Dehalogenation of Halogenated Nucleobases and Nucleosides by Organoselenium Compounds

Article abstract of DOI:10.1002/chem.201805112

Halogenated nucleosides, such as 5-iodo-2′-deoxyuridine and 5-iodo-2′-deoxycytidine, are incorporated into the DNA of replicating cells to facilitate DNA single-strand breaks and intra- or interstrand crosslinks upon UV irradiation. In this work, it is shown that the naphthyl-based organoselenium compounds can mediate the dehalogenation of halogenated pyrimidine-based nucleosides, such as 5-X-2′-deoxyuridine and 5-X-2′-deoxycytidine (X=Br or I). The rate of deiodination was found to be significantly higher than that of the debromination for both nucleosides. Furthermore, the deiodination of iodo-cytidines was found to be faster than that of iodo-uridines. The initial rates of the deiodinations of 5-iodocytosine and 5-iodouracil indicated that the nature of the sugar moiety influences the kinetics of the deiodination. For both the nucleobases and nucleosides, the deiodination and debromination reactions follow a halogen-bond-mediated and addition/elimination pathway, respectively.

Full text of DOI:10.1002/chem.201805112

A Journal of
Accepted Article
Title: Dehalogenation of Halogenated Nucleobases and Nucleosides
by Organoselenium Compounds
Authors: Santanu Mondal and Govindasamy Mugesh
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Dehalogenation of Halogenated Nucleobases and Nucleosides by
Organoselenium Compounds
Santanu Mondal and Govindasamy Mugesh*[a]
[
a] Santanu Mondal and Prof. Dr. Govindasamy Mugesh
Department of Inorganic and Physical Chemistry
Indian Institute of Science
Bangalore 560012 (India)
Email: mugesh@iisc.ac.in
Supporting information for this article is available on the WWW under
http://www.chemeurj.org/ or from the author.
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Abstract:
Halogenated nucleosides, such as 5-iodo-2'-deoxyuridine and 5-iodo-2'-deoxycytidine are
incorporated into the DNA of replicating cells to facilitate DNA-strand breaks and intra- or
inter-strand crosslinks upon UV irradiation. In this paper, we show that the naphthyl-based
organoselenium compounds can mediate the dehalogenation of halogenated pyrimidine-based
nucleosides, such as 5-X-2'-deoxyuridine, 5-X-2'-deoxycytidine (X = Br or I). The rate of
deiodination was found to be several folds higher than that of the debromination for both
nucleosides. Furthermore, the deiodination of iodo-cytidines was found to be faster than that
of iodo-uridines. The initial rates of the deiodinations of 5-iodocytosine and 5-iodouracil
indicate that the nature of the sugar moiety influences the kinetics of the deiodination. For
both the nucleobases and nucleosides, the deiodination and debromination reactions follow a
halogen bond-mediated and addition-elimination pathway, respectively.
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Introduction
Halogenated nucleosides such as 5-iodo-2'-deoxyuridine (IdUd) and 5-bromo-2'-deoxyuridine
BrdUd), have been used as radiosensitizers in combination with chemotherapeutic agents for
(
cancer by incorporating them into the DNA of dividing cells during DNA replication.[1,2] The
replacement of thymidine (T) with IdUd and BrdUd facilitates the DNA damage such as
single strand breaks (SSBs) and intra- or inter-strand crosslinks by UV irradiation.[3] The
DNA damage occurs through long range electron transfers from a ground state guanine (G) to
photoexcited halogenated nucleobase. This results in the formation of a halide ion and a
reactive uridine-5-yl radical,[4] which can abstract a proton from the adjacent 2'-deoxyribose
moiety to induce SSBs or it can react with an adjacent nucleobase to form cross-links (Figure
[
5]
1
2
A). Halogenated cytidine analogues, such as 5-iodo-2'-deoxycytidine (IdCd) and 5-bromo-
'-deoxycytidine (BrdCd), are also incorporated into the DNA of replicating cells for
[
6]
increasing the photosensitivity of the DNA. Similar to IdUd and BrdUd, the substitution of
cytidine (C) with halogenated cytidines also induces the formation of strand-breaks and intra-
strand crosslinks (Figure 1A). SSBs often lead to the formation of double strand breaks
(
DSBs), whereas cross-links results in the formation of cytotoxic damages.[7] Therefore, the
use of such halogenated nucleosides in conventional chemotherapy is restricted by their
selective uptake by the cancer cells and the dehalogenation of these nucleosides is required to
avoid DNA-damage in the normal cells.
