Synthesis and biological activity of novel acyclic versions of neplanocin A

Article abstract of DOI:10.1002/ardp.200500154

Novel acyclic Neplanocin A analogues were designed and synthesized. The coupling of the alkyl bromide 6 with nucleosidic bases (T, U, 5-FU, 5-IU, C, A) and desilylation afforded a series of novel acyclic nucleosides. The synthesized compounds 13-18 were evaluated for their antiviral and antitumor activity.

Full text of DOI:10.1002/ardp.200500154

Arch. Pharm. Chem. Life Sci. 2005, 338, 517−521
DOI 10.1002/ardp.200500154
517
Synthesis and Biological Activity of Novel Acyclic
Versions of Neplanocin A
Ying Wu, Joon Hee Hong
College of Pharmacy, Chosun University, Kwangju, Republic of Korea
Novel acyclic Neplanocin A analogues were designed and synthesized. The coupling of the alkyl
bromide 6 with nucleosidic bases (T, U, 5-FU, 5-IU, C, A) and desilylation afforded a series of novel
acyclic nucleosides. The synthesized compounds 13Ϫ18 were evaluated for their antiviral and anti-
tumor activity.
Keywords: Neplanocin A; Acyclic nucleoside; Antiviral agents; Antitumor activity
Received: June 13, 2005; Accepted: July 29, 2005
Introduction
Nucleoside analogues have been the cornerstone of antiviral
chemotherapy over the past decades. Although structure-
activity relationship studies have not led to a pharmaco-
phore model for the antiviral activities of nucleosides, some
structural features have been particularly successful. Since
the emergence of the HIV, extensive efforts have been con-
centrated on various modifications of the sugar moiety of
nucleosides, which have resulted in FDA-approved anti-HIV
agents such as AZT [1], ddC [2], ddI [3], d4T [4], 3TC [5]
and Abacavir [6]. In addition, several nucleosides used as
anti-HBV agents including L-F-ddC [7] and L-FMAU [8]
have been synthesized. The recent approval of bis-
(POC)PMPA [9] by the FDA as anti-HIV agent has strongly
warranted a further search of novel nucleosides in this class.
However, side effects [10] and the emergence of drug-resist-
ant mutants continue to be a problem with these antiviral
agents [11]. It is now clear that judicious combination
chemotherapy is the optimum way to improve the quality
of life and survival of patients infected with HIV-1. The
discovery of the potent and selective antiherpes agents,
Acyclovir [12] and Ganciclovir [13] (see Figure 1), has led
to an extensive search for more novel nucleoside analogues
with improved properties. More recently, the fermentation
product Neplanocin A [14] (Figure 1), which is a novel cyclic
carba analogue of adenosine with a cyclopentene ring, has
generated considerable attention, both synthetically and
biologically, due to the effect of the double bond on the
compound activity and potency [15].
Figure 1. Rational background to the synthesis of target
nucleosides.
Because of the unusual presence of a double bond in
Neplanocin A and the acyclic nature of Acyclovir, these two
compounds have stimulated extensive research in the syn-
thesis of new cyclic and acyclic carba-nucleoside analogues
[16] that mimic the sugar portion of naturally occurring nu-
cleosides [17]. However, with relatively few exceptions, the
activity of most conventional carbocyclic nucleosides has
been poorer than those of the corresponding ribosides. The
loss of the furan oxygen in the carba-nucleosides is believed
to have a critical effect on their antiviral activity [18]. The
incorporation of halogen atoms into organic molecules has
often been associated with profound changes in the biologi-
cal profiles of the halogenated analogues compared to their
hydrocarbon counterparts [19].
Correspondence: Joon Hee Hong, College of Pharmacy, Chosun
University, Kwangju 501-759, Republic of Korea. Phone: ϩ82 62
2
306378, Fax: ϩ82 62 2225414, e-mail: hongjh@chosun.ac.kr
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Hong et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 517−521
Scheme 1. Synthesis of unsaturated acyclic nucleosides. Reagents: (i) TBDMSCl, imidazole, CH
2
Cl
2
; (ii) triethyl phosphono-
, DMF, rt; (vii) TBAF,
acetate, NaH, THF; (iii) Br
THF, rt.
