Inhibition by Dideoxy Nucleosides
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 19 4771
5-Tetradecynyl-2′,3′-dideoxyuridine (7). This was obtained as
chromatography (TLC) was performed with Machery-Nagel Alu-
gram SiL G/uv silica gel slides (20 µM thickness). 2′,3′-Dideoxy-
cytidine (9), 2′,3′-dideoxy-5-methylcytidine (12), and (-)-3′-
thiacytidine (13) were purchased from Sigma. 2′,3′-Dideoxyuridine
(1) and 3′-fluoro-2′,3′-dideoxyuridine (20) were synthesized ac-
cording to literature procedures.16,31
5-Iodo-2′,3′-dideoxyuridine (2). Iodine monochloride (753 mg,
4.65 mmol) was added to a suspension of sodium azide (585 mg,
9.0 mmol) in acetonitrile (25 mL) at ice-bath temperature with
stirring. This mixture was stirred for another 5 min, a solution of
2′,3′-dideoxyuridine (1) (490 mg, 2.32 mmol) in acetonitrile (60
mL) was added, and the mixture was warmed at 25 °C and stirred
for 24 h. The progress of the reaction was monitored by TLC
[CHCl3/MeOH (9:1, v/v)]. Removal of the solvent in vacuo (bath
temperature of 50 °C) and purification of the residue obtained by
elution from silica gel column chromatography using CHCl3/MeOH
1
a syrup in 70% yield. H NMR (DMSO-d6) δ: 0.85 (t, 3H, CH3),
1.32 (m, 18H, 9 × CH2), 1.46 (m, 2H, â-CH2), 1.85 (m, 2H, H-3′),
2.02 and 2.25 (2m, 2H, H-2′), 2.33 (t, J ) 7.0 Hz, 2H, R-CH2),
3.52 and 3.73 (2m, 2H, H-5′), 4.03 (m, 1H, H-4′), 5.12 (t, J )
4.88 Hz, 1H, 5′-OH), 5.89 (dd, J ) 3.05, 6.41 Hz, 1H, H-1′), 8.25
(s, 1H, H-6), 11.50 (s, 1H, NH). Anal. (C23H36N2O4) C, H, N.
5-(2-Phenylethynyl)-2′,3′-dideoxyuridine (8). Compound 8 was
1
obtained as a syrup in 81% yield. H NMR (DMSO-d6) δ: 1.89
(m, 2H, H-3′), 2.03 and 2.32 (2m, 2H, H-2′), 3.57 and 3.78 (2m,
2H, H-5′), 4.06 (m, 1H, H-4′), 5.27 (t, 1H, 5′-OH), 5.91 (m, 1H,
H-1′), 7.38-7.46 (m, 5H, aromatic), 8.60 (s, 1H, H-6), 11.66 (s,
1H, NH). 13C NMR (CD3OD) δ: 25.32 (C-2′), 34.0 (C-3′), 63.10
(C-5′), 81.94 (C-â), 83.91 (C-4′), 88.23 (C-1′), 93.62 (C-R), 99.69
(C-5), 124.33, 129.99, 132.35, 144.62 (C-phenyl), 145.25 (C-6),
151.10 (C-2), 164.36 (C-4). Anal. (C17H16N2O4) C, H, N.
1
(92:8, v/v) as the eluent afforded 2 (728 mg, 87%) as a syrup. H
5-Bromo-2′,3′-dideoxyuridine (14). Bromination of the 5-posi-
tion of 2′,3′-dideoxyuridine (1) was performed with 1.1 equiv of
N-bromosuccinimide in DMF for 6 h at 25 °C to provide 14 in
NMR (DMSO-d6) δ: 1.85 (m, 2H, H-3′), 2.05 and 2.28 (2m, 2H,
H-2′), 3.55 and 3.79 (2m, 2H, H-5′), 4.07 (m, 1H, H-4′), 5.25 (m,
1H, 5′-OH), 5.90 (m, 1H, H-1′), 8.60 (s, 1H, H-6), 11.63 (s, 1H,
NH). Anal. (C9H11IN2O4) C, H, N.
1
76% yield. The H NMR of this compound was similar to that
previously reported.16
Preparation of 5-Acetylenic-2′,3′-dideoxynucleosides. A full
procedure is provided for 5-pentynyl-2′,3′-dideoxyuridine (3). For
other analogues, only brief spectroscopic data are presented.
5-Pentynyl-2′,3′-dideoxyuridine (3). Tetrakis(triphenylphos-
phine)palladium(0) (69 mg, 0.059 mmol), copper(I) iodide (23 mg,
0.118 mmol), diisopropylethylamine (0.20 mL, 1.18 mmol), and
1-pentyne (0.17 mL, 1.77 mmol) were added to a solution of 5-iodo-
2′,3′-dideoxyuridine 2 (200 mg, 0.59 mmol) in dry dimethylfor-
mamide (30 mL). The reaction mixture was stirred at room
temperature overnight under a nitrogen atmosphere (the progress
of the reaction was monitored by TLC in MeOH/CHCl3 (1:9, v/v).