The dehalogenation of the halo-uracil moiety is a key step in the DNA-repair pathway
via base-excision repair (BER).[8] Although the halogenation of nucleosides in the presence
of hydrogen peroxide and halide ion is catalysed by myeloperoxidase (MPO) and eosinophil
[
9]
peroxidase (EPO), the nature of the biomolecule specific for catalysing the dehalogenation
of halogenated nucleosides is still unknown. It has been shown that thymidylate synthase
(TSase), which catalyses the methylation of 2′-deoxyuridine-5′-monophosphate (dUMP) at
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Figure 1. (A) Intra-strand cross-link formation by 5-halo-uridine (left) and 5-halo-cytidine
right) with guanine. (B) Thymidylate synthase (TSase)-mediated methylation of 2′-
(
deoxyuridine-5′-monophosphate (dUMP) to 2′-deoxythymidine-5′-monophosphate (dTMP),
and the dehalogenation of 5-bromo and 5-iodo-2'-deoxy-5'-monophosphate (BrdUMP and
IdUMP) to dUMP.
the C5 position of the uracil to produce 2′-deoxythymidine-5′-monophosphate (dTMP) in the
presence of N5,N10-methylenetetrahydrofolate (N5,N10-methylene-THF) cofactor, also
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mediates the dehalogenation of 5-bromo- and 5-iodo-2′-deoxyuridine-5′-monophosphate
BrdUMP and IdUMP) to 2′-deoxyuridine-5′-monophosphate (dUMP) in the presence of
(
exogenous thiols (Figure 1B).[10] TSase uses its active site cysteine residue (Cys198) to
remove the halogen atom from the halogenated uracil moiety through an addition-elimination
pathway. Small-molecule thiols, such as glutathione, cysteamine, dithiothreitol are also
known to mediate the dehalogenation of halogenated nucleosides at stoichiometric
concentrations under physiologically relevant conditions.[11a,b] Previously, other methods,
such as photolysis under inert atmosphere, reduction with organotin reagents at elevated
temperature for the dehalogenation of halogenated nucleosides have been reported.[11c,d]
Recently, we reported that the naphthyl-based peri-substituted organochalcogen
compounds 1-5 (Figure 2) can mediate the dehalogenation of 5-iodo and 5-bromouracil (IU
and BrU) to produce uracil (U). These compounds also dehalogenate 5-halo-2'-deoxyuridine
(
IdUd and BrdUd) and 5-iodo-2'-uridine (IUd) to produce 2'-deoxyuridine (dUd) and uridine
Ud), respectively.[12] The rate of deiodination was found to be significantly higher than that
(
of the corresponding debromination reaction. The spectroscopic investigations indicated that
the mechanism of dehalogenation reaction depends on the nature of the halogen atom. The
deiodination reaction proceeds through the formation of a halogen bond (XB)[13] between the
iodine atom of 5-iodouracil moiety and the selenium atom, whereas the debromination
reaction follows an addition-elimination pathway similar to that observed for TSase.[10] In the
XB mechanism, the lone pair of electrons on the selenium atom non-covalently interacts with
the iodine (n→* interaction), leading to weakening of the C-I bond. On the other hand, the
addition-elimination pathway makes use of the Michael acceptor present in the uracil/uridine
compounds. This pathway involves the attack of one of the chalcogen atoms in
dichalcogenols (Figure 2) to the carbon atom adjacent to C-Br bond and the second
chalocogen atom helps in the formation of dichalcogenide as well as elimination of halide.[12]
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Figure 2. (A) Chemical structures of compounds 1-8, nucleobases (uracil (U), cytosine (C)),
nucleosides (deoxyuridine (dUd), deoxycytidine (dCd), uridine (Ud) and cytidine (Cd), and
their halogenated analogues 5-iodo and 5-bromouracil (IU and BrU), 5-iodo and 5-
bromocytosine (IC and BrC), 5-iodo and 5-bromo-2'-deoxyuridine (IdUd and BrdUd), 5-
iodo-2'-uridine (IUd), 5-iodo and 5-bromo-2'-deoxycytidine (IdCd and BrdCd) and 5-iodo
and 5-bromocytidine (ICd and BrCd).
Herein, we report that organoselenium compounds can mediate the dehalogenation of
halogenated cytidines, such as 5-iodo-2'-deoxycytidine (IdCd) and 5-bromo-2'-deoxycytidine
(BrdCd) and that the strength of halogen bonding between the iodine and selenium atoms can
be altered upon introduction of 2'-deoxyribose and ribose moiety to the halogenated
nucleobase.
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Results and discussion
The dehalogenation of halo-cytidines by organochalcogen compounds was performed in
phosphate buffer (100 mM, pH 7) at 37 °C. The chalcogenols 1-8 were freshly generated in
situ by reducing the corresponding dichalogenides with NaBH and the formation of the
4
dehalogenated products were monitored by reverse-phase high pressure liquid
chromatography (HPLC) and ESI mass spectrometry. When 5-iodo-2'-deoxycytidine (IdCd)
was treated with compound 1 bearing two thiol moieties in the peri positions, the peak
corresponding to IdCd disappeared with appearance of a new peak at around 4 min in the
HPLC chromatogram. Mass spectrometric analysis of the new compound and a comparison
of the retention time with that of standard sample indicated that IdCd underwent a facile
deiodination by compound 1 to produce dCd as the only product (Figure S6, Supporting
Information). The initial rate for the deiodination reaction was found to be 27.0 ± 1.0 x 10-2
-1

M.min . Similarly, the bromo analogue BrdCd underwent debromination reaction in the
presence of compound 1 to produce dCd.
