Synthesis and antiviral evaluation of novel open-chain analogues of neplanocin A

Article abstract of DOI:10.1080/15257770500544578

Novel acyclic nucleoside analogues were designed and synthesized as open-chain analogues of neplanocin A. The coupling of the allylic bromide with purine bases using cesium carbonate afforded a series of novel acyclic nucleosides. The synthesized compound

Full text of DOI:10.1080/15257770500544578

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Synthesis and antiviral evaluation
of novel open-chain analogues of
neplanocin A
Joon Hee Hong a , So-Young Kim b , Chang-Hyun Oh b , Kyung Ho Yoo
b & Jung-Hyuck Cho Prof. Dr. b
a College of Pharmacy , Chosun University , Kwangju, Korea
b Medicinal Chemistry Research Center , Korea Institute of Science
and Technology , Seoul, Korea
Published online: 23 Aug 2006.
To cite this article: Joon Hee Hong , So-Young Kim , Chang-Hyun Oh , Kyung Ho Yoo & Jung-Hyuck
Cho Prof. Dr. (2006) Synthesis and antiviral evaluation of novel open-chain analogues of neplanocin A,
Nucleosides, Nucleotides and Nucleic Acids, 25:3, 341-350, DOI: 10.1080/15257770500544578
To link to this article: http://dx.doi.org/10.1080/15257770500544578
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Nucleosides, Nucleotides, and Nucleic Acids, 25:341–350, 2006
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770500544578
SYNTHESIS AND ANTIVIRAL EVALUATION OF NOVEL OPEN-CHAIN
ANALOGUES OF NEPLANOCIN A
Joon Hee Hong
College of Pharmacy, Chosun University, Kwangju, Korea
2
So-Young Kim, Chang-Hyun Oh, Kyung Ho Yoo, and Jung-Hyuck Cho
Medicinal Chemistry Research Center, Korea Institute of Science
2
and Technology, Seoul, Korea
Novel acyclic nucleoside analogues were designed and synthesized as open-chain analogues of
2
neplanocin A. The coupling of the allylic bromide with purine bases using cesium carbonate afforded
a series of novel acyclic nucleosides. The synthesized compounds Ia–II were evaluated for their
antiviral activity against various viruses such as HIV, HSV-1, HSV-2, and ECMV.
Keywords Antiviral agents; Acyclic nucleosides; Neplanocin A
INTRODUCTION
The discovery of acyclovir[1] as an antiherpes agent ignited the search
for new antiviral nucleosides with a disconnected chain resulting from the
omission of bonds from the pentose or cyclopentane rings. During the
past 20 years, many new synthetic schemes for various acyclic nucleoside[2]
analogues have been discovered and many of these molecules have shown
promising antiviral activities.[3] Among them, pencyclovir is an acyclic ana-
logue of guanosine, and has been approved as an antiviral drug for treat-
ing disease caused by HSV and VZV.[4] Because of the unusual presence
of a double bond in neplanocin A[5] and the acyclic nature of pencyclovir,
these two compounds have stimulated extensive research in the synthesis of
new cyclic and acyclic nucleoside analogues that mimic the sugar portion
of naturally occurring neplanocin A. Furthermore, the recent approval of
bis(POC)PMPA by the FDA as an anti-HIV agent warrants further searches
for acyclic nucleosides as chemotherapeutic agents (Figure 1).[6]
Nevertheless, the utility of these drugs is limited due to their toxicity and
side effects, as well as the emergence of drug-resistant viral strains. Therefore,
Received 16 June 2005; accepted 29 December 2005.
Address correspondence to Prof. Dr. Jung-Hyuck Cho, Medicinal Chemistry Research Center, Korea
Institute of Science and Technology, Seoul 130-650, Korea. E-mail: jungcho@kist.re.kr
341

342
J. H. Hong et al.
FIGURE 1 Synthesis rationale of the target nucleosides.
it is essential to search for less toxic and more effective antiviral agents that
do not have a cross-resistance with the existing drugs.
