Synthesis and anti-HCV activity of 1-(1′,3′-O-anhydro-3′-C-methyl-β-d-psicofuranosyl)uracil

Article abstract of DOI:10.1016/j.tetlet.2014.09.069

Synthesis of a novel 1′,2′-oxetane-uridine bearing a 2′-C-methyl substituent, [1-(1′,3′-O-anhydro-3′-C-methyl-β-d-psicofuranosyl)uracil], is described. Key to its construction was the use of 6-O-(p-toluoyl)-1,2:3,4-di-O-isopropylidene-3-C-methyl-d-psicofu

Full text of DOI:10.1016/j.tetlet.2014.09.069

Tetrahedron Letters 55 (2014) 6216–6219
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and anti-HCV activity of 1-(10,30-O-anhydro-30-C-methyl-b-
D-psicofuranosyl)uracil
a,
a
b
a
Zofia Komsta b, , Benjamin Mayes , Adel Moussa , Montserrat Shelbourne , Alistair Stewart ,
⇑
⇑
Andrew J. Tyrrell b, Laura L. Wallis b, Alexander C. Weymouth-Wilson b, Alexander Yurek-George b
a Idenix Pharmaceuticals, 320 Bent Street, Cambridge, MA 02141, USA
b Dextra, Science and Technology Centre, Earley Gate, Whiteknights Road, Reading RG6 6BZ, UK
a r t i c l e i n f o
a b s t r a c t
Synthesis of a novel 10,20-oxetane-uridine bearing a 20-C-methyl substituent, [1-(10,30-O-anhydro-30-C-
Article history:
Received 22 July 2014
Revised 29 August 2014
Accepted 11 September 2014
Available online 18 September 2014
methyl-b-
D
-psicofuranosyl)uracil], is described. Key to its construction was the use of 6-O-(p-toluoyl)-
-psicofuranose as a nucleosidation substrate, which itself was
1,2:3,4-di-O-isopropylidene-3-C-methyl-
D
derived from D-fructose. Anti-HCV activity was examined for the corresponding triphosphate which
was not found to be an inhibitor of HCV NS5B 1b wild type polymerase in vitro. The 10,20-oxetane uridine
triphosphate without 20-C-methyl substitution was similarly inactive, however, the guanosine analog dis-
Keywords:
HCV
Psicose
played modest inhibition (IC50 = 10 lM).
Ó 2014 Elsevier Ltd. All rights reserved.
Oxetane
Bicyclic ribonucleosides
Conformational restriction
Conformationally restricted nucleosides have been investigated
extensively in the context of antisense oligonucleotides and for
their therapeutic potential as antiviral agents.1 The C30-endo
(North) sugar ring conformational preference exhibited by ribonu-
cleosides on introduction of a 20-C-methyl substituent has yielded
a class of nucleoside triphosphates (NTPs) which are highly potent
inhibitors of hepatitis C virus (HCV) NS5B polymerase; 20-C-meth-
ylcytidine 1,2 20-C-methylguanosine 2,3 and 20-F-20-C-methyluri-
dine 34 being the primary examples (Fig. 1). In the case of 3, the
corresponding prodrug sofosbuvir5 has been granted regulatory
approval, significantly augmenting the existing standard of care
for the treatment of chronic HCV, a global disease burden affecting
over 170 million people.
polymerase has not been established to date. Accordingly, these
systems were evaluated along with the novel 20-C-methyl-contain-
ing 10,20-oxetane-uridine 7 [1-(10,30-O-anhydro-30-C-methyl-b-
D-
psicofuranosyl)uracil], the synthesis of which demanded the
construction of two adjacent stereospecific quaternary centers.
10,20-Oxetane nucleosides 5 and 6 were synthesized according
to the literature procedures.9,10 The uridine derivative 5 was
obtained via the direct nucleosidation of diacetonide 8, which
resulted in 45% yield and a disappointing 0.8:1.0 b:
a
anomeric
O
NH2
O
Conformationally restricted C30-endo (North) bicyclic ribonu-
cleosides bearing a 20-O,40-C-methylene bridge, 4, have been
explored in a wide range of applications,1 however the correspond-
ing NTPs have only relatively recently been demonstrated to be
inhibitors of HCV NS5B polymerase in vitro (Fig. 2).7
N
N
NH
N
NH
NH2
N
O
O
N
O
O
O
N
HO
HO
HO
1
2
3
HO
F
HO OH
HO OH
10,20-Oxetane bicyclic nucleosides are similarly forced to adopt a
North sugar conformation,8 however the inhibitory potential of the
respective uridine 5 and guanosine 6 NTPs against HCV NS5B
Figure 1. Examples of nucleosides bearing a 20-C-methyl substituent.
