Synthesis and Anti-HBV Activity of Thiouracils Linked via S and N-1 to the 5-Position of Methyl β-D-Ribofuranoside

Article abstract of DOI:10.1081/NCN-120026404

Reverse nucleoside derivatives of 2-(methylsulfanyl)uracils 6a-d were prepared by treating of the sodium salt of 2-(methylsulfanyl)uracils (5a-d) with methyl 2,3-O-isopropylidene-5-O-p-toluenesulfonyl-β-D-ribofuranoside (2). The alkylation of 2-thiouracils 4a-d with methyl 5-deoxy-5-iodo-2,3-O-isopropylidene-D-ribofuranoside (3) afforded the corresponding S-ribofuranoside derivatives 8a-d. Deisopropylidenation of 6a-d and 8a-d afforded the corresponding deprotected derivatives 7a-d and 9a-d, respectively. The Anti-HBV activity of selected compounds was studied.

Full text of DOI:10.1081/NCN-120026404

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Synthesis and Anti-HBV Activity of Thiouracils
Linked via S and N-1 to the 5-Position of Methyl β-D-
Ribofuranoside
a
a
a
Adel A.-H. Abdel-Rahman , Ahmed E.-S. Abdel-Megied , Adel E.-S. Goda , Ibrahim F.
a
b c
Zeid & El Sayed H. El Ashry
a
Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Koam, Egypt
Department of Chemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
Department of Chemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
b
c
Version of record first published: 31 Aug 2006.
To cite this article: Adel A.-H. Abdel-Rahman , Ahmed E.-S. Abdel-Megied , Adel E.-S. Goda , Ibrahim F. Zeid & El Sayed
H. El Ashry (2003): Synthesis and Anti-HBV Activity of Thiouracils Linked via S and N-1 to the 5-Position of Methyl β-D-
Ribofuranoside, Nucleosides, Nucleotides and Nucleic Acids, 22:11, 2027-2038
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, No. 11, pp. 2027–2038, 2003
Synthesis and Anti-HBV Activity of Thiouracils Linked via S
and N-1 to the 5-Position of Methyl b-D-Ribofuranoside
1
Adel A.-H. Abdel-Rahman, Ahmed E.-S. Abdel-Megied,
1
1
1
Adel E.-S. Goda, Ibrahim F. Zeid, and El Sayed H. El Ashry
2,*
1
Department of Chemistry, Faculty of Science, Menoufia University,
Shebin El-Koam, Egypt
2
Department of Chemistry, Faculty of Science, Alexandria University,
Alexandria, Egypt
ABSTRACT
Reverse nucleoside derivatives of 2-(methylsulfanyl)uracils 6a-d were prepared
by treating of the sodium salt of 2-(methylsulfanyl)uracils (5a-d) with methyl
2
,3-O-isopropylidene-5-O-p-toluenesulfonyl-b-D-ribofuranoside (2). The alkyla-
tion of 2-thiouracils 4a-d with methyl 5-deoxy-5-iodo-2,3-O-isopropylidene-
D-ribofuranoside (3) afforded the corresponding S-ribofuranoside derivatives
8a-d. Deisopropylidenation of 6a-d and 8a-d afforded the corresponding depro-
tected derivatives 7a-d and 9a-d, respectively. The Anti-HBV activity of selected
compounds was studied.
Key Words: Thiouracil; Ribofuranoside; Nucleoside.
*
Correspondence: El Sayed H. El Ashry, Department of Chemistry, Faculty of Science,
Alexandria University, Alexandria, Egypt; Fax: 20-3-4271360; E-mail: Eelashry@link.net;
eelashry60@hotmail.com.
2
027
DOI: 10.1081/NCN-120026404
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

2028
Abdel-Rahman et al.
INTRODUCTION
The wide prevalence of Hepatitis B virus (HBV) infection and the lack of an
ideal drug to treat the virus, has a great degree of prominence. Vaccination is not
an effective therapy in chronic infections that ended by cirrhosis of the liver and=or
hepatocellular carcinoma. In this respect alpha interferon has demonstrated some
[1]
0
promise. 2 -Fluoro-5-methyl-b-L-arabino furanosyluracil (b-L-FMAU) is consid-
ered as a clinical candidate for treatment of chronic HBV infections. The 2 ,3 -
[
2]
0
0
dideoxy-b-L-cytidine (b-L-ddC) and its 5-fluoro analogue (b-L-FddC) demonstrated
equally potent activity against HBV in vitro. The unusual group of nucleosides such
0
as L-SddC [(-)-BCH-189] in which the 3 -CH group has been replaced by a hetero-
2
[3]
atom exhibits potent anti-HBV and HIV activity in vitro.
Thiated pyrimidinones, and their nucleosides are of considerable biological
importance as components of the tRNA of various microorganism, yeasts and
[4]
mammalian cells and the corresponding nucleosides such as 4-thiouridine and
5
0
[5]
-fluoro-4-thio-2 -deoxyuridine exhibit antineoplastic properties. 2 3 -Dideoxy-3 -
0
0
0
[6]
fluoro-4-thiopyrimidine has potent and selective inhibition of the retrovirus HIV.
Towards the development of nucleosides that exhibit antiviral activity, a number of
[7,8]
[9,10]
S-alkylated 2-thiouracil
and acyclic nucleoside
analogues were synthesized.
