5'-Homoneplanocin A inhibits hepatitis B and hepatitis C.

Article abstract of DOI:10.1021/jm058200e

As an outgrowth of our program to develop an efficient synthesis of 5'-homoneplanocin A, its antiviral potential was explored beyond that already in the literature. From that, this compound was found to have meaningful activity toward hepatitis B and hepa

Full text of DOI:10.1021/jm058200e

J. Med. Chem. 2005, 48, 5043-5046
5043
5′-Homoneplanocin A Inhibits Hepatitis B and Hepatitis C
Minmin Yang,† Stewart W. Schneller,*,† and Brent Korba‡
Department of Chemistry and Biochemistry, Chemistry Building, Auburn University, Auburn, Alabama 36849-5312, and
Division of Molecular Virology and Immunology, Georgetown University Medical Center, Rockville, Maryland 20850
Received February 28, 2005
As an outgrowth of our program to develop an efficient synthesis of 5′-homoneplanocin A, its
antiviral potential was explored beyond that already in the literature. From that, this compound
was found to have meaningful activity toward hepatitis B and hepatitis C, which represents
an example of one agent effective toward both viruses. These data and an improved preparation
of 5′-homoneplanocin A are reported.
Scheme 1a
Introduction
Nucleosides have provided a plentiful source of new
structural leads in antiviral drug development.1 In-
cluded in this class of compounds are the carbocyclic
nucleosides,2 which, because of the presence of a cyclo-
pentyl moiety, offer sites for modification not possible
with the typical ribofuranosyl nucleosides. One of the
most promising of this group has been the naturally
occurring neplanocin A (1).3 Its antiviral effects have
been attributed to inhibition of S-adenosyl-L-homocys-
teine (AdoHcy) hydrolase, which in turn affects viral
mRNA capping methylation.4
a Reaction conditions: (a) PhSCH2CO2Me, n-BuLi, DIPA, HMPA/
THF, 90%; (b) (i) m-CPBA, CH2Cl2; (ii) CaCO3, toluene, 83% (two
steps); (c) NaBH4, CeCl3‚7H2O, MeOH, 100%; (d) 6-chloropurine,
Ph3P, DIAD, THF, 81%.
cyclopentenol 6 for the purposes of subjecting it to a
Mitsunobu procedure9 with 6-chloropurine or adenine.
In that direction, 5 underwent a regioselective and
stereoselective 1,4-addition10 of methyl phenylthio-
acetate to yield 7. Oxidation of 7 with m-chloroperoxy-
benzoic acid (m-CPBA) followed by dehydrosulfenyla-
tion11 in refluxing toluene in the presence of a small
amount of calcium carbonate yielded, after double bond
migration into the ring, enone 8.12 Luche reduction13 of
8 cleanly afforded 6. Subjecting 6 to Mitsunubo reaction
conditions with 6-chloropurine gave the elimination
product 9 instead of the desired coupled product.
This unexpected result forced us to seek a strategy
different from that for 4 that would avoid the potential
to form the extended conjugated system 9. Thus, reduc-
tion of the ketone and ester functionalities in 8 with
diisobutylaluminum hydride (DIBAL) yielded diol 10
(Scheme 2). Selective primary alcohol protection of 10
with tert-butyldimethylsilyl chloride (TBDMSCl) af-
forded the coupling precursor 11, which was subjected
to Mitsunubo reaction conditions with adenine to afford
12. The final product 4 was obtained by deprotection of
12 with hydrochloric acid.
As with its saturated carbocyclic partner aristeromy-
cin (2), neplanocin A is susceptible to 5′-nucleotide
formation that renders it unacceptable for antiviral
therapeutic development.3a Borchardt and others5,6 have
addressed this by investigating the truncated derivative
3, which cannot serve as a substrate for nucleotide
formation. In considering other neplanocin candidates,
we were attracted to the work of Shuto,7 who found 5′-
homoneplanocin (4) to have significant antiviral activity
with no interfering cytotoxicity. To explore the antiviral
potential of 4 more thoroughly required us to develop a
practical synthesis of it. Once that was accomplished,
the effects of 4 on viruses other than those previously
evaluated7 were undertaken. The results of this study
are described here.
