Synthesis, anti-human immunodeficiency virus and anti-hepatitis B virus activities of novel oxaselenolane nucleosides [1]

Full text of DOI:10.1021/jm9703698

J . Med. Chem. 1997, 40, 2991-2993
2991
Communications to the Editor
posed during the acidification with HCl at pH 2. It was
reported15 that selenols could be readily oxidized by
oxygen in air to stable dimers which can be reduced
back to the selenols by H3PO2. On the basis of this
property of the selenols and the instability of selenoace-
tic acid, we designed and explored an approach in which
reduction of the bis(selenoacetic acid) to selenol, as well
as the method that cyclization take place in an one-pot
reaction without isolation. Thus, dimer 3 was prepared
in 81% yield by refluxing 1 with KSeCN in ethanol for
1 h followed by reduction with NaBH4 at 0 °C for 20-
30 min. In comparison to recently reported procedure
for the preparation of diselenides,16 our method has
advantages of milder reaction conditions, higher yield,
and an easier workup. Lactone 5 was then prepared
in 33% yield by the hydrolysis of 3 with refluxing
aqueous acetic acid (50%) for 24 h followed by the
reduction with H3PO2 to selenol acetic acid, which was
condensed in situ with 2-(benzoyloxy)acetaldehyde un-
der nitrogen. Diisobutylaluminum hydride (DIBAL-H)
has been the regent of choice for reduction of lactone to
lactol. However, no selective reduction of lactone in the
presence of ester was reported. For reduction of the
lactone 5, fortunately, it was found that DIBAL-H can
selectively reduce the lactone in THF, while no selectiv-
ity was observed in toluene. Thus, we were able to
prepare the cyclic acetate 7 by DIBAL-H reduction of 5
in THF followed by in situ acetylation with acetic
anhydride. Condensation of the acetate 7, without
purification, with silylated bases in the presence of
SnCl4 or TMSOTf gave inseparable mixtures of R- and
â-isomers 8a and 8b. Removal of the benzoyl protecting
group of 8a and 8b by methylamine or ammonia in
methanol gave the final nucleosides as an R/â mixture.
The R-cytosine nucleoside 10a was obtained by repeated
recrystallization of the R/â mixture from MeOH/Et2O
followed by methanol, while â-cytosine nucleoside 9a
was obtained by HPLC separation of the mother liquor
(C18 column, 20% MeOH in H2O). For the separation
of the â- and R-5-fluorocytosine nucleosides (9b and
10b), analytical HPLC (C18 column, 5-10% MeOH or
CH3CN in H2O) gave differences of retention times of
3-5 min. However, preparative HPLC showed only a
broad peak under the same conditions. Fortunately, the
individual compounds were obtained by vacuum silica
gel chromatographic separation of the R/â mixture
(EtOAc-hexanes-CHCl3-MeOH, 20-20-20-1, v/v).
The structures of the synthesized oxaselenolane nucleo-
Syn th esis, An ti-Hu m a n
Im m u n od eficien cy Vir u s a n d
An ti-Hep a titis B Vir u s Activities of Novel
Oxa selen ola n e Nu cleosid es
J infa Du,† Sergey Surzhykov,† J u Sheng Lin,‡
M. Gary Newton,§ Yung-Chi Cheng,‡
Raymond F. Schinazi,| and Chung K. Chu*,†
Department of Medicinal Chemistry, College of
Pharmacy, and Department of Chemistry,
The University of Georgia, Athens, Georgia 30602,
Department of Pharmacology, School of Medicine,
Yale University, New Haven, Connecticut 06510, and
Department of Pediatrics, Emory University School of
Medicine/ VA Medical Center, Decatur, Georgia 30033
Received J une 5, 1997
Since dioxolane1-4 and oxathiolane5-10 nucleosides
have exhibited promising antiviral and anticancer
activities, it was of interest to synthesize an isosteric
class of compounds, oxaselenolane nucleosides in search
of biologically interesting nucleosides. Despite their
structural similarity to the known 3′-heteroatom-
substituted nucleosides, the synthesis of oxaselenolane
nucleosides has been elusive. A plausible method for
the construction of oxaselenolane ring with proper
substituents has never been reported to the best of our
knowledge. 1,6-Anhydro and 1,6-epithio sugars have
been successfully used for the asymmetric syntheses of
dioxolane1-4 and oxathiolane7 nucleosides, respectively.
Recently, a 1,6-episeleno sugar has also been reported.11
However, similar procedures used for asymmetric syn-
theses of dioxolane and oxathiolane nucleosides which
involved oxidation reactions could not be applied in the
synthesis of oxaselenolane nucleosides because one of
the characteristic reactions of selenides is oxidative
elimination.12 We describe herein our preliminary
results on the synthesis and antiviral activities of
racemic oxaselenolane pyrimidine nucleosides against
HIV and HBV in vitro.
Retrosynthetic analysis of the title compounds sug-
gested that one of the key steps for the synthesis of
oxaselenolane nucleosides is to construct the oxasele-
nolane ring with proper substituents. Thus, selenol
acetic acid was selected as the precursor of the key
intermediate, oxaselenolanone 5 (Scheme 1). Seleno-
cyanate 2 was prepared by the method of Kirby13 in
excellent yield. In order to construct lactone 5, we
initially attempted to reduce the selenocyanate 2 with
NaBH414 and hydrolyze the resulting ester with aqueous
NaOH to selenol acetic acid, which could be used for
the construction of the oxaselenolane ring system 5.
However, it was found that selenol acetic acid decom-
1
sides were confirmed by elemental analyses and H and
13C NMR. Stereochemical assignments were deter-
mined based on 2D-NOESY experiments, in which a
correlation between 2′-H and 5′-H of the â-isomer 9b
was observed while an absence of this correlation in
R-isomer 10b was noted. Additionally, a correlation
between 6-H and 2′-H of the R-isomer 10b was observed
while no such correlation exhibited for the â-isomer 9b.
The assignment of stereochemistry was also supported
by the upfield chemical shifts of 2′-H (â-form) in 9a and
9b compared to that (R-form) of 10a and 10b due to
deshielding effects by heterocyclic bases. Single-crystal
* Corresponding author: Dr. C. K. Chu, Department of Medicinal
Chemistry, College of Pharmacy, The University of Georgia, Athens,
GA 30602-5379. Tel: (706) 542-5379. Fax: (706) 542-5381. E-mail:
dchu@rx.uga.edu.
† Department of Medicinal Chemistry, The University of Georgia.
‡ Department of Pharmacology, Yale University.
§ Department of Chemistry, The University of Georgia.
| Department of Pediatrics, Emory University School of Medicine/
VA Medical Center.
S0022-2623(97)00369-5 CCC: $14.00 © 1997 American Chemical Society

