Synthesis and biological evaluation of 2′-substituted-4′-selenoribofuranosyl pyrimidines as antitumor agents

Article abstract of DOI:10.1007/s12272-014-0466-6

The 2′-substituted-4′-selenoribofuranosyl pyrimidines 3a-3j were synthesized from D-ribose and assayed for anticancer activity. The 2′-azido and 2′-fluoro groups with a ribo configuration were introduced by the regioselective opening of the O₂,

Full text of DOI:10.1007/s12272-014-0466-6

Arch. Pharm. Res.
DOI 10.1007/s12272-014-0466-6
RESEARCH ARTICLE
Synthesis and biological evaluation of 20-substituted-40-
selenoribofuranosyl pyrimidines as antitumor agents
•
Varughese Alexander Jayoung Song
•
•
Jinha Yu Jung Hee Choi Jin-Hee Kim
•
•
•
Sang Kook Lee Won Jun Choi Lak Shin Jeong
•
Received: 23 June 2014 / Accepted: 3 August 2014
Ó The Pharmaceutical Society of Korea 2014
Abstract The 20-substituted-40-selenoribofuranosyl pyrim-
idines 3a–3j were synthesized from D-ribose and assayed for
anticancer activity. The 20-azido and 20-fluoro groups with a
ribo configuration were introduced by the regioselective
opening of the O2,20-anhydronucleosides with sodium azide
and (HF)x-pyridine, respectively. Among the compounds
tested, only 20-fluoro derivative 3j was found to exhibit sig-
nificant anticancer activity, but was much less potent than the
corresponding 20-arabino analogue 2c. This study will pro-
vide medicinal chemists with the insight into the identification
of structural requirements for the anticancer activity for the
developments of biologically active nucleosides.
(Ichikawa 2001; Jordheim et al. 2013). Modifications have
largely been made on the furanose ring, among which 20-sub-
stitution resulted in potent antiviral and antitumor agents
(Ichikawa 2001; Jordheim et al. 2013). For example, 1-b-D-
arabinofuranosyl-cytosine (1, ara-C) is being clinically used for
the treatment of leukemia (Ellison et al. 1968). Based on the
bioisosteric rationale, we synthesized the 40-seleno analogue,
40-Se-ara-C of 1, starting from D-ribose and evaluated it for
cytotoxicity in human cancer cell lines, but 40-Se-ara-C (2,
X = NH2, Y = H, R = OH) was less potent than 1 in human
cancer cell lines tested (Jeong et al. 2009). However, the 20-
fluoro-40-seleno analogue (2, X = NH2, Y = H, R = F)
exhibited more potent anticancer activity than 1 in a broad
range of human cancer cell lines tested except leukemia (K562)
cell lines (Jeong et al. 2009). Structure–activity relationships of
20-modified-40-selenoarabinofuranosyl pyrimidines demon-
strated that the anticancer activity is in the following order: 20-
F[20-OH [20-N3 (Kim et al. 2014). Thus, it is of great
interest to synthesize the corresponding 20-modified-40-sele-
noribofuranosyl pyrimidines 3 and to compare the anticancer
activities between arabino and ribo configurations at the 20-
position. Herein, we report the synthesis and anticancer activity
of 20-substituted-40-selenoribofuranosyl pyrimidines 3.
Keywords Antitumor activity ꢀ 40-Selenonucleosides ꢀ
Regioselective opening ꢀ Azidation ꢀ Fluorination
Introduction
Modified nucleosides have been served as valuable resources
of therapeutic agents such as antiviral and antitumor agents
V. Alexander ꢀ J. Yu ꢀ J. H. Choi ꢀ J.-H. Kim
College of Pharmacy, Ewha Womans University, Seoul 120-750,
Korea
The 20-azido and 20-fluoro groups were stereoselectively
introduced by the regioselective openings of the O2,20-an-
hydronucleoside with the azide and fluoride anions,
respectively. Herein, we report the synthesis of 20-substi-
tuted-40-selenopyrimidine nucleosides 3 and their cytotoxic
activity in various cancer cell lines (Fig. 1).
