Synthesis and antiviral activity of oxaselenolane nucleosides

Article abstract of DOI:10.1021/jm990113x

As dioxolane and oxathiolane nucleosides have exhibited promising antiviral and anticancer activities, it was of interest to synthesize isoelectronically substituted oxaselenolane nucleosides, in which the 3'-CH₂ is replaced by a selenium atom. To study structure-activity relationships, various pyrimidine and purine oxaselenolane nucleosides were synthesized from the key intermediate, (±)-2-benzoyloxymethyl-1,2-oxaselenolane 5-acetate (6). Among the synthesized racemic nucleosides, cytosine and 5-fluorocytosine analogues exhibited potent anti-HIV and anti-HBV activities. It was of interest to obtain the enantiomerically pure isomers to determine if they have differential antiviral activities. However, due to the difficult and time-consuming nature of enantiomeric synthesis, a chiral HPLC separation was performed to obtain optical isomers from the corresponding racemic mixtures. Each pair of enantiomers of Se-ddC and Se-FddC was separated by an amylose chiral column using a mobile phase of 100% 2-propanol. The results indicate that most of the anti-HIV activity of both cytosine and fluorocytosine nucleosides resides with the (-)-isomers.

Full text of DOI:10.1021/jm990113x

3906
J . Med. Chem. 2000, 43, 3906-3912
Syn th esis a n d An tivir a l Activity of Oxa selen ola n e Nu cleosid es
Chung K. Chu,*,† Li Ma,‡ Sureyya Olgen,† Claire Pierra,† J infa Du,† Giuseppe Gumina,† Elizabeth Gullen,§
Yung-Chi Cheng,§ and Raymond F. Schinazi*,‡
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia,
Athens, Georgia 30602, Department of Pharmacology, School of Medicine, Yale University, New Haven, Connecticut 06520, and
Department of Pediatrics, Emory University School of Medicine/ Veteran Affairs Medical Center, Decatur, Georgia 30033
Received March 12, 1999
As dioxolane and oxathiolane nucleosides have exhibited promising antiviral and anticancer
activities, it was of interest to synthesize isoelectronically substituted oxaselenolane nucleosides,
in which the 3′-CH2 is replaced by a selenium atom. To study structure-activity relationships,
various pyrimidine and purine oxaselenolane nucleosides were synthesized from the key
intermediate, (()-2-benzoyloxymethyl-1,2-oxaselenolane 5-acetate (6). Among the synthesized
racemic nucleosides, cytosine and 5-fluorocytosine analogues exhibited potent anti-HIV and
anti-HBV activities. It was of interest to obtain the enantiomerically pure isomers to determine
if they have differential antiviral activities. However, due to the difficult and time-consuming
nature of enantiomeric synthesis, a chiral HPLC separation was performed to obtain optical
isomers from the corresponding racemic mixtures. Each pair of enantiomers of Se-ddC and
Se-FddC was separated by an amylose chiral column using a mobile phase of 100% 2-propanol.
The results indicate that most of the anti-HIV activity of both cytosine and fluorocytosine
nucleosides resides with the (-)-isomers.
In tr od u ction
more potent and less toxic (in the case of 3TC). FTC
and 3TC analogues containing a selenium, such as
5-fluoro-1-[2-(hydroxymethyl)-1,3-oxaselenolan-5-yl]cy-
tosine (Se-FddC) and 1-[2-(hydroxymethyl)-1,3-oxasele-
nolan-5-yl]cytosine (Se-ddC), could have similar activity
as FTC or SddC since selenium is isoelectronic with
sulfur or oxygen.
During the past 10 years, 2′,3′-dideoxynucleoside
analogues have been intensively studied as potential
antiviral agents. Among 14 antiviral agents, which have
been approved by the Food and Drug Administration
for the treatment of HIV infection (6 reverse tran-
scriptase inhibitors, 3 nonnucleoside reverse tran-
scriptase inhibitors, and 5 protease inhibitors), 6 are
2′,3′-dideoxynucleoside analogues (AZT,1 ddC,2 ddI,2
d4T,3 3TC,4-8 and Abacavir9). The use of these agents
in combination with protease inhibitors has been re-
sponsible for the marked reduction of opportunistic
infections and mortality in HIV patients in the past
decade.10 However, the side effects of certain antiviral
agents and the emergence of drug-resistant viral strains
have prompted the development of additional anti-HIV
agents to circumvent these drawbacks.11-13 Partic-
ularly, 3′-heteroatom-substituted dideoxynucleosides
have proven valuable, including oxathiolane and diox-
olane nucleosides, in which the 3′-CH2 group is replaced
by a sulfur or oxygen atom. Among these modified
nucleosides, 3TC,4-8 FTC,14,15 L-OddC,16 DAPD,17 and
OTC18 are the most promising compounds. This fact
prompted us to consider an isosteric substitution of 3′-
CH2 by selenium (Se), for which preliminary results
were reported as a communication.19
Enantiomeric compounds often have different activi-
ties in biological systems since they interact with
receptors or enzymes that are chiral. The antiviral
activity of 3TC4-8 and FTC14,15 was primarily associated
with the â-enantiomers, with the (-)-enantiomers being
In general, it takes significant efforts to develop
enantiomeric synthesis. Therefore, we decided to per-
form a chiral separation of the racemic mixture of the
cytosine and 5-fluorocytosine derivatives to obtain the
enatiomeric compounds for biological evaluation.
* To whom correspondence should be addressed. For C. K. Chu: tel,
(706) 542-5379; fax, (706) 542-5381; e-mail, dchu@rx.uga.edu.
† The University of Georgia.
Resu lts a n d Discu ssion
§ Yale University.
The synthesis of â-oxaselenolane nucleosides reported
in this paper was accomplished by the condensation of
‡ Emory University School of Medicine/Veteran Affairs Medical
Center.
10.1021/jm990113x CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/13/2000

Oxaselenolane Nucleosides
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21 3907
Sch em e 1. Synthesis of Oxaselenolane Nucleosidesa
a
Reagents: (i) KSeCN, EtOH, reflux; (ii) NaBH4, EtOAc, EtOH, 0 °C; (iii) aq AcOH (50%), reflux; (iv) BzOCH2CHO, H3PO2, toluene,
reflux; (v) (1) DIBAL-H (1 M in hexanes), THF, -78 °C, (2) Ac2O, rt; (vi) silylated bases, TMSOTf, 1,2-dichloroethane, rt; (vii) MeNH2,
MeOH, rt; (viii) MeONa, MeOH, HS(CH2)OH, reflux; (ix) NH3, dimethyleneglycol dimethyl ether.
silylated bases with acetylated derivative 6, prepared
from the oxaselenolane intermediate 5 (Scheme 1).
Refluxing ethyl bromoacetate (1) with potassium sele-
nocyanate in ethanol for 1 h,20 followed by reduction of
the intermediate selenocyanate 2 with sodium borohy-
dride21 at 0 °C for 20-30 min, gave diselaneoliyl-
bis(acetic acid) diethyl ester (3) in 81% yield. Hydrolysis
of 3 with refluxing aqueous acetic acid (50%) afforded
the corresponding acid 4, which was condensed with
2-(benzoyloxy)acetaldehyde without purification, to give
lactone 5 in 33% yield. Reduction of 5 with DIBAL-H
followed by in situ acetylation gave the acetylated
oxaselenolane derivative 6, which was condensed with
the desired silylated bases without purification. Pyri-
midine oxaselenolane nucleosides were prepared under
Vorbru¨ggen conditions using TMSOTf as the catalyst.