The present work deals with the synthesis and biological activity of thiouracil
analogs linked via their S or N-1 to the primary carbon atom (C-5) of methyl
b-D-ribofuranoside. Such compounds which are known as isonucleosides or reversed
nucleosides could be promising anti-HBV agents and=or metabolized into the active
compounds after cell uptake.
RESULTS AND DISCUSSION
The preparation of methyl 2,3-O-isopropylidene-D-ribofuranoside (1) has
attracted much attention give whether it is a mixture of anomers or has a b config-
[11]
uration.
The procedure for obtaining 1 has been slightly modified by treating a
solution of dry D-ribose in dry acetone with 2,2-dimethoxypropane and dry
methanol saturated with hydrogen chloride followed by neutralization with pyridine

Thiouracils Linked Methyl b-D-Ribofuranoside
2029
Scheme 1. a) Acetone=2,2-dimethoxypropane, MeOH=HCl; b) TsCl=Py; c) NaI=DMF.
to give 1 in 75% yield as a colorless oil. Treatment of 1 with p-toluenesulfonyl chlor-
[
12]
ide in pyridine at room temperature afforded 2 in 80% yield (Sch. 1).
The NMR spectra of methyl 2,3-O-isopropylidene-b-D-ribofuranoside (1)
and methyl 2,3-O-isopropylidene-5-O-p-toluenesulfonyl-b-D-ribofuranoside (2)
[
[
11]
12]
showed conclusively, on the basis of the singlet signal for H-1, a justification for
the assignment of the b configuration of these compounds.
Methyl 5-deoxy-5-iodo-2,3-O-isopropylidene-D-ribofuranoside (3)
[
13]
was pre-
pared by treating of 2 with sodium iodide in DMF at reflux temperature to afford
[
13]
3
in 90 % yield [lit. 76%].
Methyl 5-deoxy-5-[2-(methylsulfanyl)uracil-1-yl]-2,3-O-isopropylidene-b-D-ribo-
furanosides (6a-d) were prepared in 70–84% yields according to a slightly modified
[14]
procedure of Holy
derivatives of 5a-d (Sch. 2).
by the displacement of the tosyloxy group in 2 with sodium
[
15]
Deprotection of the nucleosides 6a-d with 80% acetic acid at reflux temperature
gave the corresponding methyl 5-deoxy-5-[2-(methylsulfanyl)uracil-1-yl]-b-D-ribo-
furanosides (7a-d) in 68–75% yields. The structures were confirmed by studying H
1
1
3
and C NMR spectra.
On the other hand, the alkylation of substituted 2-thiouracils 4a-d with methyl 5-
[
13]
deoxy-5-iodo-2,3-O-isopropylidene-b-D-ribofuranoside (3) in presence of sodium
hydroxide in water and ethanol in a similar manner to that used for the alkylation
[14]
of thiouracils to afford the S-alkylated derivatives 8a-d in 78–85% yields (Sch. 3).
1
Their structures were established by H NMR analysis which showed the chemical
[
15]
shifts of S-CH in the range d 3.13–3.22 in accordance with reported
for other
2
analogues.
Deprotection of 8a-d with 80% acetic acid at reflux temperature afforded the
1
corresponding deprotected derivatives 9a-d in 70–75% yields. Their H NMR spectra
showed the disappearance of the isopropylidene group in all cases.
Preliminary viral screening against HBV indicated that compound 7b was found
to be active against HBV replication with IC ¼ 90 mM and CC > 100 mM. Com-
5
0
50
pounds 7a, 7c, 7d, 9c and 9d showed moderate viral replication inhibition and low
cytotoxicity, while compounds 9a and 9b showed high inhibition with high cytotoxi-
city (Table 1).
EXPERIMENTAL
All m.p.’s are uncorrected. Pyridine was distilled from CaH and stored over
2
molecular sieves. Other solvents were purified according to the standard procedures.

2030
Abdel-Rahman et al.
Scheme 2. a) NaH=DMF; b) 80% AcOH, reflux.
TLC was performed on plastic plates Silica Gel 60 F254 (E. Merck, layer thickness
0
in methanol, and heating at 150 C. NMR spectra were recorded on a Bruker AC
.2 mm). The detection was achieved by treatment with a solution of 15% H SO
ꢀ
2
4
1
50 FT NMR spectrometer at 250 MHz for H NMR and 62.9 MHz for
13
2
C
Table 1. Inhibition of HBV replication by selected compounds.
Inhibition (%)
Compound
1 Week
2 Weeks
3 Weeks
Cytotoxicity (%)
7
7
7
7
9
9
9
9
a
b
c
25.30
90.04
15.80
30.50
88.50
86.60
38.60
27.70
14.20
81.10
18.60
25.90
87.90
85.90
30.60
25.30
08.40
70.70
03.30
01.05
03.10
05.50
06.10
05.30
04.10
04.00
ꢁ10.90
d
a
b
c
17.70
71.30
73.30
13.40
ꢁ03.80
d

Thiouracils Linked Methyl b-D-Ribofuranoside
2031
2
Scheme 3. a) NaOH=EtOH=H O; b) 80% AcOH, reflux.
NMR with TMS as an internal standard. EI MS spectra were recorded with Finni-
gen MAT 312=AMD. The microanalyses were performed at the microanalytical
unit, University Konstanz, Germany. Viral screening against HBV was conducted
at the National Liver Institute, Menoufia University, Egypt.