Chemistry
The plan to 4 was designed to convert the conve-
niently available cyclopentenone 58 (Scheme 1) into the
This synthetic method to 4 has three advantages over
the existing route:7 (1) fewer steps from enone (5 in this
case, ent-5 in the literature7 procedure); (2) higher
overall yield (27% versus 9.5%7); (3) avoidance of the
use of an expensive palladium reagent that is necessary
for a 1,3-shift in the Shuto7 process.
* To whom correspondence should be addressed. Phone: 334-844-
5737. Fax: 334-844-5748. E-mail: schnest@auburn.edu.
† Auburn University.
‡ Georgetown University Medical Center.
10.1021/jm058200e CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/22/2005

5044 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 15
Brief Articles
Scheme 2a
Table 2. Activity of 4 against HCV Replication in AVA5 Cell
Culturesa
treatment CC50 (µM) EC50 (µM) EC90 (µM) SI (CC50/EC50
)
IFN-R
ribavirin 71 ( 1.2
216 ( 2.0
>10000b,c 1.6 ( 0.2
8.7 ( 0.8
>100c
31 ( 2.8
>6250
>100c
4
7.3 ( 0.8
30
a Values presented ((standard deviations) were calculated by
linear regression analysis using data combined from all treated
cultures. EC50 and EC90 are drug concentrations at which a 2-fold
and a 10-fold depression of HCV RNA (relative to the average
levels in untreated cultures), respectively, was observed. CC50 is
the drug concentration at which a 2-fold lower level of neutral red
dye uptake (relative to the average levels in untreated cultures)
was observed. b Concentrations for IFN-R are expressed as “IU/
mL”. c No cytotoxic or antiviral effect at the highest indicated
concentration.
a Reaction conditions: (a) DIBAL, CH2Cl2, 87%; (b) TBDMSCl,
imidazole, CH2Cl2, 88%; (c) adenine, Ph3P, DIAD, THF, 43%; (d)
HCl, MeOH, 90%.
Antiviral Results
Compound 4 was evaluated against a wide variety of
DNA viruses and RNA viruses. In addition to those
previously reported7 the following viruses were evalu-
ated: cowpox, influenza A (H1N1 and H3N2), influenza
B, pichinde, Venezuelan equine encephalitis, yellow
fever, West Nile, hepatitis B (HBV), and hepatitis C
(HCV). The most noteworthy observation from this
analysis was the ability of 4 to show activity against
HBV14 and HCV15 (Tables 1 and 2). It is true that while
4 is not as effective as the standard reference agents
used in the assays, it does offer a basis for analogue
development of one agent to treat both infections. It also
provides a very significant compound for exploring the
biochemical basis for coeffectiveness with the potential
of uncovering a common, exploitable metabolic feature
for HBV and HCV. These possibilities are under intense
pursuit in our laboratories.
at the same temperature for 30 min before it was cooled to
-70 °C. Methyl phenylthioacetate (1.00 g, 5.50 mmol) was then
added dropwise using a syringe. After the resulting pale-yellow
solution was stirred at the same temperature for 1 h, hexa-
methylphosphoramide (HMPA) (3.0 mL) was added followed
by the dropwise addition of 58 (0.77 g, 5.0 mmol) in THF (5.0
mL). This mixture was kept at -70 °C for 1 h, and saturated
NH4Cl solution (10 mL) was added to quench the reaction. The
organic layer was separated, and the aqueous layer was
extracted with EtOAc (3 × 30 mL). The combined organic
phase was dried (anhydrous MgSO4), and the solvent was
removed. The residue was purified by column chromatography
to afford 7 as a colorless liquid mixture of two diastereoisomers
(1.50 g, 90%): 1H NMR (250 MHz, CDCl3) δ 7.47 (m, 4H), 7.34
(m, 6H), 4.85 (d, J ) 5.8 Hz, 1H), 4.80 (d, J ) 5.7 Hz, 1H),
4.45 (d, J ) 5.7 Hz, 1H), 4.39 (d, J ) 5.8 Hz, 1H), 3.76 (d, J )
5.1 Hz, 1H), 3.75 (d, J ) 6.8 Hz, 1H), 3.69 (s, 3H), 3.68 (s,
3H), 2.86 (m, 4H), 2.35 (m, 2H), 1.42 (s, 6H), 1.34 (s, 3H), 1.33
(s, 3H); 13C NMR (62.9 MHz, CDCl3) δ 211.9, 211.8, 171.3,
171.1, 133.1, 133.0, 132.5, 129.3, 128.6, 128.5, 111.9, 80.1, 78.8,
53.8, 52.5, 40.2, 39.9, 38.5, 38.4, 26.6, 24.6, 24.5. Anal.