Condensation of the intermediate 6 with uracil gave a
mixture of R- and â-anomers (7a and 8a ), which were
separated by preparative TLC and individually depro-
tected with methylamine in methanol to give uracil
nucleosides 9a and 10a . In the case of thymine, N4-
benzoylcytosine, and N4-benzoyl-5-fluorocytosine, the
condensation reaction gave inseparable R/â-mixtures.
However, after deprotection with methylamine in metha-
nol, the anomers could be separated to give the final
compounds 9b, 10b, 9c, 10c, 9d , and 10d . The same
condensation method was applied for the synthesis of
purine oxaselenolane nucleosides. Thus, condensation
of the intermediate 6 with N6-benzoyladenine gave an
inseparable R/â-mixture. Both anomers 9e and 10e were
separated after deprotection with methylamine in metha-
nol. To obtain the hypoxanthine derivatives, silylated
6-chloropurine was condensed with 6 to give an R/â-
mixture 7f/8f, which was refluxed with sodium meth-
oxide and mercaptoethanol in methanol to give the
hypoxanthine derivatives 9f and 10f. Condensation of
the intermediate 6 with silylated 6-chloro-2-fluoropurine
followed by ammonolysis gave 2-amino-6-chloropurine
and 6-amino-2-fluoropurine derivatives 7h /8h and
7i/8i. The guanine derivatives 9g/10g were obtained
by refluxing 7h /8h with sodium methoxide and mer-
captoethanol in methanol.
To obtain the enantiomeric compounds, we used an
inclusion chromatography chiral column, ChiralPak AS,
using 100% 2-propanol as the mobile phase in most
cases (vide infra). The nature of the chiral stationary
phase (CSP) can explain the better separation factor and
resolution achieved for the â-isomers as compared to the
R-isomers. In fact, the chiral separation on an inclusion
CSP is based on the interaction between the molecules
of the racemate and chiral cavities in the CSP. From
comparison of the retention times in our chromato-
grams, it is evident that â-isomers, which are structur-
ally more “compact”, intrude more easily into these

3908 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21
Chu et al.
Ta ble 1. Characteristics and Purity of Resolved Enantiomers
Ta ble 3. Anti-HIV-1 Activity and Cytotoxicity of
of Oxaselenolane and Oxathiolane Nucleosides
Enantiomerically Resolved Oxaselenolane Nucleosides in
Human PBM Cells
absorption
wavelength
(nm)
tR
(min)
optical rotation
(deg)
purity
(%)
EC50 (µM) cytotoxicity IC50 (µM)
compd
purity anti-HIV-1 CEM PBM Vero
(-)-â-Se-FddC
(+)-â-Se-FddC
(-)-R-Se-FddC
(+)-R-Se-FddC
(-)-â-FTC
4.8 247.3, 285.1 -103.2 (c 0.5, MeOH)
7.7 247.3, 285.1 +96.8 (c 0.5, MeOH)
4.8 247.3, 285.1 NDa
100
100
100
90
100
100
100
96
compd
enant
(%)
activity
cells
cells
cells
â-Se-ddC (9c)
â-Se-ddC
(
-
+
(
-
+
(
-
+
(
-
+
50
2.7
0.9
3.4
>100 >100 >100
>100 >100 >100
>100 >100 >100
>100 >100 >100
>100 >100 >100
>100 >100 >100
>100 >100 >100
>100 >100 >100
>100 >100 >100
NAa >100 >100
>100 >100 >100
>100 >100 >100
≈100
≈96
50
≈100
≈94
50
≈100
≈100
50
6.6 247.3, 285.1 ND
â-Se-ddC
4.7 242.6, 285.1 -120.5 (c 0.88, EtOH)
6.9 242.6, 285.1 +113.4 (c 0.88, EtOH)
9.5 242.6, 270.9 -72.4 (c 1.0, DMSO)
11.9 242.6, 270.9 +56.4 (c 1.0, DMSO)
ND 242.6, 270.9 -46.7 (c 1.0, DMSO)
ND 242.6, 270.9 ND
R-Se-ddC (10c)
R-Se-ddC
R-Se-ddC
â-Se-FddC (9d )
â-Se-FddC
â-Se-FddC
R-Se-FddC (10d )
R-Se-FddC
R-Se-FddC
>100
>100
>100
0.73
0.2
41.9
57.1
6.4
(+)-â-FTC
(-)-â-Se-ddC
(+)-â-Se-ddC
(-)-R-Se-ddC
(+)-R-Se-ddC
100
94
a
ND ) not determined.
≈100
Ta ble 2. Anti-HIV-1 and Anti-HBV Activities of Various
Racemic Oxaselenolane Nucleosides
≈90
95.3
a
NA ) not available.
EC50 (µM)
HIV-1 HBV
cytotoxicity IC50 (µM)
Ta ble 4. Effect of Oxaselenolane Cytosine Nucleosides Against
PBM CEM Vero
PBM cells 2.2.15 cells cells cells cells
Cloned xxBRUa and M184Vb HIV-1
base
anti-HIV activity
FIc
â-uracil (9a )
>100
101
>10
>100
>10
>10
>10
>10
>100 >100 >100
>100 >100 >100
>100 >100 >100
>100 >100 >100
>100 >100 >100
>100 >100 >100
>100 >100 >100
>100 >100 >100
>100 >100 >100
>100 >100 >100
>100 >100 >100
>100 >100 >100
>100 >100 >100
>100 >100 >100
R-uracil (10a )
purity EC50
(%) (µM)
EC90
(µM)
â-thymine (9b)
R-thymine (10b)
â-cytosine (9c)
R-cytosine (10c)
â-5-fluorocytosine (9d )
R-5-fluorocytosine (10d )
â-adenine (9e)
compd
enant virus
EC50 EC90
â-Se-ddC (9c)
â-Se-ddC
â-Se-ddC
â-Se-ddC (9c)
â-Se-ddC
â-Se-ddC
(
-
+
(
-
+
xxBRU
50 1.84
6.90
0.95
35.1
337
2.7
1.2
xxBRU ≈100
0.11
8.62
50 108
>100
0.73
57.1
>50
>100
>100
>100
28.9
>100
0.07
NDa
1.2
>10
xxBRU ≈96
M184V
59
49
M184V ≈100 >50
>50
>50
>455 >53
>6 >1
>10
>10
>10
>10
>10
>10
M184V ≈96 >50
R-adenine (10e)
â-hypoxanthine (9f)
R-hypoxanthine (10f)
â-guanine (9g)
FTC-sensitive mutant. FTC/3TC-resistant mutant. c FI (fold
increase) ECx ) ECx data from M184V virus/ECx data from xxBRU
virus.
a
b
R-guanine (10g)
3TC4-8
0.008 >100 >100 >100
for both compounds) with no in vitro toxicities up to 100
µM in various cell lines (PBM, CEM, and Vero). It is
worth mentioning that the R-5-fluorocytosine derivative
10d also exhibited very weak activity against HIV (57.1
µM). We confirmed by HPLC that this activity was not
due to the contamination of the â-isomer 9d . Other than
the cytosine derivatives, the only other nucleoside
that showed antiviral activity against HIV-1 and HBV
was the â-guanine derivative 9g (EC50 28.9 µM against
HIV-1), whereas the adenine and hypoxanthine ana-
logues were inactive. These data indicate that the
isosteric substitution with selenium in place of oxygen
or sulfur still maintains some antiviral activity.