Methyl 2,3-O-Isopropylidene-b-D-ribofuranoside (1). A solution of 20.0 g
133.3 mmol) of dry D-ribose, in 400 mL of dry acetone, 40 mL of 2,2-dimethoxypro-
(
pane and 80 mL of methanol containing 8 mL of methanol saturated with hydrogen
ꢀ
ꢀ
chloride was stirred for 5 h at 0 C. The reaction mixture was stirred at 25 C for over-
night. The resulting orange solution was neutralized with pyridine and evaporated to
a yellow oil. This oil was partitioned between 200 mL of water and 100 mL of ether.
The water layer was extracted twice with 100 mL portions of ether, and the combined
ether extracts were dried over Na SO . Evaporation under reduced pressure yielded
2
4
ꢀ
[11]
a pale yellow oil which was distilled at 0.3 mm and 80 C to give 25 g, 75% [lit.
0%] of a colorless oil.
7
Methyl 2,3-O-Isopropylidene-5-O-p-toluenesulfonyl-b-D-ribofuranoside (2). p-
Toluenesulfonyl chloride (9.52 g, 50 mmol) was added in small portions to a stirred
cold solution of 1 (10 g, 49 mmol) in dry pyridine (100 mL). The reaction mixture was
stirred for overnight at room temperature. The solvent was evaporated and coeva-
porated with toluene (3 ꢂ 20 mL). The residue was dissolved in water (100 mL)
and extracted with dichloromethane (3 ꢂ 50 mL). The organic layer was dried over
Na SO and evaporated under reduced pressure to give 2 (14.04 g, 80%). M.p. 82–
2
4
ꢀ
[12]
ꢀ
1
8
4 C [lit.
83–84 C]. H NMR (CDCl ): d ¼ 1.28 (s, 3 H, CH ), 1.44 (s, 3 H,
3 4,5
3
3
CH ), 2.45 (s, 3 H, CH ), 3.22 (s, 3 H, OMe), 4.01 (d, 2 H, J ¼ 6.5 Hz, H-5),
3
4
.31 (d, 1 H, J3,4 ¼ 7.0 Hz, H-4), 4.53 (d, 1 H, J ¼ 5.9 Hz, H-3), 4.60 (d, 1 H,
2,3
J2,3 ¼ 5.9 Hz, H-2), 4.92 (s, 1 H, H-1), 7.36 (d, 2 H, J ¼ 7.9 Hz, Ar-H), 7.80 (d, 2
1
3
H, J ¼ 8.3 Hz, Ar-H). C NMR (CDCl ): d ¼ 21.5 (CH ), 24.7 (CH ), 26.2 (CH ),
3
3
3
3
5
4.9 (OMe), 69.2 (C-5), 81.3 (C-4), 83.5 (C-3), 84.8 (C-2), 109.4 (C-1), 112.6
(
C Me ), 127.9, 129.9, 132.7, 145.0 (Ar-C).
2

2032
Abdel-Rahman et al.
Methyl 5-Deoxy-5-iodo-2,3-O-isopropylidene-D-ribofuranoside (3). A stirred
solution of the tosyl derivative 2 (5 g, 14 mmol) in 50 mL of dry DMF was refluxed
with dry sodium iodide 2.37 g (15.5 mmol) for 40 min. The mixture was then cooled
and filtered from inorganic precipitate. The latter was washed with ether (3 ꢂ 50 mL)
ꢀ
and the combined filtrates were evaporated under reduced pressure in 80 C bath to a
volume of about 15 mL. To this solution was added 200 mL of water and the mixture
was extracted with ether (5 ꢂ 20 mL). The combined extracts were dried over
ꢀ
Na SO , filtered and evaporated under reduced pressure in an 80–90 C bath to give
2
4
1
3
CH ), 1.48 (s, 3 H, CH ), 3.16 (dd, 1 H, J
.95 g, 90% [lit. (13) 76%] as a colorless liquid. H NMR (CDCl ): d ¼ 1.32 (s, 3 H,
0
3
¼ 6.1Hz, J
¼ 9.9 Hz, H-5 ), 3.28
3,4
3
3
4 ,5a
5a,5b
a
(
dd, 1 H, J4,5 ¼ 6.1 Hz, H-5 ), 3.36 (s, 3 H, OMe), 4.46 (d, 1 H, J ¼ 6.1, Hz, H-
b
4
), 4.63 (d, 1 H, J ¼ 5.8 Hz, H-3), 4.77 (d, 1 H, J ¼ 5.8 Hz, H-2), 5.05 (s, 1 H,
3 3 3
2
,3
2,3
1
3
H-1). C NMR (CDCl ): d ¼ 6.6 (C-5), 25.0 (CH ), 24.4 (CH ), 55.2 (OMe), 83.0
(C-4), 85.3 (C-3), 87.4 (C-2), 109.7 (C-1), 112.6 (C Me ).