J. Song ꢀ S. K. Lee ꢀ L. S. Jeong (&)
Research Institute of Pharmaceutical Sciences, College of
Pharmacy, Seoul National University, Seoul 151-742, Korea
e-mail: lakjeong@snu.ac.kr
W. J. Choi
College of Pharmacy, Dongguk University,
Seoul 410-774, Kyungki-do, Korea
Results and discussion
W. J. Choi (&)
College of Pharmacy, Dongguk University,
Seoul 410-820, Kyungki-do, Korea
e-mail: mp89@dongguk.edu
For the synthesis of the 20-azido-20-deoxy-40-selenoribofur-
anosyl pyrimidines 3a–3f (Scheme 1), the ribo analogues
123

V. Alexander et al.
X
N
to the corresponding triazole derivatives 13, 14, and 15,
respectively by treating with POCl3, 1,2,4-triazole, and
Et3N. Treatment of 13, 14, and 15 with 28 % NH4OH
afforded the cytosine derivatives, which were further
treated with methanolic ammonia to yield the final cytosine
derivatives 3h–3j, respectively.
All the synthesized 20-substituted-40-selenonucleosides
3a–3j were tested for cytotoxic effects in several human
cancer cell lines such as colon cancer (HCT116), lung
cancer (A549), stomach cancer (SNU638), breast cancer
(T47D), prostate cancer (PC-3), and leukemia (K562) cells,
using sulforhodamine B (SRB) protein staining method
(Lee et al. 2002; Table 1).
H2N
N
Y
N
N
O
HO
O
Se
HO
R
O
OH
HO
HO
Ara-C (1)
2
X = OH or NH2
Y = H, CH3, or halogen
R = OH, F, or N3
All the uracil, thymine, and 5-halouracil derivatives 3a–
3g did not exhibit significant anticancer activity up to
100 lM in human tumor cell lines tested, irrespective of
any substitution at 20-position. In the case of the cytosine
derivatives 3h–3j, only 20-fluor derivative 3j exhibited
significant anticancer activity, but was less potent than the
corresponding arabino derivative 2c (Kim et al. 2014). In
general, the arabino derivatives were much more potent
than the corresponding ribo derivatives.
X
Y
N
N
O
HO
Se
R
HO
3
X = OH or NH2
Y = H, CH3, or Halogen
R = OH, F, or N3
Conclusions
Fig. 1 The rationale for the design of the target nucleoside 3
Based on the structure–activity relationship of the 20-
substituted-40-selenoarabinofuranosyl pyrimidines 2 (Kim
et al. 2014) as anticancer agents, novel 20-substituted-40-
selenoribofuranosyl pyrimidines 3a–3j were synthesized
from D-ribose and evaluated for anticancer activity. The
highlight of our synthetic endeavor is the regioselective
formation of O2,20-anhydronucleosides using DAST or
MsCl/DBU and the regioselective opening of the resulting
O2,20-anhydronucleosides with sodium azide and (HF)x-
pyridine for the introduction of the 20-azido and 20-fluoro
group with a ribo configuration, respectively. From this
study, 20-fluoro derivative 3j only exhibited significant
anticancer activity among the compounds synthesized and
the 20-ribo analogues were much less potent than the cor-
responding 20-arabino analogues. Although we could not
discover promising anticancer agents from this study, the
identification of structural requirements for the anticancer
activity will be extensively utilized for the developments of
biologically active nucleosides.
4a–4f (Kim et al. 2014) were protected with TIPDS group to
give the 30,50-di-O-TIPDS protected nucleosides 5a–5f,
(Kim et al. 2014) respectively. Treatment of 5a–5f with
DAST or MsCl/DBU afforded the O2,20-anhydronucleosides
6a–6f, (Kim et al. 2014) respectively. After the removal of
the TIPDS groups of 6a–6f with 3HF-Et3N, the resulting
diols 7a–7f (Kim et al. 2014) were treated with sodium
azide in DMF at 120 °C to yield the final 20-azido-20-deoxy-
40-selenoribofuranosyl pyrimidines 3a-3f. The configuration
of the 20-azido group of 3a–3f was unambiguously con-
1
firmed by H NOE experiments, as shown in Fig. 2. Strong
NOE between 20-H and H-6 was observed, but no NOE
between 20-H and 40-H was observed, confirming that 20-
azido group possesses the ribo configuration.