B
R
B
O
O
4 B = A, C, G, U
5 B = U; R = H
6 B = G, R = H
HO
HO
R = H, Me
⇑
Corresponding authors. Tel.: +44 118 935 7031; fax: +44 118 935 7384 (Z.K.);
7
B = U; R = Me
O
tel.: +1 617 995 9883; fax: +1 617 995 9801 (B.M.).
E-mail addresses: zofia.komsta@dextrauk.com (Z. Komsta), mayes.ben@idenix.
com (B. Mayes).
HO
O
HO
R
Figure 2. 20-O,40-C-methylene and 10,20-oxetane bicyclic nucleosides.
http://dx.doi.org/10.1016/j.tetlet.2014.09.069
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

Z. Komsta et al. / Tetrahedron Letters 55 (2014) 6216–6219
6217
O
N
with a 1.5:1 ratio of 12:5 observed. The analogous structure was
not formed in the case of the corresponding guanosine derivative;
the expected oxetane structure 6 was obtained following treat-
ment with either NaHMDS/THF or NaOMe/MeOH. Formation of
the [2.1.2]-bicycle 12 may potentially proceed via the protected
O
N
NH
NH
O
OMs
TolO
O
TolO
O
O
O
HO
O
O
(a)-(c)
(d),(e)
O
O
HO
OH
O
10,20-O-anhydro-1-b- -psicofuranosyluracil intermediate 13.10–13
D
HO
The initial strategy to construct the 20-C-methyl-containing
10,20-oxetane-uridine 7 utilized an analogous procedure to that
used for the synthesis of the guanosine 6 (Scheme 3). It was antic-
ipated that acetate protection at OH-3 in methyl psicofuranose 14
8
9
5
(f)-(i)
TolO
O
N
N
N
NH
NH2
OMe
TolO
Br
O
O
would facilitate a favorable b:a ratio due to neighboring group
OMs
OMs
HO
(j)
(k)-(m)
O
participation.
AcO
OAc
AcO
OAc
The synthesis of the methyl glycoside 22 started with
-fructose, which was converted into diacetonide and then
O
HO
D
10
11
6
oxidized to give ketone 1514 following literature conditions. Stere-
oselective addition of MeLi to the ketone moiety of 15 afforded 16
as a single diastereoisomer in 82% yield (Scheme 4). Isomerization
to the furanose form was achieved using a catalytic amount of sul-
furic acid in acetone, to produce the 3-C-methyl diacetonide 17 in
moderate yield.15 Stereospecific introduction of the methyl group
was confirmed by single crystal X-ray analysis (Fig. 3). Protection
of the free hydroxyl in 17 using p-toluoyl chloride in pyridine gave
the ester 18. Removal of both acetonide groups and concomitant
Fischer glycosylation was achieved by treatment with methanolic
HCl, which furnished the methyl glycoside 19 in 39% yield. In addi-
tion, the 2,3-acetonide 20 was also isolated from the reaction in
11% yield. Peracetylation was achieved in two steps by the
treatment of 19 with Ac2O in pyridine to give initially the 1,4-di-
O-acetate 21. Subsequent acetylation of the less reactive tertiary
hydroxyl, by heating in neat Ac2O with NaOAc at 120 °C, gave the
1,3,4-tri-O-acetate 22 in excellent yield.
In order to obtain a reactive nucleosidation donor, the bromin-
ation of 22 was investigated. Bromination attempts using either
HBr in AcOH or TiBr4 proved unsuccessful, with only the unstable
elimination product 23 being isolated in both cases in ꢀ50% yield
(Scheme 5). Formation of the nucleoside directly from the methyl
glycoside 22 using the persilylated nucleobase with either TMSOTf
in toluene or SnCl4 in CH3CN was also unsuccessful. Elimination
product 23 was again isolated as the major component of the reac-
tion performed in toluene, while SnCl4/MeCN conditions resulted
in formation of the oxazoline 24 (Scheme 5).