The replacement of one of the thiol moieties in compound 1 by selenol (compound 2)
leads to an almost 3 times enhancement in the reaction rate, whereas the replacement of both
the thiol moieties in 1 with selenol groups (compound 3) resulted in an almost 96-fold
increase in the rate of deiodination (Figure 3A and Table S2, Supporting Information). These
observations are consistent with the activity of the naphthyl-based selenium compounds in
the deiodination of thyroid hormones (THs) and their metabolites.[14] Interestingly, the
deiodination of IdCd by compounds 3-5 was found to be significantly higher than that of
IdUd, indicating that the nature of nucleobase plays an important role in the deiodination
reaction. This is probably due to a stronger halogen bonding of the selenium atom in
compounds 3-5 with the iodine atom of IdCd as compared to that of IdUd. In contrast to the
highly efficient deiodination by the naphthyl-based selenium compounds, the deiodination of
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Figure 3. Comparison of initial rate of deiodination of IdCd, IdUd, ICd, IUd, IC and IU (A)
and debromination of BrdCd, BrdUd, BrCd, BrC and BrU (B) by compounds 1-8. Assay
Conditions: 0.3 mM halogenated nucleoside or nucleobase, 0.6 mM organochalcogen
compound, 30 mM sodium borohydride, phosphate buffer (100 mM, pH 7), 37 °C.
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IdCd by cysteine (6) and selenocysteine (7) was found to be extremely slow, although the
rates are comparable to that of IdUd (Figure 3A and Table S2, Supporting Information).
Recently, it has been shown that the substitution of the selenium atom in compounds 2
and 3 by tellurium remarkably alters the initial rate and regioselectivity of the deiodination of
THs.[15] However, compound 8 (Figure 2), bearing a tellurol moiety, was found to be only 2
times more active than selenocysteine. Further, the activity of this compound was found to be
much lower than that of the selenium-containing compounds 3-5 for the deiodination of IdCd
(Figure 3A and Table S2, Supporting Information). The bromo analogue, 5-bromo-2'-
deoxycytidine (BrdCd) underwent debromination reaction by compounds 1-8 to produce the
corresponding debrominated derivative dCd. However, the initial rates of the debromination
reactions were found to be 4-800 times lower than that of the corresponding deiodination
reactions (Figure 3B and Table S2, Supporting Information). Furthermore, the debromination
of BrdCd by 1-8 was found to be significantly slower than that of BrdUd, which contrasts
with the corresponding deiodination reactions. Interestingly, compound 8 having a highly
-
2
-1
nucleophilic tellurol group, exhibited the highest activity (9.5 ± 0.2 x 10 M.min ) in the
series, indicating that the addition-elimination mechanism, as proposed for the debromination
of brominated uridines,[12] may also be responsible for the debromination of BrdCd by
compounds 1-8.
In addition to the dehalogenation of the halogenated deoxynucleosides, we also studied the
dehalogenation of 5-iodo- and 5-bromocytidine (ICd and BrCd) by compounds 1-8 under
physiologically relevant conditions. The presence of 2'-hydroxyl group in the sugar moiety
only mariginally increases the deiodination of ICd by compound 2. The deiodination of ICd
by compound 2 is 1.3 times faster than that of IdCd (Figure 3A and Table S2, Supporting
Information). However, the initial rates observed for the deiodination of ICd and IdCd are
comparable for other compounds 3-8 (Figure 3A), indicating that the nature of sugar residue
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on the iodinated nucleosides does not play any major role in the deiodination reactions.
Furthermore, compounds 2 and 3 exhibited almost 5- and 124-fold higher activity,
respectively, than compound 1. Similar to the deiodination of IdCd, the activity of
compounds 4 and 5 was also found to be lower than that of compound 3 for the deiodination
of ICd, indicating that the alkylamino- and hydroxymethyl-substitutions may have a steric
influence on the deiodination of ICd. For compounds 6-8, the deiodination activity increases
mariginally with an increase in the nucleophilicity of the chalcogen atom (Figure 3A and
Table S2, Supporting Information). Similar to its deoxy analogue BrdCd, 5-bromocytidine
(BrCd) also underwent debromination by compounds 1-8. However, as expected, the initial
rate of debromination was found to be almost 4-900 times lower than that of the deiodination
of ICd. A comparison of the initial rates for the debromination of BrdCd and BrCd reveals
that the nature of sugar moiety does not play any key role in the debromination. The initial
rate for the debromination of BrCd by compound 8 was found be the higher than that of other
compounds, which is in agreement with the debromination of BrdCd by compound 8 (Figure
3
B and Table S2, Supporting Information). Although an excess amount of sodium
borohydride is used to maintain the reducing environment in the assay mixture for a facile
dehalogenation, the oxidized dichalcogenides can be recovered from the assay mixture after
the reactions.