The anti-HIV-1 activity of resolved R- and â-enanti-
omers of Se-ddC and Se-FddC was evaluated (Table 3).
It was found that, like the sulfur analogues, (-)-
enantiomers are more active than their (+)-counter-
parts. The most potent compounds were (-)-â-Se-FddC
(EC50 0.2 µM) and (-)-â-Se-ddC (EC50 0.9 µM), about 3
and 12 times less potent than 3TC, respectively. Since
the viral resistance is the most important limit of
current anti-HIV therapy, we studied the effect of (-)-
â-Se-ddC against cloned xxBRU (3TC/FTC-sensitive)
and M184V (3TC/FTC-resistant) mutants. The results
indicate that (-)-â-Se-ddC was cross-resistant with its
sulfur analogues (Table 4).
a
ND ) not determined.
cavities. This results in a more efficient interaction
between molecules and CSP and, consequently, in
higher separation and resolution factors for the â-iso-
mers. Comparison between R- and â-Se-FddC as well
as FTC showed that also electrostatic factors play a role
in the chiral recognition and resolution, although not
as important as the steric factors discussed above. In
any case, optimized conditions let us achieve a baseline
separation for each pair of enantiomers. The UV spectra
and the optical rotations of the two eluted products of
each chromatography indicated that these were the
enantiomers constituting the mixture injected on the
chiral column. The optical purity was confirmed by
chiral HPLC (Table 1).
Experimental results indicated that â-Se-ddC could
not be resolved on our CSP using 2-propanol as the
mobile phase. However, when the mobile phase was
changed to 60:40 hexane:ethanol, the resolution factor
was increased from 1.04 to 1.25, and although the
resolution was not complete, the enantiomer could be
separated close to baseline level. Analogously, to achieve
a good resolution of R-Se-ddC, we had to use 100%
ethanol as the mobile phase.
The synthesized racemic nucleosides were evaluated
for antiviral activity against immunodeficiency virus
type-1 (HIV-1) and hepatitis B virus (HBV) in peripheral
blood mononuclear cells and 2.2.15 cells, respectively.
Results are shown in Table 2. The cytosine and 5-fluo-
rocytosine analogues 9c and 9d were found to exhibit
the most potent anti-HIV activity (EC50 2.69 and 5.55
µM, respectively) and anti-HBV activity (EC50 1.2 µM
Exp er im en ta l Section
Melting points were determined on a Mel-temp II apparatus
and are uncorrected. NMR spectra were recorded on a Bruker
1
400 AMX spectrometer at 400 MHz for H NMR and 100 MHz
for 13C NMR with TMS as internal standard. Chemical shifts
(δ) are reported in parts per million (ppm), and signals are
reported as s (singlet), d (doublet), t (triplet), q (quartet), m

Oxaselenolane Nucleosides
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21 3909
(multiplet), or bs (broad singlet). IR spectra were measured
on a Nicolet 510P FT-IR spectrometer. Mass spectra were
conditions. After all the starting material had reacted, the
reaction mixture was quenched with aqueous NaHCO3 solu-
tion. The resulting solid was filtered off and the filtrate was
extracted with EtOAc. The organic layer was washed with
brine, dried over anhydrous sodium sulfate and concentrated
to a residue, which was purified by silica gel column chroma-
tography (0-3% MeOH in CH2Cl2) to give 7a and 8a as a
mixture (220 mg, 33% from 5, â/R ) 1.1). The individual
enantiomers were obtained by preparative TLC after multiple
developments (5% MeOH in CHCl3): UV (MeOH) λmax 261.0
nm; HRMS calcd for C15H14N2O5Se, 383.0150; found, 383.0356.
(()-â-1-(2-H y d r o x y m e t h y l-1,3-o x a s e le n o la n -5-y l)-
u r a cil (9a ) a n d (()-R-1-(2-Hyd r oxym eth yl-1,3-oxa selen o-
la n -5-yl)u r a cil (10a ). A solution of compound 7a (70 mg, 0.18
mmol) or 8a (61 mg, 0.16 mmol) in MeOH (4.7 mL and 4.2
mL, respectively) was treated with a solution of methylamine
in water (40%, 2.3 mL and 2.0 mL, respectively) and the
resulting mixture was stirred at room temperature for 24 h.
The reaction solvents were concentrated to dryness under
reduced pressure and the residues were purified by silica gel
column chromatography (5% MeOH in CH2Cl2) to give pure
â-isomer 9a (29 mg, 58%) or R-isomer 10a (27 mg, 61%), which
were crystallized from MeOH/Et2O. 9a : mp 159-161 °C; UV
(H2O) λmax 260.5 nm (ꢀ 25100) (pH 2), 260.5 nm (ꢀ 24400) (pH
7), 260.5 nm (ꢀ 19800) (pH 11); 13C NMR (DMSO-d6) δ 161.09,
148.22, 138.56, 130.78, 100.34, 85.08, 75.92, 62.15, 25.96;
HRMS calcd for C8H10N2O4Se, 278.9884; found, 278.9889.
Anal. (C8H10N2O4Se) C, H, N. 10a : mp 129-131 °C; UV (H2O)
λmax 261.0 nm (ꢀ 34300) (pH 2), 261.0 nm (ꢀ 31000) (pH 7),
261.5 (ꢀ 25300) (pH 11); 13C NMR (DMSO-d6) δ 163.51, 150.55,
140.93, 132.96, 101.85, 87.73, 81.09, 65.22, 29.01; HRMS calcd
for C8H10N2O4Se, 278.9884; found, 278.9874. Anal. (C8H10N2O4-
Se) C, H, N.
recorded on
a Micromass Autospec high-resolution mass
spectrometer. TLC were performed on Uniplates (silica gel)
purchased from Analtech Co. Column chromatography was
performed using either silica gel 60 (220-440 mesh) for flash
chromatography or silica gel G (TLC grade, >440 mesh) for
vacuum flash column chromatography. UV spectra were
obtained on a Beckman DU 650 spectrophotometer. Elemental
analyses were performed by Atlantic Microlab, Inc., Norcross,
GA, or Galbraith Laboratories, Inc., Knoxville, TN. HPLC was
performed with a Waters HPLC system (Millipore Corp.,
Milford, MA) equipped with a model 600 controller, a model
996 photodiode array detector and a model 717 plus autosam-
pler. Millennium 2010 software was used for system control,
data acquisition and processing. A chiralyser polarimetric
detector, Perkin-Elmer model 241MC polarimeter (Wilton, CT),
was used for the determination of optical rotations.
