The synthesis and biological evaluation of novel bridging nucleoside analogues

Article abstract of DOI:10.1016/S0968-0896(01)00278-4

Novel bridging nucleoside analogues were prepared by cycloaddition reactions between pyranose glycals and barbiturate-derived, reactive thionoimides in modest yields. In all of the reactions conducted, the major cycloadducts obtained were the bottom faced adducts resulting from endo addition to the glycal. The adducts were stable to a variety of acidic reaction conditions and several of the compounds showed moderate activities against HIV-1 in primary human lymphocytes. One compound displayed anti-herpes simplex virus type-1 activity in Vero cells. Cytotoxicity measurements were also obtained. Copyright

Full text of DOI:10.1016/S0968-0896(01)00278-4

Bioorganic & Medicinal Chemistry 10 (2002) 273–281
The Synthesis and Biological Evaluation of Novel Bridging
Nucleoside Analogues
Cecilia H. Marzabadi,a,* Richard W. Francka and Raymond F. Schinazib
aDepartment of Chemistry, Hunter College-CUNY, 695 Park Avenue, NewYork, NY 10021, USA
bVeterans Affairs Medical Center and Department of Pediatrics, Emory University School of Medicine,
1670 Clairmont Road, Decatur, GA 30033, USA
Received 16 April 2001; accepted 27 July 2001
Abstract—Novel bridging nucleoside analogues were prepared by cycloaddition reactions between pyranose glycals and barbitu-
rate-derived, reactive thionoimides in modest yields. In all of the reactions conducted, the major cycloadducts obtained were the
bottom faced adducts resulting from endo addition to the glycal. The adducts were stable to a variety of acidic reaction conditions
and several of the compounds showed moderate activities against HIV-1 in primary human lymphocytes. One compound displayed
anti-herpes simplex virus type-1 activity in Vero cells. Cytotoxicity measurements were also obtained. # 2001 Elsevier Science Ltd.
All rights reserved.
Introduction
In recent years, the chemical modification of nucleo-
sides and nucleotides has resulted in compounds that
possess improved selectivity in vitro and in vivo,
improved activity against mutant viruses, increased oral
bioavailability, enhanced cellular uptake and the
appropriate hybridization to target genes on mRNA.5
The substitution of the ring atoms of the sugar
moiety with other heteroatoms has also lead to
analogues with greater potency. For example, diox-
olane6 and oxathiolane7 nucleosides have exhibited
promising antiviral and anticancer properties. Other
changes in the sugar moiety have also been effec-
tive. Hexopyranosyl nucleoside analogues have
been prepared by Eschenmoser8 and were found to
be highly efficient at duplex formation. Locked
nucleic acids in which the conformation of the ring
is fixed due to bridging are also believed to be
active because of entropically more favorable duplex
formation.9
The discovery that modified nucleoside analogues are
potentially effective therapeutic agents for the treatment
of acquired immune deficiency syndrome (AIDS) has
spurred research into new chemistry for the synthesis of
these molecules. Recent examples of selective nucleo-
side-based antiviral agents are 30-azido-30-deoxy-
thymidine (AZT, 1),1 lamivudine (3TC, 2),3 9-(2-
hydroxyethoxymethyl)guanine (acyclovir, ACV, 3)2 and
oxetanocin A44. In addition to the potential antiviral
properties of nucleoside analogues, they are also a very
important class of compounds due to their wide range of
biological activities as antitumor and antibiotic agents.
In this paper, we describe our results on the
synthesis and antiviral activities of a new class of
bridging nucleoside analogues. The compounds
described are tricyclic derivatives consisting of pyra-
nose sugars, oxathienes and nitrogen-containing
heterocyclic rings fused together. These confor-
mationally-restricted nucleoside analogues were pre-
pared by the cycloaddition reactions of glycals with
thionoimide precursors. The effectiveness of these
compounds against HIV and herpes simplex virus type-
1 (HSV-1) and their cytotoxicity in several cell lines will
be discussed.
*Corresponding author at current address: Department of Chemistry
and Biochemistry, Seton Hall University, 400 South Orange Ave.
South Orange, NJ 07079, USA. Tel.:+1-973-761-9032; fax: +1-973-
761-9772; e-mail: mazabce@shu.edu
0968-0896/02/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(01)00278-4

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C. H. Marzabadi et al. / Bioorg. Med. Chem. 10 (2002) 273–281
Background and Significance
Because of the structural similarity of the barbiturates
with the pyrimidine bases and because of the potential
high stability of the resulting adducts, we also prepared
O-linked nucleoside analogues from barbiturate-derived
thionoimides and tri-O-benzyl-d-glucal using a cyclo-
addition route.14 Herein, we report further, detailed
results of these synthetic studies with other glycals
derived from pyranose and furanose sugars and thio-
noimides prepared from N-protected and unprotected
barbituric acid.
The barbiturates are a class of compounds closely rela-
ted to the pyrimidine bases found in many nucleoside
analogues; the key difference being an additional car-
bonyl group present in the heterocyclic ring. N-glucur-
onidation of barbiturates has been determined as the
major pathway for the metabolism of these compounds
in vivo.10 However, the N-glucuronides are not stable
and have consequently not been studied as potential
therapeutic agents.11 Following N-glycosylation, the
barbiturate rings are more susceptible to hydrolysis and
decompose to their corresponding malonurates.12 O-
Glucuronidation is normally not a major metabolic
pathway for the barbiturates.
Results and Discussion
Synthesis
Barbituric acid and its N-alkylated derivatives possess
an enolizable center; two hydrogens on a carbon alpha
to two imidic carbonyls. Recently, it was demonstrated
that the reagent phthalimidosulfenyl chloride reacts
with compounds that possess enolizable hydrogens to
produce reactive acylthiones that can be trapped with
electron-rich alkenes.13 Cycloadducts were prepared
from a variety of acyl thiones and alkenes. Glycals,
which contain a vinyl ether moiety, gave excellent yields
of cycloadducts.14
Treatment of 1,3-dimethylbarbituric acid 9 with phtha-
limidosulfenyl chloride 10 afforded sulfenylated deriva-
tive 11 (Scheme 2). This compound was stable and
could be stored in the freezer for months without sig-
nificant decomposition. When needed, thionoimide 12
was generated in situ by treatment of crude 11 with 2,6-
lutidine. When 12 was formed in the presence of glycals,
the appearance of products was observed over time. The
cycloaddition reactions were monitored by taking ali-
quots at various time intervals and analyzing them by
1H NMR (300 MHz, CDCl3). Two unique resonances
were observed over time corresponding to the anomeric
protons of two cycloadducts. Both resonances were
doublets; the anomeric proton signal of the bottom face
adduct (a-d-anomer) appeared further down field (5.7–
5.9 ppm) and had a coupling constant of 2–3 Hz. The
minor adduct (b-d-anomer) had a C1 1H resonance
which was more shielded (5.4–5.6 ppm) and a smaller 3J
(1–2 Hz). Both resonances were well separated from the
glycal olefinic 1H resonances. When no additional
change in the proton NMR was observed, the reaction
was stopped.