To investigate the role of ribose and 2'-deoxyribose moiety in the dehalogenation of
halogenated cytidines, we synthesized 5-iodo and 5-bromocytosine (IC and BrC) from
cytosine (C) and studied the dehalogenation by compounds 1-8 under identical experimental
conditions. Interestingly, IC underwent a slower deiodination as compared to that of IdCd
and ICd in the presence of compounds 1-5 and a faster deiodination in the presence of
compounds 6-8 (Figure 3A and Table S2, Supporting Information). These observations
indicate that the two sets of compounds (1-5 and 6-8) may follow two different mechanisms
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(halogen bond-mediated and addition-elimination, respectively), as observed earlier for the
deiodination of iodinated uridines.[12] The introduction of ribose or 2'-deoxyribose moiety to
the iodinated nucleobases disfavours the addition-elimination pathway. Like the deiodination
of IdCd and ICd, the activity determined for compounds 2 and 3 was found to be 3- and 46-
fold higher activity than that observed for compound 1. On the other hand, the activity for
compound 4 and 5 was found to be slightly lower than that of compound 3 for the
deiodination of IC. Similar to the deiodination of IdUd and IUd, the deiodination of IC by
compounds 1-5 was found to be significantly higher than that of IU, indicating that the
strength of halogen bonding between the chalcogen and iodine atoms, and the kinetics of the
deiodination reaction may be different for the two types of iodinated nucleosides (Figure 3A,
Table S1 and S2, Supporting information). In contrast to the effect of sugar moieties on the
rate of deiodination reactions, faster reaction rates were observed for BrC which lacks the
ribose and 2'-deoxyribose sugar present in BrCd and BrdCd, respectively. However, an
opposite trend was observed for the debromination of 5-bromouracil (BrU) and 5-bromo-2'-
deoxyuridine (BrdUd) by compounds 1-7 (Figure 3B and Table S2, Supporting Information),
indicating that the nature of brominated nucleobase plays an important role in the
debromination mediated by addition-elimination pathway.
It has been reported earlier that a cooperative halogen and chalcogen bonding plays an
important role in the deiodination of iodinated uridines, but an addition-elimination pathway
is responsible for the debromination reactions.[12] To understand the formation of a halogen
bond between the iodine atom of 5-iodouracil (IU) with the selenium atom in organoselenium
compounds, we used X-ray crystallography and NMR spectroscopy. Compound 9 (Figure
−
4
A) was selected for this study as the selenolate (-Se ) nature of the selenium atom makes
this moiety a good halogen bond acceptor. Further, compound 9 is highly stable in air due to
the presence of two substituents on the nitrogen atoms. When IC was treated with compound
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Figure 4. (A) Chemical structures of compound 9 and the halogen-bonded complex 10. (B)
Single crystal X-ray structure (ball-and-stick model) of 10, indicating the Se···I halogen
7
7
bonding interaction. (C) Se NMR spectra of 9 in dimethylsulfoxide with 9:IC ratio of (a)
1
:0, (b) 1:1, (c) 1:2, (d) 1:3, (e) 1:5.
9
, the halogen-bonded complex 10 (Figure 4A) was formed. This complex was crystallized
from a mixture of 1:1 acetone and water. The single crystal X-ray structure of 10 clearly
confirms the formation of a Se···I halogen bond (Se···I distance of 3.413 Å) between the
iodine atom of IC and the selenium atom of 9 (Figure 4B).[16] The Se···I distance is almost
1
2% shorter than the sum of van der Waals radii of selenium and iodine (3.88 Å). Owing to
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the formation of Se···I halogen bond, the C-I bond in the halogen-bonded complex 10 (bond
length: 2.097 Å) is significantly elongated as compared to that of IC (average bond length:
2
.075 Å).[17] The observed C-I···Se and I···Se-C bond angles, 165.8° and 82.4°, respectively,
are also very similar to that reported for other halogen-bonded systems.[13] The formation of
halogen bond between 9 and IC was also observed in solution. When the addition of IC to
7
7
77
compound 9 was monitored by Se NMR spectroscopy, the Se NMR signal of 9 at 21.43
ppm to the downfield region gradually as shown in Figure 4C. This observation clearly
indicates the transfer of electron density from selenium to iodine and the formation of Se···I
halogen bond.