In view of the stimulating results of acyclic nucleosides and the search for
the stable and effective carba-nucleosides, compounds Ia–Ii were designed
as open-chain analogues of neplanocin A.
RESULTS AND DISCUSSION
The strategy for synthesizing the target nucleosides is based on the alky-
lation of purine bases on the allylic bromides 7, 8, and 9, which were readily
synthesized from hydroxyl ketone derivatives such as 1,3-dihydroxyacetone
1, acetol 2, and 2-hydroxyacetophenone 3 using a previously reported
procedure.[7] Conversion of allylic alcohols 4, 5, and 6 to the bromo deriva-
tives 7, 8, and 9 was accomplished by the sequential addition of NBS to a solu-
tion of the alcohol and triphenylphosphine in CH2Cl2 in high yield.[8] Direct
coupling of the allylic bromide 7–9 with purine bases in DMF with cesium
carbonates as a basic catalyst provided the desired N9-alkylated purine nu-
cleosides in 35–72% yields.[9] Deprotection of the t-butyldimethylsilyl group
(TBDMS) using tetrabutylammonium fluoride (TBAF) in tetrahydrofuran
(THF) gave the desired acyclic purine nucleosides Ia–If (Scheme 1). Prepa-
ration of the acyclic hypoxanthine nucleosides Ig–i were accomplished by
treatment of the 2N HCl (Scheme 2).

Open-Chain Analogues of Neplanocin A
343
SCHEME 1 Synthesis of adenine and 6-chloropurine–substituted acyclic nucleosides.
SCHEME 2 Synthesis of acyclic inosine nucleosides.
The bromide
7 was reacted with 2-amino-6-[(4-chlorophenyl)-
sulfanyl]purine in the presence of cesium carbonate and subsequently
treated with 2N HCl gave the acyclic guanine nucleosides Ij–l (Scheme 3).
Synthesized compounds Ia–Il were evaluated for their activity against HIV,
HSV-1, HSV-2, and ECMV. As shown in Table 1, guanine base derivatives
Ij and Ik showed moderate anti-HSV1 and -2 activity (EC50 = 32.7 and
11.7 µg/mL).
SCHEME 3 Synthesis of acyclic guanine nucleosides.

344
J. H. Hong et al.
TABLE 1 The Antiviral Activities of the Synthesized Compounds
HIV-1
HSV-1
HSV-2
ECMV
Cytotoxicity
Compounds
EC50(µg/mL)
EC50(µg/mL)
EC50(µg/mL)
EC50(µg/mL)
IC50(µg/mL)
Ia
Ib
Ic
Id
Ie
If
Ig
Ih
Ii
Ij
Ik
Il
AZT
ACV
>100
>100
>100
>100
>100
>100
>100
47.2
>100
>100
>100
>100
0.0008
ND
>100
>100
>100
79.5
>100
>100
>100
>100
>100
>100
32.7
>100
>100
>100
>100
>100
>100
>100
>100
>100
11.7
>100
>100
>100
>100
>100
>100
36.2
>100
>100
>100
>100
>100
ND
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
4.78
>100
>100
ND
>100
1.90
ND
1.90
ND
>10
Gancyclovir
ND
ND
>100
>10
ND: Not determined.
EXPERIMENTAL SECTION
All the chemicals were of reagent grade and were used as purchased.
All the moisture-sensitive reactions were performed in an inert atmosphere
with either N2 or Ar using distilled dry solvents. The melting points were
determined using a Mel-temp II laboratory device and were uncorrected. The
NMR spectra were recorded on a JEOL 300 Fourier transform spectrometer;
the chemical shifts are reported in parts per million (δ) and the signals are
quoted as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and
dd (doublet of doublets). The UV spectra were obtained using a Beckman
DU-7 spectrophotometer. The elemental analysis was performed using an
Elemental Analyzer System (Profile HV-3). TLC was performed on uniplates
(silica gel) purchased from Analtech Co.