Synthesis of the 20-deoxy-20-fluoro-40-selenoribofuranosyl
uracil (3g) is illustrated in Scheme 2. 40-Selenouridine (4a)
was treated with trityl chloride to give the 50-O-trityl deriva-
tive 8 (Jeong et al. 2009), which was treated with 1,10-thio-
carbonyl diimidazole (TCI) in toluene to yield the O2,20-
anhydronucleoside 9 (Jeong et al. 2009) as a single regioste-
reoisomer. Treatment of 9 with 3HF-pyridine in 1,4-dioxane
afforded the 20-fluoro analogue 3g with a ribo configuration.
Synthesis of the cytosine derivatives 3h-3j is depicted in
Scheme 3. The uracil derivatives, 4a, 3a, and 3g were
peracetylated to yield 10, 11, and 12, which were converted
Experimental section
General methods
1H-NMR Spectra (CDCl3, CD3OD or DMSO-d6) were
1
recorded on Varian Unity Invoa 400 MHz. The H-NMR
123

Biological evaluation of 20-substituted-40-selenoribofuranosyl pyrimidines
O
O
N
X
O
N
X
NH
N
X
NH
O
N
O
Se
O
O
O
Se
b
Si
a
HO
Si
Se
O
O
O
OH
O
Si
Si
OH OH
4a (X = H)
5a (X = H, 86%)
4b (X = CH3)
4c (X = F)
4d (X = Cl)
4e (X = Br)
4f (X = I)
6a (X = H, 77%)
5b (X = CH3, 69%)
5c (X = F, 60%)
5d (X = Cl, 78%)
5e (X = Br, 76%)
5f (X = I, 87%)
6b (X = CH3, 85%)
6c (X = F, 65%)
6d (X = Cl, 64%)
6e (X = Br, 72%)
6f (X = I, 80%)
c
O
O
N
X
X
NH
O
N
N
d
O
Se
HO
HO
Se
HO N3
HO
3a (X = H, 54%)
7a (X = H, 69%)
7b (X = CH3, 76%)
7c (X = F, 79%)
7d (X = Cl, 85%)
7e (X = Br, 86%)
7f (X = I, 89%)
3b (X = CH3, 53%)
3c (X = F, 49%)
3d (X = Cl, 52%)
3e (X = Br, 40%)
3f (X = I, 25%)
Scheme 1 Reagents and conditions: (a) TIPSCI2, pyridine, rt, 3 h; (b) DAST, MC, -78 °C, 1 h or MsCl, then DBU; (c) 3HF–Et3N, THF, 0 °C,
1 h; (d) NaN3, DMF, 120 °C, overnight
data are reported as peak multiplicities: s for singlet, d for
doublet, dd for doublet of doublets, t for triplet, q for
quartet, br s for broad singlet and m for multiplet. Coupling
constants are reported in hertz. 13C-NMR spectra (CDCl3,
CD3OD or DMSO-d6) were recorded on Varian Unity
Inova 100 MHz. 19F-NMR spectra (CDCl3, CD3OD) were
recorded on Varian Unity Inova 376 MHz. The chemical
shifts were reported as parts per million (d) relative to the
solvent peak. Optical rotations were determined on Jasco
III in appropriate solvent. UV spectra were recorded on
U-3000 made by Hitachi in methanol or water. Infrared
spectra were recorded on FT-IR (FTS-135) made by Bio-
Rad. Melting points were measured on B-540 made by
Buchi. Elemental analyses (C, H, and N) were used to
determine purity of all synthesized compounds, and the
results were within 0.4 % of the calculated values, con-
firming C95 % purity. Reactions were checked with TLC
(Merck precoated 60F254 plates). Spots were detected by
viewing under a UV light, colorizing with charring after
dipping in anisaldehyde solution with acetic acid, sulfuric
acid and methanol. Column chromatography was per-
formed on silica gel 60 (230–400 mesh, Merck). Reagents
were purchased from Aldrich Chemical Company. Sol-
vents were obtained from local suppliers. All the anhydrous
solvents were distilled over CaH2, P2O5 or sodium/benzo-
phenone prior to the reaction.
General procedure for the synthesis of 5a–5f (Kim et al.