Although any experimental evidence to support the formation of Se···I halogen
bonding between the iodinated nucleosides and organoselenium compounds is important to
understand the relative deiodination activity, our attempts to co-crystallize IdCd, ICd, IdUd
and IUd with compound 9 were unsuccessful. However, to understand whether the strength
of Se···I halogen bonding in solution depends on the nature of iodinated nucleobases or
7
7
nucleosides, we studied the change in the Se NMR chemical shifts using compound 11 as a
halogen bond acceptor (Figures 5 and 6). Unlike 2 and 3, compound 11 lacks the second
selenol/thiol moiety required for the deiodination reaction, and therefore, this compound can
only form halogen bonded adducts with iodinated nucleobases and nucleosides. When 11 was
7
7
treated with one equivalent of IC, about 2.75 ppm downfield shift was observed in the Se
NMR spectra (Figure 5B), indicating the formation of the halogen bonded complex 12. The
strength of the halogen bond in 12 appears to be significantly stronger than that of 13 having
an iodouracil moiety as halogen bond donor. In this case, a shift of only 0.94 ppm was
7
7
observed in the Se NMR spectrum when one equivalent of IU was added to 11 (Figure 5C).
This is consistent with the higher initial rates observed for IC as compared to that of IU
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(Figure 3A). Furthermore, the strength of Se···I halogen bond between 11 and IC appears to
be much stronger than that observed for the selone 9 with IC.
Figure 5. (A) Chemical structure of 11 and its possible halogen-bonded complexes 12 and 13
7
7
with IC and IU, respectively. (B) The Se NMR spectrum of 11 alone and in the presence of
7
7
one equivalent of IC. (C) The Se NMR spectrum of 11 alone and in the presence of one
equivalent of IU. Compound 11 was freshly generated by reducing the corresponding
diselenide with sodium borohydride. Assay conditions: 100 mM 11, 100 mM iodinated
nucleobase, 800 mM sodium borohydride, 1:4 DMSO:phosphate buffer (100 mM, pH 7), 25
°
C.
Interestingly, when compound 11 was treated with the cytidine derivative ICd, the
7
7
downfield shift in the Se NMR was observed to be 2.52 ppm (Figure 6B). Similarly, only a
2
.39 ppm downfield shift was observed when 11 was treated with IdCd (Figure S7B,
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Figure 6. (A) Chemical structures of the proposed halogen-bonded complexes 14-17. (B) The
7
7
77
Se NMR spectrum of 11 alone and in the presence of one equivalent of ICd. (C) The Se
NMR spectrum of 11 alone and in the presence of one equivalent of IUd. Compound 11 was
freshly generated by reducing the corresponding diselenide with sodium borohydride. Assay
conditions: 100 mM 11, 100 mM iodinated nucleobase, 800 mM sodium borohydride, 1:4
DMSO:phosphate buffer (100 mM, pH 7), 25 °C.
Supporting Information), indicating that both ICd IdCd form weaker halogen bonding than IC
with the selenol. In contrast, IUd and IdUd form stronger halogen bonding with 11 than IU.
When compound 11 was treated with IUd or IdUd, downfield shifts of 2.30 ppm and 2.57
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ppm, respectively, with respect to 11 were observed (Figure 6C and Figure S7C, Supporting
Information) and these shifts are significantly larger as compared to that of IU (Figure 5C). It
has been shown earlier that IUd and IdUd undergo faster deiodination than IU by naphthyl-
based organoselenium compounds,[12] probably due to the stronger Se···I halogen bonding
formed by these iodinated molecules as compared to that of IU. Furthermore, the faster
deiodination of IC and ICd than that of IU and IUd, respectively, can also be explained based
on the observed strength of Se···I halogen bond. In contrast, the significantly higher initial
rates for the deiodination of ICd and IdCd as compared to that of IC or the slower
deiodination of IdUd than IdCd by the selenium compounds, particularly compounds 3-5
(Figure 3A), cannot be explained only based on the halogen bonding interactions between the
halogenated nucleosides and selenium compounds lacking the second selenol/thiol moieties.
It has been shown for the thyroid hormones that the S···Se or Se···Se chalcogen bonding
between the two chalcogen atoms in the 1,8-positions of the naphthyl ring strengthen the
halogen bonding.[14c-f]
Cytidine and uridine nucleosides differ only by the presence of amino and carbonyl
functionalities, respectively, at the 4-position of the pyrimidine ring. These differences in
their structures alter the kinetics of the deiodination reaction. As shown in Figure 3A, the
initial rates for the deiodination of ICd, IdCd and IC by compounds 1-5 are significantly
higher than that of IUd, IdUd and IU, respectively. Therefore, the presence of the basic amino
group in the proximity of iodine in the cytosine-based compounds may deprotonate the
selenol to form a more reactive selenolate, which can form a stronger Se···I halogen bond. To
understand the effect of 4-amino group on the deiodination reaction, we protected the amino
group of IC with a benzoyl substitution. IC was benzoylated with benzoyl chloride in the
presence of pyridine to form N4-benzoyl-5-iodocytosine (BzIC) (Figure 7A). Surprisingly,
when BzIC was used as a substrate for the deiodination reactions by compounds 1-5, a rapid
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Figure 7. (A) Synthesis of N4-benzoyl-5-iodocytosine (BzIC) and N4-benzoyl-cytosine
BzC). (B) A comparison of the initial rates of deiodination of BzIC and IC by compounds 1-
. Assay conditions: BzIC or IC (0.3 mM), test compunds (0.6 mM), phosphate buffer (100
(
8
mM, pH 7.0), 37 °C. (C, D) Optimized geometries of the halogen-bonded adducts formed by
IC and BzIC, respectively, with a model selenolate. The Se···I distances are shown in Å unit.