For example, when reacted with the acylthione deriva-
tive of 2,4-pentanedione 6 was reacted with tri-O-ben-
zyl-d-glucal (Scheme 1), both the regioselectivity and
facial selectivity of addition to the glycal was high.
Some adducts proved to be remarkably stable and only
underwent ring opening when further derivatized and
activated with strong acids.15
When 12 was reacted with 3,4,6-tri-O-benzyl-d-glucal 5,
a mixture of a-gluco 13 and b-manno cycloadducts 14
(9:1; 64%) was obtained after 48 h. Prolonging the
reaction time gave rise to reduced yields of products.
Attempts to optimize the reaction yields by changing
the reaction solvent from DMF to THF or CH2Cl2 were
Scheme 1.
Scheme 2.

C. H. Marzabadi et al. / Bioorg. Med. Chem. 10 (2002) 273–281
275
also unsuccessful. It seems likely that the decomposition
of the intermediate thionoimide under the reaction con-
ditions of the cycloaddition is responsible for the mod-
est yields of adducts from these reactions. The
cycloadducts obtained were easily purified from residual
starting materials by silica gel column chromatography.
TBAF16 (Scheme 3) and the resulting trihydroxy
compound was purified by prep TLC (C18).
Table 2. Reaction of thionoimide with other glycals
Glycal
Reaction
time
(days)
Isolated yield
of bottom-face
adduct
Isolated
yield of top-face
adduct
The stereochemistry of the adducts was further con-
firmed by NOESY experiments (400 MHz). Irradiation
of H1 in adduct 13 produced only a single cross peak
(NCH3), whereas irradiation of H1 in adduct 14 showed
four cross-peaks (NCH3, H2, H3, and H5).
25
27
29
31
4
7
2
1
33 %, 26
11 %, 28
37 %, 30
Nd
Nda
Nd
Nd
Nd
aNd, none detected.
The barbiturate-derived thionoimide 12 reacted with a
variety of other protected glucals to give mixtures of
adducts (Table 1). In all instances, the bottom-face
adduct was obtained as the major product. In addition,
the regioselectivity remained constant in all of the
reactions tried.
Table 1. Reaction of thionoimide 12 with different protected glucals
Glucal
Reaction Isolated yield
time
(days)
Isolated
of bottom-face yield of
Scheme 3.
adduct
top-face
adduct
The free imido adducts were also accessible from barbi-
turic acid 35 (Scheme 4). Reaction of 35 with an excess
of phthalimidosulfenyl chloride afforded 36 in which
one of the nitrogens as well as the imide carbon had
been sulfenylated. Treatment of 36 with 2,6-lutidine in
the presence of 3,4,6-tri-O-acetyl-d-galactal 25 for 3
days at rt afforded, after chromatography, 57% of the
a-adduct 37 as a single isomer. Apparently, the N–S
bond was readily hydrolyzed prior to isolation. The free
imido adduct was also prepared from 3,4-di-O-acetyl-l-
rhamnal 27 (Table 3).
R1=R2=R3=Bn, 5
R1=R2=R3=Ac, 15
R1=R2=R3=TBDMS, 18
R1=H; R2=R3=DTBS, 21
R1=H; R2=R3=C(CH3)2, 23
2
6
1
7
3
58 %, 13
39 %, 16
31 %, 19
46 %, 22
23 %, 24
6 %, 14
10%, 17
< 5 %, 20
Nda
Nd
aNd, none detected.
Glycals of other sugars also gave modest yields of
cycloadducts (Table 2). The bottom-face cycloadduct 26
was obtained exclusively when tri-O-acetyl-d-galactal 25
was used as the glycal. Other sugars that were success-
fully used were 3,4-di-O-acetyl-l-rhamnal 27 and lactal
derivative 29. Attempts to prepare cycloadducts from
the ribofuranose glycal 31 were unsuccessful. After 24 h,
substantial amounts of decomposition of the sugar had
occurred leading to the formation of furan 32.
Scheme 4.
Table 3. Reaction of bis-phthalimidosulfenylated barbituric acid
with glycals
Glucal
Reaction
time
(days)
Isolated yield of
bottom-face
adduct
Isolated yield of
top-face
adduct
Reaction of thionoimide 12 with the unprotected sugar,
d-glucal 33 in DMF, appeared to give rise to one major
cycloadduct when monitored by H NMR, however the
isolation of the adducts from the reaction mixture
proved difficult. In order to obtain the unprotected
gluco adduct 34, compound 22 was desilylated using
1
25
27
3
5
57 %, 37
35 %, 38
Nda
Nd
aNd, none detected.

276
C. H. Marzabadi et al. / Bioorg. Med. Chem. 10 (2002) 273–281
Heteroaryl substituted anomeric groups have been
reported to act as excellent glycosyl donors.17 For this
reason, we sought to evaluate the reactivity of our
adducts with a variety of glycosylation promoters in
methanol. Adduct 13 was treated with triflic acid (1
equiv) in the presence of a large excess of methanol in
dichloromethane at À20 ꢀC (Scheme 5). After 3.5 h,
only unreacted starting material was obtained following
workup of the reaction mixture. Similar results were
realized when stoichiometric amounts of TMSOTf were
employed with 1,2:3,4-di-O-isopropylidene-a-d-galacto-
pyranoside (2 equiv) at rt in dichloromethane. When the
minor, top faced adduct 14 was subjected to similar
conditions, analogous results were obtained.
Biological evaluation
Several of the compounds prepared were tested against
HIV-1 in primary human peripheral blood mononuclear
(PBM) cells, and the antiviral activity was expressed by
the concentrations (mM) that inhibit 50% of viral repli-
cation (EC50) and 90% of viral replication (EC90)
(Table 4). In addition the effects of the compounds on
the growth of uninfected human PBM, CEM and Vero
cells were also determined. Compounds 13, 14, 26, 28,
30, and 34 were also tested against HSV-1 using a
plaque assay in Vero cells.
As can be seen from the data, four of the compounds
(26, 28, 30, and 38) showed activity against HIV-1 in
human PBM cells. Note that while these compounds are
moderately effective against HIV-1, they are also cyto-
toxic against human PBM and CEM cells. Only one of
the compounds tested, 26 showed activity against HSV-
1. However, the anti-HSV activity is secondary to the
cytotoxic effects in Vero cells; therefore the activity is
not specific.
Conclusions
Scheme 5.
Novel bridging nucleoside analogues were prepared by
cycloaddition reactions between glycals and barbitu-
rate-derived reactive thionoimides in modest yields. In
all of the reactions carried out, the major cycloadducts
obtained were the a-anomeric adducts arising from the
preferred endo addition. The cycloaddition reactions
were unaffected by changes in the sugar protecting
groups or in the nature of the pyranose sugar. Furanose
derivatives decomposed to the corresponding furans
under the reaction conditions employed. The solubilities
of the reactants and the stabilities of the thionoimides
had an impact on the yields of adducts obtained. The
resulting cycloadducts were stable to acid. Attempts to
cleave the C2 carbon–sulfur bond were unsuccessful.
We also attempted to cleave the C–S bond of the
cycloadduct in order to prepare the 2-deoxy derivatives.