3,3ꢁ-Bis-(t-Butyldimethylsilyloxymethyl)-prop-2-enyl bromide (7). To a
solution of compound 4 (2.30 g, 6.73 mmol) and triphenylphosphine (1.94 g,
7.4 mmol) in CH2Cl2 (20 mL), N-bromosuccinimide (1.28 g, 7.2 mmol)
was added slowly at 0◦C, stirred for 4 h at room temperature, and diluted
with CH2Cl2. The organic layer was washed with water and brine, dried over
anhydrous magnesium sulfate, and filtered through a Celite pad. The filtrate
was concentrated under vacuum and the residue was purified by quick flash
silica gel column chromatography (EtOAc/hexane, 1:10) to give the allylic
bromide 7 (2.15 g, 79%) as a yellow oil: 1H NMR (CDCl3, 300 MHz) δ 5.93
(t, J = 6.4 Hz, 1H), 4.42 (d, J = 7.2 Hz, 2H), 4.29 (s, 2H), 3.91 (s, 2H), 0.92
(s, 18H), 0.05 (s, 12H).

Open-Chain Analogues of Neplanocin A
345
(E)-4-(t-Butyldimethylsilyloxy)-3-methyl-but-2-enyl bromide (8).
Com-
pound 8 was prepared from 5 as described for 7. Yield 78%; 1H NMR (CDCl3,
300 MHz) δ 5.56 (m, 1H), 4.38 (br s, 2H), 3.91 (d, J = 6.4 Hz, 2H), 1.70 (s,
3H), 0.95 (s, 9H), 0.08 (s, 6H).
(E)-4-(t-Butyldimethylsilyloxy)-3-phenyl-but-2-enyl bromide (9).
Com-
pound 9 was prepared from 6 as described for 7. Yield 69%; 1H NMR (CDCl3,
300 MHz) δ 7.30 (d, J = 6.7 Hz, 2H), 7.21 (d, J = 6.1 Hz, 2H), 7.20 (d,
J = 6.0 Hz, 1H), 5.91 (t, J = 6.4 Hz, 1H), 4.46 (s, 2H), 3.97 (d, J = 6.7 Hz,
2H), 1.0 (s, 9H), 0.08 (s, 6H).
1-[3,3ꢁ -Bis-(t-Butyldimethylsilyloxymethyl)-prop-2-enyl]adenine (10).
A solution of the allylic bromide 7 (0.50 g, 1.22 mmol), adenine (530 mg,
3.94 mmol), and sodiume hydride (150 mg, 3.94 mmol) in anhydrous
DMF (10 mL) was stirred overnight at room temperature. The mixture was
quenched by the addition of water and diluted with ethylacetate. The organic
layer was separated and washed with brine, dried over anhydrous magnesium
sulfate, filtered, and concentrated. The residue was purified by silica gel col-
umn chromatography (EtOAc/hexane, 4:1) to give compound 10 (384 mg,
72%) as a solid: 1H NMR (CDCl3, 300 MHz) δ 8.68 (s, 1H), 8.12 (s, 1H), 5.80
(t, J = 6.4 Hz, 1H), 4.46 (s, 4H), 4.40 (d, J = 7.2 Hz, 2H), 1.0 (s, 18H), 0.08
(s, 12H); 13C NMR (CDCl3)δ 156.40, 152.87, 149.75, 142.36, 140.66, 120.33,
63.95, 58.94, 26.18, 18.42, −4.97.
The synthesis of compounds 11 and 12 were carried out by the same
procedure as described for the preparation of 10.
1-[(E )-4-(t-Butyldimethylsilyloxy)-3-methyl-but-2-enyl]adenine (11).
Yield 64%; 1H NMR (CDCl3, 300 MHz) δ 8.38 (s, 1H), 7.79 (s, 1H), 5.75
(t, J = 7.05 Hz, 1H), 4.84 (d, J = 7.17 Hz, 2H), 4.08 (s, 2H), 1.79 (s, 3H),
0.89 (s, 9H) 0.05 (s, 6H); 13C NMR (CDCl3)δ 155.44, 152.95, 150.01, 141.43,
139.93, 119.62, 116.39, 67.79, 40.79, 25.87, 18.35, 13.70, −5.38.
