Synthesis and biological evaluation of novel selenonucleosides

Article abstract of DOI:10.1080/15257770802088803

A series of novel selenonucleoside analogues with 1,4-oxaselenane as the carbohydrate fragment has been synthesized from their corresponding dimesylated seconucleosides treated with NaHSe solution and subsequent deprotection. The synthesized selenonucleos

Full text of DOI:10.1080/15257770802088803

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Synthesis and Biological Evaluation of
Novel Selenonucleosides
Yao Chen a , Yingdan Peng a , Jiancun Zhang a & Lei Fu a
a School of Pharmacy, Shanghai Jiaotong University , Shanghai, P. R.
China
b Guangzhou Institute of Biomedicine and Health, Chinese Academy
of Science , Guangzhou, P. R. China
Published online: 11 Aug 2008.
To cite this article: Yao Chen , Yingdan Peng , Jiancun Zhang & Lei Fu (2008) Synthesis and Biological
Evaluation of Novel Selenonucleosides, Nucleosides, Nucleotides and Nucleic Acids, 27:8, 1001-1008,
DOI: 10.1080/15257770802088803
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Nucleosides, Nucleotides and Nucleic Acids, 27:1001–1008, 2008
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770802088803
SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL
SELENONUCLEOSIDES
Yao Chen,1 Yingdan Peng,1 Jiancun Zhang,2 and Lei Fu1
1School of Pharmacy, Shanghai Jiaotong University, Shanghai, P. R. China
2Guangzhou Institute of Biomedicine and Health, Chinese Academy of Science, Guangzhou,
P. R. China
A series of novel selenonucleoside analogues with 1,4-oxaselenane as the carbohydrate fragment
2
has been synthesized from their corresponding dimesylated seconucleosides treated with NaHSe
solution and subsequent deprotection. The synthesized selenonucleoside analogues were evaluated
as potential antitumor agents.
Keywords Synthesis; biological evaluation; selenonucleoside; 1,4-oxaselenane
Nucleoside analogues have played an important role in antitumor and
antiviral therapies over the past decades. Today, nucleoside analogues are
still one of the most important classes of drugs in these therapeutic areas.
For example, the FDA approved another nucleoside analogue, Tyzeka
(telbivudine) for the treatment of patients with chronic hepatitis B virus
(HBV) in 2006.[1] Structurally, nucleosides consist of a purine or pyrimidine
base linked to a carbohydrate moiety usually in the forms of ribose or
deoxyribose. Many nucleoside based drugs have their carbohydrate frag-
ments modified or have a heteroatom introduced into the carbohydrate
moiety, such as 3ꢁ-azido-3ꢁ-deoxythymidine (AZT, zidovudine), acyclovir
(ACV), lamivudine (3TC). Interestingly, some of them, such as AZT, also
showed antitumor activity[2]in addition to its anti-HIV activity.[3] Among
the heteroatom substituted carbohydrate fragments, selenium is of great
interest to chemists as selenium has a long history of association with human
health. At the molecular level, selenium is an essential component of the
Received 6 November 2007; accepted 27 February 2008.
This research was financially supported by an Innovation Grant (08ZZ12) from the Shanghai
Municipal Education Commission.
Address correspondence to Lei Fu, School of Pharmacy, Shanghai Jiaotong University, Shanghai
200240, P. R. China; E-mail: leifu@sjtu.edu.cn or Jiancun Zhang, Guangzhou Institute of Biomedicine
and Health, Chinese Academy of Science, Guangzhou510663, P. R. China E-mail: zhang jiancun@
gibh.ac.cn.
1001

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Y. Chen et al.
