Structure-activity relationships of (E)-5-(2-bromovinyl)uracil and related pyrimidine nucleosides as antiviral agents for herpes viruses

Article abstract of DOI:10.1021/jm990543n

A series of (E)-5-(2-bromovinyl)uracil analogues and related nucleosides was synthesized, and their antiviral activities were evaluated. (E)-5-(2- Bromovinyl)-2'-deoxy-L-uridine (L-BVDU, 2), 1-(β-L-arabinofuranosyl)-(E)-5- (2-bromovinyl)uracil (L-BVAU, 4)

Full text of DOI:10.1021/jm990543n

2538
J . Med. Chem. 2000, 43, 2538-2546
Str u ctu r e-Activity Rela tion sh ip s of (E)-5-(2-Br om ovin yl)u r a cil a n d Rela ted
P yr im id in e Nu cleosid es a s An tivir a l Agen ts for Her p es Vir u ses
Yongseok Choi,† Ling Li,‡ Sue Grill,‡ Elizabeth Gullen,‡ Chang Soo Lee,† Giuseppe Gumina,† Eisaku Tsujii,‡
Yung-Chi Cheng,‡ and Chung K. Chu*,†
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia,
Athens, Georgia 30602-2352, and Department of Pharmacology, Yale University School of Medicine,
New Haven, Connecticut 06520
Received November 1, 1999
A series of (E)-5-(2-bromovinyl)uracil analogues and related nucleosides was synthesized, and
their antiviral activities were evaluated. (E)-5-(2-Bromovinyl)-2′-deoxy-L-uridine (L-BVDU, 2),
1-(â-L-arabinofuranosyl)-(E)-5-(2-bromovinyl)uracil (L-BVAU, 4), (E)-5-(2-bromovinyl)-1-(2-deoxy-
2-fluoro-â-L-ribofuranosyl)uracil (L-FBVRU, 8) and (E)-5-(2-bromovinyl)-1-(2-deoxy-2-fluoro-â-
L-arabinofuranosyl)uracil (L-FBVAU, 10) were synthesized via appropriate 5-iodouracil ana-
logues from L-arabinose. D- and L-Oxathiolane and -dioxolane derivatives 13, 16, 20, 21, and
29-34 were prepared by glycosylation reaction of the oxathiolane and dioxolane intermediates
with silylated uracil analogues using TMSI as the coupling agent. The synthesized compounds
were evaluated in cell cultures infected with the following viruses: varicella zoster virus (VZV),
Epstein Barr virus (EBV), and herpes simplex virus types 1 and 2 (HSV-1 and HSV-2). Among
the tested compounds, â-L-CV-OddU (29), â-L-BV-OddU (31), and â-L-IV-OddU (33) exhibited
potent in vitro antiviral activity against VZV with EC50 values of 0.15, 0.07, and 0.035 µM,
respectively, and against EBV with EC50 values of 0.49, 0.59, and 3.91 µM, respectively.
In tr od u ction
lems have led to several interesting nucleosides such
as 4′-thio-BVDU13 and the carbocyclic analogue carba-
BVDU.14 However, the carba derivatives, which are
resistant to degradation and have antiviral activities
comparable to those of the parent compounds in cell
culture, exhibit poor in vivo activity.14,15
Varicella zoster virus (VZV), a member of the γ-herpes
virus family, is a causative agent for primary infections
(varicella and chicken pox) as well as recurrent diseases
(zoster and shingles) in humans.1 One of the major
complications of shingles is the postherpetic neuralgia,
which is characterized by persistent acute pain induced
after the VZV reactivation and the resolution of a skin
rash.2 The course of varicella is generally benign in
immunocompetent patients; however, in immunocom-
promised patients, particularly patients suffering from
acquired immune deficiency syndrome (AIDS), trans-
plant recipients, and cancer patients, VZV infections can
be life-threatening.3,4 The current treatment for immu-
nocompromised and immunocompetent patients, such
as pregnant women or premature infants, is based on
acyclovir (ACV).5 More recently, valaciclovir and fam-
ciclovir, prodrugs of acyclovir and penciclovir (PCV),
have been approved for the treatment of VZV infection.6
However, low efficacy and/or low oral bioavailability of
these agents,7 as well as the emergence of drug-resistant
virus strains,8 prompted the development of new anti-
viral agents for the treatment of VZV infection. Among
them, (E)-5-(2-bromovinyl)uracil (BVU) analogues, such
as (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU)9 and
1-(â-D-arabinofuranosyl)-(E)-5-(2-bromovinyl)uracil
(BVAU),10 have been found to exhibit potent anti-VZV
activity in vitro as well as in vivo. However, metabolic
instability of BVDU by pyrimidine nucleoside phosphor-
ylase,11 as well as the drug interaction of BVAU with
5-FU,12 limits their use. Efforts to address these prob-
Since the discovery of 3TC as an anti-HIV agent, a
number of L-nucleosides have been synthesized and
identified as potent antiviral agents, such as 3TC,16
FTC,17 L-OddC,18 and L-FMAU.19 Some L-nucleosides
have shown different substrate specificities toward
catabolic as well as anabolic enzymes, such as nucleo-
side kinases and deaminases, resulting in reduced
toxicity, increased potency, and metabolic stability.20 In
view of these interesting biological properties of L-
nucleosides, it was of interest to synthesize (E)-5-(2-
bromovinyl)uracil substituted L-nucleosides as potential
antiviral agents. Herein, we describe the structure-
activity relationships of the title compounds against
varicella zoster virus, Epstein Barr virus, and herpes
virus types 1 and 2.
Resu lts a n d Discu ssion
Ch em istr y. The syntheses of (E)-5-(2-bromovinyl)-
2′-deoxy-L-uridine (L-BVDU, 2) and 1-(â-L-arabinofura-
nosyl)-(E)-5-(2-bromovinyl)uracil (L-BVAU, 4) were ac-
complished via 2′-deoxy-L-5-iodouridine (â-L-IUdR, 1)
and 1-(â-L-arabinofuranosyl)-5-iodouracil (â-L-I-ara-U,
3), respectively, from L-arabinose based on the method
published by Holy21 and the Heck reaction22 with minor
modifications as shown in Scheme 1.
Several routes for the syntheses of 2′-deoxy-2′-fluoro-
â-D-ribonucleosides have been previously reported, in-
cluding the opening of 2,2′-anhydronucleosides with a
fluorinating agent (HF/dioxane or KF/crown ether),23,24
* To whom correspondence should be addressed. Tel: (706) 542-
5379. Fax: (706) 542-5381. E-mail: dchu@rx.uga.edu.
† The University of Georgia.
‡ Yale University School of Medicine.
10.1021/jm990543n CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/06/2000