Disela n ed iyl-bis(a cetic a cid ) Dieth yl Ester (3). Ethyl
bromoacetate (1) (25.0 g, 0.15 mol) was added to a solution of
potassium selenocyanate (14.4 g, 0.10 mol) in ethanol (250 mL)
and the mixture was refluxed for 1 h, filtered, and washed
with EtOAc (250 mL). To the combined filtrate was added
NaBH4 (0.95 g, 25.0 mmol) portionwise at 0 °C in 20 min and
the reaction mixture was stirred at 0 °C for an additional 10
min. After the starting material had disappeared (TLC), the
reaction solvent was evaporated and the residue was parti-
tioned between water and EtOAc. The organic layer was
washed with brine and dried over anhydrous Na2SO4. The
solvents were evaporated under reduced pressure and the
residue was coevaporated with toluene to remove excess
bromoacetate, giving an oily residue that was purified by silica
gel chromatography (0-30% EtOAc in hexane) to give 3 as an
oil (13.5 g, 81.3%): IR (film) 1728, 1260 cm-1
.
â-(()-1-(2-Ben zoyloxym eth yl-1,3-oxa selen ola n -5-yl)th -
ym in e (7b ) a n d R-(()-1-(2-Ben zoyloxym et h yl-1,3-oxa -
selen ola n -5-yl)th ym in e (8b). A solution of crude acetate 6
[prepared from 1.45 g (5.0 mmol) of 5] in CH2Cl2 (60 mL) was
added to persilylated thymine [prepared by refluxing thymine
(1.89 g, 15 mmol) with (NH4)2SO4 in HMDS (50 mL) for 4 h
and removal of the solvent under reduced pressure]. A 1 M
solution of SnCl4 in CH2Cl2 (10 mL, 10 mmol) was then added
and the reaction was continued at room temperature for 30
min. The resulting mixture was diluted with EtOAc (50 mL)
and quenched with aqueous NaHCO3. The salts were filtered
off and the filtrate was extracted with EtOAc. The organic
layer was washed with brine, dried over anhydrous Na2SO4
and concentrated to dryness. The residue was purified by silica
gel column chromatography (0-10% MeOH in CH2Cl2) to give
7b and 8b as a mixture (150 mg, 7.6% from 5, â/R ) 2/1): UV
(MeOH) λmax 265.0 nm; HRMS calcd for C16H16N2O5Se, 397.0340;
found, 397.0303.
(()-â-1-(2-H yd r oxym et h yl-1,3-oxa selen ola n -5-yl)t h y-
m in e (9b) a n d (()-R-1-(2-Hyd r oxym eth yl-1,3-oxa selen o-
la n -5-yl)th ym in e (10b). A solution of methylamine in water
(40%, 5 mL) was added to a solution of the mixture 7b/8b (150
mg, 0.38 mmol) in MeOH (10 mL), and the resulting mixture
was stirred at room temperature for 24 h. The reaction mixture
was then concentrated to dryness under reduced pressure, and
the residue was purified by preparative TLC (5%, then 7%
MeOH in CH2Cl2 repeatedly developed) to give â-isomer 9b
(16 mg, 14.5%) and R-isomer 10b (13 mg, 11.8%). 9b: mp 200-
202 °C; UV (H2O) λmax 266.0 (ꢀ 10014) (pH 2), 266.0 (ꢀ 10968)
(pH 7), 265.5 nm (ꢀ 8546) (pH 11); 13C NMR (DMSO-d6) δ
163.5, 150.2, 136.0, 109.8, 86.5, 76.8, 63.8, 27.1, 11.7; MS (FAB)
292.8 (M+). Anal. (C9H12N2O4Se) C, H, N. 10b: mp 144-145.5
°C; UV (H2O) λmax 266.5 nm (ꢀ 10133) (pH 2), 266.5 nm (ꢀ
11524) (pH 7), 266.5 nm (ꢀ 8918) (pH 11); 13C NMR (DMSO-
d6) 163.5, 149.8, 135.6, 109.0, 86.6, 79.7, 64.6, 28.0, 11.8; MS
(FAB) 293.0 (MH+). Anal. (C9H12N2O4Se) C, H, N.
(()-2-Ben zoyloxym eth yl-1,3-oxa selen ola n -5-on e (5). A
solution of compound 3 (7.30 g, 22.0 mmol) and aqueous acetic
acid (50%, 300 mL) was refluxed for 24 h. The reaction solvent
was concentrated to dryness under reduced pressure and then
coevaporated with toluene twice to give crude diselanediyl-
bis(acetic acid) (4). 2-Benzoyloxyacetaldehyde (14.6 g, 69.5
mmol) was added slowly to the solution of the acid 4 in toluene
(250 mL) and the mixture was gently refluxed under N2. H3-
PO2 (50%, 16.5 mL) was added slowly to the above reaction
mixture and the reaction mixture was refluxed using a Dean-
Stark apparatus to remove water until all the aldehyde had
reacted (20-30 min). The reaction mixture was diluted with
EtOAc (100 mL) and partitioned between water and EtOAc.
The combined organic layer was washed with brine and dried
over anhydrous Na2SO4. The solvents were removed under
reduced pressure and the syrupy residue was purified by silica
gel column chromatography (10-30% EtOAc in hexanes) to
give 5 (4.2 g, 33%) as a yellow oil: IR (film) 1767, 1720, 1273
cm-1 13C NMR (CDCl3) δ 174.3, 166.3, 134.0, 130.2, 129.6,
;
129.0, 70.5, 67.7, 24.1; MS (FAB) 286.6 (MH+). Anal. (C11H10O4-
Se) C, H.
(()-â-1-(2-Ben zoyloxym et h yl-1,3-oxa selen ola n -5-yl)-
u r a cil (7a ) a n d (()-R-1-(2-Ben zoyloxym eth yl-1,3-oxa sele-
n ola n -5-yl)u r a cil (8a ). A 1 M solution of DIBAL-H in hexanes
(3.5 mL, 3.5 mmol) was slowly added to a solution of 5 (500
mg, 1.75 mmol) in THF (10 mL) at -78 °C and the reaction
mixture was stirred at -78 °C for 1 h. Then, acetic anhydride
(0.5 mL, 5.25 mmol) was added dropwise and the resulting
mixture was allowed to warm to room temperature and stirred
for 3 more h. The mixture was diluted with EtOAc (10 mL)
and washed successively with brine (10 mL), water (10 mL),
and then extracted with EtOAc. The combined organic layers
were dried over anhydrous Na2SO4, and then the solvent was
evaporated under reduced pressure to give crude acetate 6 as
a syrup. The solution of crude 6 in CH2Cl2 (18 mL) was added
to persilylated uracil [prepared by refluxing uracil (588 mg,
5.25 mmol) with (NH4)2SO4 (35 mg) in HMDS (17 mL) for 3 h
and removal of the solvent under reduced pressure]. TMSOTf
(17 mL, 10.5 mmol) was then added and the resulting mixture
was stirred for 3 h at room temperature under anhydrous
(()-â-1-(2-Ben zoyloxym eth yl-1,3-oxa selen ola n -5-yl)-N4-
ben zoylcytosin e (7c) a n d (()-R-1-(2-Ben zoyloxym eth yl-
1,3-oxa selen ola n -5-yl)-N4-ben zoylcytosin e (8c). A solution
of crude acetate 6 [prepared from 1.4 g (5.0 mmol) of 5] in CH2-
Cl2 (50 mL) was added to persilylated N4-benzoylcytosine

3910 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21
Chu et al.