2
, pyridine, CCl
4
; (iv) Dibal-H, CH
2
Cl
2
; (v) PPh
3
, NBS, CH
2
Cl
2
; (vi) bases, CsCO
3
In view of the stimulating results of carboacyclic nucleosides
9, 12, 13] and as part of our ongoing drug discovery efforts
to search for less toxic and more effective antiviral agents,
this study aimed to synthesize bromovinyl nucleosides as
acyclic analogues of Neplanocin A (see Scheme 1).
in good agreement with those of the appropriate model
compounds [23]. Deprotection of the t-butyldimethylsilyl
group (TBDMS) using tetrabutylammonium fluoride
(TBAF) in tetrahydrofuran (THF) gave the desired nucleos-
ides 13Ϫ18.
[
Results and discussion
Chemistry
Biological activity studies
Antiviral activity assays against HIV-1 were performed for
all the final nucleosides, and their results are shown in Table
In order to couple the allylic alcohol derivative with the
adenine base using a nucleophilic substitution type reaction,
the alcohol 5 was subjected to a mesylation reaction (MsCl,
1
. Unfortunately, none of them showed any anti-HIV-1 ac-
tivity in MT-4 cells. Compounds 14 and 15 exhibited potent
anti-HIV-1 activities, but these inhibitory effects were
associated with a nonspecific cytotoxicity to MT-4 cells.
TEA, CH Cl ). Unexpectedly, the reaction had a low yield
2
2
(
20Ϫ30%) and was irreproducible. Therefore, our attention
was turned to allylic bromide 6, which was readily synthe-
sized from hydroxy ketone derivatives such as acetol 1 using
a previously reported similar procedure [20]. Conversion of
allylic alcohols 5 to the bromo derivatives 6 was ac-
complished by the sequential addition of NBS to a solution
of the alcohol and triphenylphosphine in CH Cl , in high
Because of the outstanding cytotoxic effects of compound
14 and 15 to the MT-4 cell line, we further studied the cyto-
toxic effects of both compounds on several cancer cell lines.
Therefore, based on the cytotoxicity of 14 and 15, their
cytotoxic potentials were evaluated in cultured human lung
cells (as shown in Table 2). Relative cell viability compared
with untreated cells of lines A 549 (human lung cancer) or
Col2 (human colon cancer) was decreased to 60.3 and
51.5%, respectively, after treatment of cells with compound
14 (50 µg/mL). Compound 15 also showed similar cyto-
2
2
yield [21]. Direct coupling of the allylic bromide 6 with
bases (T, U, 5-FU, 5-IU, C, A) in DMF with cesium carbon-
1
ate as a basic catalyst provided the desired N -alkylated
9
pyrimidine derivatives (7Ϫ11), and the N -alkylated purine
derivative 12 in the case of adenine [22]. The UV data were
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Arch. Pharm. Chem. Life Sci. 2005, 338, 517−521
Acyclic Versions of Neplanocin A
519
Table 1. Anti-HIV-1 activities of the synthesized compounds.
(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 per-
formed using an Elemental Analyzer System (Profile HV-3). TLC
was performed on Uniplates (silica gel) purchased from Analtech
Co. Dry THF was obtained by distillation from Na and benzo-
phenone when the solution became purple.