After the mixture was stirred overnight, 20 drops of 5% disodium
salt of EDTA/H2O were added to the reaction mixture and then
concentrated in vacuo. The resulting residue was purified on a silica
gel column using CHCl3/MeOH (96:4, v/v) to yield 3 (120 mg,
73%) as a syrup. 1H NMR (DMSO-d6) δ: 0.96 (t, J ) 7.3 Hz, 3H,
CH3), 1.52 (m, 2H, â-CH2), 1.84 (m, 2H, H-3′), 1.98-2.30 (m,
2H, H-2′), 2.32 (t, J ) 7.0 Hz, 2H, R-CH2), 3.53 and 3.70 (2m,
2H, H-5′), 4.05 (m, 1H, H-4′), 5.13 (t, J ) 4.88 Hz, 1H, 5′-OH),
5.89 (dd, J ) 3.05, 6.71 Hz, 1H, H-1′), 8.28 (s, 1H, H-6), 11.50 (s,
1H, NH). 13C NMR (CD3OD) δ: 13.86 (CH3), 22.21, 23.15, 25.53,
(2 × CH2 and C-2′), 33.81 (C-3′), 63.28 (C-5′), 72.77 (C-â), 83.69
(C-4′), 87.99 (C-1′), 94.71 (C-R), 100.49 (C-5), 144.29 (C-6),
151.19 (C-2), 164.77 (C-4). Anal. (C14H18N2O4) C, H, N.
5′-O-Acetyl-2′,3′-dideoxyuridine (15). To an ice-cooled (0 °C)
solution of 2′,3′-dideoxyuridine (1) (1 g, 4.71 mmol) in anhydrous
pyridine (50 mL) was added acetic anhydride (0.54 mL, 5.68 mmol)
dropwise. The reaction mixture was stirred at 0 °C for 1 h and
then at room temperature for 24 h. Pyridine was removed in vacuo
followed by coevaporation with ethanol (2 × 25 mL). The resulting
residue was purified on a silica gel column using CHCl3/MeOH
(98:2, v/v) to yield 15 (1.17 g, 97.5%) as a syrup. 1H NMR (CDCl3)
δ: 1.76-2.14 (br m, 3H, H-2′ and H-3′), 2.12 (s, 3H, -OAc),
2.42-2.53 (m, 1H, H-2′), 4.28-4.35 (m, 3H, H-4′ and H-5′), 5.73
(d, 1H, J ) 7.93 Hz, H-5), 6.05 (m, 1H, H-1′), 7.65 (d, 1H, J )
7.93 Hz, H-6), 8.90 (s, 1H, NH). Anal. (C11H14N2O5) C, H, N.
5′-O-Acetyl-5-chloro-2′,3′-dideoxyuridine (16). 5′-O-Acetyl-
2′,3′-dideoxyuridine 15 (1.15 g, 4.52 mmol) and N-chlorosuccin-
imide (0.79 g, 5.92 mmol) were dissolved in anhydrous pyridine
(50 mL). The reaction mixture was heated for 45 min at 90 °C.
Pyridine was removed in vacuo followed by coevaporation with
ethanol (2 × 25 mL). The resulting residue was purified on a silica
gel column using CHCl3/MeOH (98:2, v/v) to yield 16 (1.23 g,
93.8%) as a white solid. Mp 175-177 °C, dec. 1H NMR (CDCl3)
δ: 1.79-2.18 (br m, 3H, H-2′ and H-3′), 2.20 (s, 3H, -OAc),
2.45-2.55 (m, 1H, H-2′), 4.34-4.44 (m, 3H, H-4′ and H-5′), 6.05
(m, 1H, H-1′), 8.00 (s, 1H, H-6), 8.85 (s, 1H, NH). Anal. (C11H13-
ClN2O5) C, H, N.
5-Decynyl-2′,3′-dideoxyuridine (4). This was obtained as a
1
5-Chloro-2′,3′-dideoxyuridine (17). This compound was syn-
thesized by deacetylation of 16 (620 mg, 2.15 mmol) using a
saturated solution of ammonia in methanol (20 mL) in 86.8% yield.