1-[(E )-4-(t-Butyldimethylsilyloxy)-3-phenyl-but-2-enyl]adenine (12).
Yield 67%; 1H NMR (CDCl3, 300 MHz) δ 7.78 (s, 1H), 7.56 (s, 1H), 7.37
(d, J = 7.7 Hz, 2H), 7.28 (d, J = 7.4 Hz, 2H), 7.19 (d, J = 6.3 Hz, 1H), 5.87
(t, J = 7.8 Hz, 1H), 4.69 (s, 2H), 4.59 (d, J = 7.10 Hz, 2H) 0.89 (s, 9H), 0.08
(s, 6H); 13C NMR (CDCl3)δ 154.92, 152.08, 147.90, 144.83, 142.65, 134.96,
128.49, 127.77, 126.28, 113.51, 75.36, 48.87, 20.81, 14.74, −6.42.
1-[3,3ꢁ -Bis-(t-Butyldimethylsilyloxymethyl)-prop-2-enyl] 6-chloropurine
(13).
A solution of the allylic bromide 7 (2.0 g, 4.88 mmol), 6-chloropurine
(1.75 g, 11.23 mmol) and cesium carbonate (2.07 g, 6.35 mmol) in anhydrous
DMF (30 mL) was stirred overnight at room temperature. The mixture was

346
J. H. Hong et al.
quenched by the addition of water and diluted with ethylacetate. The organic
layer was separated and washed with brine, dried over anhydrous magnesium
sulfate, filtered, and concentrated. The residue was purified by silica gel col-
umn chromatography (EtOAc/hexane, 1:1) to give compound 13 (1.32 mg,
56%) as a solid: 1H NMR (CDCl3, 300 MHz) δ 8.74 (s, 1H), 8.17 (s, 1H), 5.78
(t, J = 7.47 Hz, 1H), 5.05 (d, J = 7.4 Hz, 2H), 4.35 (s, 2H), 4.18 (s, 2H),
0.88 (d, J = 8.97 Hz, 18H), 0.06 (d, J = 9.0 Hz, 12H); 13C NMR (CDCl3)δ
151.85, 151.69, 150.87, 145.04, 144.88, 131.58, 117.70, 64.28, 59.56, 40.94,
25.83, 18.31.
The synthesis of compounds 14 and 15 were carried out by the same
procedure as described for the preparation of 11.
1-[(E)-4-(t-Butyldimethylsilyloxy)-3-methyl-but-2-enyl]-6-chloropurine
(14).
Yield 35%; 1H NMR (CDCl3, 300 MHz) δ 8.70 (s, 1H), 8.09 (s, 1H),
5.72 (t, J = 6.69 Hz, 1H), 4.90 (d, J = 7.3 Hz, 2H), 4.03 (s, 2H), 1.77 (s,
3H), 0.83 (s, 9H), 0.003 (s, 6H); 13C NMR (CDCl3)δ 151.82, 150.78, 144.70,
142.43, 131.55, 130.06, 115.19, 66.86, 41.37, 25.81, 18.30, 13.74, −5.32.
1-[(E)-4-(t-Butyldimethylsilyloxy)-3-phenyl-but-2-enyl]-6-chloropurine
1
(15).
Yield 39%; H NMR (CDCl3, 300 MHz) δ 8.78 (br s, 1H), 7.58 (s,
1H), 7.35–728. (m, 5H), 5.53 (t, J = 7.3 Hz, 1H), 4.43 (d, J = 7.3 Hz, 2H),
4.08 (s, 2H), 0.92 (s, 9H), 0.07 (s, 6H); 13C NMR (CDCl3)δ 160.62, 150.48,
148.13, 142.93, 115.47, 67.10, 45.16, 25.90, 18.40, 13.74, −5.32.
1- [3,3ꢁ-Bis-(t-Butyldimethylsilyloxymethyl)-prop-2-enyl]-4-amino-6-[(4-
chlorophenyl)sulf anyl]-9H-purine (16).