2
General Procedure for the Preparation of 6a-d. To a stirred suspension of 2-
methylsulfanyl)uracils (5a-d) (5 mmol) in dry DMF (20 mL) was added NaH
0.12 g, 5 mmol) and after almost complete evolving of hydrogen, the mixture was
(
(
ꢀ
heated to 80 C for 1 h. Then compound 2 (1.79 g, 5 mmol) was added, the reaction
ꢀ
mixture was stirred for additional 10–12 h (TLC) at 80 C, cooled to room tempera-
ture and filtered. The mixture was evaporated to dryness at reduced pressure and
purified with silica gel column chromatography using 2% MeOH in CHCl to give
3
6
a-d in 70–84% yields.
Methyl 5-Deoxy-5-[2-(methylsulfanyl)uracil-1-yl]-2,3-O-isopropylidene-b-D-ribo-
1
furanosides (6a). Yield ¼ 1.23 g, 75% as a white foam. H NMR (CDCl3):
d ¼ 1.32 (s, 3 H, CH ), 1.48 (s, 3 H, CH ), 2.53 (s, 3 H, SCH ), 3.31 (s, 3 H,
3
3
3
0
0
OMe), 4.38–4.41 (m, 2 H, H-5 ), 4.46–4.52 (m, 1 H, H-4 ), 4.64 (d, 1 H, J
0
0
0
,3
¼ 5.9 Hz,
2
0
0
Hz, H-3 ), 4.77 (d, 1 H, J
0
0
¼ 5.9 Hz, H-2 ), 5.00 (s, 1 H, H-1 ), 6.44 (d, 1 H,
2
,3
1
3
J5,6 ¼ 5.0 Hz, H-5), 8.23 (d, 1 H, J ¼ 4.9 Hz, H-6). C NMR (CDCl ): d ¼ 13.6
5,6 3
0 0 0
SCH ), 24.6 (CH ), 26.1 (CH ), 54.4 (OMe), 66.1 (C-5 ), 81.5 (C-4 ), 83.8 (C-3 ),
3 3 3
(
8
0
0
4.8 (C-2 ), 103.3 (C-1 ), 109.0 (C-5), 112.6 (CMe ), 157.1 (C-6), 167.7 (C-2), 171.7
2
C-4). EI-MS: (positive mode); m=z: 328 [M ]. Anal. Calcd for C H N O S
1
þ
(
4
20
2
5
(328.38): C 51.20, H 6.13, N 8.53. Found: C 51.00, H 6.15, N 8.48.
Methyl 5-Deoxy-5-[5-methyl-2-(methylsulfanyl)uracil-1-yl]-2,3-O-isopropylidene-
1
b-D-ribofuranosides (6b). Yield ¼ 1.43 g, 84% as a white foam. H NMR (CDCl ):
3
d ¼ 1.33 (s, 3 H, CH ), 1.50 (s, 3 H, CH ), 2.09 (s, 3 H, CH ), 2.52 (s, 3 H, SCH ),
3
3
3
3
0
3
4
.32 (s, 3 H, OMe), 4.43 (d, 2 H, J
0
13
0
0
0
¼ 6.3 Hz, H-5 ), 4.54 (d, 1 H, J
0
0
¼ 6.5 Hz, H-
4
,5
3 ,4
0
), 4.64 (d, 1 H, J
0
0
0
¼ 5.9 Hz, H-3 ), 4.77 (d, 1 H, J
0 0
2 ,3
¼ 5.9 Hz, H-2 ), 5.01 (s, 1 H,
2
,3
H-1 ), 8.07 (s, 1 H, H-6). C NMR (CDCl ): d ¼ 11.7 (CH ), 13.6 (SCH ), 24.6
3
3
3
0
0
0
0
(
CH ), 26.1 (CH ), 54.3 (OMe), 66.1 (C-5 ), 81.5 (C-4 ), 83.9 (C-3 ), 84.9 (C-2 ), 109.1
3
3
0
(C-1 ), 112.1 (C-5), 112.5 (CMe ), 156.5 (C-6), 166.3 (C-2), 168.5 (C-4). EI-MS: (posi-
tive mode); m=z: 342 [M ]. Anal. Calcd for C H N O S (342.40): C 52.61, H 6.47,
2
þ
1
5
22
2
5
N 8.18. Found: C 52.50, H 6.36, N 7.99.

Thiouracils Linked Methyl b-D-Ribofuranoside
2033
Methyl 5-Deoxy-5-[6-methyl-2-(methylsulfanyl)uracil-1-yl]-2,3-O-isopropylidene-
1
b-D-ribofuranosides (6c). Yield ¼ 1.37 g, 80% as a white foam. H NMR (CDCl ):
3
d ¼ 1.33 (s, 3 H, CH ), 1.49 (s, 3 H, CH ), 2.36 (s, 3 H, CH ), 2.53 (s, 3 H,
3
3
3
0
0
SCH ), 3.32 (s, 3 H, OMe), 4.32–4.38 (m, 2 H, H-5 ), 4.45–4.54 (m, 1 H, H-4 ),
3
0
0
4
.63 (d, 1 H, J
0
0
¼ 5.9 Hz, H-3 ), 4.75 (d, 1 H, J
0 0
¼ 5.8 Hz, H-2 ), 5.01 (s, 1 H,
2
,3
2 ,3
0
13
H-1 ), 6.27 (s, 1 H, H-5). C NMR (CDCl ): d ¼ 13.4 (SCH ), 23.2 (CH ), 24.5
3
3
3
0 0 0 0
CH ), 25.9 (CH ), 54.2 (OMe), 65.8 (C-5 ), 81.4 (C-4 ), 83.8 (C-3 ), 84.7 (C-2 ),
3 3
(
0
101.5 (C-1 ), 108.9 (C-5), 112.0 (CMe ), 167.4 (C-6), 168.2 (C-2), 170.9 (C-4). EI-
MS: (positive mode); m=z: 342 [M ]. Anal. Calcd for C H N O S (342.40): C
2
þ
1
5
22
2
5
52.61, H 6.47, N 8.18. Found: C 52.52, H 6.40, N 8.02.