2014)
To a solution of 4a–4f in pyridine was added TIPDSCl2
(1.5 equiv.) at 0 °C and the mixture was allowed to stir at
room temperature for 3 h. The reaction mixture was con-
centrated, and the residue co-evaporated three times with
123

V. Alexander et al.
O
O
O
N
Me
NH
NH
NH
O
O
N
O
a
AcO
AcO
H6
HO
Se
Se
NOE (2.03%)
N
HO
H2'
H3'
X
HO
X
Se
10 (X = OH)
11 (X = N3)
12 (X = F)
4a (X = OH)
3a (X = N3)
3g (X = F)
H1
H4'
HO
N3
b
NO NOE
3b
N
N
NH2
N
1
Fig. 2 H NOE of 20-azido-40-selenoribofuranosyl thymine (3b)
N
N
N
O
c
O
N
HO
O
AcO
AcO
O
Se
Se
NH
NH
a
HO
X
X
O
N
O
N
TrO
3h (X = OH) (50% from 4a)
3i (X = N3) (76% from 3a)
3j (X = F) (59% from 8)
13 (X = OH)
14 (X = N3)
15 (X = F)
HO
72%
Se
Se
OH OH
OH OH
Scheme 3 Reagents and conditions: a Ac20, rt, 15 h; b 1,2,4-triazole,
Et3N, POCI3, CH3CN, rt, 15 h; c NH4OH, 1,4-dioxane, rt, 15 h, then,
NH3, MeOH, rt, 15 h
8
4a
b
97%
NaHCO3 solution, dried (MgSO4), filtered, and evaporated.
The residue was purified by flash silica gel column chro-
O
O
N
NH
matography
(dichloromethane:ethyl
acetate:metha-
N
c
O
Se
nol = 20:20:1) to give the anhydro derivatives 6a–6f.
O
N
TrO
HO
Se
18%
General procedure for the synthesis of 7a–7f (Kim et al.
2014)
OH
OH F
3g
9
To a solution of 6a–6f (1 equiv.) in dry THF were added
Et3Nꢀ3HF (3 equiv.) and triethylamine (3 equiv.) at 0 °C.
After being stirred at the same temperature for 30 min, the
reaction mixture was allowed to warm to room temperature
and stirred for additional 30 min. The reaction mixture was
evaporated and the residue was purified by silica gel col-
umn chromatography (dichloromethane:ethyl ace-
tate:methanol = 10:10:1) to give 7a–7f.
Scheme 2 Reagents and conditions: (a) TrCI, pyridine, rt, 15 h;
(b) TCI, toluene, 100 °C, 15 h; (c) (HF)x-pyridine, 1,4-dioxane,
125 °C, 2 d
toluene. The residue was purified by silica gel column
chromatography (hexane:ethyl acetate = 2:1) to give 5a–
5f.
General procedure for the synthesis of O2,20-anhydro
General procedure for the synthesis of 3a–3f
nucleosides 6a–6f (Kim et al. 2014)
To a stirred solution of compound 7a–7f (Kim et al. 2014)
(1 equiv.) in dry N,N-dimethylformamide was added
sodium azide (2 equiv.) and the mixture was stirred at
120 °C for 15 h. The reaction mixture was evaporated and
the residue was purified by silica gel column chromatog-
raphy (dichloromethane/methanol = 8:1) to give 3a–3f.
To a stirred solution of 5a–5f (1 equiv.) in dichloromethane
was added DAST (2 equiv.) at -78 °C, and the reaction
mixture was stirred at the same temperature for 1.5 h. Then
saturated NaHCO3 solution was added at 0 °C and the
reaction mixture was partitioned between dichloromethane
and water. The organic layer was washed with saturated
123

Biological evaluation of 20-substituted-40-selenoribofuranosyl pyrimidines
Table 1 Anticancer activity of the synthesized 20-substituted-40-selenonucleosides, 3h–3j in several human cancer cell lines
NH2
N
O
N
HO
Se
R1
R
2
OH
Compound no.