A solution of the allylic bromide
7 (1.55 g, 3.78 mmol), 2-amino-6-[(4-chlorophenyl)sulfanyl]purine (2.41 g,
8.70 mmol) and cesium carbonate (1.85 g, 5.67 mmol) in anhydrous
DMF (30 mL) was stirred overnight at room temperature. The mixture
was quenched by the addition of water and diluted with ethylacetate. The
organic layer was separated and washed with brine, dried over anhydrous
magnesium sulfate, filtered, and concentrated. The residue was purified by
silica gel column chromatography (EtOAc/hexane, 1:3) to give compound
1
16 (800 mg, 35%) as a solid: H NMR (CDCl3, 300 MHz) δ 7.70 (s, 1H),
7.57 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 5.74 (t, J = 7.2 Hz, 1H),
4.80 (d, J = 6.6 Hz, 4H), 4.40 (d, J = 7.3 Hz, 2H), 0.90 (d, J = 5.9 Hz,
18H), 0.08 (d, J = 8.5 Hz, 12H); 13C NMR (CDCl3)δ 170.12, 163.28, 149.50,
144.31, 140.98, 137.24, 116.36, 69.28, 63.20, 37.82, 20.66, 14.84, −6.36.
1-[(E )-4-(t-Butyldimethylsilyloxy)-3-methyl-but-2-enyl]-4-amino-6-[(4-
1
chlorophenyl)sulfan yl]-9H-purine (17).
Yield 23%; H NMR (CDCl3,
300 MHz) δ 7.67 (s, 1H), 7.58 (d, J = 6.5 Hz, 2H), 7.38 (d, J = 6.6 Hz, 2H),
5.72 (t, J = 7.2 Hz, 1H), 4.69 (d, J = 7.1, 2H), 4.06 (s, 2H), 1.76 (s, 3H),

Open-Chain Analogues of Neplanocin A
347
0.91 (s, 9H), 0.08 (s, 6H); 13C NMR (CDCl3)δ 154.93, 152.48, 147.93, 144.85,
139.57, 130.67, 129.26, 117.10, 75.40, 48.94, 20.76, 14.89, 12.80, −6.32.
1-[(E )-4-(t-Butyldimethylsilyloxy)-3-phenyl-but-2-enyl]-4-amino-6-[(4-
1
chlorophenyl)sulfan yl]-9H-purine (18).
Yield 21%; H NMR (CDCl3,
300 MHz) δ 8.78 (br s, 1H), 7.56–7.44 (m, 5H), 7.41 (d, J = 7.2 Hz, 2H),
7.38 (d, J = 7.2 Hz, 2H), 5.53 (t, J = 7.3 Hz, 1H), 4.43 (d, J = 7.3 Hz, 2H),
4.08 (s, 2H), 0.92 (s, 9H), 0.07 (s, 6H); 13C NMR (CDCl3) δ 160.62, 150.48,
148.13, 142.93, 115.47, 67.10, 45.16, 25.90, 18.40, 13.74, −5.32.
1-[3,3ꢁ-Bis-(Hydroxymethyl)-prop-2-enyl]adenine (Ia).
To a solution of
compound 10 (250 mg, 0.54 mmol) in THF (5 mL), TBAF (3.23 mL, 1.0 M
solution in THF) at 0◦C was added. The mixture was stirred at room temper-
ature for 4 h and concentrated. The residue was purified by silica gel column
chromatography (MeOH/CH2Cl2, 1:2) to give compound Ia (46 mg, 36%)
as a white solid: mp 207–213◦C;UV (H2O) λmax 261.0 nm; 1H NMR (DMSO-
d6, 300 MHz) δ 8.12 (s, 1H), 7.20 (s, 1H), 5.61 (t, J = 7.32 Hz, 1H), 4.87
(d, J = 7.4 Hz, 2H), 4.13 (d, J = 5.48 Hz, 2H), 3.95 (d, J = 5.49 Hz, 2H);
13C NMR (DMSO-d6)δ 154.49, 152.09, 147.92, 144.96, 140.99, 119.43, 63.26,
62.86, 57.25, 31.14; Anal calc for C10H13N5O2: C, 51.06; H, 5.57; N, 29.77.