Treatment of adduct 13 with Raney nickel (W2) in
THF/ethanol resulted in substantial overreduction and
formation of 3,4,6-tri-O-benzyl-d-glucal 5 as the major
product (Scheme 6).
Four of the cycloadducts showed moderate activity
against HIV-1 in human PBM cells. These compounds
were the bottom face adducts of 1,3-dimethyl barbituric
acid with tri-O-acetyl-d-galactal (26), di-O-acetyl-l-
Scheme 6.
Table 4. Antiviral activity and cytotoxicity of selected cycloadductsa
Anti-HIV-1 activity
in PBM cells
Anti-HSV-1 activity
in vero cells
Cytotoxicity in:
PBM
CEM
Vero
Adduct
EC50, (mM)
EC90, (mM)
EC50, (mM)
EC90, (mM)
IC50, (mM)
IC50, (mM)
IC50, (mM)
13
14
34
26
30
28
37
38
>100
>100
>100
13.6
100
100
100
47.7
331
>100
>100
>100
61.0
>100
>100
—
>100
>100
>100
>100
>100
!100
—
>100
>100
>100
39.0
36.5
>100
>100
16.7
>100
12.6
>100
>100
>100
61.7
>100
>100
>100
>100
107
100
29.0123
>100
41.4
46.2
>100
70.0
>100
100
>100
14.3
—
—
aAZT and acyclovir used as positive controls for the HIV and HSV-1 assays, had an EC50 of 0.004 and 0.1 mM, respectively.

C. H. Marzabadi et al. / Bioorg. Med. Chem. 10 (2002) 273–281
277
rhamnal (28), 6,6-di-O-(tert-butyldiphenylsilyl)-3,2,3,4-
tetra-O-acetyl-d-lactal (30) and the b-adduct of bar-
bituric acid with di-O-acetyl-l-rhamnal (38). One of
these compounds 26, also showed activity against
HSV-1 in Vero cells. From a structure–activity per-
spective, all of these compounds possess an axially
disposed substituent at the C4 position of the sugar in
the 4C1 conformation that may account for the observed
activities. Deprotection of the hydroxyl groups in the
gluco series (34) and of the imide nitrogens in both the
galacto (37) and rhamno (38) adducts gave rise to either
static or diminished antiviral activities. These com-
pounds were also shown to be cytotoxic in several
mammalian cell lines resulting in a therapeutic index of
approximately two for the best candidate, the galacto
adduct 28.
General procedure for cycloaddition reactions. To a stir-
red suspension of glycal (1 equiv) and barbiturate-S-
phthalimide (1.1 equiv) in dry solvent (0.5–1.0 M con-
centration) and molecular sieves (3 A), 2,6-lutidine (1
equiv) was added as a single portion. The mixture was
stirred at rt and the reaction progress was monitored by
1H NMR (300 MHz, CDCl3) until no change in glycal
concentration was detected (1–7 days). The mixture was
quenched with saturated aq NH4Cl, and was washed
with CH2Cl2 (3ꢁ). The combined organics were washed
with water, then with brine, and were dried (MgSO4),
filtered and concentrated in vacuo.
Cycloaddition with 3,4,6-tri-O-benzyl-D-glucal. To a
solution of 3,4,6-tri-O-benzyl-d-glucal 5 (0.19 g, 0.47
mmol) and barbiturate-S-phthalimide 11 (0.21 g, 0.52
mmol) in dry DMF (2.5 mL), powdered sieves (0.3 g)
and 2,6-lutidine (0.053 mL, 0.47 mmol) were added. The
mixture was stirred at rt for 2 days, then was quenched
with aq NH4Cl and worked up as previously decribed.
A crude product (0.41 g) was obtained which was chro-
matographed (SiO2; 33–55% ethyl acetate in petroleum
ether) to afford 3,4,6-tris-O-(phenylmethyl)-2-thio-1-O,2-S-
(1,2,3,6 - tetrahydro - 1,3 - dimethyl - 2,6 - dioxo - 4,5 - pyr-
imidinediyl)-a-d-glucopyranose (13) as a white powder
(0.16 g, 0.28 mmol, 58%): mp 60–63 ꢀC; [a]D +84.1ꢀ (c
0.9, CHCl3). IR (thin film) 2918, 1742, 1702, 1646, 1456,
Experimental
All reagents were obtained from commercial sources
and were used without further purification. Dry DMF
was purchased from Aldrich Chemical Company. THF
was distilled from Na/benzoquinone ketyl and CH2Cl2
was distilled from P2O5. Column chromatography was
carried out on silica gel (Merck; 230–400 mesh) using
1
gradients of ethyl acetate in petroleum ether. H and
13C NMR spectra were recorded on a Varian EM360
(300 MHz) instrument. These spectra are reported in
ppm relative to tetramethylsilane as internal standard.
NOESY spectra were recorded on a Jeol 400 MHz
spectrometer. Optical rotations were measured in a
Rudolph Autopol II polarimeter under standard condi-
tions. Chemical ionization and FAB mass spectra were
obtained in the positive ion mode. Microanalyses were
performed at Robertson MicrolitLaboratory (Madison,
NJ, USA).
1362, 1199, 1130, and 1028 cmÀ1. H NMR d 7.40–7.26
1
(m, 13H), 7.17–7.13 (m, 2H), 5.85 (d. 1H, J=2.7 Hz),
4.97–4.65 (m, 3H), 4.63–4.52 (m, 3H), 3.95 (dd, 1H,
J=10.1, 2.7 Hz), 3.86–3.70 (m, 3H), 3.63 (dd, 1H,
J=10.8, 8.7 Hz), 3.38 (s, 3H), 3.37 (s, 3H), 3.31 (dd, 1H,
J=10.8, 3.0 Hz); 13C NMR d 160.3, 151.1, 150.1, 137.5,
137.4, 128.4, 128.3, 127.9, 127.8, 99.8, 80.7, 77.8, 77.1,
75.3, 74.1, 73.6, 67.8, 42.1, 29.1, 28.3. MS (DEP/PCI)
(m/z) (rel. intensity) 434 (100) (MÀC6H6O3N2S +
NH+4 ). Anal. calcd For C33H34O7N2S.H2O: C, 63.86; H,
5.80, N, 4.51. Found: C, 63.72, H, 5.93, N, 4.33. Further
elution afforded 3,4,6-tris-O-(phenylmethyl)-2-thio-1-O,2-
S-(1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-4,5-pyr-
imidinediyl)-b-d-mannopyranose (14) as an oil (0.02 g,
3.0ꢁ10À5 mol, 6%): [a]D +42.9 (c 0.3, CHCl3). IR
(neat) 3012, 2942, 2883, 1731, 1701, 1637, 1454, 1366,
1,3-Dimethyl-2-thiophthalimido-barbituric acid (11). To
a solution of 1, 3-dimethylbarbituric acid 9 (0.33 g, 2.1
mmol) in dry THF (4 mL) at 5 ꢀC, a solution of phtha-
limidosulfenyl chloride 10 (0.65 g, 2.3 mmol) in dry
CH2Cl2 (4 mL) was added. The mixture was stirred for
1 h, then was triturated with n-pentane (50mL) and was
warmed to rt. A beige solid was formed and was col-
lected by vacuum filtration and dried in vacuo to afford
1
1261, 1184, 1096, and 1014 cmÀ1. H NMR d 7.35–7.26
(m, 13H), 7.17–7.15 (m, 2H), 5.47 (d, 1H, J=0.9 Hz),
4.80(Abq, 2H), 4.57–4.49 (m, 4H), 3.98 (m, 2H), 3.83
(d, 1H, J=1.8 Hz), 3.76–3.65 (m, 3H), 3.37 (s, 3H), 3.36
(s, 3H); 13C NMR d 160.6, 150.1, 149.4, 137.8, 137.7,
137.0, 128.5, 128.4, 128.1, 127.9, 127.8, 123.6, 94.5, 79.7,
76.6, 74.9, 73.5, 73.1, 71.3, 69.1, 40.2, 29.4, 28.4. MS
1
11 (0.77g, 1.94 mmol, 92%): H NMR (DMSO-d6) d
11.31 (br s), 7.81 (s, 4H), 3.14 (s, 3H), 3.09 (s, 3H); 13C
NMR d 168.9, 163.8, 151.9, 134.1, 132.5, 122.7, 28.3,
28.2.