IC50 (lM)a
g
HCT116b
A549c
SNU638d
T47De
PC–3f
K562
3h (R1 = H, R2 = OH)
3i (R1 = H, R2 = N3)
3j (R1 = H, R2 = F)
2a (R1 = OH, R2 = H)h
2b (R1 = N3, R2 = H)i
2c (R1 = F, R2 = H)h
Ara-C (1)h
[100
[100
27.8
7.13
78.3
1.1
[100
[100
92.9
8.83
80.1
0.47
1.90
[100
[100
19.1
4.72
85.2
0.14
0.15
[100
[100
20.1
8.91
78.4
0.79
2.72
[100
[100
15.5
4.54
75.1
0.58
55.9
[100
[100
10.3
86.6
62.3
0.63
0.05
5.3
a
Measured using SRB method
b
Human colon cancer cell lines
c
Human lung cancer cell lines
d
Human stomach cancer cell lines
e
Human breast cancer cell lines
f
Human prostate cancer cell lines
g
Human leukemia cell lines
h
Jeong et al. (2009)
i
Kim et al. (Kim et al. 2014)
1
2112 cm-1 (N3); H NMR (400 MHz, CD3OD) d 7.95 (s,
1H), 6.51 (d, J = 8.8 Hz, 1H), 4.47 (t, J = 2.8 Hz, 1H),
4.16 (dd, J = 3.6, 8.8 Hz, 1H), 3.89–3.81 (m, 2H),
3.62–3.58 (m, 1H), 1.91 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 166.1, 152.7, 139.1, 112.7, 76.9, 70.8, 64.8, 55.2,
51.8, 12.5; MS (ESI) m/z 348.0211 (M?H?); Calc. for
C10H13N5O4Se:C, 34.69; H, 3.78; N, 20.23. Found: C,
34.87; H, 3.87; N, 20.43.
1-((2R,3R,4S,5R)-3-Azido-tetrahydro-4-hydroxy-5-
(hydroxymethyl) selenophen-2-yl) pyrimidine-
2,4(1H,3H)-dione (3a)
White solid; yield: 54 %; mp 202–206 °C (decomposed);
[a]2D0 -100.80 (c 0.25, CH3OH); UV (CH2Cl2) kmax
1
266 nm; IR (KBr) 2 107 cm-1 (N3); H NMR (400 MHz,
CD3OD) d 8.14 (d, J = 8.0 Hz, 1H), 6.48 (d, J = 8.4 Hz,
1H), 5.80 (d, J = 8.0 Hz, 1H), 4.47 (t, J = 3.2 Hz, 1H),
4.14 (dd, J = 3.6, 8.4 Hz, 1H), 3.89–3.80 (m, 2H),
3.63–3.59 (m, 1H); 13C NMR (100 MHz, CDCl3) d 165.8,
152.5, 143.8, 103.7, 76.9, 71.1, 64.8, 55.4, 51.8; MS (ESI)
m/z 371.9613 (M?K?); Calc. for C9H11N5O4Se: C, 32.54;
H, 3.34; N, 21.08. Found: C, 32.14; H, 3.45; N, 19.98.
1-((2R,3R,4S,5R)-3-Azido-tetrahydro-4-hydroxy-5-
(hydroxymethyl) selenophen-2-yl)-5-fluoropyrimidine-
2,4(1H,3H)-dione (3c)
White solid; Yield: 49 %; mp 213-216 °C (decomposed);
[a]2D0 -48.5 (c 1.07, CH3OH); UV (CH3OH) kmax 272 nm;
IR (KBr) 2 115 cm-1 (N3); 1H NMR (400 MHz, CD3OD) d
8.35 (d, J = 6.8 Hz, 1H), 6.46 (dd, J = 2.0, 8.4 Hz, 1H),
4.46 (t, J = 3.2 Hz, 1H), 4.13 (dd, J = 3.2, 8.4 Hz, 1H), 3.85
(d, J = 5.6 Hz, 2H), 3.59–3.62 (m, 1H); 13C NMR
(100 MHz, CD3OD) d 159.2 (d, JC–F = 26.2 Hz), 151.2,
141.7 (d, JC–F = 233.3 Hz), 127.6 (d, JC–F = 34.9 Hz),
1-((2R,3R,4S,5R)-3-Azido-tetrahydro-4-hydroxy-5-
(hydroxymethyl) selenophen-2-yl)-5-
methylpyrimidine-2,4(1H,3H)-dione (3b)
White solid; yield: 53 %: mp 88–92 °C; [a]2D0 -78.06 (c
0.36, CH3OH); UV (CH2Cl2) kmax 271 nm; IR (KBr)
123

V. Alexander et al.
77.0, 71.2, 64.5, 56.1, 51.9; 19F NMR (CD3OD) d 162.7; MS
(ESI) m/z 351.9955 (M?H?); Calc. for C9H10FN5O4Se: C,
30.87; H, 2.88; N, 20.00. Found: C, 30.98; H, 2.48; N, 20.04.