(C17H20O5S) C, H, S.
Compound 4 affected none of the other new viruses
assayed.16
Experimental Section
Methyl 2-((3aR,6aR)-4,6a-Dihydro-2,2-dimethyl-4-oxo-
3aH-cyclopenta[d][1,3]dioxol-6-yl)acetate (8). To a solu-
tion of 7 (3.23 g, 9.60 mmol) in CH2Cl2 (100 mL) at -78 °C
was added a solution of m-CPBA (2.50 g, 77%, 11.1 mmol) in
CH2Cl2 (40 mL). The mixture was gradually warmed to -40
°C and stirred at this temperature for 2.5 h. Sodium bisulfite
solution (0.75 g in 30 mL of H2O) was added to quench the
reaction. The organic layer was separated, washed with
saturated Na2CO3 (2 × 30 mL), and dried (anhydrous Na2SO4).
The solvent was removed to afford the intermediate sulfoxide
as a white foam. This white foam was dissolved in toluene (120
mL), and calcium carbonate (1.00 g, 10 mmol) was added. The
mixture was brought to reflux for 12 h. The solvent was
removed and the residue was purified by column chromatog-
raphy to afford 8 as colorless liquid (1.80 g, 83%): 1H NMR
(250 MHz, CDCl3) δ 6.13 (s, 1H), 5.23 (dd, J ) 5.7, 0.6 Hz,
1H), 4.51 (d, J ) 5.7 Hz, 1H), 3.76 (s, 3H), 3.55 (qq, J ) 17.6,
17.6, 0.8 Hz, 2H), 1.44 (s, 3H), 1.39 (s, 3H); 13C NMR (62.9
MHz, CDCl3) δ 201.7, 168.6, 168.5, 131.6, 115.5, 80.0, 77.7,
52.5, 35.6, 27.4, 26.3. Anal. (C11H14O5) C, H.
All melting points were recorded on a Meltemp II melting
point apparatus, and the values were uncorrected. The com-
bustion analyses were performed at Atlantic Microlab, Nor-
1
cross, GA. H and 13C NMR spectra were recorded on Bruker
AC 250 spectrometer (operated at 250 and 62.9 MHz, respec-
tively) or Bruker AV 400 spectrometer (operated at 400 and
100 MHz, respectively), all referenced to internal tetrameth-
ylsilane (TMS) at 0.0 ppm. The reactions were monitored by
thin-layer chromatography (TLC) using 0.25 mm Whatman
Diamond silica gel 60-F254 precoated plates with visualization
by irradiation with a Mineralight UVGL-25 lamp. Column
chromatography was performed on Whatman silica, 230-400
mesh, 60 Å, and elution was done with the indicated solvent
system. Yields refer to chromatographically and spectroscopi-
cally (1H and 13C NMR) homogeneous materials.
