Synthesis and antiviral activity of D- and L-2′-azido-2′,3′-dideoxy-4′-thiopyrimidine and purine nucleosides

Article abstract of DOI:10.1081/NCN-100002346

Novel D- and L-2′-azido-2′,3′-dideoxy-4′-thionucleosides were synthesized starting from L- and D-xylose via D- and L-4-thioarabitol derivative as key intermediates and evaluated for antiviral activity, respectively. When the final nucleosides were tested against HIV-1, HSV-1, HSV-2, and HCMV, they were found to be only active against HCMV without cytotoxicity up to 100 μg/ml.

Full text of DOI:10.1081/NCN-100002346

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SYNTHESIS AND ANTIVIRAL ACTIVITY OF D- AND
L-2′-AZIDO-2′,3′-DIDEOXY-4′-THIOPYRIMIDINE AND
PURINE NUCLEOSIDES
Lak Shin Jeong a , Yun Ha Kim a , Hea Ok Kim b , Su Jeong Yoo a , Yong Hee Park a , Sook
Hee Yeon a , Moon Woo Chun c & Hee-Doo Kim d
a College of Pharmacy, Ewha Womans University , Seoul, Korea
b College of Medicine, Yonsei University , Seoul, Korea
c College of Pharmacy, Seoul National University , Seoul, Korea
d College of Pharmacy, Sookmyung Women's University , Seoul, Korea
Published online: 07 Feb 2007.
To cite this article: Lak Shin Jeong , Yun Ha Kim , Hea Ok Kim , Su Jeong Yoo , Yong Hee Park , Sook Hee Yeon , Moon Woo
Chun & Hee-Doo Kim (2001) SYNTHESIS AND ANTIVIRAL ACTIVITY OF D- AND L-2′-AZIDO-2′,3′-DIDEOXY-4′-THIOPYRIMIDINE
AND PURINE NUCLEOSIDES, Nucleosides, Nucleotides and Nucleic Acids, 20:4-7, 665-668
To link to this article: http://dx.doi.org/10.1081/NCN-100002346
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 665–668 (2001)
SYNTHESIS AND ANTIVIRAL ACTIVITY
OF D- AND L-2ꢀ-AZIDO-2ꢀ,3ꢀ-DIDEOXY-4ꢀ-
THIOPYRIMIDINE AND PURINE NUCLEOSIDES
Lak Shin Jeong,1,∗ Yun Ha Kim,1 Hea Ok Kim,2 Su Jeong Yoo,1
Yong Hee Park,1 Sook Hee Yeon,1 Moon Woo Chun,3
and Hee-Doo Kim4
1College of Pharmacy, Ewha Womans University, Seoul, Korea
2College of Medicine, Yonsei University, Seoul, Korea
3College of Pharmacy, Seoul National University, Seoul, Korea
4College of Pharmacy, Sookmyung Women’s University, Seoul, Korea
ABSTRACT
Novel D- and L-2ꢀ-azido-2ꢀ,3ꢀ-dideoxy-4ꢀ-thionucleosides were synthesized
starting from L- and D-xylose via D- and L-4-thioarabitol derivative as key
intermediates and evaluated for antiviral activity, respectively. When the final
nucleosides were tested against HIV-1, HSV-1, HSV-2, and HCMV, they were
found to be only active against HCMV without cytotoxicity up to 100 µg/ml.
INTRODUCTION
Since 3ꢀ-azido-3ꢀ-deoxythymidine (AZT) has been discovered as anti-AIDS
drug, a series of 2ꢀ,3ꢀ-dideoxynucleosides with azido substituent at 2ꢀ, 3ꢀ or 4ꢀ posi-
tion of furanose moiety have been synthesized and many of them have shown potent
antiviral activity (1). The 4ꢀ-thionucleosides have also shown promising biological
activities such as antitumor and antiviral activities (2), but their structure-activity
relationships have not been studied due to their synthetic difficulties. Recently, our
laboratory developed very efficient synthetic procedure of 4-thioarabitol derivative
which could be converted to the various 2ꢀ-substituted-4ꢀ-thionucleosides (3).
∗Corresponding author.
665
ꢁ
C
Copyright 2001 by Marcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
666
JEONG ET AL.
B
HO
S
S
N3
B
HO
N3
B = pyrimidines and purines
Figure 1.
Utilizing this procedure, it was interesting to design and synthesize 2ꢀ-
azido-2ꢀ,3ꢀ-dideoxy-4ꢀ-thionucleosides since the corresponding 2ꢀ-azido-2ꢀ,3ꢀ-
dideoxynucleosides exhibited potent antiviral activity. In addition to D-nucleosides,
we also wanted to synthesize the corresponding L-nucleosides because many
L-nucleosides were found to be more potent than the corresponding D-nucleosides
and to compare their antiviral activities.
Here, we wish to report the synthesis and antiviral activity of D- and L-2ꢀ-azido-
2ꢀ,3ꢀ-dideoxy-4ꢀ-thionucleosides starting from L-xylose and D-xylose, respectively.
RESULTS AND DISCUSSION
For the synthesis of the desired azido substituted nucleosides, L-2-azido-4-
thiosugar acetate 7 was first synthesized and then condensed with pyrimidine and
purine bases. Synthesis of the key intermediate 7 is shown in Scheme 1.
D-Xylose was converted to the L-4-thioarabitol derivative 1 according to the
very efficient method developed by our laboratory (2). Debenzylation (84%) of
1 with boron trichloride at −78◦C gave diol 2 which was selectively silylated to
give 3 in 76% yield. Barton’s deoxygenation of 3 afforded deoxygenated material
4 (70%). Treatment of benzoate 4 with methanolic ammonia produced compound
5 (78%) which was converted to the azide 6 in two steps (84%). Oxidation of 6
with mCPBA (98%) followed by refluxing of the sulfoxide 6 with acetic anhydride
gave the glycosyl donor 7.
HO
O
S
S
S
RCl
ref. 2
BCl3
OH
OH
OH
OBn
D-Xylose
HO
RO
BnO
O
O
OBz
OBz
OBz
Ph
2
3
1
Si C(CH3)3
Ph
R =
1) PhOC(S)Cl
2) n-Bu3SnH
S
S
S
N3
S
N3
1) MsCl
2) NaN3
1) mCPBA
2) Ac2O
NH3
OAc
RO
RO
RO
RO
OH
OBz
7
5
6
4
Scheme 1.