pyridine (0.15 mL, 5.91 mmol) and the mixture was heated
to 125 °C for 2 d. The mixture was evaporated and the
residue was purified by silica gel column chromatography
(dichloromethane:methanol = 10:1) to give 3g (33.4 mg,
1
1-((2R,3R,4S,5R)-3-Azido-tetrahydro-4-hydroxy-5-
(hydroxymethyl)selenophen-2-yl)-5-chloropyrimidine-
2,4(1H,3H)-dione (3d)
18 %) as a white solid: UV (CH2Cl2) kmax 265 nm; H
NMR (400 MHz, CD3OD) d 8.17 (d, 1H, J = 8.0 Hz),
6.46 (dd, 1H, J = 14.0, 6.0 Hz), 5.79 (d, 1H, J = 8.0 Hz),
5.21 (ddd, 1H, J = 50.0, 6.0 and 3.2 Hz), 4.39 (ddd, 1H,
J = 13.2, 4.4 and 3.2 Hz), 3.93 (dd, 1H, J = 12.0, 5.6 Hz),
3.85 (dd, 1H, J = 12.0, 5.6 Hz), 3.62 (m, 1H); FAB-MS
m/z 310 (M?H?).
White solid; Yield: 52 %; mp 144–146 °C; [a]2D0 -32.85 (c
0.7, CH3OH); UV kmax (CH3OH) 271 nm; IR (KBr)
1
2 115 cm-1 (N3); H NMR (400 MHz, CD3OD) d 8.47 (s,
1H), 6.44 (d, J = 8.0 Hz, 1H), 4.46 (t, J = 3.2 Hz, 1H), 4.17
(dd, J = 3.6, 8 Hz, 1H), 3.86 (d, J = 5.2 Hz, 2H), 3.64–3.60
(m, 1H); 13C NMR (100 MHz, CD3OD) d 161.3, 151.7,
140.8, 110.0, 77.1, 71.4, 64.3, 56.0, 52.0; MS (ESI): m/z
389.9471 (M?Na?); Calc. for C9H10ClN5O4Se: C, 29.48; H,
2.75; N, 19.10. Found: C, 29.76; H, 2.45; N, 19.09.
General procedure for the synthesis of cytosine
derivatives 3h, 3i, and 3j
A solution of 4a, 3a, and 8 (1 equiv.) in anhydrous pyridine
was treated with acetic anhydride (10 equiv.), and the
mixture was stirred at room temperature for 15 h. The
mixture was evaporated and the residue was diluted with
dichloromethane. This solution was washed consecutively
with dilute HCl, saturated NaHCO3 solution and brine. The
organic layer was dried (MgSO4), filtered and evaporated.
The residue was purified by silica gel column chromatog-
raphy (hexane:ethyl acetate = 1:1) to give pereacetylated
compound 9, 10, and 11, respectively as white foams.
To a solution of 9, 10, and 11 in acetonitrile were added
1,2,4-triazole (1 equiv.), phosphorus oxychloride (1.1
equiv.), and triethylamine (1.1 equiv.) and the mixture was
stirred at room temperature for 15 h. The mixture was
diluted with dichloromethane and the organic layer was
washed with saturated NaHCO3 solution, brine, dried
(MgSO4), filtered and evaporated to give 12, 13, and 14,
respectively. To a solution of crude 12, 13, and 14 in 1,4-
dioxane was added ammonium hydroxide (28 %), and the
mixture was stirred at room temperature for 15 h. After
removal of all volatiles, the residue was dissolved in
methanolic ammonia (3 mL) and stirred again for 15 h.
The reaction mixture was evaporated, and the residue was
purified by silica gel column chromatography (dichloro-
methane:methanol = 6:1) to give 3 h, 3i, and 3j,
respectively.
1-((2R,3R,4S,5R)-3-Azido-tetrahydro-4-hydroxy-5-
(hydroxymethyl) selenophen-2-yl)-5-bromopyrimidine-
2,4(1H,3H)-dione (3e)
White solid; yield, 40 %; mp 116–121 °C; [a]2D0 -21.86 (c
0.7, CH3OH); UV kmax (CH3OH) 269 nm; IR (KBr)
1
2 113 cm-1 (N3); H NMR (400 MHz, CD3OD) d 8.57 (s,
1H), 6.42 (d, J = 8.0 Hz, 1H), 4.46 (t, J = 3.2 Hz, 1H), 4.18
(dd, J = 3.2, 8.0 Hz, 1H), 3.86 (d, J = 5.2 Hz, 2H), 3.64-
3.61 (m, 1H); 13C NMR (100 MHz, CD3OD) d 161.4, 151.9,
143.4, 97.8, 77.1, 71.5, 64.2, 56.0, 52.0; MS (ESI): m/z
409.9006 [M-H]-; Calc. for C9H10BrN5O4Se: C, 26.30; H,
2.45; N, 17.04. Found: C, 26.54; H, 2.55; N, 17.01.