(DEP/PCI)
(m/z)
(rel.
intensity)
434
(100)
N-2-Bis-thiophthalimido-barbituric acid (36). To a solu-
tion of barbituric acid 35 (0.10 g, 0.78 mmol) in THF (2
mL) at 5 ꢀC was added a solution of phthalimidosul-
fenyl chloride 10 (0.65 g, 3.0 mmol) in CH2Cl2 (2 mL).
The mixture was stirred for 45 min, then warmed to rt
and stirred for an additional 15 min. It was triturated
with n-pentane (20mL) and the resulting white powder
was collected by vacuum filtration (0.59 g, 0.90 mmol):
1H NMR (DMSO-d6) d 11.29 (br s, 1H), 8.93–8.88 (m,
1H), 8.10–7.79 (m, 4H), 2.52 (s, 1H); 13C NMR d 167.2,
165.8, 146.1, 141.7, 135.5, 134.3, 132.8, 132.0, 127.7,
124.3, 123.1.
(MÀC6H6O3N2S
+
NH+4 ). Anal. calcd for
C33H34O7N2S: C, 65.76; H, 5.69; N, 4.64. Found: C,
65.49; H, 5.94; N, 4.38.
Cycloaddition with 3,4,6-tri-O-acetyl-D-glucal. To a
solution of tri-O-acetyl-d-glucal 15 (0.17 g, 0.6 mmol)
and barbiturate-S-phthalimide 11 (0.21 g, 0.7 mmol) in
dry DMF (2 mL) containing powdered 3 A molecular
sieves (0.15 g), 2,6-lutidine (0.07 mL, 0.6 mmol) was
added as a single portion. The mixture was stirred at rt
for 6 days, then was worked up in the usual manner.
The crude product (0.31 g) was chromatographed (SiO2,

278
C. H. Marzabadi et al. / Bioorg. Med. Chem. 10 (2002) 273–281
40–80% ethyl acetate in petroleum ether) and afforded
3,4,6-tri-O-acetyl-2-thio-1-O,2-S-(1,2,3,6-tetrahydro-1,3-
dimethyl-2,6-dioxo-4,5-pyrimidinediyl)-a-d-glucopyr-
anose (16) as a white powder (0.12g, 0.2 mmol, 39%):
mp 173–176; [a]D +170.8ꢀ (c 0.56; CHCl3). IR (thin
film) 2950, 1749, 1659, 1588, 1507, 1221, 1144 and 1014
cmÀ1. 1H NMR d 5.89 (d, 1H, J=2.7 Hz), 5.18–5.15 (m,
2H), 4.38–4.31 (m, 1H), 4.26–4.18 (m, 2H), 3.45–3.40
(m, 1H), 3.42 (s, 3H), 3.33 (s, 3H), 2.12 (s, 3H), 2.08 (s,
3H), 2.01 (s, 3H); 13C NMR d 170.3, 169.7, 169.2, 159.9,
150.3, 149.9, 98.1, 80.4, 70.7, 68.4, 67.6, 61.2, 39.9, 28.9,
28.2, 20.5, 20.4, 20.3. MS (ES) (m/z) (rel. intensity) 295
(26), 357 (100), 459 (M+H) (32), 481 (M+Na) (78),
497 (M+K) (3). Anal. calcd for C18H22O10SN2: C,
46.99; H, 5.16; N; 6.08. Found: C, 47.18; H, 4.96; N,
6.08. Further elution afforded 3,4,6-tri-O-acetyl-2-thio-
1-O,2-S-(1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-4,5-
pyrimidinediyl)-b-d-mannopyranose (17) as a clear oil
(0.03 g, 6.0ꢁ10À5 mol, 10%): [a]D À16.8ꢀ (c 0.5;CHCl3).
IR (thin film) 2963, 1750, 1703, 1657, 1634, 1486, 1456,
1368, 1227 and 1047 cmÀ1. 1H NMR 5.59 (d, 1H, J=1.5
Hz), 5.54 (dd, 1H, J=9.6, 9.3 Hz), 5.29 (dd, 1H, J=9.3,
4.8 Hz), 4.24–4.22 (m, 2H), 3.92 (dd, 1H, J=4.5, 1.5
Hz), 3.93–3.85 (m, 1H), 3.41 (s, 3H), 3.36 (s, 3H), 2.10
(s, 3H), 2.09 (s, 3H), 2.07 (s, 3H); 13C NMR d 170.4,
169.7, 169.0, 160.2, 149.8, 148.9, 93.6, 83.2, 71.6, 64.9,
62.1, 40.6, 29.8, 29.6, 28.6, 20.8, 20.7 (2C). MS (ES) (m/
z) (rel. intensity) 295 (100), 357 (84), 481 (M+Na) (27);
HRMS (FAB+) calcd for C18H22O10SN: 459.107342;
Found: 459.107600
added as a single portion. The mixture was stirred at rt
for one week, then was worked up as previously descri-
bed to afford crude product (0.48 g). Column chroma-
tography (SiO2; 2:1 petroleum ether/ethyl acetate)
afforded 4,6-O-(tert-butyldimethylsilanyl)-2-thio-1-O,2-S-
(1,2,3,6 - tetrahydro - 1,3 - dimethyl - 2,6 - dioxo - 4,5-pyr-
imidinediyl)-a-d-glucopyranose (22) as a white, waxy
solid (0.15 g, 0.32 mmol, 46%): mp 135–145 (d); [a]D
+79.1ꢀ (c 0.85, CHCl3). IR (thin film) 3445, 2936, 2861,
1
1701, 1688, 1472, 1135, 1090, and 1022 cmÀ1. H NMR
d 5.83 (d, 1H, J=2.7 Hz), 4.24–4.21 (m, 1H), 3.97–3.85
(m, 3H), 3.63–3.57 (m, 2H), 3.41 (s, 3H), 3.33 (s, 3H),
3.23 (dd, 1H, J=10.2, 2.7 Hz), 1.07 (s, 9H), 0.98 (s, 9H);
13C NMR d 160.3, 150.9, 149.9, 99.1, 80.4, 77.4, 69.4,
69.0, 65.9, 60.5, 42.2, 28.9, 28.2, 27.2, (2C), 26.7 (2C),
22.5, 19.8, 14.0. MS (ES) (m/z) (rel. intensity) 473
(M+H) (100), 495 (M+Na) (13). Anal. calcd For
C20H32N2O7SSi : C, 50.82; H, 6.83; N, 5.93. Found: C,
50.53; H, 6.51; N, 5.67.