Methyl 5-Deoxy-5-[2-(methylsulfanyl)-6-propyluracil-1-yl]-2,3-O-isopropylidene-
1
b-D-ribofuranosides (6d). Yield ¼ 1.29 g, 70% as a white foam. H NMR (CDCl ):
3
d ¼ 0.95 (t, 3 H, J ¼ 7.4 Hz, CH ), 1.33 (s, 3 H, CH ), 1.50 (s, 3 H, CH ), 1.63–1.75
3
3
3
(
4
3
m, 2 H, CH ), 2.53 (s, 3 H, SCH ), 2.55–2.58 (m, 2 H, CH ), 3.32 (s, 3 H, OMe),
2 3 2
0
0
.36–4.40 (m, 2 H, H-5 ), 4.49–4.52 (m, 1 H, H-4 ), 4.63 (d, 1 H, J
0
0
0
¼ 5.9 Hz, H-
2
,3
0
0
13
), 4.76 (d, 1 H, J2
0
0
¼ 5.9 Hz, H-2 ), 5.01 (s, 1 H, H-1 ), 6.26 (s, 1 H, H-5).
C
,3
NMR (CDCl ): d ¼ 13.7 (CH ), 14.0 (SCH ), 21.7 (CH ), 25.0 (CH ), 26.4 (CH ),
3
3
3
2
3
3
0
0
0
0
3
1
9.4 (CH ), 54.8 (OMe), 66.2 (C-5 ), 81.9 (C-4 ), 84.3 (C-3 ), 85.2 (C-2 ), 101.5 (C-
2
0
), 109.3 (C-5), 112.6 (CMe ), 168.7 (C-6), 171.2 (C-2), 171.7 (C-4). EI-MS: (positive
2
þ
mode); m=z: 370 [M ]. Anal. Calcd for C H N O S (370.46): C 55.11, H 7.07, N
1
7
26
2
5
7.56. Found: C 54.97, H 6.95, N 7.47.
General Procedure for the Preparation of 7a-d. Compounds 6a-d (0.25 g) were
refluxed in 80% aqueous acetic acid (10 mL) for 2 h. The solvents were removed in
vacuo. Water (4 ꢂ 5 mL) and then EtOH (3 ꢂ 5 mL) were coevaporated from the
remaining residue. The residue was purified by column chromatography using 5%
MeOH in CHCl to give 7a-d in 68-75% yields.
3
Methyl 5-Deoxy-5-[2-(methylsulfanyl)uracil-1-yl]-b-D-ribofuranoside (7a). Yield¼
ꢀ
1
0
3
(
.16 g, 73%. M.p. ¼ 160 C. H NMR (CDCl ): d ¼ 2.50 (s, 3 H, SCH ), 3.37 (s,
3
3
0
0
0
0
H, OMe), 4.41–4.51 (m, 3 H, H-4 , H-5 ), 4.66–4.78 (m, 2 H, H-2 , H-3 ), 5.05
0
0
0
s, 1 H, H-1 ), 5.23 (brs, 1 H, 3 -OH), 5.58 (brs, 1 H, 2 -OH), 6.48 (d, 1 H,
1
3
J5,6 ¼ 5.0 Hz, H-5), 8.22 (d, 1 H, J ¼ 5.0 Hz, H-6). C NMR (CDCl ): d ¼ 13.4
5,6
3
0
0
0
0
(
SCH ), 54.5 (OMe), 66.2 (C-5 ), 81.5 (C-4 ), 84.1 (C-3 ), 86.6 (C-2 ), 104.3 (C-
3
0
1
m=z: 288 [M ]. Anal. Calcd for C H N O S (288.31): C 45.82, H 5.59, N 9.71.
), 108.0 (C-5), 158.1 (C-6), 168.1 (C-2), 172.1 (C-4). EI-MS: (positive mode);
þ
1
1
16
2
5
Found: C 45.63, H 5.45, N 9.59.
Methyl 5-Deoxy-5-[5-methyl-2-(methylsulfanyl)uracil-1-yl]-b-D-ribofuranosides
1
ꢀ
(
CH ), 2.51 (s, 3 H, SCH ), 3.35 (s, 3 H, OMe), 4.46–4.58 (m, 3 H, H-4 , H-5 ),
7b). Yield ¼ 0.17 g, 75%. M.p. ¼ 171 C. H NMR (CDCl ): d ¼ 2.10 (s, 3 H,
3
0
0
3
3
0
0
4
1
(
.70 (d, 1 H, J
0
0
0
¼ 5.9 Hz, H-3 ), 4.80 (d, 1 H, J
0 0
¼ 5.9 Hz, H-2 ), 5.01 (s, 1 H, H-
2
,3
2 ,3
0
0
13
), 5.30 (brs, 1 H, 3 -OH), 5.35 (brs, 1 H, 2 -OH), 8.00 (s, 1 H, H-6). C NMR
0
0
CDCl ): d ¼ 11.7 (CH ), 13.5 (SCH ), 54.3 (OMe), 66.2 (C-5 ), 81.5 (C-4 ), 83.4
3
3
3
0
0
0
(
C-3 ), 84.5 (C-2 ), 108.9 (C-1 ), 111.0 (C-5), 155.5 (C-6), 167.0 (C-2), 169.0 (C-4).