FIGURE 1 The title compounds.
active sites of certain enzymes for the protection of cellular components
against oxidative and free radical damage.[4]
Selenonucleosides have been synthesized and studied for their antiviral
and antitumor activities. Structure-activity relationship studies on selenazo-
furin revealed that Se was essential for cytotoxicity and the inhibitory activity
against inosine monophosphate dehydrogenase (IMPDH).[5] Selenazofurin
and oxaselenolane nucleosides also were reported to exhibit antitumor
activities.[6] Furthermore, certain dioxolane and oxathiolane nucleosides
have exhibited potent antiviral and anticancer activities. It was reported
that 1,4-oxaselenolane derivatives with aromatic groups showed antitumor
activities,[7] in which the 1,4-oxaselenolane rings were found to be an
essential fragment for their antitumor activities. Among the nucleoside
analogues with six-membered carbohydrate fragments, 2,3-dihydro-4H-
pyrannucleoside and l,5-anhydrohexitol nucleosides exhibited significant
antitumor activity.[8],[9] Therefore, it was of interest to synthesize and
evaluate isoelectronically substituted oxaselenolane nucleosides.
We are interested in further exploring potential applications of
selenium-incorporated nucleosides. We introduced 1,4-oxaselenine ring as
the carbohydrate fragment into nucleosides to study their antitumor and an-
tiviral activities. Herein we reported the synthesis of novel selenonucleosides
by coupling an 1,4-oxaselenolane ring with uracil, adenine, cytosine and
guanine (Figure 1). We also reported our preliminary biological evaluation
of these compounds for their in vitro antitumor activities.
RESULTS AND DISCUSSIONS
The title compounds 1a–d were synthesized according to Scheme 1. The
5ꢁ OH group in compounds 2a–d was protected with dimethoxytrityl group
to yield compounds 3a–d,[10] which were further oxidized by NaIO4 and
subsequently reduced by NaBH4 to give compounds 4a–d.[11] Compounds
4a–d were activated by the mesylation of OH groups at 2ꢁ and 3ꢁ positions.[12]
The activated 5a–d were then reacted with a seleniferous nucleophile
NaHSe to form the 1,4-oxaselenine ring, and then deprotected sequentially
with saturated methanolic ammonia and acetic acid to yield the final
products 1a–d. The yields and characterization data for compounds 2a–d
to 5a–d were consistent with those reported.

Evaluation of Novel Selenonucleosides
1003
SCHEME 1 Synthetic route for compounds 1a–d. a, DMTCl/Pyr, rt.; b, NaIO4/CH3OH, rt; c,
NaBH4/CH3OH, rt; d, MsCl/Pyr, rt.; e, NaHSe, dioxane-water, 90◦C; f, NH3/CH3OH, rt; g, 80%AcOH,
rt.
We found that the activation of 2ꢁ and 3ꢁ OH groups in 4a–d made the
2ꢁ and 3ꢁ carbon atoms more favorable for the seleniferous nucleophilic
attack. Sodium hydrogen selenide was selected as the selenium source in
the reaction for its ease of preparation and better stability than other
selenium reagents. An aqueous solution of NaHSe was prepared according
to the literature.[13] The mole ratio of activated seconucleosides and NaHSe
was controlled at about 1:5 and a large excess NaHSe caused partial
deprotection of the amino group of 5b-d or 6b-d by NaHSe, thus, the yields
of 6b-d were slightly lower than that of 6a. In comparison to the preparation
of other 1,4-oxaselenine rings in the literature,[14] a higher yield and more
convenient separation were achieved.
Treating compounds 6a–d sequentially with saturated methanolic am-
monia, 80% aqueous acetic acid and then chromatographic separation
afforded the titled compounds as white solids in good yield.
The structures of 1a–d were confirmed by their NMR and HRMS data.
The 3ꢁ-C and 5ꢁ-C of 1a–d showed a characteristic chemical shift of 15–30
ppm due to the interaction with neighboring selenium atom. Coincidently,
the H3 and H5 peaks in 1b and 1d were partially overlapped with DMSO
and H2O peaks. However, their presence was confirmed by the H-HCOSY
2D-NMR which indicated a strong correlation between H1 and H3 as well as
H5 and H6, respectively.
In conclusion, a selenium atom was successfully introduced into the
carbohydrate fragment to form a series of novel selenium-containing nu-
cleoside analogues in good yields.