Cycloaddition with 4,6-O-isopropylidene-D-glucal. To a
solution of 4,6-O-isopropylidene-d-glucal 23 (0.2 g, 1.1
mmol) and barbiturate-S-phthalimide 11 (0.85 g, 1.3
mmol) in dry DMF (3 mL), 2,6-lutidine (0.13 mL, 1.1
mmol) and molecular sieves (0.3 g) was added. The
mixture was stirred at rt for 3 days, then worked-up as
previously described to afford crude product (0.5 g).
Column chromatography (SiO2; 50–80% ethyl acetate
in petroleum ether) afforded 4,6-O-isopropylidene-2-thio
-1-O,2-S-(1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-4,5-
pyrimidinediyl)-a-d-glucopyranose (24) as an oil (0.1 g,
0.26 mmol, 23%): [a]D +2.3ꢀ (c 0.8, CHCl3). IR (neat)
3440, 2993, 2945, 1703, 1633, 1485, 1378, 1204, and
Cycloaddition with 3,4,6-tris(O-tert-butyldimethylsilyl)-
D-glucal. To a solution of glucal 18 (0.11 g, 0.2 mmol)
and barbiturate-S-phthalimide 11 (0.20 g, 0.34 mmol) in
dry DMF (2 mL) containing powdered 3 A molecular
sieves (0.14 g), 2,6-lutidine (0.03 mL, 0.2 mmol) was
added as a single portion. The mixture was stirred at rt
for 24 h then was worked up as previously described to
afford crude product (0.15 g). Column chromatography
(SiO2, 5–20% ethyl acetate in petroleum ether) afforded
3,4,6-tris-O-(tert-butyldimethylsilyl) - 2 - thio - 1 - O,2 - S -
(1,2,3,6 - tetrahydro - 1,3 - dimethyl - 2,6 - dioxo - 4,5 - pyr-
imidinediyl)-a-d -glucopyranose (19) (0.05g, 6.9ꢁ10À5
mol, 31%) as a white powder: mp 125–127 ꢀC; [a]D
+1.8ꢀ (c 0.5, CHCl3). IR (thin film) 2931, 1701, 1650,
1558, 1540, 1507, 1458, 1257 and 1097 cmÀ1. 1H NMR d
5.65 (d, 1H, J=2.4 Hz), 4.19–4.11 (m, 2H), 4.95
(apparent t, 1H, J=3.6 Hz), 3.79–3.71 (m, 2H), 3.63
(apparent t, 1H, J=3.0Hz), 3.33 (s, 3H), 3.31 (s, 3H),
0.89 (s, 9H), 0.86 (s, 9H), 0.76 (s, 9H), 0.09 (s, 3H), 0.08
(s, 3H), 0.07 (s, 3H), 0.05 (s, 3H), 0.03 (s, 3H), 0.003 (s,
3H); 13C NMR d 160.3, 150.2, 149.9, 96.7, 83.4, 79.5,
76.9, 74.1, 68.3, 62.9, 36.5, 28.9, 28.1, 25.8 (6C), 25.6
(6C), 18.2, 17.9, 17.8. MS (DEP/PCI) (m/z) (rel. inten-
sity) 360 (22), 374 (100), 506 (24), 675 (M+H) (1). Anal.
calcd for C30, H58,O7, N2,Si3: C, 52.02; H, 8.67; N, 4.04.
Found: C, 52.43, H, 8.62; N, 3.65.
1
1129 cmÀ1. H NMR d 5.87 (d, 1H, J=3.3 Hz), 3.99–
3.95 (m, 1H), 3.89–3.67 (m, 4H), 3.43 (s, 3H), 3.40–3.38
(m, 1H), 3.33 (s, 3H), 3.23 (dd, 1H, J=9.9, 3.0Hz), 1.56
(s, 3H), 1.44 (s, 3H); 13C NMR d 160.6, 151.6, 150.0,
100.3, 99.6, 79.6, 73.9, 66.8, 66.7, 61.7, 43.5, 29.2, 28.8,
28.4, 18.9. MS (DEP/PCI) (m/z) (rel. intensity) 129 (65),
146 (81), 187 (81), 204 (100), 372 (M) (36), 390 (M+NH+4 )
(50). Anal. calcd For C15H20O7SN2: C, 48.39; H, 5.38.
Found: C, 48.24; H, 5.77.
Cycloaddition with 3,4,6-tri-O-acetyl-D-galactal. To a
solution of tri-O-acetyl-d-galactal 25 (0.31g, 1.2 mmol)
and barbiturate-S-phthalimide 11 (0.46g, 1.4 mmol) in
dry DMF (3 mL) containing 3 A molecular sieves (0.15
g), 2,6-lutidine (0.13 mL, 1.2 mmol) was added as a
single portion. The mixture was stirred at rt for 4 days,
then worked-up as described to afford crude product
(0.4 g). Column chromatography (SiO2; 40–70% ethyl
acetate in petroleum ether) afforded 3,4-6-tri-O-acetyl-
2-thio-1-O,2-S-(1,2,3,6-tetrahydro - 1,3 - dimethyl - 2,6 -
dioxo-4,5-pyrimidinediyl)-a-d-galactopyranose (26) (0.19
g, 33%) as a white powder: mp 160–161 ꢀC (ether:hex-
anes); [a]D +128ꢀ (c 1.6, CHCl3). IR (thin film) 1748,
1700, 1647, 1540, 1508, 1371, 1230, 1144, and 1026
1
cmÀ1. H NMR d 5.93 (d, 1H, J=2.7 Hz), 5.45 (br d,
Cycloaddition reaction with 4,6-O-tert-butyldimethylsila-
nyl-D-glucal. To a solution of glycal 2115 (0.2 g, 0.7
mmol) and barbiturate-S-phthalimide 11 (0.3 g, 0.8
mmol) in dry DMF (3 mL) containing powdered 3 A
mol sieves (0.24 g), 2,6-lutidine (0.08 mL, 0.7 mmol) was
1H, J=3 Hz), 4.98 (dd, 1H, J=11.7, 3.0Hz), 4.41
(apparent t, 1H, J=6.4 Hz), 4.17 (apparent d, 2H,
J=6.6 Hz), 3.65 (dd, 1H, J=11.7, 2.7), 3.40(s, 3H),
3.33 (s, 3H), 2.17 (s, 3H), 2.06 (s, 3H), 2.03 (s, 3H); 13C
NMR d 170.2, 169.8, 169.7, 150.1, 149.9, 98.9, 77.4,

C. H. Marzabadi et al. / Bioorg. Med. Chem. 10 (2002) 273–281
279
77.0, 69.7, 66.7, 65.5, 61.2, 36.1, 29.1, 28.4, 20.6, 20.5
(2C). MS (ES) (m/z) (rel. intensity) 459 (M+H) (100),
481 (M+Na) (70). Anal. calcd for C18H22O10SN2: C,
46.99; H, 5.16; N, 6.08. Found: C, 47.12; H, 5.03, N,
5.84.
