
M ) C H N O : 322.1317. Found: 322.1343.
3
19
18
2
Scheme 2.

Q.H. Song et al. / Bioorganic Chemistry 31 (2003) 357–366
361
2
[
.4. Preparation of 2.4 (6Z,8Z)-2,4-dimethyl-8-phenyl-7-oxa-2,4-diazabicyclo
4.2.0]octane-3,5-dione
Compound (2) was obtained by following the procedure described above using
DMU (0.7 g, 5 mmol) and benzaldehyde (1.06 g, 10 mmol). This gave 0.13 g of 2,
1
yield 10.6%, mp 104–106 °C; H NMR (DMSO, 400 MHz) d 2.85 (s, 3H), 3.13 (s,
3
H), 4.33 (dd, J ¼ 5:6 Hz, J ¼ 8:8 Hz, 1H), 5.23 (d, J ¼ 8:8 Hz, 1H), 5.73 (d,
1
2
13
J ¼ 5:6 Hz, 1H), 7.43 (m, 5H); C NMR (CDCl , 100 MHz) d 167.03, 151.69,
3
ꢀ
1
1
38.98, 129.23, 129.18, 125.19, 91.15, 71.74, 58.70, 34.33, 28.11; IR 1715, 1665 cm ;
þ
TOFMS (EI) Calcd. for (M ) C13
H
14
N
2
O
3
: 246.1004. Found: 246.1014. The PS-NO-
(see Fig. 1) shows signals of correlation between the
H(d 5.21), 8H(d 5.64), and 1H(d 4.23), respectively. It indicates that the three pro-
tons, 6H, 1H, and 8H are at the same side of oxetane ring.
ESY spectrum of 2 in CDCl
3
6
3
Fig. 1. The PS-NOESY spectrum of 2 in CDCl . Here have signals of correlation between the 6H(d 5.21),
8H(d 5.64), and 1H(d 4.23), respectively.

362
Q.H. Song et al. / Bioorganic Chemistry 31 (2003) 357–366
3
. Results and discussion
3
.1. Fluorescence quenching experiments
The excitation wavelength of the sensitizer was chosen to ensure that none of the
light was absorbed by the oxetane, and fluorescence intensity obtained from its fluo-
rescence peak. Both oxetane 1 and 2 would quench fluorescence of some electron-rich
compounds, so fluorescence quenching experiments were performed. Solutions of the
3
sensitizers were prepared in spectroscopic grade CH CN, and their fluorescence in-
tensities were measured with varying concentrations of added oxetane. In each case
the fluorescence intensity decreased as oxetane was added. The results of the fluores-
cence scans were analyzed by the Stern–Volmer equation, ðF
0
ꢀ F Þ=F ¼ s
s
k
values were obtained from the slopes of Stern–Volmer plots. One example is
q
½Qꢁ. The
s
s q
k
shown in Fig. 2, which is generated by the fluorescence quenching of MHA by oxe-
tane 1. Using literature values [32] for the lifetimes of fluorescence (s ), the quenching
s
rate constants (k ) were obtained and listed in Table 1. These values are at or near the
q
9
ꢀ1 ꢀ1
diffusion limit, ranging from 0.46 to 27 ꢂ 10 M s . We note that the strongest ex-
cited state electron donor, DMA, gives the highest k values for 1.
q
3
.2. The photolysis experiments
We measured product distribution of each case by HPLC and the results are listed
in Table 1. The photosensitizers in Table 1 are able to photosensitize the splitting of
oxetanes. The most efficient splitting reaction is seen in the presence of the strongest
electron donor DMA. Direct irradiation without a sensitizer also leads to splitting of
oxetanes. Besides the splitting reaction, few side products were also observed. Be-
cause DMU and benzophenone/benzaldehyde are unstable under the photolysis con-
dition, the side products would result from secondary photolysis of the substrates.
Fig. 2. Stern–Volmer analysis of the fluorescence quenching of MHA by oxetane 1 (kex at 300 nm, fluo-
rescence intensity obtained from its fluorescence peak 365 nm).