EC50, µg/mL§
CC50, µg/mL#
1
1
1
1
1
1
3
4
5
6
7
8
> 100
3.36
1.81
> 100
> 100
> 100
0.0005
> 100
< 3.46
< 1.81
> 100
> 100
> 100
1.0
Chemistry
2-(tert-Butyldimethylsilyloxy)-acetone (2)
AZT
To a stirred solution of compound acetol (20 g, 0.27 mmol) and
§
imidazole (27 g, 0.405 mmol) in CH Cl2 (300 mL), t-butyldimeth-
ylsilyl chloride (44 g, 0.297 mmol) was added at 0°C. The mixture
was stirred at the same temperature for 5 h and concentrated under
reduced pressure. The residue was extracted using EtOAc, dried
Indicative of 50% cytostatic concentration in virus-infected
MT-4 cells.
Indicative of 50% survival concentration in virus-uninfected
MT-4 cells.
2
#
over MgSO
fied by silica gel column chromatography (EtOAc/n-hexane, 1:10)
to give 2 (39.6 g, 78%) as a colorless oil. 1H-NMR (CDCl
, 300
4
, filtered and then concentrated. The residue was puri-
3
13
MHz): δ 4.05 (s, 2H), 2.07 (s, 3H), 0.84 (s, 9H), Ϫ0.01 (s, 6H); C-
NMR (CDCl ): δ 208.96, 69.47, 25.67, 18.19, Ϫ5.61; Anal calcd.
for C H O Si: C, 57.39; H, 10.70; Found: C, 57.21; H, 10.50.
Table 2. Cytotoxic potential of 14 and 15 in cultured human
cancer cells.
3
9
20
2
Compounds
A549§
Col2#
(E)-4-(tert-Butyldimethylsilyloxy)-3-methyl-but-2-enoic acid ethyl
ester (3)
60.3‡
58.3‡
51.5
‡
1
1
4
5
Sodium hydride (60% in mineral oil, 1.11 g, 27.75 mmol) was sus-
pended in anhydrous THF. To the mixture was slowly added triethyl
phosphonoacetate (4.21 g, 27.75 mmol) at 0°C and stirred for 1 h
at room temperature. Compound 2 (5.18 g, 27.5 mmol) was added
to the reaction mixture at 0°C, stirred for 1 h at room temperature
and extracted with EtOAc. 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
‡
49.5
§
Human lung carcinoma cells.
Human colon carcinoma cells.
Percentage (%) of survival compared to control cultures at a test
#
‡
concentration of 50 µg/mL.
and the residue was purified by silica gel column chromatography
1
(
EtOAc/n-hexane, 1:15) to give 3 (4.26 g, 60%) as a yellow oil. H-
NMR (CDCl
3
, 300 MHz): δ 5.99 (s, 1H), 4.19 (q, J ϭ 6.9 Hz, 2H),
toxicity to lung cells; 58.3% survival of control in lung can-
cer cells, and 49.5% in colon cancer cells.
4
0
1
.13 (s, 2H), 1.96 (s, 3H), 1.96 (s, 3H), 1.22 (t, J ϭ 6.8 Hz, 3H),
13
.90 (s, 9H), 0.09 (s, 6H); C-NMR (CDCl
13.35, 66.21, 59.51, 25.83, 18.09, Ϫ5.36; Anal calcd. for
Si: C, 60.42; H, 10.14. Found: C, 60.37; H, 9.97.
3
): δ 167.02, 157.06,
13 26 3
C H O
Conclusion
(
E)-2-Bromo-4-(tert-butyldimethylsilyloxy)-3-methyl-but-2-enoic
A simple synthetic method for synthesizing novel acyclic
Neplanocin A analogues from a ketone derivative was devel-
oped in this study. When the synthesized compounds were
tested against HIV-1, compound 14 and 15 exhibited toxi-
city non-related to any anti-HIV-1 activity. Although we
could not find good anti-HIV agents in this study, findings
of some anticancer activity in this series will allow this class
of nucleosides to be a new template for the development of
new anticancer agents.
acid ethyl ester (4)
To a stirred solution of compound 3 (300 mg, 1.16 mmol) in CCl
4
under nitrogen was added bromine (203 mg, 1.27 mmol) followed
by slow addition of triethylamine (0.242 mL, 1.74 mmol) in an ice
bath. The reaction mixture was stirred for 5 h at 0°C, filtered and
washed with CCl . The filtrate was washed with 2 N HCl and then
with sodium bicarbonate solution, dried with anhydrous MgSO
4
4
and concentrated. The residue was purified by silica gel column
chromatography (EtOAc/n-hexane, 1:20) to give 4 (200 mg, 51%).