Tri-O-acetyl-D-galactal free amido barbiturate cyclo-
adduct. To a solution of tri-O-acetyl-d-galactal 25 (0.12
g, 0.42 mmol) and bis-phthalimidosulfenylated bar-
biturate 36 (0.31 g, 0.47 mmol) in dry DMF (3 mL)
was added 2,6-lutidine (0.05 mL, 0.42 mmol). The reac-
tion mixture was stirred at rt for 3 days, then was
worked up as previously described. Column chro-
matography (SiO2; 50% ethyl acetate in petroleum
ether) afforded 3,4,6-tri-O-acetyl-2-thio-1-O,2-S-(1,2,3,6-
tetrahydro-2,6-dioxo-4,5-pyrimidinediyl)-a-d-galacto-
pyranose (37) (0.14 g, 0.24 mmol, 57%) as a brown oil:
[a]D +20.3ꢀ (c 1.4; CH3OH). IR (neat) 3374, 2924,
Cycloaddition reaction with 3,4-di-O-acetyl-L-rhamnal.
To a solution of 3,4-di-O-acetyl-l-rhamnal 27 (0.17 g,
0.78 mmol), and barbiturate-S-phthalimide 11 (0.33 g,
0.85 mmol) in dry DMF (3 mL) containing 3 A mole-
cular sieves (0.2 g), 2,6-lutidine (0.09 mL, 0.78 mmol)
was added as a single portion. The mixture was stirred
at rt for 1 week, then worked up to afford a crude pro-
duct (0.28 g). Column chromatography (SiO2; 33–66%
ethyl acetate in petroleum ether) afforded 3,4-di-O-ace-
tyl-2-thio-1-O,2-S-(1,2,3,6-tetrahydro-1,3-dimethyl-2,6-
1
1744, 1566, 1413, 1370, 1233 and 1046 cmÀ1. H NMR
(CD3OD) d 6.07 (d, 1H, J=3 Hz); 5.45 (br d, 1H,
J=2.1 Hz), 5.14 (dd, 1H, J=11.7, 3.0Hz), 4.56
(apparent t, 1H, J=6.6 Hz), 4.17 (d, 2H, J=6.3 Hz),
3.76 (dd, 1H, J=11.7, 3.0Hz), 2.17 (s, 3H), 2.03 (s, 3H),
2.02 (s, 3H); 13C NMR d 172.0, 171.7, 171.3, 164.5,
155.1, 155.0, 100.4, 80.2, 70.9, 68.8, 66.8, 62.9, 37.7,
20.7, 20.6 (2C). MS (ES) (m/z) (rel. intensity) 459
(M+K) (8), 430 (M+) (22), 429 (M-H) (100); HRMS
(FAB+) calcd For C16H18N2O10S: 431.075900. Found
431.076042.
dioxo-4,5-pyrimidinediyl)-a-d-rhamnopyranose
(28)
(0.04 g, 8.25ꢁ10À5 mol, 11%) as a white powder:
mp 186–188 ꢀC; [a]D –30.1ꢀ (c 0.7, CHCl3). IR (neat)
2936, 1751, 1690, 1636, 1507, 1472, 1457, 1374, 1232,
1
1140, 1046, and 1009 cmÀ1. H NMR d 5.81 (d, 1H,
J=3.0Hz), 5.90 (dd, 1H,
J=10.8, 9.3 Hz), 4.88
(apparent t, J=9.6 Hz), 4.13–4.04 (m, 1H), 3.40
(s, 3H), 3.36 (dd, 1H, J=7.8, 3.0Hz), 3.32 (s, 3H), 2.05
(s, 3H), 1.28 (d, 1H, J=6.3 Hz); 13C NMR d 169.7,
169.5, 160.0, 150.5, 150.0, 134.1, 123.4, 98.4, 73.8, 69.0,
67.7, 40.5, 29.2, 28.4, 20.7, 17.5. MS (ES) (m/z) (rel.
intensity) 299 (100), 423 (M+Na) (37). HRMS
(FAB+) calcd for C16H21N2O8S: 401.102000. Found:
401.101863.
Di-O-acetyl-L-rhamnal free amido barbiturate cycload-
duct. To a solution of rhamnal 27 (0.11 g, 0.52 mmol)
and bis-phthalimidosulfenylated barbiturate 36 (0.34 g,
0.52 mmol) in dry DMF (3 mL) was added 2,6-lutidine
(0.06 mL, 0.52 mmol). The mixture was stirred at rt for
5 days then was worked up as previously described.
Column chromatography (SiO2; 50% ethyl acetate in
petroleum ether) afforded the 3,4-di-O-acetyl-2-thio-1-
O,2-S-(1,2,3,6-tetrahydro-2,6-dioxo-4,5-pyr-
Cycloaddition reaction with 6,60-di-O-(tert-butyldiphenyl-
silyl)-3,20,30,40-tetra-O-acetyl-D-lactal. To a solution of
lactal 29 (0.09 g, 9.5ꢁ10À5 mol) and barbiturate-S-
phthalimide 11 (0.08 g, 0.2 mmol) in dry DMF (1 mL)
containing powdered 3 A molecular sieves (0.15 g), 2,6-
lutidine (0.016 mL, 0.1 mmol) was added. The mixture
was stirred at rt for 2 days, then worked up as pre-
viously described to afford crude product (0.13 g). Col-
umn chromatography (SiO2; 1:1:1 hexanes/Et2O/
CH2Cl2) afforded 6,60-di-O-(tert-butyldiphenyl)-3,20,30,40
-tetra-O-acetyl-2-thio-1-O,2-S-(1,2,3,6-tetrahydro-1,3-
dimethyl-2,6-dioxo-4,5-pyrimidinediyl)-a-d-lactopyr-
anose (30) (0.04 g, 3.5ꢁ10À5mol, 37%) as a white pow-
der: mp 144–149 ꢀC; [a]D +32.8ꢀ (c 0.9, CHCl3). IR
(thin film) 3015, 2932, 2858, 1751, 1706, 1684, 1659,
imidinediyl)-b-l-rhamnopyranose (38) (0.07 g, 0.18
mmol, 35%) as a white film: [a]DÀ23.4ꢀ (c 0.8; CHCl3).
IR (thin film) 3160, 1714, 1682, 1651, 1622, 1514, 1434,
1
1378. 1294, 1232, 1152, 1131, 1099 and 1045 cmÀ1. H
NMR (CD3OD) d 5.94 (d, 1H, J=3 Hz), 5.14–5.04 (m,
1H), 4.95–4.87 (m, 1H), 4.11 (qd, 1H, J=9, 6 Hz), 3.64
(dd, 1H, J=9, 3 Hz), 2.05 (s, 3H), 2.02 (s, 3H), 1.24 (d,
1H, J=6 Hz); 13C NMR (CD3OD) d 171,7, 171.3,
164.5, 155.1, 151.3, 100.1, 80.5, 75.2, 70.2, 69.0, 41.5,
20.7 (2C), 17.8; HRMS (FAB+) calcd for
C14H16N2O8S : 373.070400. Found: 373.070563.