SAR of (E)-5-(2-Bromovinyl)uracil
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 13 2539
Sch em e 1. Synthesis of l-BVDU and L-BVAUa
a
Reagents: (i) (a) Pd(OAc)2, Ph3P, methyl acrylate, 1,4-dioxane, (b) NaOH, (c) c-HCl, (d) K2CO3, NBS, DMF.
Sch em e 2. Synthesis of l-FBVRU and L-FBVAUa
a
Reagents: (i) (a) p-TsOH, DHP, DMF, (b) NaOH, MeOH, H2O; (ii) (a) DAST, pyridine, CH2Cl2, (b) p-TsOH, MeOH, (c) Ac2O, pyridine;
(iii) (a) ICl, CH2Cl2, (b) NH3/MeOH; (iv) (a) Pd(OAc)2, Ph3P, methyl acrylate, 1,4-dioxane, (b) NaOH, (c) c-HCl, (d) K2CO3, NBS, DMF.
the coupling of a suitably blocked 2-deoxy-2-fluororibo-
furanoside with appropriate heterocyclic bases,25 an
enzyme-catalyzed transglycosylation,26 the nucleophilic
displacement of 2′-O-trifluoromethanesulfonyl arabino-
nucleosides by tetra-n-butylammonium fluoride (TBAF),27
and the direct introduction of fluorine atom by diethyl-
aminosulfur trifluoride (DAST) to an arabinonucleo-
side.28 Thus, the last methodology was adopted for the
synthesis of pyrimidine 2′-deoxy-2′-fluoro-â-L-ribofura-
nosyl nucleoside 8 because a reliable yield was achieved
in a relatively large scale (Scheme 2). Thus, 2,2′-
anhydro-L-uridine was prepared from L-arabinose in two
steps according to a literature procedure,21 which was
treated with 3,4-dihydropyran in DMF followed by
saponification to give 5 in 40% overall yield from 2,2′-
anhydro-L-uridine. Compound 5 was then treated suc-