Tol = 4-toluoyl
Scheme 1. Reagents and conditions: (a) silylated uracil, TMSOTf, CH3CN, 0 °C to rt,
16 h, 23% and 20% b; (b) MsCl, py, rt, 16 h, 95%; (c) TFA/H2O (9:1), rt, 2 h, 87%; (d)
a
NaHMDS, THF, 0 °C to rt, 3 h; (e) NH3, MeOH, rt, 48 h, 60% (over 2 steps); (f) HCl,
MeOH, rt, 24 h, 65%; (g) MsCl, py, rt, 2 h; (h) TFA/H2O (9:1), rt, 1 h; (i) Ac2O, py, rt,
2 h, 69% (over 3 steps); (j) HBr, AcOH, CH2Cl2, rt, 3 h; (k) silylated N2-acetyl-O6-
diphenylcarbamoylguanine, SnCl4, CH3CN, 80 °C, 1 h; (l) TFA/H2O (9:1), rt, 0.5 h 30%
(over 3 steps); (m) NaOMe, MeOH, rt, 64 h, 81%.
O
O
N
O
N
NH
NH
NH
N
O
O
OMs
O
TolO
HO
HO
(a)
O
O
O
+
OH
O
HO
O
HO
OH
9
5
12
(b)
O
N
Tol = 4-toluoyl
TolO
N
O
O
HO
OH
13
Scheme 2. Reagents and conditions: (a) NaOMe, MeOH, rt, 64 h; (b) (i) NaHMDS,
THF, 0 °C to rt, 3 h, (ii) NaOMe, MeOH, rt.
As the methyl psicofuranoside 22 proved to be unsuitable, alterna-
tive nucleosidation substrates were investigated. Based on a reported
synthesis of [1-(10,30-O-anhydro-b-
D-psicofuranosyl)thymine], oxe-
U
OMe
HO
TolO
O
O
tane 27 was identified as an analogous potential intermediate for
OR
O
HO
AcO
OAc
O
O
7
14
RO
O
O
O
O
O
O
O
(a)
(b)
Tol = 4-toluoyl
O
O
O
OH
O
O
Scheme 3. Retrosynthetic analysis of oxetane 7.
O
O
15
16
17
R = OH
(c)
18 R = Tol
ratio. The analogous 1,2-oxetane guanosine 6 was obtained via the
nucleosidation of the bromide 11 with N2-acetyl-O6-diphenylcar-
bamoylguanine, giving predominantly the b anomer (30% yield
over 3 steps following the removal of the diphenylcarbamoyl pro-
tection), due to the neighboring group participation of the acetate.
The methyl glycoside 10 was synthesized in four steps from the
diacetonide 8 in 45% overall yield (Scheme 1).
Interestingly, during the cyclization of 9 into the desired oxe-
tane uridine 5, the regioisomeric 10-C,30-O-methylene bridged bicy-
clic nucleoside 1211 was also obtained. When NaHMDS in THF was
used, the [2.1.2]-bicyclic product was formed only in trace
amounts (<5% yield) (Scheme 2). However, upon treating the mes-
ylate 9 with NaOMe in MeOH, the synthesis of 12 was favored,
(d)
OMe
O
TolO
OMe
OMe
TolO
(f)
TolO
OH
O
O
(e)
OAc
OH
+
O
O
AcO
OR
R = H
HO
OH
21
22 R = Ac
19
20
Tol = 4-toluoyl
Scheme 4. Reagents and conditions: (a) MeLi, LiBr, Et2O, rt, 0.5 h, 82%; (b) H2SO4,
2,2-dimethoxypropane, acetone, rt, 20 h, 58%; (c) p-toluoyl chloride, py, rt, 3 h, 94%;
(d) HCl, MeOH, rt to 40 °C, 18 h, 19 (39%) and 20 (11%); (e) Ac2O, py, rt, 18 h, 98%; (f)
Ac2O, NaOAc, 120 °C, 20 h, 91%.