1004
Y. Chen et al.
The synthesized compounds were evaluated in vitro for their activities
in various tumor cell lines A549 (human lung tumor cell), LOVO (human
colon tumor cell), and HL60 (human leukemia cell). Cytarabine (Ara-C)
was chosen as a reference. Preliminary data showed only 1d weakly inhibited
LOVO cells, and the others have no inhibitory activities against these tumor
cell lines. The difference in activity among four bases suggests that the
inhibitory activity might be base dependent. Further preparation with the
1,4-oxaselenine fragment attached to various modified bases is in progress.
EXPERIMENTAL
Melting points were determined by the use of an electrothermal appara-
tus (Mel-Temp 1002, Shanghai Wanheng Precision Instruments, Co., Ltd.,
China). 1H NMR and 13C NMR spectra were recorded on a Varian Gemini
1
2000 spectrometer (Varian, USA; H NMR 300 MHz, 13C NMR 75 MHz).
Analytical thin-layer chromatography (TLC) was performed using silica gel
60 F254 glass plates (Merck, Germany), and compound spots were visualized
by UV light (254 nm). HRMS spectrometric analyses were confirmed by
Micromass LCT (ESI-TOF-MS, Waters, Great Britain) system that utilizes the
electro-spray ionization method. All chemical reagents were commercially
available.
Sodium borohydride (2.3 g, 61 mmol) in 25ml of water was added
dropwise to the flask containing powder of selenium (2.3 g, 29 mmol)
suspended in water (25 mL) with vigorous stirring in ice-water bath. After
the selenium powder was consumed, the ice-water bath was removed, the
solution was kept stirring at room temperature for 30 minutes under
nitrogen atmosphere. The resulting colorless solution of NaHSe was ready
for use without further treatment.
EXPERIMENTAL
1-(6-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-1,4-oxaselenan-2-
yl)pyrimidine-2, 4(1H, 3H)-dione (6a). Under a nitrogen atmosphere,
NaHSe aqueous solution (about 5 mmol, 9 mL) was injected into the
solution of 5a (704 mg, 1 mmol in 50 mL dioxane). The mixture was stirred
at 90◦C for 12 hours, then the solvent was removed under vacuum, the
residue was dissolved in CH2Cl2 (70 mL) and washed with 5% sodium
bicarbonate solution (2 × 35 mL). The organic layer was separated
and concentrated under reduced pressure. The residue was purified by
column chromatography (petroleum ether-ethyl acetate 1:1, v/v) to give
compounds 6a (518 mg, 0.872 mmol) in 87.2% yield as a white solid, m.p.
1
120–122◦C, H NMR (CD3CN, 300 MHZ), δ 8.96 (s, H-2, CONHCO, 1H),
7.51 (d, J = 6.0 Hz, H-6, 1H), 6.82–7.52 (H of DMT, 13H), 5.84 (dd, J =
1.5Hz and 8.4 Hz, H-5, 1H), 5.65 (dd, J = 1.2 Hz and 6.3 Hz, H-2ꢁ, 1H), 4.20
(m, H-6ꢁ, 1H), 3.76 (s, OCH3, 6H) 2.98–3.16 (m, CH2OH, 2H), 2.93 (t, J

Evaluation of Novel Selenonucleosides
1005
= 8.4 Hz, H-3ꢁa,1H), 2.73 (t, J = 8.7 Hz, H-3ꢁb, 1H), 2.50 (d, J = 13.5 Hz,
H5ꢁa, 1H), 2.47 (d, J = 13.8 Hz, H5ꢁa, 1H), HRMS-ESI (m/z): (M+Na+)
calcd forC30H30N2O6Se, 617.1167, found, 617.1176.