2034
Abdel-Rahman et al.
þ
EI-MS: (positive mode); m=z: 302 [M ]. Anal. Calcd for C H N O S (302.34):
1
2
18
2
5
C 47.67, H 6.00, N 9.26. Found: C 47.50, H 5.91, N 9.12.
Methyl 5-Deoxy-5-[6-methyl-2-(methylsulfanyl)uracil-1-yl]-b-D-ribofuranosides
1
ꢀ
(
7c). Yield ¼ 0.15 g, 70%. M.p. ¼ 143 C. H NMR (CDCl ): d ¼ 2.30 (s, 3 H,
3
0
0
CH ), 2.52 (s, 3 H, SCH ), 3.35 (s, 3 H, OMe), 4.40–4.58 (m, 3 H, H-4 , H-5 ),
3
3
0
0
4 ¼ 5.8 Hz, H-2 ), 5.05 (s, 1 H,
H-1 ), 5.29 (brs, 1 H, 3 -OH), 5.59 (brs, 1 H, 2 -OH), 6.30 (s, 1 H, H-5).
.68 (d, 1 H, J
0
0
0
¼ 5.9 Hz, H-3 ), 4.72 (d, 1 H, J
0
0
0
2
,3
2 ,3
0
13
C
0
0
NMR (CDCl ): d ¼ 13.4 (SCH ), 25.9 (CH ), 54.2 (OMe), 65.8 (C-5 ), 81.0 (C-4 ),
3
3
3
0
0
0
8
(
3.2 (C-3 ), 84.5 (C-2 ), 102.0 (C-1 ), 107.8 (C-5), 168.2 (C-6), 169.1 (C-2), 171.0
þ
C-4). EI-MS: (positive mode); m=z: 302 [M ]. Anal. Calcd for C H N O S
5
1
2
18
2
(302.34): C 47.67, H 6.00, N 9.26. Found: C 47.47, H 5.89, N 9.15.
Methyl 5-Deoxy-5-[2-(methylsulfanyl)-6-propyluracil-1-yl]-b-D-ribofuranosides
1
ꢀ
(
7d). Yield ¼ 0.15 g, 68%. M.p. ¼ 166 C. H NMR (CDCl ): d ¼ 0.90 (t, 3 H,
3
J ¼ 7.4 Hz, CH ), 1.60–1.74 (m, 2 H, CH ), 2.50 (s, 3 H, SCH ), 2.65–2.73 (m, 2
3 2 3
0
0
H, CH ), 3.35 (s, 3 H, OMe), 4.40–4.50 (m, 3 H, H-4 , H-5 ), 4.68 (d, 1 H,
2
0
0
0
J2
(
0
0
¼ 5.9 Hz, H-3 ), 4.78 (d, 1 H, J
0 0
¼ 5.9 Hz, H-2 ), 5.06 (s, 1 H, H-1 ), 5.31
,3
2 ,3
0
0
13
brs, 1 H, 3 -OH), 5.63 (brs, 1 H, 2 -OH), 6.30 (s, 1 H, H-5). C NMR (CDCl ):
3
0
d ¼ 13.7 (CH ), 13.9 (SCH ), 21.8 (CH ), 39.3 (CH ), 54.5 (OMe), 66.5 (C-5 ), 81.8
3
3
2
2
0
0
0
0
(
1
C-4 ), 83.8 (C-3 ), 84.5 (C-2 ), 102.0 (C-1 ), 108.3 (C-5), 169.0 (C-6), 172.1 (C-2),
72.4 (C-4). EI-MS: (positive mode); m=z: 330 [M ]. Anal. Calcd for C H N O S
þ
1
4
22
2
5
(330.39): C 50.89, H 6.71, N 8.47. Found: C 50.67, H 6.60, N 8.33.
General Procedure for the Preparation of 8a-d. A solution of substituted 2-
thiouracils (4a-d) (10 mmol), 3 (3.14 g, 10 mmol) and sodium hydroxide (0.4 g,
ꢀ
1
0 mmol) in water (20 mL) and ethanol (40 mL) was stirred at 60 C for 1 h. The
mixture was allowed to cool. The solvents were removed under reduced pressure.
The residue was purified by column chromatography using 3% MeOH in CHCl3
to give 8a-d in 78–85% yields.