2540 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 13
Choi et al.
Sch em e 3. Synthesis of (E)-5-(2-Bromovinyl)-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)uracila
a
Reagents: (i) (a) 5-(E)-bromovinyluracil, TBDMSOTf, 2,4,6-collidine, CH2Cl2, (b) TMSI; (ii) NaBH4.
Sch em e 4. Synthesis of (E)-5-(2-Halovinyl)-1-(2-hydroxymethyl-1,3-dioxolan-5-yl)uracila
a
Reagents: (i) (a) 5-(E)-bromovinyluracil, TBDMSOTf, 2,4,6-collidine, CH2Cl2, (b) TMSI; (ii) TBAF, CH3CN.
cessively with DAST, p-TsOH, and Ac2O in pyridine to
give the key intermediate 6 in 41% yield after crystal-
lization from EtOH. Treatment of 6 with ICl in refluxing
CH2Cl229 followed by ammonolysis with saturated NH3/
MeOH afforded the 5-iodouracil analogue 7, which was
converted to the (E)-5-(2-bromovinyl)uracil analogue 8
by palladium-catalyzed coupling of methyl acrylate
followed by hydrolysis and decarboxylation in the pres-
ence of N-bromosuccinimide and potassium carbonate.
2′-Deoxy-2′-fluoro-â-L-arabinofuranosyl nucleoside 10
was prepared by a similar procedure via L-FIAU (9),
whose synthesis had previously been accomplished by
our group (Scheme 2).19,30 Thus, 5-iodouracil analogue
9 was transformed to 10 by a method similar to the
synthesis of compound 8.
cording to the methods of J ones et al.34 from the
condensation of 5-formyluracil with malonic acid, fol-
lowed by the treatment with halosuccinimide. The
treatment of the chloride 11 with persilylated (E)-5-(2-
bromovinyl)uracil in CH2Cl2 in the presence of TMSI
afforded the expected cis-nucleoside as the major isomer
1
(cis:trans 30:1 by H NMR) in 87% yield. Reduction of
compound 12 with NaBH4 in EtOH provided the desired
nucleoside 13 in 70% yield. The L-enantiomer 16 was
also obtained by condensation of 14 with (E)-5-(2-
bromovinyl)uracil followed by reduction.
Glycosylations of the dioxolane moieties with the
appropriate uracil bases were also performed by using
TMSI as the catalyst (Scheme 4). Interestingly, although
TMSI-mediated coupling of the chiral dioxolane sugar
with a protected hydroxymethyl substituent at the
2-position is known to be nonstereoselective,35 the
condensation of 17 using TMSI gave the â-isomer as a
major in a ratio of 3:1. Deprotection of 18 and 19 with
TBAF in CH3CN provided the free nucleosides 20 and
The oxathiolane and dioxolane intermediates 11, 14,
17, and 22, used in the synthesis of the corresponding
bromovinyl nucleosides (Schemes 3 and 4), were pre-
pared by the reported methods with minor modifica-
tions.31-33 (E)-5-(2-Halovinyl)uracils were prepared ac-