Methyl 2-((3aR,6S,6aR)-Tetrahydro-2,2-dimethyl-4-
oxo-3aH-cyclopenta[d][1,3]dioxol-6-yl)-2-(phenylthio)-
acetate (7). To a solution of diisopropylamine (0.85 mL, 6.1
mmol) in THF (15 mL) was added dropwise n-BuLi (2.60 mL,
2.5 M in hexanes, 6.50 mmol) at 0 °C. The solution was stirred
Table 1. Relative Potency of 4 against HBV Replication in 2.2.15 Cellsa
extracellular virion DNA
intracellular RI
SI (CC50/EC90)
compd
CC50 (µM)
EC50 (µM)
EC90 (µM)
EC50 (µM)
EC90 (µM)
virion
RI
lamivudine
4
2675 ( 94
1213 ( 78
0.06 ( 0.007
0.53 ( 0.06
0.17 ( 0.02
7.7 ( 0.6
0.23 ( 0.02
6.1 ( 0.7
0.69 ( 0.07
27 ( 2.8
11630
158
3877
45
a Values presented ((standard deviations) were calculated by linear regression analysis (two to four experiments, four to six replicates
per concentration). EC50 and EC90 are drug concentrations at which a 2-fold and a 10-fold depression of HBV DNA (relative to the average
levels in untreated cultures), respectively, was observed. CC50 is the drug concentration at which a 2-fold depression of neutral red dye
uptake (relative to the average levels in untreated cultures) was observed. The EC90 values were used for the calculation of the selectivity
indexes (SI) because at least a 3-fold depression of HBV RI levels is typically required to achieve statistical significance in this assay
system.17 RI is the HBV DNA replication of intermediates.

Brief Articles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 15 5045
1
Methyl 2-((3aS,4S,6aR)-4,6a-Dihydro-4-hydroxy-2,2-di-
methyl-3aH-cyclopenta[d][1,3]dioxol-6-yl)acetate (6). To
a solution of 8 (0.63 g, 2.8 mmol) and CeCl3‚7H2O (0.89 g, 2.4
mmol) in MeOH (15 mL) at 0 °C was added portionwise NaBH4
(0.15 g, 3.9 mmol). The mixture was stirred at the same
temperature for 1.5 h before the reaction was quenched with
H2O (10 mL). Methylene chloride (30 mL) was added to the
mixture, and the organic phase was separated. The aqueous
phase was extracted with CH2Cl2 (2 × 15 mL). The combined
organic phases were washed with brine and dried (anhydrous
Na2SO4). Evaporation of the solvent afforded 6 as a clean
product (0.64 g, 100%) as determined by NMR with no further
purification necessary: 1H NMR (250 MHz, CDCl3) δ 5.69 (s,
1H), 5.01 (d, J ) 5.4 Hz, 1H), 4.77 (t, J ) 5.4 Hz, 1H), 4.58
(m, 1H), 3.70 (s, 3H), 3.23 (s, 2H), 2.80 (br, 1H), 1.41 (s, 6H);
13C NMR (62.9 MHz, CDCl3) δ 171.0, 138.3, 133.3, 112.6, 84.3,
78.0, 73.5, 52.1, 33.4, 27.7, 26.8. Anal. (C11H16O5) C, H.
(2Z)-Methyl 2-((3aS,6aR)-2,2-Dimethyl-3aH-cyclopenta-
[d][1,3]dioxol-6(6aH)-ylidene)acetate (9). To a suspension
of 6 (0.64 g, 2.8 mmol), Ph3P (1.08 g, 4.2 mmol), and 6-chlo-
ropurine (0.65 g, 4.2 mmol) in THF (20 mL) at 0 °C was added
a solution of diisopropyl azodicarboxylate (DIAD) (0.85 g, 4.2
mmol) in THF (10 mL). The mixture was warmed to room
temperature and then stirred for 2 h. The solvent was removed
and the residue was purified by column chromatography to
afford 9 as a colorless liquid (0.48 g, 81%): 1H NMR (250 MHz,
CDCl3) δ 7.35 (d, J ) 5.8, 1H), 6.50 (dt, J ) 5.8, 1.9 Hz, 1H),
5.95 (s, 1H), 5.15 (dd, J ) 5.6, 1.9 Hz, 1H), 5.00 (d, J ) 5.6
Hz, 1H), 3.74 (s, 3H), 1.41 (s, 3H), 1.38 (s, 3H); 13C NMR (62.9
MHz, CDCl3) δ 167.5, 158.9, 143.8, 133.0, 114.1, 112.9, 81.9,
79.9, 51.5, 27.6, 26.4.