Methyl
5-Deoxy-2,3-O-isopropylidene-5-(uracil-2-yl)-thio-b-D-ribofuranosides
1
(
8a). Yield ¼ 2.57 g, 82% as a white foam. H NMR (CDCl ): d ¼ 1.33 (s, 3 H,
3
0
CH ), 1.50 (s, 3 H, CH ), 3.13–3.20 (m, 2 H, H-5 ), 3.32 (s, 3 H, OMe), 4.46–4.55
3
3
0
0
(
2
m, 1 H, H-4 ), 4.62 (d, 1 H, J
0
0
¼ 5.9 Hz, H-3 ), 4.78 (d, 1 H, J
0 0
¼ 5.9 Hz, H-
5,6
2
,3
2 ,3
0
0
), 5.00 (s, 1 H, H-1 ), 6.40 (d, 1 H, J ¼ 5.0 Hz, H-5), 8.22 (d, 1 H, J ¼ 4.9 Hz,
þ
13 18 2 5
5
,6
H-6). EI-MS: (positive mode); m=z: 314 [M ]. Anal. Calcd for C H N O S
(314.35): C 49.67, H 5.77, N 8.91. Found: C 49.50, H 5.81, N 8.99.
Methyl 5-Deoxy-2,3-O-isopropylidene-5-(5-methyluracil-2-yl)-thio-b-D-ribofura-
1
nosides (8b). Yield ¼ 2.78 g, 85% as a white foam. H NMR (CDCl ): d ¼ 1.31
3
0
(
3
s, 3 H, CH ), 1.50 (s, 3 H, CH ), 2.05 (s, 3 H, CH ), 3.14–3.20 (m, 2 H, H-5 ),
3
3
3
0
0
.32 (s, 3 H, OMe), 4.54 (m, 1 H, H-4 ), 4.69 (d, 1 H, J
0
0
0
¼ 5.9 Hz, H-3 ), 4.81
2
,3
0
(d, 1 H, J2
mode); m=z: 328 [M ]. Anal. Calcd for C H N O S (328.38): C 51.20, H 6.13, N
0
0
¼ 5.9 Hz, H-2 ), 5.01 (s, 1 H, H-1 ), 8.05 (s, 1 H, H-6). EI-MS: (positive
,3
þ
1
4
20
2
5
8
.53. Found: C 51.00, H 6.09, N 8.41.

Thiouracils Linked Methyl b-D-Ribofuranoside
2035
Methyl 5-Deoxy-2,3-O-isopropylidene-5-(6-methyluracil-2-yl)-thio-b-D-ribofura-
1
nosides (8c). Yield ¼ 2.62 g, 80% as a white foam. H NMR (CDCl ): d ¼ 1.31
3
0
0
(
3
4
s, 3 H, CH ), 1.50 (s, 3 H, CH ), 2.30 (s, 3 H, CH ), 3.13–3.19 (m, 2 H, H-5 ),
3
3
3
0
.30 (s, 3 H, OMe), 4.45–4.55 (m, 1 H, H-4 ), 4.65 (d, 1 H, J
0
0
0
¼ 5.9 Hz, H-3 ),
2
,3
0
.78 (d, 1 H, J2
0
0
¼ 5.8 Hz, H-2 ), 5.00 (s, 1 H, H-1 ), 6.25 (s, 1 H, H-5). EI-MS:
,3
þ
(
H 6.13, N 8.53. Found: C 51.07, H 6.18, N 8.61.
positive mode); m=z: 328 [M ]. Anal. Calcd for C H N O S (328.38): C 51.20,
1
4
20
2
5
Methyl 5-Deoxy-2,3-O-isopropylidene-5-(6-propyluracil-2-yl)-thio-b-D-ribofura-
1
nosides (8d). Yield ¼ 2.81 g, 78% as a white foam. H NMR (CDCl ): d ¼ 0.95 (t,
3
3
CH ), 2.55–2.65 (m, 2 H, CH ), 3.15–3.22 (m, 2 H, H-5 ), 3.31 (s, 3 H, OMe),
H, J ¼ 7.5 Hz, CH ), 1.33 (s, 3 H, CH ), 1.50 (s, 3 H, CH ), 1.66–1.75 (m, 2 H,
2 2
3
3
3
0
0
0
4
.49–4.57 (m, 1 H, H-4 ), 4.65 (d, 1 H, J
0
0
0
¼ 5.9 Hz, H-3 ), 4.78 (d, 1 H,
2
,3
0
J2
m=z: 360 [M ]. Anal. Calcd for C H N O S (360.43): C 53.31, H 6.71, N 7.77.
0
0
¼ 5.9 Hz, H-2 ), 5.01 (s, 1 H, H-1 ), 6.25 (s, 1 H, H-5). EI-MS: (positive mode);
,3
þ
1
6
24
2
5
Found: C 53.11, H 6.67, N 7.63.
General Procedure for the Preparation of 9a-d. Compounds 8a-d (0.25 g) were
refluxed in 80% aqueous acetic acid (10 mL) for 2 h. The solvents were removed
in vacuo and were coevaporated with water (4 ꢂ 5 mL) and EtOH (3 ꢂ 5 mL). The
residue was purified by column chromatography using 6% MeOH in CHCl to give
3
9a-d in 70–75% yields.
Methyl 5-Deoxy-5-(uracil-2-yl)-thio-b-D-ribofuranosides (9a). Yield ¼ 0.15 g,
ꢀ
1
0
7
2%. M.p. ¼ 110 C. H NMR (CDCl ): d ¼ 3.22–3.30 (m, 2 H, H-5 ), 3.35 (s, 3 H,
3
0
0
0
OMe), 4.40–4.50 (m, 1 H, H-4 ), 4.66–4.76 (m, 2 H, H-2 , H-3 ), 5.05 (s, 1 H, H-
0
0
0
1
5
), 5.25 (brs, 1 H, 3 -OH), 5.60 (brs, 1 H, 2 -OH), 6.40 (d, 1 H, J ¼ 5.0 Hz, H-
þ
5
,6
), 8.20 (d, 1 H, J5,6 ¼ 5.0 Hz, H-6). EI-MS: (positive mode); m=z: 274 [M ]. Anal.