2992 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 19
Sch em e 1. Synthesis of Oxaselenolane Nucleosides
Communications to the Editor
Ta ble 1. Anti-HIV and Anti-HBV Activities of Racemic
Oxaselenolane Nucleosides in Vitro
anti-HIV activity anti-HBV activity
toxicity (IC50, µM)
in PBM cells
in 2.2.15 cells
compd
(EC50, µM)a
(EC50, µM)
PBM CEM Vero
9a (â)
9b (â)
10a (R)
10b (R)
3TC
0.88
0.51
2.4
1.2
>100 >100 >100
>100 >100 >100
>100 >100 >100
>100 >100 >100
>100 >100 >100
1.2
NDb
ND
>10
0.0710
0.0089
a
PBM ) peripheral blood mononuclear. b ND ) not determined.
F igu r e 1. ORTEP drawing of oxaselenolane 5-fluorocytosine
nucleoside 9b.
In summary, the first synthetic method for novel class
of oxaselenolane nucleosides has been developed, which
led to cytosine and 5-fluorocytosine nucleosides with
potent anti-HIV and anti-HBV activities. The synthesis
and biological evaluation of related purine and pyrimi-
dine analogs, as well as the preparation of optically pure
oxaselenolane nucleosides are in progress in our labo-
ratories.
X-ray crystallography (P ) 121.5°, corresponding to the
conformation 1E, Figure 1) of 5-fluorocytosine analog
(â-9b) further supported the above stereochemical as-
signments.
Antiviral evaluations of the cytosine and 5-fluorocy-
tosine analogs (9a and 9b) showed potent anti-HIV
activity (EC50 0.88 and 0.51 µM, respectively) and anti-
HBV activity (EC50 1.2 µM for both compounds) with
no toxicities up to 100 µM in various cell lines (PBM,
CEM, and Vero). It is interesting to note that the
R-isomer (10a ) also exhibited moderately potent anti-
viral activity against HIV with no toxicities up to 100
µM in PBM, CEM, and Vero cells, which is akin to the
previous studies.17 As with racemic BCH-189 and FTC,
the 5-fluoro derivative 9b was more potent than the
cytosine analog 9a against HIV-1 infected primary
lymphocytes (Table 1).8-10 In order to compare the
relative activities of the synthesized oxaselenolane
nucleosides against HIV and HBV, the activity data of
3TC were also included in Table 1.
Ack n ow led gm en t. This research was supported by
U.S. Public Health Service Research grants (AI 33655
and AI 32351) from the National Institute of Allergy
and Infectious Diseases and the Department of Veterans
Affairs. We thank A. McMillan, S. Schlueter Wirtz, and
A. Handley for their excellent technical assistance.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails (4 pages). Ordering information is given on any current
masthead page.
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