N-(9-(6-((Bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-1, 4-oxaselenan-2-yl)-
9H-purin-6-yl) ben-zamide (6b). Under nitrogen atmosphere, NaHSe aque-
ous solution (about 5 mmol, 9 mL) was injected into the solution of 5b (831
mg, 1 mmol in 50 mL dioxane). The mixture was stirred at 90◦C and the
reaction was monitored by TLC. After 10 h, the solvent was removed under
vacuum, the residue was dissolved in CH2Cl2 (75 mL) and washed with 5%
sodium bicarbonate solution (2 × 35 mL). The organic layer was separated
and concentrated under reduced pressure. The residue was purified by
column chromatography (petroleum ether–ethyl acetate 2:3, v/v) to give
compounds 6b (545 mg, 0.756 mmol) in 75.6% yield as a white solid, m.p.
116–118◦C, 1H NMR (CD3CN, 300 MHZ), δ 9.31 (s, H-6, CONHC N, 1H),
8.71 (s, H-8, 1H), 8.33 (s, H-2, 1H), 7.45–8.05 (H of PhCO-, 5H), 6.78–7.40
(H of DMT, 13H), 6.17 (dd, J = 1.5 Hz and 8.1 Hz, H-2ꢁ, 1H), 4.35 (m,
H-6ꢁ, 1H), 3.74 (s, OCH3, 6H), 3.56 (t, J = 9.0 Hz, H-3ꢁa, 1H), 2.97–3.16
(m, CH2OH, 2H), 2.83(d, J = 8.1 Hz, H-5ꢁa, 1H), 2.80 (t, J = 9.0 Hz, H-3ꢁb,
1H), 2.53 (d, J = 9.3 Hz, H-5ꢁb, 1H), HRMS-ESI (m/z): (M+H+) calcd for:
C38H35N5O5Se, 722.1882, found, 722.1882.
N-(1-(6-((Bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-1,4-oxaselenan-2-
yl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzamide (6c). Compound 5c (807 mg,
1 mmol) was treated by the similar procedure as described for 5b, and
purified by column chromatography (petroleum ether–ethyl acetate 1:2,
v/v) to give compounds 6c (504 mg, 0.723 mmol) in 72.3% yield as a white
1
solid, m.p. 208–210◦C, H NMR (DMSO-d6, 300MHZ), δ 11.27 (s, H-4,
CONHC N, 1H), 8.15 (d, J = 4.6 Hz, H-6, 1H), 7.47–8.02 (H of PhCO-,
5H), 7.40 (d, J = 5.7 Hz, H-5, 1H), 6.83–7.39 (H of DMT, 13H), 5.95 (dd,
J = 1.2 Hz and 7.5Hz, H-2ꢁ, 1H), 4.22 (m, H-6ꢁ, 1H), 3.73 (s, OCH3,
6H), 3.08–3.13 (m, CH2OH a, 1H), 2.95–3.10 (t, J = 8.4 Hz, H-3ꢁa, 1H),
2.91–2.96 (m, CH2OH b, 1H) 2.65 (d, J = 13.2 Hz, H-5ꢁ, 2H), 2.65 (t, J =
8.4 Hz, H-3ꢁb, 1H), HRMS-ESI (m/z): (M+Na+) calcd for C37H35N3O6Se,
720.1589, found, 720.1588.
N-(9-(6-((Bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-1,4-oxaselenan-2-
yl)-6-oxo-6,-dihydro-1H-purin-2-yl)isobutyramide (6d). Compound 5d (813
mg, 1 mmol) was treated by the similar procedure as described for 5b,
and purified by column chromatography (petroleum ether-ethyl acetate
1:2, v/v) to give compounds 6d (482 mg, 0.685 mmol) in 68.5% yield as
1
a white solid, m.p. 141–143◦C, H NMR (DMSO-d6, 300 MHZ), δ 12.10
(s, H-2, CONHC N, 1H), δ 11.70 (s, H-1, CONHC N, 1H), 8.21 (s, H-8,
1H), 6.75–7.35 (H of DMT, 13H), 5.91 (dd, J = 1.2 Hz and 8.1 Hz, H-2ꢁ,
1H), 4.23 (m, H-6ꢁ, 1H), 3.69 (s, OCH3, 6H), 3.55(t, J = 8.7 Hz, H-3ꢁa,
1H), 2.85–3.06 (m, CH2OH, 2H), 2.79 (d, J = 11.2 Hz, H-5ꢁa, 1H), 2.75

1006
Y. Chen et al.
(t, J = 8.4 Hz, H-3ꢁb, 1H), 2.64 (d, J = 11.5 Hz, H-5ꢁb, 1H), 2.59–2.69 [m,
(CH3)2CH-CO, 1H], 1.10 (d, J = 8.4 Hz, CH3CH-, 3H), 1.09 (d, J = 8.4
Hz, CH3CH-, 3H), HRMS-ESI (m/z): (M+Na+) calcd for C35H37N5O6Se,
726.1807, found, 726.1816.