1,3-Dimethyl-barbituric acid ꢀ-D-glucopyranose cycload-
duct (34). To a solution of bis silyl cycloadduct 21 (0.27
g, 0.57 mmol) in dry THF at 5 ꢀC, TBAF (1.14 mL; 1.14
mmol) was added as a single portion. The mixture was
stirred for 2.5 h, then TMSCl (0.07 mL, 0.57 mmol) was
added. After stirring for an additional 15 min, the mix-
ture was concentrated in vacuo. Preparative TLC (RP,
C18) using 20:1 CH3CN/H2O afforded 2-thio-1-O,2-S-
(1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-4,5-pyrimid-
inediyl)-a-d-glucopyranose (34) (0.12 g, 0.36 mmol,
63%) as a beige oil: [a]D +16.4ꢀ (c 2.3; CH3OH). IR
(thin film) 3389, 2961, 1727, 1674, 1574, 1470, 1416,
1
1559, 1472, 1456, 1368, 1218, 1112, and 1009 cmÀ1. H
NMR d 7.73–7.68 (m, 5H), 7.62–7.57 (m, 5H), 7.48–7.35
(m, 10H), 5.84 (d, 1H, J=3.0Hz), 5.52 (d, 1H, J=3.0
Hz), 5.06 (dd, 1H, J=11.1, 9.6 Hz), 5.00–4.89 (m, H),
4.70(d, 1H, J=7.5 Hz), 4.15 (apparent t, 1H, J=9.6
Hz), 3.99–3.89 (m, 1H), 3.83 (d, 1H, J=9.9 Hz), 3.73–
3.66 (m, 1H), 3.57–3.50(m, 1H), 3.36 (s, 3H), 3.32 (s,
3H), 3.25 (dd, 1H, J=11.4, 3.6 Hz), 2.01 (s, 3H), 1.98 (s,
3H), 1.81 (s, 3H), 1.79 (s, 3H), 1.10(s, 9H), 1.04 (s, 9H);
13C NMR d170.6, 170.4, 169.9, 169.5, 160.8, 150.9,
150.7, 100.7, 99.5, 81.4, 77.9, 77.6, 75.4, 74.7, 73.7, 72.1,
70.4, 68.1, 67.4, 61.6, 61.5, 41.2, 29.9, 29.1, 27.7 (3C),
27.5 (3C), 21.4 (2C), 20.2, 19.8. MS (ES) (m/z) (rel.
intensity) 149 (64); 205 (77), 279 (46), 301 (49), 391 (44),
535 (72), 975 (100), 1161 (M+Na) (7). Anal. calcd for
C58H68O16N2Si2S: C, 61.16; H, 5.98; N, 2.46. Found: C,
60.90; H, 6.37; N, 2.24.
1
1366, 1273 and 1072 cmÀ1. H NMR (CD3CN) d 5.71
(d, 1H, J=3 Hz), 3.64–3.60(m, 1H), 3.36 (dd, 1H,
J=7.5, 2.1 Hz), 3.15 (s, 3H), 3.07 (s, 3H), 3.03–2.99
(m, 1H), 2.04 (br s, 2H), 1.12 (br s, 1H); 13C NMR d
162.1, 153.2, 151.7, 101.2, 77.0, 72.2, 70.6, 62.4, 43.9,
30.0, 29.1, 28.5.

280
C. H. Marzabadi et al. / Bioorg. Med. Chem. 10 (2002) 273–281
5. Uhlmann, E.; Peyman, A. Chem. Rev. 1990, 90, 543.
Antiviral and cytotoxicity assays
6. (a) Kim, H. O.; Ahn, S. K.; Alves, A. J.; Beach, J. W.;
Jeong, L. S.; Choi, B. G.; van Roey, P.; Schinazi, R. F.; Chu,
C. K. J. Med. Chem. 1992, 35, 1987. (b) Kim, H. O.; Schinazi,
R. F.; Shanmuganathan, K.; Jeong, L. S.; Beach, J. W.;
Nampalli, S.; Cannon, D. L.; Chu, C. K. J. Med. Chem. 1993,
36, 519. (c) Kim, H. O.; Schunazi, R. F.; Nampalli, S.; Can-
non, D. L.; Alves, A. J.; Jeong, L. S.; Beach, J. W.; Chu, C. K.
J. Med. Chem. 1993, 36, 30. (d) Kim, H. O.; Shanmuganathan,
K.; Alves, A. J.; Jeong, L. S.; Beach, J. W.; Schinazi, R. W.;
Chang, C.-N.; Cheng, Y.-C.; Chu, C. K. Tetrahedron Lett.
1992, 33, 6899.
7. (a) Coates, J. A.; Cammack, N.; Jenkinson, H. J.; Mutton,
I. M.; Pearson, A. B.; Storer, R.; Cameron, J. M.; Penn, C. R.
Antimicrob. Agents Chemother. 1992, 36, 202. (b) Jeong, L. S.;
Schinazi, R. F.; Beach, J. W.; Kim, H. O.; Shanmuganthan,
K.; Nampalli, S.; Chun, M. W.; Chung, W. K.; Choi, B. G.;
Chu, C. K. J. Med. Chem. 1993, 36, 2627. (c) Schinazi, R. F.;
Chu, C. K.; Peck, A.; McMillan, A.; Mathis, R.; Cannon, D.;
Jeong, L. S.; Beach, J. W.; Choi, B. G.; Yeola, S.; Liotta, D. C.
Antimicrob. Agents Chemother. 1992, 36, 672. (d) Furman,
P. A.; Davis, M.; Liotta, D. C.; Paff, M.; Frick, L. W.; Nelson,
D.; Dornsife, J. E.; Wurster, J. A.; Fyfe, J. A.; Tuttle, J. V.;
Miller, W. H.; Condreay, L.; Avereet, D. R.; Schinazi, R. F.;
Painter, G. R. Antimicrob. Agents Chemother. 1992, 36, 2686.
(e) Schinazi, R. F.; McMillan, A.; Cannon, D.; Mathis, R.;
Lloyd, R.; Peck, A.; Sommadossi, J. P.; St. Clair, M.; Wilson,
J.; Furman, P. A.; Painter, G.; Choi, W. B.; Liotta, D. C.
Antimicrob. Agents Chemother. 1992, 36, 2423.
Anti-HIV-1 activity of the compounds was determined
in human PBM cells as described previously.18 Stock
solutions (20–40 mM) of the compounds were prepared
in sterile DMSO and then diluted to the desired con-
centration in growth medium. Cells were infected with
the prototype HIV-1LAI at a multiplicity of infection of
0.01. Virus obtained from the cell supernatant was
quantitated on day 6 after infection by a reverse tran-
ꢂ
scriptase assay using (rA)n (dT)12À18 as template-primer.