The values in parentheses indicate the charges on iodine atoms (AU) and the Se···I halogen
-1
bonding (XB) energies are given in kcal.mol .
deiodination of BzIC to BzC was observed. The formation of BzC was confirmed by mass
spectrometric analysis and comparing the HPLC profile of the deiodinated product with that
of an authentic sample of BzC. Furthermore, the initial rates for the deiodination of BzIC by
compound 1-5 were found to be almost 2-10 times faster than that of IC (Figure 7B). In
contrast, the initial rates for the deiodination of BzIC by compounds 6-8 are almost similar to
or even lower than that of IC when an addition-elimination pathway is followed. These
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results indicate that the benzoyl substitution on IC may alter the charge on the iodine atom
and the strength of Se···I halogen bond. To understand the effect of benzoyl group on the
charge of iodine atom, density functional theory (DFT) calculations were performed on IC
and BzIC. The geometries were optimized using B3LYP hybrid functional and 6-31+G*
basis set for all atoms except iodine for which 6-311G** was used. Natural bond orbital
(NBO) analysis using the similar functional and basis sets on the optimised geometries
indicated that the positive potentials or σ-holes[18] on the iodine atom of BzIC and IC are
0
.258 and 0.212, respectively. When a model selenolate, methyl selenolate (MeSe¯) was used
as halogen bond acceptor, both IC and BzIC formed halogen bond with MeSe¯ (Figure 7C
and 7D) with Se···I distances of 2.987 Å and 2.921 Å, respectively. When the halogen
-1
bonding energies were calculated, it was observed that BzIC (45.1 kcal.mol ) forms a
-1
stronger halogen bond with MeSe¯ than IC (34.6 kcal.mol ). These results also suggest that
the faster deiodination of IC/ICd/IdCd by compounds 1-5 as compared to that of
IU/IUd/IdUd is probably not due to the presence of the basic amino group, but it depends on
the strength of cooperative halogen- and chalcogen bond.
It has been reported that the replacement of both the selenium atoms in compound 3
by tellurium atoms not only increases the initial rate, but also alters the regioselectivity of
deiodination of thyroid hormones.[15] The tellurium-substituted compound has been shown to
form a stronger halogen bonding with the thyroid hormones. However, owing to the facile
dehalogenation of halogenated nucleosides, we have used compound 8 having a single
tellurium substitution. The rate of deiodination of the iodinated nucleosides by compound 8
was found to be slower than that observed for compounds 3-5 having two selenium-
substitutions. Detailed kinetic analyses on the dehalogenation reactions revealed that
compound 8 mediates the deiodination reactions by the addition-elimination pathway
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Chemistry - A European Journal
10.1002/chem.201805112
proposed for the debromination reactions as well as for the dehalogenation mediated by
small-molecule thiols.[11b]
Conclusion
In this paper, we showed that the naphthyl-based organoselenium compounds can mediate the
dehalogenation of halogenated cytidines, which are known to be potential DNA
photosensitizers. The deiodination reactions are found to be much faster than the
debromination reactions. As observed in the case of halogenated uridines, the deiodination of
iodinated cytidines follow a halogen bond-mediated pathway, whereas the debromination
reactions follow an addition-elimination mechanism. The formation of halogen bonding by 5-
7
7
iodocytosine in the presence of selenium-containing compounds has been confirmed by Se
NMR spectroscopic and X-ray crystallographic investigations. The attachment of 2'-
deoxyribose and ribose sugars to the iodinated nucleobase generally enhance the rate of
deiodination, possibly by strengthening the Se···I halogen bond. Furthermore, the initial rates
for the deiodination of the iodinated cytidines were found to be several folds higher than that
of the corresponding iodinated uridines, suggesting that a cooperative halogen and chalcogen
bonding plays a key role in the deiodination. Taken together, this study suggests the potential
of the organoselenium compounds to mediate the dehalogenation of the mutagenic
halogenated pyrimidine nucleobases and nucleosides.
Experimental Section
Materials and Methods
5
-Iodouracil,
5-iodouridine,
5-iodo-2′-deoxyuridine,
5-bromouracil,
5-bromo-2′-
deoxyuridine, uracil, uridine, 2′-deoxyuridine, L-selenocystine, selenium and tellurium
powders were obtained from Sigma-Aldrich. L-Cystine was bought from GL Biochem
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Chemistry - A European Journal
10.1002/chem.201805112
(Shanghai) Ltd. n-Butyllithium (n-BuLi) was obtained from Acros Chemical Co. (Belgium).