1
H-NMR (CDCl
3
, 300 MHz): δ 4.45 (s, 2H), (q, J ϭ 7.2 Hz, 2H),
2
.01 (s, 3H), 1.29 (t, J ϭ 7.2 Hz, 3H), 0.83 (s, 9H), 0.06 (s, 6H);
13
C-NMR (CDCl
3
) δ 163.72, 151.55, 109.31, 100.52, 64.01, 62.08,
25BrO Si: C,
Experimental
General
25.71, 21.09, 18.24, 13.98, Ϫ5.55; Anal calcd. for C13
H
3
46.29; H, 7.47. Found: C, 46.01; H, 7.51.
All the chemicals were of reagent grade and were used as purchased.
All the moisture-sensitive reactions were performed in an inert at-
mosphere with either N or Ar, using distilled dry solvents. The
2
(
(
E)-2-bromo-4-(tert-butyldimethylsilyloxy)-3-methyl-but-2-en-1-ol
5)
melting points were determined using a Mel-temp II laboratory de-
vice and were uncorrected. The NMR spectra were recorded on a
JEOL 300 Fourier transform spectrometer; the chemical shifts are
reported in parts per million (d) and the signals are quoted as s
2 2
To a solution of compound 4 (5.0 g, 14.82 mmol) in CH Cl
(200 mL), DIBALH (31.12 mL, 1.0 M solution in hexane) was ad-
ded slowly at 0°C, and stirred for 1 h at the same temperature. To
the mixture, methanol (30 mL) was added. The mixture was then
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Arch. Pharm. Chem. Life Sci. 2005, 338, 517−521
stirred at room temperature for 3 h, and the resulting solid was
filtered through a Celite pad. The filtrate was concentrated under
vacuum, and the residue was purified by silica gel column chroma-
1-[(E)-2-Bromo-4-(tert-butyldimethylsilyloxy)-3-methyl-but-2-enyl]
5-iodouracil (10)
Compound 10 was prepared from 6 as described for 7. Yield 68%.
tography (EtOAc/n-hexane, 1:20) to give compound 5 (4.07 g, 93%)
1
1
3
H-NMR (CDCl , 300 MHz): δ 9.21 (br s, 1H), 7.72 (s, 1H), 4.83
as a colorless oil. H-NMR (CDCl
(
3
, 300 MHz): δ 4.42 (s, 2H), 4.24
13
13
(s, 2H), 4.27 (s, 2H), 1.93 (s, 3H) 0.90 (s, 18H), 0.32 (s, 6H); C-
NMR (CDCl , 75 MHz): δ 161.46, 151.10, 146.85, 141.33, 116.37,
8.94, 62.35, 50.89, 25.80, 22.54, 18.57, Ϫ5.67; Anal calcd. for
24BrIN Si: C, 34.97; H, 4.69; N, 5.44. Found: C, 34.40; H,
.58; N, 5.61.
3
s, 2H), 1.94 (s, 3H), 0.90 (s, 9H), 0.06 (s, 6H); C-NMR (CDCl ,
7
5 MHz): δ 136.45, 112.38, 68.11, 65.21, 25.83, 18.56, 13.56, Ϫ5.48;
3
6
C
4
2
Anal calcd. for C11H23BrO Si: C, 44.74; H, 7.85. Found: C, 44.50;
15
H
2 3
O
H, 7.74.