6218
Z. Komsta et al. / Tetrahedron Letters 55 (2014) 6216–6219
nucleosidation (Scheme 6).12 The formation of 27 was achieved in four
steps starting from the 2,3-acetonide-protected 20 (Scheme 6). Treat-
ment of 20 with MsCl and pyridine gave mesylate 25 from which the
acetonide protection was removed using TFA/H2O. Subsequent oxe-
tane ring closure was effected using NaOMe in MeOH, with concomi-
tant removal of the p-toluoyl ester. Reprotection with p-toluoyl
chloride furnished the key ditoluoyl ester protected 1,3-anhydro-3-
C-methyl intermediate 27. Treatment of 27 with persilylated uracil
and SnCl4, however, resulted in the opening of the oxetane ring and
in the incorporation of acetonitrile giving 28 in 30% yield; no nucleos-
idation products were observed.
10,20-Oxetane nucleosides have alternatively been synthesized
by the nucleosidation of related analogs of 18 bearing 1,2:3,4-di-
O-isopropylidene protection (Scheme 7).8a,10 Various conditions
were screened using 18 as the nucleosidation substrate (Table 1)
in order to both effect base coupling and form the desired b-ano-
mer. In this instance, the use of silylated uracil in CH3CN with
TMSOTf as the promoter (entry 1, Table 1) yielded the required
nucleoside 30 in 30% yield with a 3.5:1 a:b anomer ratio. One third
of the diacetonide starting material 18 was recovered, however,
neither elevation of the reaction temperature, nor using BF3ꢁOEt
as the catalyst was beneficial, resulting instead in substrate degra-
dation (entries 2 and 3). Silylation of uracil using BSA resulted in an
improved a:b ratio but at the expense of the coupling yield, with
60% starting material recovered (entry 4). Increasing the reaction
time did not lead to any improvement in conversion and only
Figure 3. ORTEP drawing of the X-ray crystallographic structure of 17 (CCDC
1006958).
further increased the
a-selectivity (entry 5). The use of other less
polar solvent systems and/or SnCl4 as a promoter was also investi-
gated (entries 6–9), however, no improvement was observed over
the original conditions.
AcO
O
(b), (c)
or (d)
TolO
OMe
OAc
TolO
TolO
O
(a)
O
OAc
CHO
N
To rule out the possibility that, through participation, the
p-toluoyl protecting group was influencing the stereochemical out-
come of the nucleosidation, the reaction with p-methoxy benzyl
protected 29 was attempted using the preferred conditions for
18. In this case (entry 10), none of the desired nucleoside was
formed and elimination of the starting material was accompanied
by loss of the PMB protection to give furan 32 (Scheme 7).16
Opening of diacetonide 18 with azide was also explored due to
the potential for subsequent construction of the nucleobase.
N-Glycosidation with azide nucleophiles has been reported for
related psicofuranosyl systems, in which the b-azide was obtained
preferentially in ratios of up to 18:1.17 As with the Vorbrüggen
conditions18 using uracil, the reaction of 18 with TMSN3 in the
presence of TMSOTf produced the anomeric azide in 30% yield,
O
AcO
AcO
24
22
23
Tol = 4-toluoyl
Scheme 5. Reagents and conditions: (a) persilylated nucleobase, CH3CN, SnCl4,
80 °C, 2 h; (b) HBr in AcOH, CH2Cl2, 0 °C to rt, 1.5 h; (c) TiBr4, EtOAc, CH2Cl2, rt, 1 h;
(d) persilylated nucleobase, toluene, TMSOTf, 80 °C to reflux, 6 h.
TolO
OMe
TolO
OMe
O
O
HO
OMe
O
OH
OMs
O
(a)
(b), (c)
O
O
O
O
HO
(d)
20
25
26
Tol = 4-toluoyl
with the undesired
ratio.
a isomer again preferentially formed in a 6:1
TolO
OMe
Utilizing the preferred nucleosidation conditions for 18,
(6 equiv silylated uracil, CH3CN, 2 equiv TMSOTf, rt, 16 h), the uri-
dines a-30 and b-30 were isolated, along with an inseparable a:b
anomer mixture of the TMS protected 33 (Scheme 8). Conversion
of 33 to generate additional 30 was achieved cleanly using AcOH
and H2O. Thus the desired 30-C-methyl-psicofuranosyl uracil b-30
O
TolO
OMe
O
OH
O
(e)
O
TolO HN
TolO
28
27
Scheme 6. Reagents and conditions: (a) MsCl, py, rt, 18 h, 88%; (b) TFA/H2O (9:1),
rt, 0.5 h; (c) NaOMe, MeOH, rt, 18 h; (d) p-toluoyl chloride, py, rt, 19 h, 46% (over 3
steps); (e) persilylated uracil, MeCN, SnCl4, 85 °C, 20 h, 30% (28).