[prepared by refluxing N4-benzoylcytosine (2.2 g, 10 mmol)
with (NH4)2SO4 (100 mg) in HMDS (50 mL) for 4 h and
removal of the solvent under reduced pressure]. TMSOTf (2.2
g, 10 mmol) was then added, and the mixture was stirred at
room temperature for 1 h. The reaction was quenched with
saturated aqueous NaHCO3 solution. The resulting solid was
filtered off and the filtrate was extracted with EtOAc. The
organic layer was washed with brine and dried over anhydrous
Na2SO4. The solvent was evaporated under reduced pressure
to give a residue, which was purified by silica gel column
chromatography (0-5% MeOH in CHCl3) to give a syrup. This
was dissolved in a small amount of MeOH and was allowed to
stay overnight at room temperature to afford a white solid that
was filtered to give 7c and 8c as a mixture (250 mg, 10.3%
from 5, â/R ) 2/1): UV (MeOH) λmax 304.5 nm; HRMS calcd
for C22H19N3O5Se, 486.0568; found, 486.0573.
(DMSO-d6) δ 157.8, 153.2, 137.3, 134.9, 88.6, 80.9, 65.5, 29.4;
MS (FAB) 295.0 (MH+). Anal. (C8H10FN3O3Se) C, H, N.
(()-â-9-(2-Ben zoyloxym eth yl-1,3-oxa selen ola n -5-yl)-N6-
ben zoyla d en in e (7e) a n d (()-R-9-(2-Ben zoyloxym eth yl-
1,3-oxa selen ola n -5-yl)-N6-ben zoyla d en in e (8e). A solution
of acetate 6 [prepared from 630 mg of 5 (1.9 mmol)] in 1,2-
dichloroethane (5 mL) was added to persilylated N6-benzoy-
ladenine [prepared by refluxing N6-benzoyladenine (530 mg,
2.6 mmol) with (NH4)2SO4 (30 mg) in HMDS (10 mL)]. TMSOTf
(0.5 mL, 2.6 mmol) was then added, and the reaction mixture
was stirred at room temperature for 22 h. The reaction was
quenched with saturated aqueous NaHCO3 solution and the
resulting solid was filtered off. The filtrate was extracted with
EtOAc and the organic layer was washed with brine and dried
over anhydrous Na2SO4 and concentrated to dryness. The
residue was purified by flash chromatography (0-3% MeOH
in CHCl3) to give 7e and 8e as a mixture (260 mg, 27% from
5, â/R ) 1): UV (MeOH) λmax 228.5, 279.0 nm; HRMS calcd
for C23H19N5O4Se, 510.0703; found, 510.0680.
(()-â-9-(2-H yd r oxym et h yl-1,3-oxa selen ola n -5-yl)a d e-
n in e (9e) a n d (()-R-9-(2-Hyd r oxym eth yl-1,3-oxa selen o-
la n -5-yl)a d en in e (10e). A solution of methylamine in water
(40 wt %, 2 mL) was added to a solution of the mixture 7e/8e
(260 mg, 0.51 mmol) in MeOH (10 mL), and the mixture was
stirred at room temperature for 24 h. The reaction was then
quenched with saturated aqueous NaHCO3 solution and the
resulting solid was filtered off. The filtrate was extracted with
EtOAc and the organic layer was washed with brine, dried
over anhydrous Na2SO4 and concentrated to dryness. The
residue was purified by preparative TLC (5% and 8% MeOH
in CHCl3, developed twice) and extracted with 10% MeOH in
EtOAc to give two yellow solids, which were triturated with
Et2O and filtered to give pure â-isomer 9e (10 mg, 6.5%) and
R-isomer 10e (10 mg, 6.5%). 9e: mp 230-232 °C; UV (H2O)
λmax 258.5 nm (ꢀ 10881) (pH 2), 259.5 nm (ꢀ 12760) (pH 7),
260.0 nm (ꢀ 10964) (pH 11); MS (FAB) 302.0 (MH+). Anal.
(C9H11N5O2Se) C, H, N. 10e: mp 175-177 °C; UV (H2O) λmax
257.5 nm (ꢀ 10128) (pH 2), 259.0 nm (ꢀ 11992) (pH 7), 259.5
nm (ꢀ 10836) (pH 11); MS (FAB) 302.0 (MH+). Anal. (C9H11
N5O2Se) C, H, N.
(()-â-1-(2-H yd r oxym e t h yl-1,3-oxa se le n ola n -5-yl)cy-
tosin e (9c) a n d (()-R-1-(2-Hyd r oxym eth yl-1,3-oxa selen o-
la n -5-yl)cytosin e (10c). A solution of methylamine in water
(40 wt %, 10 mL) was added to a solution of the mixture 7c/
8c (200 mg, 0.413 mmol) in MeOH (20 mL), and the resulting
mixture was stirred at room temperature for 8 h. After
checking for completeness by TLC, the reaction mixture was
concentrated to dryness at 30 °C, and the residue purified by
a silica gel column (10-20% MeOH in CHCl3) to give 9c and
10c as a mixture (65 mg, 57%, â/R ) 2/1). Fractional recrys-
tallization from MeOH/Et2O gave the pure R-isomer 10c (25
mg): mp 237-238 °C; UV (H2O) λmax 278.5 (ꢀ 8367) (pH 2),
270.0 (ꢀ 6041) (pH 7), 270.0 nm (ꢀ 6308) (pH 11); 13C NMR
(DMSO-d6) δ 165.2, 154.5, 140.7, 93.7, 87.8, 80.2, 64.7, 29.0;
MS (FAB) 277.8 (M+). Anal. (C8H11N3O3Se) C, H, N. The
mother liquor, enriched with â-isomer, was repeatedly purified
by preparative HPLC (C-18 column, 20% MeOH in H2O, flow
rate: 50 mL/min), to give â-isomer 9c (15 mg): mp 173-175
°C; UV (H2O) λmax 278.0 (ꢀ 8787) (pH 2), 269.5 (ꢀ 6344) (pH 7),
269.5 nm (ꢀ 6364) (pH 11); MS (FAB) 278.0 (MH+). Anal.
(C8H11N3O3Se‚1/3H2O) C, H, N.