(
E)-Bromo-4-(tert-butyldimethylsilyloxy)-3-methyl-2-but-2-enyl
1
-[(E)-2-Bromo-4-(tert-butyldimethylsilyloxy)-3-methyl-but-2-enyl]
bromide (6)
cytosine (11)
To a solution of compound 5 (2.04 g, 6.93 mmol) and tri-
phenylphosphine (3.63 g, 13.86 mmol) in CH Cl (30 mL), N-
bromosuccinimide (4.93 g, 13.86 mmol) was added slowly at 0°C,
stirred for 5 h at room temperature, and diluted with CH Cl . The
organic layer was washed with water and brine, dried over anhy-
drous magnesium sulfate and filtered through a Celite pad. The
filtrate was concentrated under vacuum, and the residue was puri-
fied by quick flash silica gel column chromatography (EtOAc/n-hex-
Compound 11 was prepared from 6 as described for 7. Yield 68%.
H-NMR (CDCl , 300 MHz): δ 7.38 (d, J ϭ 7.5 Hz, 1H), 5.78 (d,
3
2
2
1
J ϭ 7.5 Hz, 1H), 4.72 (s, 1H), 4.35 (s, 1H), 4.11 (s, 2H), 1.89 (s, 3H)
2
2
.89 (s, 18H), 0.15 (s, 6H); 13C-NMR (CDCl
54.90, 141.30, 118.82, 115.16, 98.97, 64.63, 52.76, 25.80, 21.91,
8.22, Ϫ5.47; Anal calcd. for C15 26BrN Si: C, 46.39; H, 6.75;
0
1
1
3
, 75 MHz): δ 166.06,
H
3 2
O
N, 10.82. Found: C, 46.21; H, 6.67; N, 10.89.
ane, 1 : 30) to give the allylic bromide 6 (2.16 g, 87%) as a yellow
1
oil. H-NMR (CDCl
3
, 300 MHz): δ 4.61 (s, 2H), 3.94 (s, 2H), 1.87
9-[(E)-2-Bromo-4-(tert-butyldimethylsilyloxy)-3-methyl-but-2-enyl]
adenine (12)
1
3
(
s, 3H), 0.87 (s, 9H), 0.03 (s, 6H); C-NMR (CDCl
3
, 75 MHz): d
42.21, 110.38, 67.78, 38.89, 25.67, 18.33, 13.91, Ϫ5.48; Anal calcd.
OSi: C, 36.89; H, 6.19. Found: C, 37.08; H, 5.93.
1
Compound 12 was prepared from 6 as described for 7. Yield 68%.
for C11H22Br
2
1
3
H-NMR (CDCl , 300 MHz): δ 8.26 (s, 1H), 7.75 (s, 1H), 6.09 (br
s, 2H), 4.70 (s, 2H), 4.21 (s, 2H), 1.91 (s, 3H) 0.86 (s, 18H), 0.25 (s,
6H); 13C-NMR (CDCl , 75 MHz): d 155.67, 152.78, 150.43, 141,98,
1
-[(E)-2-Bromo-4-(tert-butyldimethylsilyloxy)-3-methyl-but-2-enyl]
3
thymine (7)
141.02, 119.49, 118.12, 63.72, 51.22, 25.81, 22.04, 18.20, Ϫ5.32;
Anal calcd. for C16
C, 46.88; H, 6.21; N, 17.19.
5
H26BrN OSi: C, 46.60; H, 6.35; N, 16.98. Found:
A solution of the allylic bromide 6 (318 mg, 0.89 mmol), thymine
169 mg, 1.34 mmol) and cesium carbonate (436 mg, 1.34 mmol) in
(
anhydrous DMF (5 mL) was stirred overnight at room temperature.
The mixture was quenched by the addition of water and diluted
with ethyl acetate. The organic layer was separated and washed with
brine, dried over anhydrous magnesium sulfate, filtered and concen-
trated. The residue was purified by silica gel column chromatogra-
1
-[(E)-2-Bromo-4-hydroxy-3-methyl-but-2-enyl] thymine (13)
To a solution of compound 7 (181 mg, 0.45 mmol) in THF (5 mL),
TBAF (0.675 mL, 1.0 M solution in THF) at 0°C was added. The
mixture was stirred at room temperature for 6 h, and concentrated.