Found: C, 51.11; H, 5.68; N, 29.92.
The synthesis of compounds Ib–If was carried out by the same procedure
as described for the preparation of Ia.
1-[(E )-4-(Hydroxy)-3-methyl-but-2-enyl]adenine (Ib).
Yield 25%; mp
1
178–183◦C; UV (H2O) λmax 259.0 nm; H NMR (DMSO-d6, 300 MHz) δ
8.13 (s, 1H), 7.18 (s, 1H), 5.66 (s, 1H), 4.80 (d, J = 6.0 Hz, 2H), 4.45 (s, 2H),
1.80 (s, 3H); 13C NMR (DMSO-d6)δ 170.52, 156.40, 152.93, 147.95, 140.85,
135.37, 122.36, 68.22, 21.06, 14.34; Anal calc for C10H13N5O: C, 54.78; H,
5.98; N, 31.94. Found: C, 54.87; H, 6.18; N, 32.03.
1-[(E )-4-(Hydroxy)-3-phenyl-but-2-enyl]adenine (Ic).
Yield 19%; mp
175–184◦C;UV (H2O) λmax 260.0 nm; 1H NMR (DMSO-d6, 300 MHz) δ 8.68
(s, 1H), 8.12 (s, 1H), 7.22 (m, 5H), 5.75 (t, J = 7.3 Hz, 1H), 4.40 (s, 2H),
4.20 (s, 2H) ; 13C NMR (DMSO-d6)δ 154.92, 152.08, 147.97, 144.80, 142.65,
134.90, 128.46, 127.77, 126.28, 113.59, 72.54, 48.82; Anal calc for C15H15N5O:
C, 64.04; H, 5.37; N, 24.90. Found: C, 63.89; H, 5.48; N, 25.10.
1-[3,3ꢁ-Bis-(Hydroxymethyl)-prop-2-enyl]-6-chloropurine (Id).
Yield
1
83%; mp 202–211◦C (dec); UV (H2O) λmax 262.0 nm; H NMR (D2O,
300 MHz) δ 8.56 (s, 1H), 8.44 (s, 1H), 5.78 (t, J = 7.15 Hz, 1H), 5.01 (d,
J = 7.12 Hz, 2H), 4.30 (s, 2H), 4.12 (s, 2H); 13C NMR (D2O) δ 154.92,
151.39, 149.71, 143.07, 128.45, 121.11, 63.15, 57.02, 41.57; Anal calc for

348
J. H. Hong et al.
C10H11ClN4O2: C, 47.16; H, 4.35; N, 22.00. Found: C, 47.11; H, 4.56; N,
22.10.
1-[(E )-4-(Hydroxy)-3-methyl-but-2-enyl]-6-chloropurine
(Ie). Yield
26%; mp 170–173◦C; UV (H2O) λmax 262.5 nm; 1H NMR (CDCl3, 300 MHz)
δ 8.71 (s, 1H), 8.12 (s, 1H), 5.75 (t, J = 6.6 Hz, 1H), 5.05 (d, J = 7.9 Hz, 2H),
4.11 (s, 2H), 1.85 (s, 3H) ; 13C NMR (CDCl3)δ 151.90, 151.62, 150.83, 144.80,
142.54, 131.44, 116.18, 66.78, 41.48, 14.01; Anal calc for C10H11ClN4O: C,
50.32; H, 4.65; N, 23.47. Found: C, 50.44; H, 4.40; N, 23.23.
1-[(E )-4-(Hydroxy)-3-phenyl-but-2-enyl]-6-chloropurine
(If). Yield
39%; mp 167–172◦C; UV (H2O) λmax 263.0 nm; 1H NMR (CDCl3, 300 MHz)
δ 8.73 (s, 1H), 7.96 (s, 1H), 7.35 (m, 5H), 6.07 (t, J = 6.9 Hz, 1H), 4.87 (d,
J = 6.9 Hz, 2H), 4.41 (s, 2H); 13C NMR (CDCl3)δ 152.01, 147.38, 145.38,
144.71, 136.24, 128.96, 128.61, 128.46, 125.70, 118.46, 66.47, 42.32; Anal
calc for C15H13ClN4O: C, 59.91; H, 4.36; N, 18.63. Found: C, 59.79; H, 4.28;
N, 18.87.