ORDER
REPRINTS
D- AND L-2ꢀ-AZIDO-2ꢀ,3ꢀ-DIDEOXY-4ꢀ-THIONUCLEOSIDES
667
Y
N
Y
X
S
X
N
N
N3
O
S
N3
N
+
N
OTMS
RO
O
OAc
N
S
N3
TMSOTf
RO
Y
X
7
RO
8b (X = H, Y = OH)
9b (X = CH3, Y = OH)
10b (X = H, Y = NHBz)
Ph
8a (X = H, Y = OH)
9a (X = CH3, Y = OH)
10a (X = H, Y = NHBz)
R =
Si C(CH3)3
Ph
1) n-Bu4NF
8a and 8b
9a and 9b
11a (R = H, X = H, Y = OH)
12a (R = H, X = CH3, Y = OH)
11b (R = H, X = H, Y = OH)
12b (R = H, X = CH3, Y = OH)
+
2) BzCl
3) NH3
1) NH3
1) NH3
10a
13b (R = H, X = H, Y = NH2)
10b
13a (R = H, X = H, Y = NH2)
2) n-Bu4NF
2) n-Bu4NF
Scheme 2.
Synthesis of the desired pyrimidine nucleosides is depicted in Scheme 2. The
glycosyl donor 7 was condensed with silylated uracil, thymine and N4-benzoylcyto-
sine in the presence of TMSOTf to give the inseparable anomeric mixture of
protected nucleosides 8a/8b (87%) and 9a/9b (61%) and separable mixture of
10a (30%) and 10b (31%) after silica gel column chromatography, respectively.
Desilylation of 8a/8b and 9a/9b with tetra-n-butylammonium fluoride also
afforded the inseparable mixture of the final nucleosides, respectively, which for
the separation of anomers, were benzoylated at 70◦C to give the O,N-dibenzoates.
Dibenzoates were easily separated by silica gel column chromatography whose
each anomers were treated with methanolic ammonia to yield the L-uracil derivative
11a and 11b and the L-thymine derivative 12a and 12b, respectively. The cytosine
derivatives 10a and 10b were each deprotected to give the L-cytosine nucleosides
13a (75%) and 13b (70%).
Synthesis of the purine nucleosides is shown in Scheme 3. Condensation of 7
with silylated 6-chloropurine gave the inseparable mixture of protected nucleosides
Cl
N
N
S
15a (R = H, X = Cl)
N3
N
N
N
S
N3
RO
n-Bu4NF
TMS
OAc
N
+
N
TMSOTf
RO
15b (R = H, X = Cl)
N
14 (X = Cl)
7
X
NH3
NH3
16a (X = NH2)
15a (X = Cl)
HSCH2CH2OH
18a (X = OH)
16b (X = NH2)
15b (X = Cl)
MeNH2
MeNH2
HSCH2CH2OH
18b (X = OH)
17a (X = NHMe)
17b (X = NHMe)
Scheme 3.

ORDER
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668
JEONG ET AL.
14 (71%) which was deprotected to give β-L-anomer 15a (55%) and α-L-anomer
15b (34%). Each L-anomer was converted to the L-adenine (16a, 16b), L-N6-
methyladenine (17a, 17b), and L-hypoxanthine (18a, 18b) derivatives, respectively.
The corresponding D-nucleosides (ent-11a, ent-11b, ent-12a, ent-12b, ent-13a,
ent-13b, ent-15a, ent-15b, ent-16a, ent-16b, ent-17a, ent-17b, ent-18a, and ent-
18b) were synthesized starting from L-xylose using the same method used in the
preparation of L-nucleosides.
Antiviral assays against HIV-1, HSV-1, HSV-2, and HCMV were performed
on the D- and L-final nucleosides (4). All compounds did not exhibit any significant
antiviral activity except anti-HCMV activity. D-purine analogues exhibited signif-
icant anti-HCMV activity among which N6-methyladenine derivatives (ent-17a
and ent-17b) were found to be the most potent, while L-derivatives did not show
anti-HCMV activity.
ACKNOWLEDGMENTS
This research was supported by the grant of the Good Health R & D Project,
Ministry of Health and Welfare, Korea (HMP-98-D-4-0057).
REFERENCES
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