â-(()-1-(2-Ben zoyloxym eth yl-1,3-oxa selen ola n -5-yl)-N4-
b en zoyl-5-flu or ocyt osin e (7d ) a n d R-(()-1-(2-Ben zoyl-
oxymethyl-1,3-oxaselenolan-5-yl)-N4-benzoyl-5-fluorocytosine
(8d ). A solution of crude acetate 6 [prepared from 4.28 g of 5
(15.0 mmol)] in CH2Cl2 (30 mL) was added to persilylated N4-
benzoyl-5-fluorocytosine [prepared by refluxing N4-benzoyl-5-
fluorocytosine (3.5 g, 15.0 mmol) in CHCl3 (60 mL) with HMDS
(10 mL) for 5 h with (NH4)2SO4 (100 mg) and removal of the
solvent under reduced pressure]. TMSOTf (4.3 mL, 22.0 mmol)
was then added, and the mixture was stirred at room tem-
perature for 3 h. The reaction was quenched with NaHCO3,
the resulting solid was filtered off and the filtrate was
extracted with CHCl3. The combined organic layers were
washed with brine and dried over anhydrous Na2SO4. The
solvent was evaporated under reduced pressure and the
residue was purified by silica gel column chromatography (5-
50% EtOAc in hexanes) to give 7d and 8d as a mixture (2.0 g,
26% from 5, â/R ) 1.6): UV (MeOH) λmax 323.0 nm, 259.0 nm,
228.5 nm; HRMS calcd for C22H18FN3O5Se, 504.0474; found,
504.0473.
(()-â-9-(2-Ben zoyloxym eth yl-1,3-oxa selen ola n -5-yl)-6-
ch lor op u r in e (7f), a n d (()-R-9-(2-Ben zoyloxym eth yl-1,3-
oxa selen ola n -5-yl)-6-ch lor op u r in e (8f). A solution of crude
acetate 6 [prepared from 1.0 g of 5 (3.5 mmol)] in CH2Cl2 (40
mL) was added to silylated 6-chloropurine [prepared by
refluxing 6-chloropurine (650 mg, 4.2 mmol) with (NH4)2SO4
(70 mg) in HMDS (10.8 mL) for 3 h and removal of the solvent
under reduced pressure]. TMSOTf (0.8 mL, 4.2 mmol) was then
added, and the reaction mixture was stirred at room temper-
ature under argon for 22 h. The reaction was quenched with
saturated aqueous NaHCO3 solution, and the resulting solid
was filtered off. The filtrate was extracted with CH2Cl2 and
the organic layer was washed with brine, dried over anhydrous
Na2SO4, and concentrated to dryness. The residue was purified
by silica gel column chromatography (0-10% MeOH in CH2-
Cl2) to give 7f and 8f as a mixture (310 mg, 21% from 5, â/R )
0.9): UV (CH2Cl2) λmax 264.0 nm; HRMS calcd for C16H13
ClN4O3Se, 424.9920; found, 424.9928.
-
(()-â-1-(2-Hyd r oxym eth yl-1,3-oxa selen ola n -5-yl)-5-flu -
or ocytosin e (9d ) a n d (()-R-1-(2-Hyd r oxym eth yl-1,3-oxa -
selen ola n -5-yl)-5-flu or ocytosin e (10d ). A solution of com-
pound 7d and 8d (2 g, 3.85 mmol) in saturated methanolic
ammonia (50 mL) was stirred at room temperature for 20 h.
Then, the reaction mixture was evaporated to dryness under
reduced pressure and the residue was purified by silica gel
chromatographic column chromatography (0-15% MeOH in
CHCl3) to give â-isomer 9d and R-isomer 10d as a mixture
(0.82 g, 73%, R/â ) 1.2). The individual isomers were obtained
by another silica gel column chromatography (EtOAc:hexanes:
EtOH:CHCl3 ) 5:5:1:2). 9d : mp 192-194 °C; UV (H2O) λmax
280.0 (ꢀ 8573) (pH 7), 289.0 (ꢀ 10636) (pH 2), 280.0 nm (ꢀ 7511)
(pH 11); 13C NMR (DMSO-d6) δ 157.7, 153.3, 137.6, 135.2, 88.3,
78.2, 64.0, 28.9; MS (FAB) 295 (M+). Anal. (C8H10FN3O3Se) C,
H, N. 10d : mp 220-223 °C; UV (H2O) λmax 279.5 (ꢀ 7654) (pH
7), 287.5 (ꢀ 9095) (pH 2), 281.0 nm (ꢀ 6949) (pH 11); 13C NMR
(()-â-9-(2-Hydr oxym eth yl-1,3-oxaselen olan -5-yl)h ypox-
a n th in e (9f) a n d (()-R-9-(2-Hyd r oxym eth yl-1,3-oxa sele-
n ola n -5-yl)h yp oxa n th in e (10f). A solution of 7f and 8f (300
mg, 0.7 mmol), 2-mercaptoethanol (0.2 mL, 2.8 mmol) and
NaOMe (152 mg, 2.8 mmol) in MeOH (35 mL) was refluxed
for 5 h under argon atmosphere. The resulting mixture was
cooled to room temperature, neutralized with Dowex H+ resin
and filtered. The filtrate was evaporated to dryness under
reduced pressure to give a residue that was purified by silica
gel column chromatography (0-8% of MeOH in CH2Cl2) to give
â-isomer 9f and R-isomer 10f as a mixture (99 mg, 87%, â/R )
3/2). The individual enantiomers were separated by prepara-
tive TLC (10% MeOH in CH2Cl2 repeatedly developed) and
crystallized from MeOH. 9f: mp 192-194 °C; UV (H2O) λmax
248.5 nm (ꢀ 17100) (pH 2), 251.0 nm (ꢀ 21900) (pH 7), 254.0 (ꢀ
31800) (pH 11); 13C NMR (DMSO-d6) δ 155.8, 147.2, 145.3,

Oxaselenolane Nucleosides
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21 3911
137.8, 123.3, 86.3, 77.7, 63.5, 27.1; HRMS calcd for C9H10O3N4-
Se, 303.0037; found, 303.0028. Anal. (C9H10N4O3Se) C, H, N.
10f: mp 178-180 °C; UV (H2O) λmax 249.0 nm (ꢀ 14100) (pH
2), 250.0 nm (ꢀ 18500) (pH 7), 253.5 (ꢀ 18500) (pH 11); 13C
NMR (DMSO-d6) δ 156.9, 148.2, 146.4, 138.3, 124.4, 86.9, 81.4,
64.7, 29.4; HRMS calcd for C9H10N4O3Se, 303.0037; found,
303.0060. Anal. (C9H10N4O3Se) C, H, N.
treatment with 2 M methanolic ammonia solution (1 mL) at
room temperature for 1 h. After removal of the solvent and
drying under vacuum, R-D- and R-L-Se-ddC were obtained as
white solids.
Samples (10 mg) were dissolved in 1 mL of methanol. The
flow rates were 1.2 mL/min and 1.0 mL/min for R- and â-Se-
FddC, respectively. For â-Se-ddC, the mobile phase was 60:
40 hexane:ethanol, and the flow rate was 0.6 mL/min. For
R-Se-ddC acetate, the mobile phase was 100% ethanol and the
flow rate was 0.6 mL/min. The identity of each pair of
enantiomers was confirmed by their UV spectra prior to
collection from several runs. The mobile phase solutions were
evaporated under vacuum and the residues dissolved in
methanol for further tests. The total amount of each enanti-
omers collected was about 3 mg. The optical purity of the
separated enantiomers was determined by chiral HPLC and
optical rotation.