5
-iodocytidine, 5-iodo-2′-deoxycytidine, 5-bromocytidine, 5-bromo-2′-deoxycyidine were
or d
-DMSO as a solvent. H (400 MHz), C (100.56 MHz) and Se (76.29 MHz)
NMR spectra were recorded using a Bruker 400 MHz NMR spectrometer. Chemical shift
purchased from carbosynth Limited. Liquid state NMR spectra were recorded in CDCl
3
4
-
1
13
77
MeOH or d
6
1
13
77
values are cited with respect to SiMe
standard.
4
as internal ( H and C) and Me Se ( Se) as external
2
Dehalogenation Assay
The dehalogenation reactions were performed in phosphate buffer (100 mM, pH 7.00) at 37
C. Compounds 1-5 and 8 were freshly generated in the assay mixture by reducing the
°
corresponding oxidised dichalcogenides with sodium borohydride. Cystine and selenocystine
was reduced with sodium borohydride to generate cysteine (6) and selenocysteine (7),
respectively. Dehalogenation assays were performed in 1.7 mL HPLC sample vials and the 1
mL final reaction mixture contained 0.3 mM halogenated nucleobase or nucleoside, 0.6 mM
mimic and 30 mM sodium borohydride. HPLC experiments were performed on a Waters
Alliance system (Milford, MA) containing a 2695 separation module and a 2996 photodiode-
array (PDA) detector. The HPLC system was controlled with EMPOWER software (Waters
corporation, Milford, MA). A built-in autosampler was used for sample injection. The
dehalogenated products were separated by a reversed-phase HPLC column (Princeton C18
column, 5µm, 150 mm × 4.6 mm) with gradient elution using acetonitrile/ammonium acetate-
acetic acid buffer (15 mM, pH 4) as the mobile phase. The formation of dehalogenated
products were monitored at λ = 265 nm or λ = 290 nm (for IC) and quantified by comparing
the peak areas with that of standard samples. The initial rates of the dehalogenation reactions
were determined by considering the 5-10% conversions of the substrates.
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Synthesis
The corresponding dichalcogenides of dichalcogenols used in this study have been
synthesized following the literature procedure.[14]
IC. A mixture of iodine (1.37 g, 5.4 mmol) in saturated solution of potassium iodide (3 mL)
was added dropwise to a suspension of cytosine (500 mg, 4.5 mmol) in water with vigorous
stirring. The mixture was allowed to stir for 2 hours at room temperature. Then the reaction
mixture was made alkaline (pH ~ 9) with 20% potassium carbonate followed by the
destruction of unreacted iodine with 1M sodium thiosulphate solution. The reaction mixture
was filtered and the solid product was washed thoroughly with water and cold ethanol. The
crude product was purified by reversed phase HPLC and characterised by H, 13C NMR
1
1
spectroscopy and mass spectrometry. Yield: 610 mg, 58%. H NMR (d
6
-DMSO) δ (ppm):
13
7
.76 (s, 1H), 6.49 (s, 1H); C NMR (d -DMSO) δ (ppm): 165.4, 156.6, 150.3, 56.0; ESI-MS
6
+
(m/z) calculated for C
4
H
4
N
3
O
1
I [M+H] : 237.9477, found 237.9526.
1
BrC. 5-bromocytosine was synthesized by following a similar procedure reported by Reigan
et al.[19] Bromine (0.7 mL, 13.5 mmol) was added dropwise to a suspension of cytosine (1 g,
9
mmol) in water with vigorous stirring. After stirring for 2 hours at room temperature, the
reaction mixture was made alkaline (pH ~ 9) with 20% potassium carbonate. The resulting
white solid was filtered, washed thoroughly with cold water and cold ethanol. The crude
product was purified by reversed phase HPLC and characterised by H, 13C NMR
1
1
spectroscopy and mass spectrometry. yield: 700 mg, 41%. H NMR (d
6
-DMSO) δ (ppm):
1
3
9
8
.15 (s, 2H), 8.34 (s, 1H), 8.13 (s, 1H); C NMR (d
6
-DMSO) δ (ppm): 160.9, 151.5, 147.5,
+
5.9; ESI-MS (m/z) calculated for C Br
4
H
4
N
3
O
1
1
[M+H] : 189.9616, found 189.7496.
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Chemistry - A European Journal
10.1002/chem.201805112
BzIC. Benzoyl chloride (0.2 mL, 1.6 mmol) was added dropwise to a suspension of 5-
iodocytosine (300 mg, 1.3 mmol) in pyridine (10 mL) at 0 °C and the mixture was allowed to
stir at room temperature for 6 hours. Then ethanol (5 mL) was added to the mixture at 0 °C
and the mixture was stirred for 30 minutes. After that water (30 mL) was added to the
solution and the mixture was further stirred for 15 hours. The mixture was filtered and the
resulting solid was washed thoroughly with cold water and cold ethanol. The crude N4-
benzoyl-5-iodocytosine (BzIC) was purified by reversed phase HPLC and was characterized
1
1
by H NMR spectroscopy and mass spectrometry. Yield: 150 mg, 35%. H NMR (d -DMSO)
6
δ (ppm): 12.88 (s, 1H), 11.96 (s, 1H), 8.25 (d, J = 6.8 Hz, 2H), 8.19 (s, 1H), 7.61 (t, J = 8 Hz,
+
1
H), 7.52 (t, J = 8 Hz, 2H); ESI-MS (m/z) calculated for C11
H
8
N
3
O
2
I
1
[M+Na] : 363.9559,
found 364.0505.