Q.H. Song et al. / Bioorganic Chemistry 31 (2003) 357–366
363
Table 1
Splitting reaction of oxetanes 1 and 2 in the presence of various photosensitizers
a
ꢃ
Sensitizer
E
ox=V
Reactant E =V Yield %
k
(M (10 M s ))
q
s
s
ꢀ
ðk Þ
q
ox
1 9
ꢀ1 ꢀ1
SCE in oxetane SCE
Conversion
PhC(O)R DMU
CH
3
CN
c
None
1
1
7
18
55
86
52
89
d
Photosensitizers
Aniline
b
+0.98
+0.78
+0.53
1
1
1
2
1
1
1
)2.77
)2.86
)3.00
12
21
33
20
16
20
8
56
50
25
45
52
18
<6
52
64
65
78
45
44
6
92(5.5)
53(11)
79(27)
256(85)
74(10)
69(3.5)
28(0.46)
b
b
p-Toluidine
DMA
e
MHA
+0.81
)2.65
)2.46
)2.07
b
1-Naphthylamine +0.54
Phenanthrene
b
+1.50
a
Sensitizer and oxetane were prepared as 2 ml, N
2
3
-saturated CH CN solution in a Pyrex (>290 nm)
tube, respectively, unless otherwise indicated. Samples were irradiated for 10 min with a 300 W high
pressure Hg lamp.
b
From [32].
Direct photolysis without sensitizer carried out in a Pyrex tube (>290 nm, 4 mM oxetane 1) irradiated
c
6
6
0 min, in a quartz tube (2 mM oxetane 1) irradiated 10 min, respectively.
d
Direct photolysis without sensitizer carried out in a Pyrex tube (>290 nm, 4 mM oxetane 1) irradiated
0 min, in a quartz tube (2 mM oxetane 1) irradiated 10 min, respectively.
e
From [30].
This is also reason why the yields of benzophenone and DMU in sensitized photol-
ysis reaction with DMA and 1-naphthylamine are unequal.
On the basis of energetic grounds, energy transfer mechanisms can be excluded in
the splitting reactions. Both 1 and 2 are transparent under light at wavelength more
than 300 nm, and we can estimate the singlet energies of oxetanes 1 and 2 at more
ꢀ
1
than 399 kJ mol . The excited singlet energies of the sensitizers are not more than
ꢀ
1
3
62 kJ mol (for aniline). In addition, the acceptor electron site should be the uracil
moiety of the oxetanes. This is based on the likely reduction potentials of functional
groups presented in 1 and 2. The uracil residue of the oxetane has a saturated 5,6
bond and can be considered analogous to the DMU cyclobutane dimer with a reduc-
tion potential of ca. )2.3 V (vs SCE). The unconjugated benzene ring(s) on the ke-
tone/aldehyde portion of the oxetane would be much more difficult to reduce as
benzene has a reduction potential of ca. )3.2 V [33]. Therefore, the pyrimidine ring
is the most energetically favorable location for single-electron reduction [26].
3.3. Calculation of free energy changes of electron transfer reactions from excited
singlet sensitizers to the oxetane
The free energy changes (DG) of the putative electron transfer reactions from
excited singlet sensitizers to oxetane 1 were calculated according to Rehm–Weller
equation [34]:
ꢀ
1
2
0
DG ðkJ mol Þ ¼ 96:5½E ðDÞ ꢀ E ðAÞ ꢀ e =eR
þ
ꢀ
D A
ꢁ ꢀ DE0;0;
ð1Þ
ox
red