1-[3,3ꢁ-Bis-(Hydroxymethyl)-prop-2-enyl] hypoxanthine (Ig).
A solu-
tion of 13 (200 mg, 0.41 mmol) in 5 mL of 2N-HCl was heated under re-
flux for 4 h. After cooled, the reaction mixture was poured into water and
ethyl ether, and the aqueous layer was neutralized with 1N-NaOH, and then
was freeze-dried. The residue was recrystallized from MeOH to afford Ig
(70.0 mg, 76.1%) as a white solid; mp 204–209◦C (dec); UV (H2O) λmax
248.5 nm; 1H NMR (D2O, 300 MHz): δ 7.97 (s, 1H) , 7.92 (s, 1H) , 5.69 (t,
J = 6.4 Hz, 1H) , 4.80 (d, J = 6.7 Hz, 1H) , 4.25 (s, 2H) , 4.10 (s, 2H); 13
C
NMR (D2O) δ 159.01, 148.98, 147.28, 142.57, 141.20, 122.76, 121.54, 62.98,
56.72, 41.06; Anal calc for C10H12N4O3: C, 50.84; H, 5.12; N, 23.72. Found:
C, 50.90; H, 5.28; N, 23.90.
The synthesis of compounds Ih–Ii was carried out by the same procedure
as described for the preparation of Ig.
1-[(E )-4-(Hydroxy)-3-methyl-but-2-enyl] hypoxanthine (Ih).
Yield 27%;
1
mp 197–199◦C; UV (H2O) λmax 249.0 nm; H NMR (CD3OD, 300 MHz) δ
8.09 (s, 1H), 8.03 (s, 1H), 5.70 (s, 1H), 4.29 (s, 2H), 3.99 (d, J = 7.2 Hz, 2H),
1.85 (s, 3H); 13C NMR (MeOH) δ 179.10, 148.84, 147.23, 141.25, 139.84,
117.33, 66.02, 40.69, 22.85, 12.49; Anal calc for C10H12N4O2: C, 54.54; H,
5.49; N, 25.44. Found: C, 54.80; H, 5.44; N, 25.33.
1-[(E )-4-(◦Hydroxy)-3-phenyl-but-2-enyl] hypoxanthine (Ii).
Yield 40%;
1
mp 184-189 C; UV (H2O) λmax 248.0 nm; H NMR (CDCl3, 300 MHz) δ
8.02 (s, 1H), 7.76 (s, 1H), 7.36 (m, 5H), 6.00 (t, J = 6.3 Hz, 1H), 4.74 (d,
J = 6.9 Hz, 2H), 4.29 (s, 2H); 13C NMR (CDCl3)δ 179.10, 164.99, 150.72,
146.43, 138.67, 137.17, 128.04, 127.73, 126.16, 124.30, 119.27, 65.46, 41.59;

Open-Chain Analogues of Neplanocin A
349
Anal calc for C15H14N4O2: C, 63.82; H, 5.00; N, 19.85. Found: C, 63.88; H,
5.08; N, 19.87.
1-[3,3ꢁ-Bis-(Hydroxymethyl)-prop-2-enyl] guanine (Ij).
A solution of 16
(300 mg, 0.51 mmol) in 6 mL of 2N HCl was heated under reflux for 4 h. After
cooled, the reaction mixture was poured into water and ethyl ether, and the
aqueous layer was neutralized with 1N-NaOH, and then was freeze dried. The
residue was recrystallized from MeOH to afford Ij (97.0 mg, 78.0%) as a white
solid; mp 270–277◦C (dec); UV (H2O) λmax 252.0 nm; 1H NMR (DMSO-d6,
300 MHz) δ 7.63 (s, 1H), 5.54 (t, J = 6.9 Hz, 1H), 4.66 (d, J = 7.0 Hz, 2H),
4.08 (d, J = 5.4 Hz, 2H), 3.94 (d, J = 5.3 Hz, 2H); 13C NMR (DMSO-d6)δ
157.29, 154.15, 151.34, 144.45, 140.02, 137.46, 119.63, 62.75, 57.38, 39.12;
Anal calc for C10H13N5O3: C, 47.81; H, 5.22; N, 27.87. Found: C, 47.89; H,
5.09; N, 27.88.