BzC. N4-benzoyl cytosine was synthesized by following a previously reported procedure
with minor modifications.[20] Briefly, a suspension of cytosine (300 mg, 2.7 mmol) in
pyridine (10 mL) was treated with benzoyl chloride (1.1 mL, 9.5 mmol) dropwise at 0 °C and
the mixture was allowed to attain room temperature during 6 hours. Ethanol (5 mL) was
added to the mixture at 0 °C and after 30 minutes, water (30 mL) was added to the solution
followed by stirring for 15 hours at room temperature. The resulting solid was filtered and
was washed thoroughly with cold water and cold ethanol. Crude N4-benzoyl cytosine (BzC)
1
was purified by reversed phase HPLC and was characterized by H NMR spectroscopy and
1
mass spectrometry. Yield: 500 mg, 86%. H NMR (d
6
-DMSO) δ (ppm): 7.96 (t, J = 8 Hz,
2
H), 7.86 (s, 1H), 7.62 (t, J = 8 Hz, 1H), 7.51 (t, J = 8 Hz, 2H), 7.21 (s, 1H); ESI-MS (m/z)
+
calculated for C11
H
10
N
3
O [M+Na] : 238.0592, found 238.0784.
2
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Chemistry - A European Journal
10.1002/chem.201805112
Single Crystal X-Ray Crystallography
Halogen-bonded complex (10) between IC and selone 9 was recrystallized from a 1:1 mixture
of acetone and water. IC and 9 were mixed thoroughly followed by grinding with a mortar
and pestle. The mixture was suspended in acetone and was dissolved with the addition of
dropwise water and gentle heating. The resulting solution was left at room temperature to
grow the crystals of halogen-bonded complex by slow evaporation.
The single crystal X-ray diffraction data were collected on a Bruker SMART APEX
CCD diffractometer utilizing SMART/SAINT software.[21] Graphite-monochromatized Mo-
Kα radiation of wavelength 0.71073 Å was used to collect the intensity data at room
temperature. Both the structures were solved by SHELX-97 program incorporated in WinGX.
Empirical absorption corrections were applied with SADABS.[22,23] All the non-hydrogen
atoms were refined by anisotropic displacement coefficients. The hydrogen atoms on the
carbon, nitrogen and oxygen were included in geometric positions and the given thermal
parameters are equivalent to 1.2 times to those of atoms to which they were attached. The
crystallographic data are given below.
Crystal data for 10
C
19
H
20
I
2
N
8
O
2
Se, F
w
= 725.19, Triclinic P -1, a = 9.2214(18) Å, b = 9.4723(18) Å, c =
3
1
5.314(3) Å, α = 107.598(4)Å, β = 90.984(4) Å, γ = 104.652(4) Å, V = 1227.2(4) Å , Z = 2,
-3
-1
MoK
α
radiation ( = 0.71073 Å), T = 296(2) K, ρcalcd (gcm ) = 1.962, μ (MoK
α
) (mm ) =
2
a
4
0
.078, Collected reflections = 5564, Unique reflections = 2610, GOF (F ) = 1.029, R1 =
b
.0740, wR2 = 0.1784.
aR1 = Σ||F
b
2−F
2)2}/Σ{w(F
) }] .
2 2 1/2
o
|−|F
c
||/Σ|F
o
|. wR2 = [Σ{w(F
o
c
o
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Chemistry - A European Journal
10.1002/chem.201805112
Computational Methods
All the DFT calculations were performed in Gaussian03 and Gaussian09 suites of quantum
chemical programme.[24] Geometry optimisation and natural bond orbital (NBO) calculations
were performed using the hybrid Becke 3-Lee-Yang-Parr (B3LYP) exchange correlation
functional and 6-31+G* basis sets for all the atoms except iodine for which 6-311G** basis
set was used.[25,26]
Acknowledgements
This work was financially supported by the Science and Engineering Research Board
(
SERB), New Delhi, India. SM thanks Indian Institute of Science, Bangalore for a research
fellowship. GM acknowledges the SERB for the award of J. C. Bose National Fellowship
Grant No. SB/S2/JCB-067/2015).
(
Keywords: dehalogenation • halogenated nucleoside • iodine • halogen bonding • selenium
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Table of Contents
Dehalogenation of halogenated nucleosides, which are potential DNA-photosensitizers, by
organoselenium compounds are described. Attachment of 2'-deoxyribose or ribose sugar to
the halogenated nucleobases significantly enhances the rate of deiodination reactions. The
Se···I halogen bonding plays an important role in the kinetics of the deiodination reactions.
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