364
Q.H. Song et al. / Bioorganic Chemistry 31 (2003) 357–366
where EoxðDÞ and EredðAÞ are half-wave potentials of electron donors and acceptors,
respectively. DE0;0 is the lowest energy level of excited singlet sensitizer obtained from
2
0
their fluorescence spectroscopy. The ꢀe =eR
þ
ꢀ
is the solvation energy of an ion
pair D A . It is )0.06 V in acetonitrile [35]. In the case of the same oxetane, Ered(A)
D
A
þ
ꢀ
2
0
and e =eR
þ
ꢀ
are constant, (Eox ꢀ DE0;0=96:5) is its excited state oxidation potential,
D A
ꢃ
ꢃ
E =V. E is obtained from literature values for the oxidation potential (E ) and the
ox
ox
ox
ꢃ
singlet state energy, DE0 from its fluorescence spectra. Calculated E are listed in
Table 1. As E becomes increasingly negative, k increases. From this result, a
qualitative generalization can be made. The correlation of k
with the electron transfer mechanism as follows. Singlet excited state of sensitizer
;0
ox
ꢃ
ox
q
ꢃ
q
and E is consistent
ox
1
ꢃ
Åþ
( S ) transfers an electron to the oxetane (Ox) to give sensitizer radical cation (S )
Åꢀ
and oxetane radical anion (Ox ). The oxetane anion would rapidly split to form
Åꢀ
DMU and carbonyl compound radical anion (CC ). In the case of 1,3-dimethyl-
7
ꢀ1
thymine-derived oxetane anion, the splitting process was >5 ꢂ 10 s [27]:
hm
1
ꢃ
S! S
ET
Splitting
1
S þ Ox!S þ OxÅꢀ ! S þ CCÅꢀ þ DMU
ꢃ
Åþ
Åþ
3.4. Uracil and thymine oxetane: a comparison of the synthesis and photosensitized
splitting
Oxetane 3 was synthesized by the [2 + 2] photocycloaddition of 1,3-dimethylthy-
mine (DMT) and benzophenone according to the procedure used for the synthesis
of 1 and 2. We have found that the formation of DMT-based oxetane is faster
(
for example 3, irradiation for only 5 h) and the yields (3, 40%) are higher than those
of DMU-based oxetanes. The same results were obtained from repeating the synthe-
sis many times.
Photocycloadditions of pyrimidine with aromatic carbonyl compounds, which are
Patern oꢀ –B u€ chi reactions, are generally considered to proceed through a diradical in-
termediate [36]. In the reaction process of pyrimidine and aromatic carboxyl com-
pounds, the carboxyl compounds were excited to form singlet excited state, then
3
ꢃ
transited to triplet excite state ( CC ) via intersystem crossing. It is well known that
this is the n–p* transition, and electron density for O atom of carboxyl group would
decrease. Hence, O atom of CC , as an electrophilic center, attacks C6 of pyrimidine
to produce a diradical intermediate 4. So the first step in the photocycloaddition be-
3
ꢃ
3
ꢃ
tween CC and pyrimidine is an electrophilic reaction. Generally, O atom of triplet
carbonyl compound tending to attack the more electron-rich carbon among C@C of
enamine [37]. Using Gaussian 98 program [38], we calculated to obtain the electron
densities at C6 of DMT and DMU, 1.32 and 1.18, respectively. Therefore, O atom of
3
ꢃ
CC more easily attack C6 of DMT than DMU. In addition, stability of the dirad-
ical intermediate 4 is also a possible important factor. The result can be used to ex-
plain why the formation of thymine-based (6-4) photoproducts in DNA under UV
light occurs more easily.

Q.H. Song et al. / Bioorganic Chemistry 31 (2003) 357–366
365
However, the rates of the photosensitized splitting of DMU oxetanes are faster
ꢀ
1
than those of DMT oxetanes [26,27]. The k
q s
s of aniline is 91 M for DMU oxetane
ꢀ
1
1
, and 81 M for DMT oxetane 3 [26]. In the case of DMA, the k for 3 is
q
10
ꢀ1 ꢀ1
10
ꢀ1 ꢀ1
1
.79 ꢂ 10 M
s
[27], and 2.7 ꢂ 10 M
s for 1. Splitting of the oxetane by
accepting an electron produces an oxetane anion, and the property of the oxetane
anion would be an important factor to determine splitting reaction rate of oxetane.
The detailed mechanism warrants further investigation.
4
. Summary
The photochemical behavior of the DMU-derived oxetanes is in many ways sim-
ilar to that of the oxetane intermediates in the putative photoreactivating process of
6-4) photoproduct by the DNA photolyase. Splitting of the oxetanes can be pro-
(
moted either by direct irradiation or by sensitization with electron donors. It appears
that cycloreversion is a general behavior of pyrimidine oxetane anion radicals. The
reactions proceed clearly with a number of substrates and give side products in small
quantities due to secondary photolysis. The results provide further support for the
ET repair mechanism involving oxetane intermediates. The electron-transfer mecha-
nism is attractive because the (6-4) product photolyase and CPD photolyases show
sequence identity suggesting a common mechanism. In addition, the active form of
the catalytic cofactor in both photolyases is a fully reduced flavin.
Acknowledgments
The authors are grateful for financial support by the National Natural Science
Foundation of China (30000036), the Doctoral Programme from the State Educa-
tion Commission of China (2000035821), and the Foundation of University of
Science and Technology of China.
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