The residue was purified by silica gel column chromatography
phy (EtOAc/n-hexane/MeOH, 4:1:0.2) to give compound 7 (244
1
mg, 68%) as a solid. H-NMR (CDCl
3
, 300 MHz): δ 8.42 (br s,
(
MeOH/CH
white solid: mp 174Ϫ176°C; UV (H
DMSO-d , 300 MHz): δ 11.47 (br s, 1H), 7.33 (s, 1H), 5.10 (t, J ϭ
.0 Hz, 1H), 4.68 (s, 2H), 3.95 (s, 2H), 1.90 (s, 3H), 1.81 (s, 3H);
2
Cl
2
, 1:5) to give compound 13 (105 mg, 81%) as a
1
3
1
1
H), 7.14 (s, 1H), 4.65 (s, 2H), 4.25 (s, 2H), 1.86 (s, 3H), 1.82 (s,
O) λmax 268.5 nm. 1H-NMR
1
3
2
H), 0.96 (s, 9H), 0.13 (s, 6H); C-NMR (CDCl
41.50, 139.74, 118.29, 110.52, 63.27, 50.99, 25.81, 22.18, 18.33,
2.38, Ϫ5.38; Anal calcd. for C16 27BrN Si: C, 47.64; H, 6.75;
3
): δ 163.91, 150.67,
(
6
6
H
2
O
3
13
C-NMR (DMSO-d
6.60, 65.67, 43.33, 16.38, 12.07; Anal calcd. for C10
6
): δ 163.66, 149.13, 136.09, 116.68, 110.44,
13BrN : C,
N, 6.94. Found: C, 47.87; H, 6.66; N, 6.90.
9
4
H
2 3
O
1.54; H, 4.53; N, 9.69. Found: C, 41.30; H, 4.62; N, 9.81.
1
-[(E)-2-Bromo-4-(tert-butyldimethylsilyloxy)-3-methyl-but-2-enyl]
uracil (8)
1-[(E)-2-Bromo-4-hydroxy-3-methyl-but-2-enyl] uracil (14)
Compound 8 was prepared from 6 as described for 7. Yield 64%.
H-NMR (CDCl , 300 MHz): δ 8.75 (br s, 1H), 7.32 (d, J ϭ 7.8
3
Compound 14 was prepared from 8 as described for 13. Yield 77%;
O) λmax 263.5 nm. 1H-NMR (DMSO-d
6
,
3
1
mp 161Ϫ163°C; UV (H
00 MHz): δ 11.57 (br s, 1H), 7.30 (d, J ϭ 7.9 Hz, 1H), 5.48 (d,
J ϭ 7.8 Hz, 1H), 5.03 (t, J ϭ 5.4 Hz, 1H), 4.62 (s, 2H), 4.10 (s,
2
Hz, 1H), 5.59 (d, J ϭ 7.8 Hz, 1H), 4.72 (s, 2H), 4.30 (s, 2H), 1.90
1
3
(
s, 3H) 0.88 (s, 18H), 0.15 (s, 6H); C-NMR (CDCl
3
, 75 MHz): δ
63.46, 150.67, 144.05, 141.98, 117.86, 102.04, 63.29, 51.46, 25.82,
2.20, 18.27, Ϫ5.37; Anal calcd. for C15 25BrN Si: C, 46.27; H,
.47; N, 7.19. Found: C, 46.49; H, 6.31; N, 7.28.
1
2
6
13
2
1
C
3
H), 1.91 (s, 3H); C-NMR (DMSO-d
40.31, 117.34, 103.78, 64.56, 44.34, 16.20; Anal calcd. for
11BrN : C, 39.29; H, 4.03; N, 10.18. Found: C, 30.37; H,
.87; N, 10.30.