1-(6-(Hydroxymethyl)-1,4-oxaselenan-2-yl)pyrimidine-2,4(1H,3H)-dione (1a).
Compound 6a (297 mg, 0.5 mmol) was treated with 80% acetic acid
aqueous solution (10 mL) for 1 h at room temperature. After evaporation
in vacuum, the residue was chromatographed on a silica column using
methylene chloride—methanol (33:1, v/v) to give 1a (128 mg, 0.438 mmol)
1
in 87.6% yield as a white solid, m.p. 79–81◦C, H NMR (methanol-d4, 300
MHZ), δ 7.74 (d, J = 8.1Hz, H-6, 1H), 5.92 (dd, J = 1.8 Hz and 10.5 Hz,
H-2ꢁ, 1H), 5.90 (d, J = 8.4 Hz, H-5, 1H), 4.07–4.16 (m, H-6ꢁ, 1H), 3.58 (t, J =
3.9 Hz, CH2OH, 2H), 2.98 (t, J = 10.8 Hz, H-3ꢁa, 1H), 2.72 (t, J = 11.4 Hz,
H-3ꢁb, 1H), 2.54 (d, J = 12.0 Hz, H-5ꢁa, 1H), 2.42 (d, J = 12.6 Hz, H-5ꢁb, 1H).
13C NMR (Methanol-d4, 75 MHZ) δ 16.83 and 18.61 (CH2SeCH2), 65.14
(CH2OH), 83.79 (C-6ꢁ), 83.81 (C-2ꢁ), 101.48 (C-5), 140.92 (C-6), 150.36
(C-2), 164.88 (C-4), HRMS-ESI (m/z): (M+Na+) calcd for C9H12N2O4Se,
314.9860, found, 314.9863.
(6-(6-Amino-9H-purin-9-yl)-1,4-oxaselenan-2-yl)methanol (1b). The solu-
tion of compounds 6b (361mg, 0.5mmol) in methanolic ammonia (50 mL,
saturated at 0◦C) was kept stirring for 24 hours at room temperature. The
solvent was removed in vacuum, and then treated with 80% acetic acid
aqueous solution (10 mL), and purified on silica gel column chromatog-
raphy with methylene chloride—methanol (15: 1, v/v) as eluent, the title
compounds 1b (133 mg, 0.422 mmol) were obtained in 84.4% yield as a
white solid, m.p. 194–196◦C, 1H NMR (DMSO-d6, 300 MHZ), δ 8.34 (s, H-8,
1H), 8.14 (s, H-2, 1H), 7.30 (s, NH2, 2H), 5.94 (dd, J = 1.5 and 10.8 HZ,
H-2ꢁ, 1H), 4.87(br, OH, 1H), 3.99–4.09(m, H-6ꢁ, 1H), 3.60 (t, J = 10.8
HZ, H-3ꢁa,1H), 3.27–3.42 (partially overlapped with H2O peaks, CH2OH,
2H), 2.78 (d, J = 12.3 HZ, H-3ꢁb, 1H), 2.49–2.66 (m, H-5ꢁ, 2H). 13C NMR
(DMSO-d6, 75 MHZ) δ: 18.35 and 19.38 (CH2SeCH2), 65.20 (CH2OH),
83.21 (C-6ꢁ), 83.43 (C-2ꢁ), 119.22 (C-5), 139.18 (C-8), 149.28 (C-4), 153.39
(C-2), 156.73 (C-6). H-H COSY (300 MHZ): H2ꢁ (δ = 5.94) was associated
with H-3ꢁa (δ = 3.60), H-3ꢁb (δ = 2.78), H6ꢁ (δ = 3.99–4.09) was correlated
with H-5ꢁa (δ = 2.49–2.66), H6ꢁ (δ = 3.99–4.09) was associated with CH2OH
(δ = 3.27–3.42), OH (δ = 4.87) was correlated with CH2OH (δ = 3.27–3.42),
H-3ꢁa (δ = 3.60) was associated with H-3ꢁb (δ = 2.78). HRMS-ESI (m/z):
(M+Na+) calcd for C10H13N5O2Se, 338.0132, found, 338.0137.