was isolated in 8% overall yield from 18 along with the
a anomer
in 22% yield. Synthesis of the target 10,20-oxetane uridine 7 was
achieved by the treatment of b-30 with mesyl chloride and pyri-
dine to give 34, followed by cleavage of the acetonide protecting
group with TFA/H2O. Treatment of the diol 35 with NaHMDS in
THF effected closure of the oxetane ring and was accompanied
by loss of the toluoyl ester to give the desired 20-C-methyl-contain-
ing 10,20-oxetane-uridine 7 in good yield. In contrast to 6, perform-
ing the reaction with NaOMe in MeOH furnished only the oxetane
7 and no [2.1.2]-bicyclic derivative was isolated.
O
NH
RO
O
HO
O
O
O
N
O
OH
CHO
RO
+
O
O
O
O
O
The three oxetane nucleosides 5, 6, and 7 were evaluated in a
whole cell-based HCV replicon assay and none was found to pos-
18 R = 4-toluoyl
29 R = PMB
30 R = 4-toluoyl
31 R = PMB
32
sess inhibitory activity (EC50 >45
lM) nor cytotoxicity (CC50
Scheme 7. See Table 1 for conditions.
>100 M). Against the purified HCV NS5B 1b wild type polymerase,
l

Z. Komsta et al. / Tetrahedron Letters 55 (2014) 6216–6219
6219
Table 1
Solvent, temperature, and promoter screening for the synthesis of 30
Entrya
Sugar
Solvent
Promoterc
Temp (°C)
Time (h)
Ratio b:
a
Yield of 30 (%)
1
2
3
18
18
18
18
18
18
18
18
18
29
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CHCl3
CHCl3
TBME/CH2Cl2
TBME/CH2Cl2
CH3CN
TMSOTf
TMSOTf
BF3ꢁOEt
TMSOTf
TMSOTf
TMSOTf
SnCl4
TMSOTf
SnCl4
TMSOTf
rt
90
rt
rt
16
16
16
18
64
2
1:3.5
—
—
1:2
1:4
1:5
—
—
—
—
30
—
—
10
<10
10
—
Trace
Trace
—
4b
5b
6
rt
rt to 50
rt to 50
rt
rt
rt
7
8
9
10
2
16
16
16
a
Persilylated uracil was used in all examples. Uracil was treated with (NH4)2SO4 and HMDS at 130 °C. Sugar was added as a solution, in the indicated solvent, to the crude
silylated uracil.
b
Persilylated uracil was generated in situ by treatment of the sugar and uracil with BSA in CH3CN at 90 °C.
Promoters were added to a solution of the base and sugar at 0 °C and then warmed to the indicated temperature.
c
J. Bilello, C. Chapron, M. La Colla, L. Lallos, J. McCarville, M. Seifer
and I. Serra.
(b)
O
N
O
N
NH
NH
TolO
O
O
Supplementary data
O
(a)
O
OTMS
O
OH
TolO
TolO
+
O
O
O
O
Supplementary data (experimental procedures, characteriza-
tion data and 1H and 13C NMR spectra for all new compounds)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.09.069.
O
O
O
O
18
33
30
Tol = 4-toluoyl
(c)
References and notes
O
N
O
O
1. (a) Veedu, R. N.; Wengel, J. Chem. Biodivers. 2010, 7, 536–542; (b) Jepsen, J. S.;
Sorensen, M. D.; Wengel, J. Oligonucleotides 2004, 14, 130–146; (c) Campbell, M.
A.; Wengel, J. Chem. Soc. Rev. 2011, 40, 5680–5689.
2. Pierra, C.; Amador, A.; Benzaria, S.; Cretton-Scott, E.; D’Amours, M.; Mao, J.;
Mathieu, S.; Moussa, A.; Bridges, E. G.; Standring, D. N.; Sommadossi, J.-P.;
Storer, R.; Gosselin, G. J. Med. Chem. 2006, 49, 6614–6620.