1H NMR of 17 was similar to that previously reported.17
syrup in 88% yield. H NMR (DMSO-d6) δ: 0.85 (t, J ) 7.0 Hz,
3H, CH3), 1.32 (m, 10H, 5 × CH2), 1.45 (m, 2H, â-CH2), 1.88 (m,
2H, H-3′), 1.98-2.30 (m, 2H, H-2′), 2.33 (t, J ) 7.0 Hz, 2H,
R-CH2), 3.52 and 3.72 (2m, 2H, H-5′), 4.04 (m, 1H, H-4′), 5.14 (t,
J ) 4.9 Hz, 1H, 5′-OH), 5.90 (dd, J ) 3.05, 6.41 Hz, 1H, H-1′),
8.26 (s, 1H, H-6), 11.52 (s, 1H, NH). 13C NMR (CD3OD) δ: 14.48
(CH3), 20.24, 23.72, 25.60, 30.04, 30.11, 30.27, 30.34, 33.02 (7 ×
CH2 and C-2′), 33.80 (C-3′), 63.35 (C-5′), 72.64 (C-â), 83.69 (C-
4′), 88.00 (C-1′), 94.94 (C-R), 100.55 (C-5), 144.24 (C-6), 151.19
(C-2), 164.79 (C-4). Anal. (C19H28N2O4) C, H, N.
5′-O-Acetyl-5-chloro-4-thio-2′,3′-dideoxyuridine (18). To a
dried mixture of 5-chloro-5′-O-acetyl-2′,3′-dideoxyuridine 16 (600
mg, 2.08 mmol) and Lawesson’s reagent (1.17 g, 2.88 mmol) was
added dry 1,4-dioxane (30 mL). The reaction mixture was refluxed
for 9 h and after cooling concentrated in vacuo. The crude product
thus obtained was purified on a silica gel column using CHCl3/
MeOH (99.5:0.5, v/v) to yield 18 (530 mg, 83.7%) as a yellow
solid. Mp 165-167 °C, dec. 1H NMR (CDCl3) δ: 1.81-2.23 (m,
3H, H-2′ and H-3′), 2.20 (s, 3H, -OAc), 2.44-2.57 (m, 1H, H-2′),
4.34-4.46 (m, 3H, H-4′ and H-5′), 6.00 (m, 1H, H-1′), 8.06 (s,
1H, H-6), 9.90 (s, 1H, NH). Anal. (C11H13ClN2O4S) C, H, N, S.
5-Chloro-4-thio-2′,3′-dideoxyuridine (19). Compound 18 (480
mg, 1.57 mmol) was treated with a saturated solution of ammonia
in methanol at 0 °C for 6 h. The reaction mixture was concentrated
in vacuo. The crude product thus obtained was purified on a silica
gel column using CHCl3/MeOH (98:2, v/v) to yield 19 (334 mg,
80.7%) as a yellow solid. Mp 66-68 °C. 1H NMR (DMSO-d6) δ:
1.78-1.89 (m, 2H, H-3′), 2.13-2.49 (m, 2H, H-2′), 3.54 and 3.82
(2m, 2H, H-5′), 4.09 (m, 1H, H-4′), 5.32 (t, 1H, 5′-OH), 5.84 (m,
1H, H-1′), 8.68 (s, 1H, H-6), 13.06 (s, 1H, NH). Anal. (C9H11-
ClN2O3S) C, H, N, S.
5-Dodecynyl-2′,3′-dideoxyuridine (5). This compound was
obtained as a syrup in 72% yield. 1H NMR (DMSO-d6) δ: 0.85 (t,
J ) 7.0 Hz, 3H, CH3), 1.33 (m, 14H, 7 × CH2), 1.46 (m, 2H,
â-CH2), 1.85 (m, 2H, H-3′), 2.02 and 2.25 (2m, 2H, H-2′), 2.33 (t,
J ) 7.0 Hz, 2H, R-CH2), 3.53 and 3.72 (2m, 2H, H-5′), 4.03 (m,
1H, H-4′), 5.12 (t, 1H, 5′-OH), 5.89 (dd, J ) 3.05, 6.41 Hz, 1H,
H-1′), 8.25 (s, 1H, H-6), 11.50 (s, 1H, NH). Anal. (C21H32N2O4)
C, H, N.
5-Tridecynyl-2′,3′-dideoxyuridine (6). Compound 7 was ob-
1
tained as a syrup in 64% yield. H NMR (DMSO-d6) δ: 0.84 (t,
3H, CH3), 1.35 (m, 16H, 8 × CH2), 1.47 (m, 2H, â-CH2), 1.87 (m,
2H, H-3′), 2.04 and 2.22 (2m, 2H, H-2′), 2.35 (t, J ) 7.0 Hz, 2H,
R-CH2), 3.55 and 3.72 (2m, 2H, H-5′), 4.04 (m, 1H, H-4′), 5.12 (t,
1H, 5′-OH), 5.90 (dd, J ) 3.05, 6.40 Hz, 1H, H-1′), 8.25 (s, 1H,
H-6), 11.50 (s, 1H, NH). Anal. (C22H34N2O4) C, H, N.