6
): δ 163.65, 151.21, 145.45,
H
2 3
O
9
H
2 3
O
1
5
-[(E)-2-Bromo-4-(tert-butyldimethylsilyloxy)-3-methyl-but-2-enyl]
-fluorouracil (9)
1-[(E)-2-Bromo-4-hydroxy-3-methyl-but-2-enyl] 5-fluorouracil (15)
Compound 15 was prepared from 9 as described for 13. Yield 87%;
Compound 9 was prepared from 6 as described for 7. Yield 60%.
1
2 6
mp 160Ϫ163°C; UV (H ,
O) λmax 270.5 nm. 1H-NMR (DMSO-d
H-NMR (CDCl
3
, 300 MHz): δ 9.00 (br s, 1H), 7.51 (d, J ϭ 5.6
Hz, 1H), 4.77 (s, 2H), 4.41 (s, 2H), 1.92 (s, 3H) 0.89 (s, 18H), 0.23 (s,
300 MHz): δ 11.87 (br s, 1H), 7.76 (d, J ϭ 6.0 Hz, 1H), 5.05 (t, J ϭ
1
3
13
6
1
H); C-NMR (CDCl
27.81, 101.32, 64.26, 52.32, 25.67, 22.32, 18.43, Ϫ5.47; Anal calcd.
24BrFN Si: C, 44.23; H, 5.94; N, 6.88. Found: C, 44.06;
H, 6.01; N, 7.08.
3
, 75 MHz): δ 165.23, 153.67, 143.21, 140.98,
5.2 Hz, 1H), 4.80 (s, 2H), 4.32 (s, 2H), 1.90 (s, 3H); C-NMR
(DMSO-d
43.82, 16.67; Anal calcd. for C
9.56. Found: C, 36.68; H, 3.47; N, 9.77.
6
): δ 165.76, 154.78, 144.66, 139.26, 126.91, 109.78, 63.92,
for C15
H
2
O
3
9
H
10BrFN : C, 36.88; H, 3.44; N,
2 3
O
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Arch. Pharm. Chem. Life Sci. 2005, 338, 517−521
Acyclic Versions of Neplanocin A
521
1
-[(E)-2-Bromo-4-hydroxy-3-methyl-but-2-enyl] 5-iodouracil (16)
[5] R. F. Schinazi, C. K. Chu, A. Peck, A. McMillan, R. Mathis,
D. Cannon, L. S. Jeong et al., Antimicrob. Agents Chemother.
Compound 16 was prepared from 10 as described for 13. Yield 83%;
1992, 36, 672Ϫ676.
1
mp 178Ϫ180°C; UV (H
2
O) λmax 286.0 nm. H-NMR (DMSO-d
6
,
[
6] S. M. Daluge, S. S. Good, M. B. Faletto, W. H. Miller, M.
H. StClair, L. R. Boone, M. Tisdale et al., Antimicrob. Agents
Chemother. 1997, 41, 1082Ϫ1093.
3
2
1
00 MHz): δ 11.70 (br s, 1H), 7.96 (s, 1H), 5.00 (br s, 1H), 4.61 (s,
1
3
H), 4.14 (s, 2H), 1.97 (s, 3H); C-NMR (DMSO-d
51.21, 146.71, 140.34, 115.67, 170.78, 63.67, 44.28, 16.75; Anal
10BrIN : C, 26.96; H, 2.51; N, 6.99. Found: C,
7.17; H, 2.36; N, 7.29.
6
): δ 161.78,
[
[
7] T. S. Lin, M. Z. Luo, M. C. Liu, S. B. Pai, G. E. Dutschman,
calcd. for C
9
H
2 3
O
Y. C. Cheng, J. Med. Chem. 1994, 37, 798Ϫ8031.
2
8] C. K. Chu, T. W. Ma, K. Shanmuganathan, C. G. Wang, Y. J.
Xiang, S. B. Pai, G. Q. Yao, J. P. Sommadossi, Y. C. Cheng,
Antimicrob. Agents Chemother. 1995, 39, 979Ϫ981.