4-Amino-1-(6-(hydroxymethyl)-1,4-oxaselenan-2-yl)pyrimidin-2(1H)-one (1c).
Compound 6c (349 mg, 0.5 mmol) was treated by the similar procedure
described for 6b, and purified on silica gel column chromatography with
methylene chloride-methanol (12:1, v/v) as eluent. The title compounds 1c
(118 mg, 0.388 mmol) was obtained in 81.1% yield as a white solid, m.p.

Evaluation of Novel Selenonucleosides
1007
1
320–322◦C, H NMR(methanol-d4, 300 MHZ), δ 7.72 (d, J = 7.2 Hz, H-6,
1H), 5.94 (dd, J = 1.5 HZ and 10.5 HZ, H-2ꢁ, 1H), 5.90 (d, J = 7.8 Hz, H-5,
1H), 4.05–4.16 (m, H-6ꢁ, 1H), 3.58 (t, J = 5.4 Hz, CH2OH, 2H), 2.86 (t, J
= 11.4 Hz, H-3ꢁa, 1H), 2.72 (t, J = 11.7 Hz, H-3ꢁb, 1H), 2.58 (d, J = 11.4
Hz, H-5ꢁa, 1H),2.43 (d, J = 12.6 Hz, H-5ꢁb, 1H), 13C NMR (Methanol-d4,
75 MHZ) δ: 16.95 and 19.30 (CH2SeCH2), 65.26 (CH2OH), 83.60 (C-6ꢁ),
84.60 (C-2ꢁ), 94.94 (C-5), 141.09 (C-6), 156.16 (C-2), 166.35 (C-4), HRMS-
ESI (m/z): (M+Na+) calcd for C9H13N3O3Se, 314.0020, found, 314.0016.
2-Amino-9-(6-(hydroxymethyl)-1,4-oxaselenan-2-yl)-1H-purin-6(9H)-one (1d).
Compound 6d (352 mg, 0.5 mmol) was treated by the similar procedure
described for 1b, and purified on silica gel column chromatography with
methylene chloride-methanol (10:1, v/v). The title compounds 1d (141
mg, 0.432 mmol) was obtained in in 85.2% yield as a white solid, m.p.
1
130–133◦C, H NMR (DMSO-d6, 300 MHZ), δ 11.01 (s, H-1, 1H), 7.87 (s,
H-8, 1H), 6.74 (s, NH2, 2H), 5.72 (dd, J = 1.2 and 10.5 Hz, H-2ꢁ, 1H), 4.91
(br, OH, 1H), 3.89–4.00 (m, H-6ꢁ, 1H), 3.28–3.46 (partially overlapped
with H2O peaks, CH2OH, H-3ꢁa, H-3ꢁb, 4H), 2.51–2.72 (partially overlapped
with DMSO-d6 peaks, H5ꢁa, H5ꢁb, 2H), 13C NMR (DMSO-d6, 75 MHZ) δ
18.33 and 19.62 (CH2SeCH2), 65.19 (CH2OH), 82.73 (C-6ꢁ), 83.52 (C-2ꢁ),
116.92 (C-5), 135.30 (C-8), 150.87(C-4), 154.77(C-2), 157.74(C-6), HRMS-
ESI (m/z): (M+Na+) calcd for C10H13N5O3Se, 354.0081, found, 354.0087.
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