(()-â-9-(2-Ben zoyloxym eth yl-1,3-oxa selen ola n -5-yl)-6-
ch lor o-2-flu or op u r in e (7g) a n d (()-R-9-(2-Ben zoyloxy-
m eth yl-1,3-oxaselen olan -5-yl)-6-ch lor o-2-flu or opu r in e (8g).
A solution of crude acetate 6 [prepared from 1.38 g of 5 (4.86
mmol)] in 1,2-dichloroethane (50 mL) was added to silylated
6-chloro-2-fluoropurine [prepared by refluxing 6-chloro-2-fluo-
ropurine (1.0 g, 5.83 mmol) with (NH4)2SO4 (120 mg) in HMDS
(23 mL) for 4 h and removal of the solvent under reduced
pressure]. TMSOTf (1.06 mL, 6.80 mmol) was then added, and
the resulting mixture was stirred at room temperature under
argon for 2 h. The reaction was quenched with saturated
aqueous NaHCO3 solution and the resulting solid was filtered
off. The filtrate was extracted with EtOAc and the combined
organic layers were washed with brine, dried over anhydrous
Na2SO4, and concentrated to dryness. The residue was purified
by silica gel column chromatography (CHCl3) to give 7g/8g
(1.64 g, 76.3% from 5, â/R ) 1) as a mixture: UV (CH2Cl2)
λmax 269.5 nm; HRMS calcd for C16H12ClFN4O2Se, 424.9826;
found, 424.9825.
(()-â-9-(2-Ben zoyloxym eth yl-1,3-oxa selen ola n -5-yl)-2-
a m in o-6-ch lor opu r in e (7h ), (()-R-9-(2-Ben zoyloxym eth yl-
1,3-oxa selen ola n -5-yl)-2-a m in o-6-ch lor op u r in e (8h ), (()-
â-9-(2-Ben zoyloxym eth yl-1,3-oxa selen ola n -5-yl)-6-a m in o-
2-flu or op u r in e (7i) a n d (()-R-9-(2-Ben zoyloxym eth yl-1,3-
oxa selen ola n -5-yl)-6-a m in o-2-flu or op u r in e (8i). A mixture
of 7g and 8g (1.64 g, 3.7 mmol) was dissolved in dimethyl-
eneglycol dimethyl ether (59 mL) and dry ammonia gas was
bubbled into the mixture at room temperature for 15 h. The
solvent was evaporated under reduced pressure and the
residue was purified by silica gel column chromatography
(CHCl3) to give 7h /8h (0.5 g, 32%, â/R ) 3/2) and 7i/8i (134
mg, 46%, â/R ) 1/2) as a mixture. 7h /8h : UV (CH2Cl2) λmax
309.5 nm; HRMS calcd for C16H14ClN5O2Se, 440.0038; found,
440.0029. 7i/8i: UV (CH2Cl2) λmax 259.5 nm; HRMS calcd for
C16H14FN5O2Se, 424.0403; found, 424.0324.
Ack n ow led gm en t. This research was supported by
U.S. Public Health Service Research Grants AI 32321
and AI 33655 from the National Institutes of Health
and by the Department of Veterans Affairs.
1
Su p p or tin g In for m a tion Ava ila ble: Tables of H NMR
data and elemental analyses. This material is available free
of charge via the Internet at http://pubs.acs.org.
Refer en ces
(1) Mitsuya, H.; Weinhold, K. J .; Furman, P. A.; St Clair, M. H.;
Lehrman, S. N.; Gallo, R. C.; Bolognesi, D.; Barry, D. W.; Broder,
S. 3′-Azido-3′-deoxythymidine (BW A509U): an antiviral agent
that inhibits the infectivity and cytopathic effect of human
T-lymphotropic virus type III/lymphadenopathy-associated virus
in vitro. Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 7096-7100.
(2) Mitsuya, H.; Broder, S. Inhibition of the in vitro infectivity and
cytopathic effect of human lymphotropic-T virus type III/
lymphadenopathy-associated virus (HTVL III/LAV) by 2′,3′-
dideoxynucleosides. Proc. Natl. Acad. Sci. U.S.A. 1986, 83,
1911-1915.
(3) Riddler, S. A.; Anderson, R. E.; Mellors, J . W. Antiretroviral
activity of stavudine (2′,3′-didehydro-3′-deoxythymidine, D4T).
Antiviral Res. 1995, 27, 189-203.
(()-â-9-(2-Hyd r oxym eth yl-1,3-oxa selen ola n -5-yl) gu a -
n in e (9g) a n d (()-R-9-(2-Hyd r oxym eth yl-1,3-oxa selen o-
la n -5-yl)gu a n in e (10g). A solution of 7h and 8h (500 mg,
0.11 mmol), 2-mercaptoethanol (0.28 mL, 0.4 mmol), and
NaOMe (216 mg, 0.4 mmol) in MeOH (50 mL) was refluxed
for 22 h under argon atmosphere. The resulting mixture was
cooled to room temperature, neutralized with Dowex H+ resin,
filtered, and evaporated to dryness under reduced pressure.
The residue was purified by silica gel column chromatography
(0-5% of MeOH in CH2Cl2) to give â-isomer 9g and R-isomer
10g as a mixture (200 mg, 55%, â/R ) 1). The individual
enantiomers were obtained by preparative TLC (5% MeOH in
CH2Cl2 repeatedly developed) and crystallized from MeOH.
9g: mp 236-238 °C; UV (H2O) λmax 255.0 nm (ꢀ 10400) (pH
2), 254.0 nm (ꢀ 10900) (pH 7), 262.0 (ꢀ 9300) (pH 11); MS (FAB)
317.0 (MH+). Anal. (C9H11N5O3Se‚2/5H2O) C, H, N. 10g: mp
214-217 °C; UV (H2O) λmax 254.0 nm (ꢀ 33700) (pH 2), 254.0
nm (ꢀ 22600) (pH 7), 265.0 (ꢀ 19700) (pH 11); MS (FAB) 317.0
(MH+) Anal. (C9H11N5O3Se‚1/5H2O) C, H, N.
Ch ir a l HP LC Sep a r a tion . R-D/L-Se-ddC was acetylated
before starting the HPLC separation on a chiral column
(ChiralPak AS). Thus, acetic anhydride (0.1 mL) was added
to an ice-cooled solution of R-D/L-Se-ddC (8 mg), 4-(dimethy-
lamino)pyridine (2 mg), and Et3N (0.2 mL) in dry DMF (1 mL).
The resulting solution was stirred at 0 °C to room temperature
overnight under argon. After removal of the solvent by
evaporation under reduced pressure, the residue was treated
with CHCl3 (20 mL) and water (10 mL). The organic layers
were combined, washed with water and brine, and concen-
trated. The resulting white solid was subjected to chiral HPLC
separation without further purification. After the chiral sepa-
ration, R-D- and R-L-Se-ddC acetates were deprotected by
(4) Coates, J . A. V.; Cammack, N.; J enkinson, H. J .; Mutton, I. M.;
Pearson, B. A.; Storer, R.; Cameron, J . M.; Penn, C. R. The
separated enantiomers of 2′-deoxy-3′-thiacytidine (BCH 189)
both inhibit human immunodeficiency virus replication in vitro.