1
-[(E)-2-Bromo-4-hydroxy-3-methyl-but-2-enyl] cytosine (17)
[
9] M. N. Arimilli, C. U. Kim, J. Dougherty, A. Mulato, R. Oliyai,
J. P. Shaw, K. C. Cundy, N. Bischofberger, Antiviral Chem.
Chemother. 1997, 8, 557Ϫ564.
Compound 17 was prepared from 11 as described for 13. Yield 75%;
1
mp 157Ϫ160°C; UV (H
3
4
2
O) λmax 273.0 nm. H-NMR (DMSO-d
00 MHz) d 7.41 (d, J ϭ 7.6 Hz, 1H), 5.80 (d, J ϭ 7.6 Hz, 1H),
.92 (t, J ϭ 5.6 Hz, 1H), 4.62 (s, 2H), 4.09 (s, 2H), 1.88 (s, 3H);
6
,
[
10] W. B. Parker, Y.-C. Cheng, J. NIH Res. 1994, 6, 57Ϫ61.
[11] P. A. Chatis, C. S. Crumpacker, Antimicrob. Agents Chemother.
992, 36, 1589Ϫ1595.
1
3
C-NMR (DMSO-d
6
): δ 166.62, 153.31, 140.87, 117.21, 114.87,
12BrN : C, 39.43;
1
9
9.62, 65.21, 44.76, 16.65; Anal calcd. for C
9
H
3 2
O
[
[
[
[
[
12] H. J. Schaeffer, L. Beauchamp, P. DeMiranda, G. B. Elion, D.
H, 4.41; N, 15.33. Found: C, 39.65; H, 4.61; N, 15.21.
J. Bauer, P. Collins, Nature 1978, 272, 583Ϫ585.
13] F. M. Hamzeh, P. S. Lietman, Antimicrob. Agents Chemother.
9
-[(E)-2-hydroxy-4-hydroxy-3-methyl-but-2-enyl] adenine (18)
1991, 35, 1818Ϫ1823.
14] R. Borchardt, B. Keller, U. Patel-Thrombre, J. Biol. Chem.
1984, 259, 4353Ϫ4358.
15] V. E. Marquez in Advances in Antiviral Drug Design, Vol. 2,
JAI Press, 1996, pp 89Ϫ146, and references therein.
16] L. A. Agrofoglio, S. R. Challang, Acyclic, Carbocyclic and L-
Nucleosides, Kluwer Academic Publisher, 1998, 18Ϫ173.
Compound 18 was prepared from 12 as described for 13. Yield 80%;
1
mp 181Ϫ183°C; UV (H
3
5
2
O) λmax 261.0 nm. H-NMR (DMSO-d
6
,
00 MHz): δ 8.16 (s, 1H), 8.05 (s, 1H), 7.21 (br s, 2H), 5.07 (t, J ϭ
1
3
.4 Hz, 1H), 4.72 (s, 2H), 4.27 (s, 2H), 1.87 (s, 3H); C-NMR
, 75 MHz): δ 155.97, 152.36, 150.04, 141,42, 140.87, 119.25,
17.67, 66.02, 45.28, 17.20; Anal calcd. for C10 12BrN O: C, 40.29;
(
CDCl
3
1
H
5
H, 4.06; N, 23.49. Found: C, 40.05; H, 4.18; N, 23.31.
[17] M. N. Arimilli, C. U. Kim, J. Dougherty, A. Mulato, R. Oliyai,
J. P. Shaw, K. C. Cundy, N. Bischofberger, Antiviral Chem.
Chemother. 1997, 8, 557Ϫ564.
[
18] D. L. Earnshaw, T. H. Bacon, S. J. Darlison, K. Edmonds, R.
M. Perkins, R. A. Vere Hodge, Antimicrob. Agents Chemother.
1992, 36, 2747Ϫ2757.
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[
1
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