3. Eldrup, A. B.; Allerson, C. R.; Bennett, C. F.; Bera, S.; Bhat, B.; Bhat, N.;
Bosserman, M.; Brooks, J.; Burlein, C.; Carroll, S. S.; Cook, P. D.; Getty, K.;
MacCoss, M.; McMasters, D. R.; Olsen, D. B.; Prakash, T. P.; Prhavc, M.; Song, Q.;
Tomassini, J. E.; Xia, J. J. Med. Chem. 2004, 47, 2283–2295.
NH
NH
NH
(e)
(d)
O
OMs
TolO
N
O
N
O
OMs
O
HO
TolO
O
O
O
O
O
HO
HO
OH
7
35
34
Scheme 8. Reagents and conditions: (a) persilylated uracil, TMSOTf, CH3CN, 0 °C to
rt, 16 h; (b) AcOH, H2O, THF, rt to 40 °C, 0.5 h; (c) MsCl, py, rt, 16 h; (d) TFA/H2O
(9:1), 40 °C, 1 h, 68% (over 2 steps); (e) NaHMDS, THF, 0 °C to rt, 2 h, 61%.
4. Sofia, M. J.; Bao, D.; Chang, W.; Du, J.; Nagarathnam, D.; Rachakonda, S.; Reddy,
P. G.; Ross, B. S.; Wang, P.; Zhang, H.-R.; Bansal, S.; Espiritu, C.; Keilman, M.;
Lam, A. M.; Steuer, H. M. M.; Niu, C.; Otto, M. J.; Furman, P. A. J. Med. Chem.
2010, 53, 7202–7218.
5. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeeting
Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM371877.pdf 25
November 2013.
6. Mohd Hanafiah, K.; Groeger, J.; Flaxman, A. D.; Wiersma, S. T. Hepatology 2013,
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Moussa, A.; Sarkar, R.; Seifer, M.; Serra, I.; Stewart, A. Bioorg. Med. Chem. Lett.
2014, 24, 2699–2702.
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Pradeepkumar, P. I.; Isaksson, J.; Petit, C.; Chattopadhyaya, J. Angew. Chem., Int.
Ed. 2001, 41, 3402–3405.
the corresponding oxetane uridine triphosphate 5-TP and 20-C-
methyl oxetane uridine triphosphate 7-TP were both inactive
(IC50 >100
ever, was observed to be a modest inhibitor of HCV NS5B polymer-
ase (IC50 = 10 M). In the case of oxetane guanosine 6, inefficient
l
M).19 The oxetane guanosine triphosphate 6-TP, how-
l
processing of the free nucleoside to the respective nucleoside tri-
phosphate by cellular kinases may explain the absence of activity
observed in the replicon assay. Although subsequent phosphoryla-
tions could potentially be compromised, this issue might be cir-
cumvented by incorporation of a monophosphate prodrug kinase
by-pass strategy.
9. Pradeepkumar, P. I.; Cheruku, P.; Plashkevych, O.; Acharya, P.; Gohil, S.;
Chattopadhyaya, J. J. Am. Chem. Soc. 2004, 126, 11484–11499.
10. (a) Bogucka, M.; Nauš, P.; Pathmasiri, W.; Barman, J.; Chattopadhyaya, J. Org.
Biomol. Chem. 2005, 3, 4362–4372; (b) Tkachenko, O. V.; Sentjureva, S. L.;
Vepsäläinen, J.; Mikhailopulo, I. A. Synlett 2005, 1683–1686.
In summary, 20-C-methyl-containing 10,20-oxetane-uridine 7
ˇ
´
11. Hrebabecky, H.; Farkaš, J. Collect. Czech. Chem. Commun. 1974, 39, 1098–1106.
12. Roivainen, J.; Vepsäläinen, J.; Azhayev, A.; Mikhailopulo, I. A. Tetrahedron Lett.
2002, 43, 6553–6555.
[1-(10,30-O-anhydro-30-C-methyl-b-
D
-psicofuranosyl)uracil], was
synthesized from 6-O-(p-toluoyl)-1,2:3,4-di-O-isopropylidene-3-
C-methyl-
D
-psicofuranose and its anti-HCV activity was examined
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sine. The respective triphosphate of 10,20-oxetane guanosine 6-TP
was found to possess modest activity against the NS5B 1b wild
type polymerase.
Acknowledgments
Mrs. L. Morris is gratefully acknowledged for performing sam-
ple analysis. In vitro biology assays were performed at Idenix by
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