Antimicrob. Agents Chemother. 1992, 36, 202-205.
(5) Beach, J . W.; J eong, L. S.; Alves, A. J .; Pohl, D.; Kim, H. O.;
Chang, C.-N.; Doong, S.-L.; Schinazi, R. F.; Cheng, Y.-C.; Chu,
C. K. Synthesis of enantiomerically pure (2′R,5′S)-(-)-1-[2-
(hydroxymethyl)oxathiolan-5-yl]cytosine as a potent antiviral
agent against hepatitis B virus (HBV) and human immunode-
ficiency virus (HIV). J . Org. Chem. 1992, 57, 2217-2219.
(6) Dienstag, J . L.; Perrillo, R. P.; Schiff, E. R.; Bartholomew, M.;
Vicary, C.; Rubin, M. A preliminary trial of lamivudine for
chronic hepatitis B infection. N. Engl. J . Med. 1995, 333, 1657-
1661.
(7) Schinazi, R. F.; Chu, C. K.; Peck, A.; McMillan, A.; Mathis, R.;
Cannon, D.; J eong, L.-S.; Beach, J . W.; Choi, W.-B.; Yeola, S.;
Liotta, D. C. Activities of the four optical isomers of 2′,3′-dideoxy-
3-thiacytidine (BCH-189) against human immunodeficiency
virus type 1 in human lymphocytes. Antimicrob. Agents Chemoth-
er. 1992, 36, 672-676.
(8) Soudeyns, H.; Yao, X.-J .; Gao, Q.; Belleau, B.; Draus, J .-L.;
Nguyen-Ba, N.; Spira, B.; Wainberg, M. A. Anti-human immu-
nodeficiency virus type 1 activity and in vitro toxicity of 2′-deoxy-
3′-thiacytidine (BCH-189), a novel heterocyclic nucleoside ana-
logue. Antimicrob. Agents Chemother. 1991, 35, 1386-1390.
(9) Daluge, S. M.; Good, S. S.; Faletto, M. B.; Miller, W. H.; StClair,
M. H.; Boone, L. R.; Tisdale, M.; Parry, N. R.; Reardon, J . E.;
Dornsife, R. E.; Averett, D. R.; Krenitsky, T. A. 1592U89, A novel
carbocyclic nucleoside analogue with potent, selective anti-
human immunodeficiency virus activity. Antimicrob. Agents
Chemother. 1997, 41, 1082-1093.
(10) Cohen, J . AIDS. Trials ethics questioned. Science 1997, 276,
520-523.
(11) Larder, B. A.; Barby, G.; and Richman, D. D. HIV with reduced
sensitivity to zidovudine (AZT) isolated during prolonged therapy.
Science 1989, 43, 1731-1734.

3912 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 21
Chu et al.
(12) Richman, D. D.; Fischl, M. A.; Grieco, M. H.; Gottlieb, M. S.;
Volberding, P. A.; Laskin, D. L.; Leedom, J . M.; Groopman, J .
E.; Mildvan, D.; Hirsch, M. S.; J ackson, G. G.; Durack, D. T.;
Nusinoff-Lehrman, S. The toxicity of azidothymidine (AZT) in
the treatment of patients with AIDS and AIDS-related complex-a
double-blind, placebo-controlled trial. N. Engl. J . Med. 1987, 317,
192-197.
(13) Yarchoan, R.; Thomas, R. V.; Allain, J . P.; McAtee, N.; Dubinsky,
R.; Mitsuya, H.; Lawley, T. J .; Safai, B.; Myers, C. E.; Perno, C.
F.; Klecker, R. W.; Wills, R. J .; Fischl, M. A.; McNeely, M. C.;
Pluda, J . M.; Leuther, M.; Collin, J . M.; Broder, S. Phase-1
studies of 2′,3′-dideoxycytidine in severe human immunodefi-
ciency virus-infected as a single agent and alternating with
zidovudine (AZT). Lancet 1988, 1, 76-81.
(14) Schinazi, R. F.; McMillan, A.; Cannon, D.; Mathis, R.; Lloyd, R.
M.; Peck, A.; Sommadossi, J .-P.; St Clair, M.; Wilson, J .; Furman,
P. A.; Painter, G.; Choi, W.-B.; Liotta, D. C. Selective inhibition
of human immunodeficiency viruses by racemates and enanti-
omers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-
cytosine. Antimicrob. Agents Chemother. 1992, 36, 2423-2431.
(15) Furman, P. A.; Davis, M.; Liotta, D. C.; Paff, M.; Frick, L. W.;
Nelson, D. J .; Dornsife, R. E.; Wurster, J . A.; Wilson, L. J .; Fyfe,
J . A.; Tuttle, J . V.; Miller, W. H.; Condrey, L.; Averett, D. R.;
(16) Grove, K. L.; Guo, X.; Liu, S.-H.; Gao, Z. L.; Chu, C. K.; Cheng,
Y.-C. Anticancer activity of â-L-dioxolane-cytidine,
a novel
nucleoside analogue with the unnatural L-configuration. Cancer
Res. 1995, 55, 3008-3011.
(17) Schinazi, R. F.; McClure, H. M.; Boudinot, F. D.; Xiang, Y. J .;
Chu, C. K. Development of (-)-â-D-2,6-diaminopurine dioxolane
as a potential antiviral agent. Antiviral Res. 1994, 23, S81.
(18) Mansour, T. S.; J in, H. L.; Wang, W.; Hooker, E. U.; Ashman,
C.; Cammack, N.; Salomon, H.; Belmonte, A. R.; Wainberg, M.
A. Anti-human immunodeficiency virus and anti-hepatitis B
virus activities and toxicities of the enantiomers of 2′-deoxy-3′-
oxa-4′-thiocytidine and their 5-fluoro analogues in vitro. J . Med.
Chem. 1995, 38, 1-4.
(19) Du, J .; Surzhykov, S.; Lin, J . S.; Newton, M. G.; Cheng, Y.-C.;
Schinazi, R. F.; Chu, C. K. Synthesis, anti-human immunode-
ficiency virus and anti-hepatitis B virus activities of novel
oxaselenolane nucleosides. J . Med. Chem. 1997, 40, 2991-2993.
(20) Kirby, G. W.; Trethewey, A. N. Selenoaldehydes formed by 1,2-
elimination and trapped as Diels-Alder adducts. J . Chem. Soc.,
Chem. Commun. 1986, 1152-1154.
(21) Pinto, B. M.; Sandoval-Ramirez, J .; Sharma, R. D. A convenient
synthesis of 4,4′-dimethylaminodiphenyl diselenide and 4,4′-
dinitrodiphenyl diselenide. Synth. Commun. 1986, 16, 553-557.
(22) Gunther, W. H. H. Hypophosphorous acid, a novel reagent for
the reduction of diselenides and the selenol-catalyzed reduction
of disulfides. J . Org. Chem. 1966, 31, 1202-1205.
Schinazi, R. F.; Painter, G. R. The anti-hepatitis
B virus
activities, cytotoxicities, and anabolic profiles of the (-) and (+)
enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-
5-yl] cytosine. Antimicrob. Agents Chemother. 1992, 36, 2686-
2692.
J M990113X