1-((2R,3R,4S,5R)-3-Azido-tetrahydro-4-hydroxy-5-
(hydroxymethyl) selenophen-2-yl)-5-iodopyrimidine-
2,4(1H,3H)-dione (3f)
White solid; yield, 25 %; mp 198–202 °C (decomposed);
[a]2D0 -53.20 (c 0.10, CH3OH); UV kmax (CH3OH)
1
289 nm; IR (KBr) 2 115 cm-1 (N3); H NMR (400 MHz,
CD3OD) d 8.61 (s, 1H), 6.39 (d, J = 8.0 Hz, 1H), 4.44 (t,
J = 3.2 Hz, 1H), 4.16 (dd, J = 3.4, 7.8 Hz, 1H), 3.85 (d,
J = 5.2 Hz, 2H), 3.63–3.59 (m, 1H); 13C NMR (100 MHz,
CD3OD) d 162.6, 152.3, 148.5, 77.1, 71.6, 69.4, 64.2, 55.9,
52.0; MS (ESI): m/z 481.8838 (M?Na?); Calc. for C9-
H10IN5O4Se: C, 23.60; H, 2.20; N, 15.29. Found: C, 23.61;
H, 2.43; N, 15.09.
4-Amino-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-
(hydroxymethyl) tetrahydroselenophen-2-yl)pyrimidin-
2(1H)-one (3h) (Jeong et al. 2008)
White solid; yield, 50 %; mp 150-153 °C; UV (MeOH)
kmax 277 nm; MS (FAB) m/z 307 (M?); [a]D20 -260.0;
(c 0.17, CH3OH); 1H NMR (CD3OD) d 3.56–3.63 (m, 1H),
3.80 (dd, 1H, J = 5.6, 11.6 Hz), 3.90 (dd, 1H, J = 6.4,
11.6 Hz), 4.21 (t, 1H, J = 3.6 Hz); 4.32 (dd, 1H, J = 3.0,
6.8 Hz); 5.95 (d, 1H, J = 7.6 Hz); 6.27 (d, 1H,
J = 7.2 Hz); 8.13 (d, 1H, J = 7.6 Hz); 13C NMR
1-((2R,3R,4S,5R)-3-fluoro-4-hydroxy-5-
(hydroxymethyl) tetrahydroselenophen-2-
yl)pyrimidine-2,4(1H,3H)-dione (3g)
To a solution of 9 (Jeong et al. 2009) (314 mg,
0.591 mmol) in 1,4-dioxane (6 mL) was added (HF)x-
123

Biological evaluation of 20-substituted-40-selenoribofuranosyl pyrimidines
Acknowledgments This work was supported by the Grants from
Mid-career Research Program (2010-0026203) through the National
Research Foundation, Korea, and the Research Resettlement for the
New Faculty of Seoul National University (2014).
(CD3OD) d 59.1, 66.2, 76.5, 80.5, 96.7, 144.7, 159.0,
167.4; Anal. Calcd for C9H13N3O4Se: C, 35.31; H, 4.28; N,
13.72. Found: C, 35.13; H, 3.98; N, 13.38.
4-Amino-1-((2R,3R,4S,5R)-3-azido-tetrahydro-4-
hydroxy-5-(hydroxymethyl) selenophen-2-
yl)pyrimidin-2(1H)-one (3i)
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°
White solid; yield, 76 %; mp 115–120 C; [a]2D0 -83.42 (c
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1
White solid; Yield, 59 %; UV (CH3OH) kmax 276 nm; H
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6.48 (dd, 1H, J = 14.4, 5.6 Hz), 5.97 (d, 1H, J = 7.2 Hz),
5.17 (ddd, 1H, J = 50.0, 5.6 and 3.2 Hz), 4.35 (ddd, 1H,
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123