Calcd for C H N O S (274.29): C 43.78, H 5.14, N 10.21. Found: C 43.61, H
1
0
14
2
5
5.03, N 10.11.
Methyl 5-Deoxy-5-(5-methyluracil-2-yl)-thio-b-D-ribofuranosides (9b). Yield ¼
ꢀ
1
0
(
J2
1
.16 g, 75%. M.p. ¼ 152 C. H NMR (CDCl ): d ¼ 2.11 (s, 3 H, CH ), 3.12–3.18
3
3
0
0
m, 2 H, H-5 ), 3.31 (s, 3 H, OMe), 4.46–4.56 (m, 1 H, H-4 ), 4.75 (d, 1 H,
0
0
0
0
0
¼ 5.9 Hz, H-3 ), 4.86 (d, 1 H, J
0 0
¼ 5.9 Hz, H-2 ), 5.01 (s, 1 H, H-1 ), (brs,
,3
2 ,3
0
0
H, 3 -OH), 5.62 (brs, 1 H, 2 -OH), 8.02 (s, 1 H, H-6). EI-MS: (positive mode);
þ
m=z: 288 [M ]. Anal. Calcd for C H N O S (288.31): C 45.82, H 5.59, N 9.71.
1
1
16
2
5
Found: C 45.70, H 5.61, N 9.80.
Methyl 5-Deoxy-5-(6-methyluracil-2-yl)-thio-b-D-ribofuranosides (9c). Yield ¼
ꢀ
1
0
(
J2
.15 g, 71%. M.p. ¼ 123 C. H NMR (CDCl ): d ¼ 2.35 (s, 3 H, CH ), 3.20–3.30
3
3
0
0
m, 2 H, H-5 ), 3.31 (s, 3 H, OMe), 4.40–4.50 (m, 1 H, H-4 ), 4.62 (d, 1 H,
0
0
0
0
0
¼ 5.9 Hz, H-3 ), 4.71 (d, 1 H, J
0 0
¼ 5.8 Hz, H-2 ), 5.01 (s, 1 H, H-1 ),
,3
2 ,3
0
0
(
mode); m=z: 288 [M ]. Anal. Calcd for C H N O S (288.31): C 45.82, H 5.59,
brs, 1 H, 3 -OH), 5.58 (brs, 1 H, 2 -OH), 6.27 (s, 1 H, H-5). EI-MS: (positive
þ
1
1
16
2
5
N 9.71. Found: C 45.75, H 5.41, N 9.60.

2036
Abdel-Rahman et al.
Methyl 5-Deoxy-5-(6-propyluracil-2-yl)-thio-b-D-ribofuranosides (9d). Yield ¼
1
0
CH ), 1.60–1.75 (m, 2 H, CH ), 2.50–2.64 (m, 2 H, CH ), 3.20–3.28 (m, 2 H,
.15 g, 70% as awhite foam. H NMR (CDCl ): d ¼ 0.98 (t, 3 H, J ¼ 7.3 Hz,
3
3
2
2
0
0
H-5 ), 3.31 (s, 3 H, OMe), 4.40–4.53 (m, 1 H, H-4 ), 4.63 (d, 1 H, J
0
0
0
¼ 5.9 Hz,
2
,3
0
0
0
H-3 ), 4.73 (d, 1 H, J
OH), 5.60 (brs, 1 H, 2 -OH), 6.31 (s, 1 H, H-5). EI-MS: (positive mode); m=z:
0
0
¼ 5.9 Hz, H-2 ), 5.02 (s, 1 H, H-1 ), 5.30 (brs, 1 H, 3 -
2
,3
0
þ
3
C 49.28, H 6.26, N 8.64.
16 [M ]. Anal. Calcd for C H N O S (316.39): C 49.35, H 6.37, N 8.85. Found:
1
3
20
2
5
Biological Activity Studies. The hepatoplastoma cell line (Hep G2-2.2.15) was
16]
[
used to evaluate the antiviral effect of the tested compounds against HBV.
cells were incubated in growth medium [RPMI-1640, 10% heat-inactivated fetal-calf
The
ꢀ
serum (FCS)] and antibiotics at 37 C, 5% CO with and without tested compounds.
2
The average production HBV virion DNA from cell cultures with addition of differ-
ent concentration of a tested compound was expressed relatively to HBV virion
DNA in cultures without the tested compound. Quantition of HBV-DNA was done
using a semiquantitative nested PCR followed by DIG PCR ELISA as previously
[17]
described.
The cytotoxic effect of the compounds was accessed by culturing the
Hep G2-2.2.15 cells in the presence of compounds as described for the viability of
their cells were analyzed using a MTT-assay.
ACKNOWLEDGMENTS
The authors thank DANIDA for the support of this work at Menoufia Univer-
sity, through the project ‘‘Development of New Drugs Against Hepatitis’’ and
Prof. Dr. R. R. Schmidt for making available the spectral measurements at Konstanz
University.
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Received September 5, 2002
Accepted August 5, 2003