The DMSO present in the diluted solution (<0.1%)
had no effect on the virus yield. The anti-HSV-1 assays
were performed in Vero cells by a plaque assay using
strain F, as described previously.19
The toxicity of the compounds was assessed in human
peripheral blood mononuclear (PBM), Vero (African
Green monkey kidney) and CEM cells, as described
previously.18 After incubation, actively metabolizing
cells were quantified using the CellTiter 96 Cell Pro-
liferation Assay (MTT, Promega, Madison, WI, USA),
as described by the manufacturer. The antiviral EC50,
EC90 and cytotoxicity IC50 were obtained from the
concentration-response curve using the median effective
method described previously.20
8. (a) Bohringer, M.; Roth, H.-J.; Hunziker, J.; Gobel, M.;
Krishnan, R.; Giger, A.; Schweizer, B.; Schreiber, J.; Leu-
mann, C.; Eschenmoser, A. Helv. Chim. Acta 1992, 75, 1416.
(b) Hunziker, J.; Roth, H.-J.; Bohringer, M.; Giger, A.; Die-
derischsen, U.; Gobel, M.; Krishnan, R.; Jaun, B.; Leumann,
C.; Eschenmoser, A. Helv. Chim. Acta 1993, 76, 259.
9. (a) For some examples, see: Herdewijn, P. Liebig Ann.
1996, 1337. (b) Bolli, M.; Litten, J. C.; Schultz, R.; Leumann,
C. J. Chem. Biol. 1996, 3, 197. (c) Marquez, V. E.; Siddiqui,
M. A.; Ezzitouni, A.; Russ, P.; Wang, J.; Wagner, R. W.;
Matteucci, M. D. J. Med. Chem. 1996, 39, 3739. (d) Wang, J.;
Matteucci, M. Bioorg. Med. Chem. Lett. 1997, 7, 229. (e) Zou,
R.; Matteucci, M. Tetrahedron Lett. 1996, 37, 941. (f) Van
Aerschot, A.; Verheggen, I.; Hendrix, C.; Herdewijn, P.
Agnew. Chem. Int. Ed. Engl. 1995, 34, 1338.
Supporting information available
1H and 13C spectra for all compounds. NOESY spectra
for compounds 13 and 14 (32 pages).
Acknowledgements
This research was supported at Hunter by NIH grants
(GM51216 and RR03037) and by PSC-CUNY. R.F.S.
is supported by NIH grant AI-32351 and by the
Department of Veterans Affairs. C.M. gratefully
acknowledges The Clare Booth Luce Fund for a Pro-
fessorship at Seton Hall University.
10. (a) Tang, B. K.; Kalow, W.; Grey, A. A. Drug Metab.
Disp. 1979, 7, 315. (b) Mohri, K.; Uesugi, T.; Kamisaka, K.
Xenobiotica 1985, 15, 615.
11. (a) Soine, W. H.; Soine, P. J.; England, T. M.; Overton,
B. W.; Merat, S. Carbohydr. Res. 1989, 193, 105. (b) Neigh-
bors, S. M.; Soine, W. H.; Paibir, S. G. Carbohydr. Res. 1995,
269, 259.
12. Vest, F. B.; Soine, W. H.; Westkaemper, R. B. Med.
Chem. Res. 1994, 4, 170.
References and Notes
1. Mitsuya, H.; Weinhold, K. J.; Furman, P. A.; St. Clair,
M. H.; Nusinoff-Lehrmann, S.; Gallo, R. C.; Bolognesi, D.;
Barry, D. W.; Broder, S. Proc. Natl. Acad. Sci. U.S.A. 1985,
82, 7096.
2. (a) Chang, C.-N.; Doong, S.-L.; Zhou, J. H.; Cheng, Y. J.
Biol. Chem. 1992, 267, 13938. (b) Chang, C.-N.; Skalski, V.;
Zhou, J. H.; Cheng, Y. J. Biol. Chem. 1992, 267, 22414. (c)
Beach, J. W.; Jeong, L. S.; Alves, A. J.; Pohl, D.; Kim, H. O.;
Chang, C.-N.; Coong, S.-L.; Schinazi, R. F.; Cheng, Y.-C.;
Chu, C. K. J. Org. Chem. 1992, 57, 2217. (d) Coates, J. A.;
Cammack, N.; Jenkinson, H. J.; Mutton, I. M.; Pearson, B. A.;
Storer, R.; Cameron, J. M.; Penn, C. R. Antimicrob. Agents
Chemother. 1992, 36, 202. (e) Schinazi, R. F.; Chu, C. K.;
Peck, A.; McMillan, A.; Mathis, R.; Cannon, D.; Jeong, L.-S.;
Beach, S. J.; Choi, W. B.; Yeola, S.; Liotta, D. C. Antimicrob.
Agents Chemother. 1992, 36, 672. (f) Khan, N.; Bastola, S. R.;
Witter, K. G.; Scheiner, P. Tetrahedron Lett. 1999, 40, 8989.
3. Schaeffer, H. J.; Beauchamp, L.; de Miranda, P.; Elion,
G. B.; Bauer, D. J.; Collins, P. Nature 1978, 272, 583.
4. Hoshino, H.; Shimizu, N. J. Antbiot. 1987, 40, 1077.
13. (a) Capozzi, G.; Nativi, C.; Menichetti, S.; Rosi, A.; Valle,
G. Tetrahedron 1992, 48, 9023. (b) Capozzi, G.; Franck, R. W.;
Mattioli, M.; Menichetti, S.; Nativi, C.; Valle, G. J. Org.
Chem. 1995, 60, 6416.
14. Capozzi, G.; Dios, A.; Franck, R. W.; Geer, A.; Marza-
badi, C.; Menichetti, S.; Nativi, C.; Tamarez, M. Agnew.
Chem. Int. Ed. Engl. 1998, 35, 777.
15. (a) Marzabadi, C. H.; Franck, R. W. Chem. Commun.
1996, 2651. (b) Franck, R. W.; Marzabadi, C. H. J. Org.
Chem. 1998, 63, 2197. (c) Capozzi, G.; Mannocci, F.; Meni-
chetti, S.; Nativi, C.; Paoletti, S. Chem. Commun. 1997, 2291.
16. Hoberg, J. O. Carbohydr. Res. 1997, 300, 365.
17. (a) Vankar, Y. D.; Vankar, P. S.; Behrendt, M.; Schmidt,
R. R. Tetrahedron 1991, 47, 9985. (b) Huchel, U.; Schmidt, C.;
Schmidt, R. R. Eur. J. Org. Chem. 1998, 1353.
18. Schinazi, R. F.; McMillan, A.; Cannon, D.; Mathis, R.;

C. H. Marzabadi et al. / Bioorg. Med. Chem. 10 (2002) 273–281
281
Lloyd, R. M.; Peck, A.; Sommadossi, J. P.; St. Clair, M.;
Wilson, J.; Furman, P. A.; Painter, G.; Choi, W.-B.; Liotta,
D. C. Antimicrob. Agents Chemother. 1992, 36, 2423.
19. Schinazi, R. F.; Chou, T.-C.; Scott, R. T.; Yao, X.;
Nahmias, A. J. Antimicrob. Agents Chemother. 1986, 30, 491.
20. Belen’kii, M. S.; Schinazi, R. F. Antiviral Res. 1994, 25, 1.