(3aS,4S,6aR)-4,6a-Dihydro-6-(2-hydroxyethyl)-2,2-di-
methyl-3aH-cyclopenta[d][1,3]dioxol-4-ol (10). To a solu-
tion of 8 (1.18 g, 5.22 mmol) in anhydrous CH2Cl2 (50 mL) at
-50 °C was added diisobutylaluminum hydride (DIBAL) (20.0
mL, 1 M in CH2Cl2, 20.0 mmol) dropwise. The mixture was
stirred at the same temperature for 4 h before the reaction
was quenched with MeOH (5 mL). Tartrate solution (20 mL)
was added, and the mixture was warmed to room temperature
and then stirred for 1 h. The organic phase was separated,
and the aqueous solution was extracted with CH2Cl2 (3 × 10
mL). The combined organic phases were dried (anhydrous Na2-
SO4). The solvent was removed under vacuum to cleanly afford
10 as a colorless liquid (0.90 g, 87%) of sufficient purity (NMR)
for use in the next step: 1H NMR (250 MHz, CDCl3) δ 5.61 (s,
1H), 4.88 (d, J ) 5.5 Hz, 1H), 4.77 (t, J ) 5.6 Hz, 1H), 4.54
(m, 1H), 3.76 (m, 2H), 2.79 (m, 2H), 2.44 (m, 2H), 1.45 (s, 3H),
1.41 (s, 3H); 13C NMR (62.9 MHz, CDCl3) δ 142.8, 131.5, 112.3,
84.6, 77.6, 73.1, 60.6, 31.9, 27.4, 26.3. Anal. (C10H16O4) C, H.
(3aS,4S,6aR)-6-[2-(tert-Butyldimethylsilanyloxy)ethyl]-
4,6a-dihydro-2,2-dimethyl-3aH-cyclopenta[d][1,3]dioxol-
4-ol (11). To an ice-chilled solution of 10 (0.90 g, 4.5 mmol) in
CH2Cl2 (40 mL) was added imidazole (0.48 g, 7.1 mmol) and
tert-butyldimethylsilyl chloride (TBDMSCl) (0.76 g, 5.0 mmol).
The mixture was stirred at room temperature for 12 h. The
resulting precipitate was removed by filtration, and the filtrate
was evaporated. The residue was purified by column chroma-
tography (EtOAc/hexanes ) 1:4) to afford 11 as a colorless oil
(1.24 g, 88%): 1H NMR (250 MHz, CDCl3) δ 5.53 (s, 1H), 4.84
(d, J ) 5.5 Hz, 1H), 4.70 (t, J ) 5.5 Hz, 1H), 4.51 (m, 1H),
3.76 (m, 2H), 2.68 (d, J ) 10 Hz, 1H, OH), 2.37 (m, 2H), 1.39
(s, 3H), 1.38 (s, 3H), 0.86 (s, 9H), 0.02 (s, 6H); 13C NMR (62.9
MHz, CDCl3) δ 143.2, 130.7, 112.4, 85.2, 77.8, 73.7, 61.4, 31.6,
27.9, 27.0, 26.1, 18.4, -5.1. Anal. (C16H30O4Si) C, H.
121-122 °C (lit.7 133-134 °C); H NMR (250 MHz, CDCl3) δ
8.40 (s, 1H), 7.69 (s, 1H), 6.34 (br, 2H), 5.63 (d, J ) 12.4 Hz,
2H), 5.29 (d, J ) 5.5 Hz, 1H), 4.62 (d, J ) 5.5 Hz, 1H), 3.90
(m, 2H), 2.55 (m, 2H), 1.47 (s, 3H), 1.37 (s, 3H), 0.90 (s, 9H),
0.09 (s, 6H); 13C NMR (62.9 MHz, CDCl3) δ 155.9, 153.4, 150.4,
150.0, 138.5, 123.0, 120.3, 112.6, 85.6, 84.4, 64.5, 60.7, 32.2,
27.6, 26.3, 26.1, 18.4, -5.1. Anal. (C21H33N5O3Si) C, H, N.
(3Z)(1S,2R,5R)-5-(6-Aminopurin-9-yl)-3-(2-hydroxyeth-
yl)cyclopent-3-ene-1,2-diol (4). Compound 12 (0.40 g, 0.93
mmol) was dissolved in a mixture of MeOH (10 mL) and 1 N
HCl (10 mL), and the resulting solution was stirred at room
temperature for 5 h. Basic resin (Amberlite IR 67) was added
to neutralize the solution, which was followed by filtration.