The synthesis of compounds Ik–Il was carried out by the same procedure
as described for the preparation of Ij.
1-[(E )-4-(Hydroxy)-3- methyl -but-2-enyl] guanine (Ik).
Yield 77%; mp
229–241◦C (dec); UV (H2O) λmax 251.5 nm; 1H NMR (DMSO-d6, 300 MHz) δ
7.56 (s, 1H), 5.52 (d, J = 5.76 Hz, 1H), 4.54 (d, J = 6.7 Hz, 2H), 4.06 (s, 2H),
1.68 (s, 3H); 13C NMR (DMSO-d6)δ 176.09, 158.31, 155.25, 151.58, 140.62,
136.81, 118.10, 65.76, 25.45, 14.06; Anal calc for C10H13N5O2: C, 51.06; H,
5.57; N, 29.77. Found: C, 51.22; H, 5.49; N, 29.89.
1-[(E )-4-(Hydroxy)-3-phenyl -but-2-enyl] guanine (Il).
Yield 51%; mp
188–193◦C; UV (H2O) λmax 252.0 nm; 1H NMR (CD3OD, 300 MHz) δ 7.56
(s, 1H), 7.40 (m, 5H), 5.98 (t, J = 6.9 Hz, 1H), 4.60 (d, J = 6.8 Hz, 2H),
4.28 (s, 2H); 13C NMR (MeOD-d4)δ 179.10, 164.23, 150.82, 146.34, 138.67,
137.17, 128.04, 127.74, 126.16, 124.30, 119.27, 65.46, 41.55; Anal calc for
C15H15N5O2: C, 60.60; H, 5.09; N, 23.56. Found: C, 60.51; H, 5.11; N, 23.77.
CONCLUSION
A very simple synthetic method for synthesizing novel acyclic purine nu-
cleosides from ketone derivatives was developed in this study. When the syn-
thesized compounds were tested against several viruses such as HIV, HSV-1,
HSV-2, and ECMV, the guanine base derivatives Ij and Ik showed moderate
anti-HSV-1 and-2 activity (EC50 = 32.7 and 11.7 µg/mL).
Evaluation of Anti-HSV-1 and HSV-2 Activity
CCL 18 cells in stationary phase were infected with the virus at 2-4 CCID50
multiplicity of infection (MOI) per well in 96-well plates. After 2 h incubation

350
J. H. Hong et al.
at 37◦C for the viral adsorption, the medium was aspirated off to remove the
unadsorped viral particles and 100 µL MEM containing 2% FBS and each
compound wasappliedto eachwellandfurtherincubatedfor6days. Antiviral
activity was measured microscopically or fluorometrically. For microscopic
observation, the cells were fixed with 70% ethanol and stained with 2.5%
Giemsa solution for 2 h, rinsed with distilled water, and air dried. Antivi-
ral activity was expresses as the IC50, the concentration required to inhibit
virus-induced CPE by 50%. IC50 values were estimated from semi-logarithmic
graphic plots of the percentage of CPE as a function of the concentration
of the test compound. For fluorometric assay, the cells were washed twice
with 100 µL of phosphate-buffered saline (PBS). One hundred microliters
of 5 µg/mL fluorescein diacetate (FDA, Sigma) was added to each well and
the plates were incubated for 30 min at 37◦C. The FDA solution was removed
by aspiration and wells were washed with 100 µL PBS. The fluorescence in-
tensity (as absolute fluorescent units, AFU) in each well was measured with a
fluorescent microplate reader equipped with a 485-nm excitation filter and
a 538-nm emission filter.
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