The filtrate was removed under vacuum and the residue was
purified by column chromatography (EtOAc/MeOH/NH4OH )
6:2:1) to provide 4 as a white solid (0.23 g, 90%): mp 181-
182 °C; 1H NMR (250 MHz, DMSO-d6) δ 8.15 (s, 1H), 8.08 (s,
1H), 7.34 (br, 2H), 5.62 (s, 1H), 5.33 (s, 1H), 4.44 (d, J ) 5.4
Hz, 1H), 4.23 (t, J ) 5.2 Hz, 1H), 3.62 (t, J ) 6.8 Hz, 2H), 2.35
(t, J ) 6.8 Hz, 2H); 13C NMR (62.9 MHz, DMSO-d6) δ 155.7,
152.0, 149.6, 147.5, 139.6, 125.0, 119.2, 76.4, 74.6, 64.6, 59.0,
32.6.7
HBV Antiviral Analysis. HBV antiviral analyses were
conducted as previously described.17 In brief, confluent cultures
of 2.2.15 cells were maintained on 96-well flat-bottomed tissue
culture plates in RPMI1640 medium with 2% fetal bovine
serum.17 Cultures (six for each test concentration on two
replicate plates) were treated with nine consecutive daily doses
of the test compounds. Medium was changed daily with fresh
test compounds. HBV DNA levels were assessed 24 h after
the last treatment by quantitative blot hybridization.17 Uptake
of neutral red dye by semiquantitative analysis of the absor-
bance of internalized dye at 510 nM (A510) was used to
determine the relative level of toxicity 24 h following the last
treatment (three cultures per test concentration).17 For these
analyses, cultures of 2.2.15 cells were maintained on 96-well
plates seeded at the same time with the identical pool of stock
cells used for the antiviral analyses and maintained in an
identical manner.
HCV Antiviral Analysis. AVA5 cells (Huh 7 cells contain-
ing the subgenomic HCV replicon BB7)18 were used for these
studies as previously described.19 Stock cultures were main-
tained in a subconfluent state in this culture medium with 1
mg/mL G418 (Invitrogen, Inc.).18 Cells for antiviral analysis
were seeded into 24-well tissue culture plates (Nunc, Inc.) and
grown for 3 days in the presence of G418. G418 was then
removed for the duration of the antiviral treatments to
eliminate potential loss of cells due to the reduction of HCV
replicon (and G418 resistance) copy number. Cultures (rapidly
dividing, three cultures per concentration) were treated for 3
consecutive days with the test compounds. Medium was
replaced daily with fresh test compounds. Analysis of HCV
RNA was performed 24 h following the last addition of test
compounds by quantitative blot hybridization.18 Toxicity analy-
ses in AVA5 cells were performed as described above. The
interferon-R (IFN-R) was purchased from PBL Biomedical
Laboratories.
Acknowledgment. This research was supported by
funds from the Department of Health and Human
Services (Grant AI 56540), which is appreciated. We are
also indebted to the following individuals for providing
additional antiviral data: Dr. Erik De Clercq, Rega
Institute, Leuven, Belgium; Dr. Earl Kern, University
of Alabama at Birmingham, Birmingham, AL; Dr.
Robert Sidwell, Utah State University, Logan, UT.
(3aS,4S,6aR)-9-{6-[2-(tert-Butyldimethylsilanyloxy)-
ethyl]-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]-
dioxol-4-yl}-9H-purin-6-ylamine (12). To a suspension of
11 (1.10 g, 3.50 mmol), Ph3P (0.99 g, 3.8 mmol), and adenine
(0.54 g, 4.0 mmol) in dry THF (40 mL) at 0 °C was added
dropwise a solution of DIAD (0.77 mL, 3.8 mmol) in THF (5
mL). The mixture was stirred at room temperature for 12 h
and then at 50 °C for 8 h. The solvent was removed and the
residue was purified by column chromatography (EtOAc/
hexanes ) 4:1) to give 12 as a white solid (0.63 g, 43%): mp
Supporting Information Available: Results from el-
emental analyses. This material is available free of charge via
the Internet at http://pubs.acs.org.
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