SAR of (E)-5-(2-Bromovinyl)uracil
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 13 2541
Ta ble 1. Structure-Activity Relationships of (E)-5-(2-Bromovinyl)uracil Analogues and Related Pyrimidine Nucleosides
EC50 (µM) cytotoxicity (ID50
HSV-1 (KOS)
)
compd
VZV (Ellen)
EBV
HSV-2 (333)
CEM
Mta
2 (L-BVDU)
4 (L-BVAU)
>50
>50
>50
>50
NDb
12.5
26
>30
0.15
>30
0.07
>30
0.035
>30
>30
17
>50
>50
ND
ND
ND
>50
>50
>50
>50
>50
>50
>50
>50
18
>50
36
>50
33
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
8 (L-FBVRU)
10 (L-FBVAU)
13 (â-D-BV-SddU)
16 (â-L-BV-SddU)
20 (â-D-BV-OddU)
21 (R-D-BV-OddU)
29 (â-L-CV-OddU)
30 (R-L-CV-OddU)
31 (â-L-BV-OddU)
32 (R-L-BV-OddU)
33 (â-L-IV-OddU)
34 (R-L-IV-OddU)
â-L-Br-OddU38
â-L-I-OddU38
ACV
ND
>50
>50
0.49
>50
0.59
>50
3.91
>50
0.19
0.033
19.7
ND
>200
>25
>200
>25
>200
>25
>200
>200
>200
>200
>200
>200
2.0
13.6
18
PCV
BVDU
BVAU
0.14
0.05
0.001
>50
47
a
b
Mt, mitochondrial toxicity. ND, not determined.
21 in high yields.36 Similarly, (E)-5-(2-halovinyl)uracil
analogues 29-34, possessing a dioxolane moiety with
L-configuration, were obtained. The E-configurations of
the synthesized nucleosides were identified by the
coupling constant (13.6 Hz) for the vinyl protons in the
1H NMR spectrum37 and confirmed in comparison with
physical data of the corresponding D-isomers.
Recently, we reported the anti-EBV activity of L-
dioxolane uracil nucleosides, among which L-I-OddU
was the most potent anti-EBV agent.38 As observed for
VZV, it appeared that the anti-EBV activity of L-
dioxolane nucleosides was related to the size of the
halogen atoms of the pyrimidine moiety. Both anti-EBV
activity of L-dioxolane nucleosides with halogenated
uracils (Cl, Br, and I: EC50 0.6, 0.19, and 0.033 µM,
respectively)38 and anti-VZV activity of their halovinyl
analogues (EC50 0.15, 0.07, and 0.035 µM) increased
with the increasing size of the halogen atoms. Interest-
ingly, (E)-5-(2-halovinyl)uracil analogues 29, 31, and 33
exhibited moderate to potent anti-EBV activity with
EC50 values of 0.49, 0.59, and 3.91 µM, respectively, and
5-halouracil analogues did not exhibit significant anti-
VZV activity. From these results, it may be concluded
that the structural requirements of substrates for virus-
encoded thymidine kinase or viral DNA polymerase of
EBV are different from that of VZV.
An tivir a l Activity. In vitro antiviral results are
listed in Table 1. The efficacy of the synthesized
compounds as potential antiviral agents was tested in
cell cultures infected with the following viruses: vari-
cella zoster virus (VZV), Epstein Barr virus (EBV), and
herpes simplex virus types 1 and 2 (HSV-1 and HSV-
2). Cytotoxicity and mitochondrial toxicity were evalu-
ated in CEM cells. Acyclovir (ACV), penciclovir (PCV),
BVDU, and BVAU were included as positive controls.
From these studies, it was found that only L-dioxolane
derivatives exhibited significant antiviral activity. L-
Dioxolane nucleosides 29, 31, and 33 showed potent and
selective anti-VZV and anti-EBV activity, and other
compounds including the L-oxathiolane nucleoside did
not show any significant antiviral activity. The anti-
VZV activity of L-dioxolane nucleosides appears to be
related to the size of the halogen atoms on the pyrimi-
dine moiety in increasing order (Cl, Br, and I) with EC50
values of 0.15, 0.07, and 0.035 µM, respectively. In
comparison to ACV (EC50 2 µM), which is the most
prescribed regimen in clinics, the chloro derivative 29
exhibited 13-fold higher activity against VZV. The
bromo 31 and iodo 33 derivatives were 30 and 60 times,
respectively, more potent than ACV. In comparison to
PCV (EC50 0.15 µM), the chloro derivative 29 showed
equivalent potency and the bromo 31 and iodo 33
derivatives exhibited 2- and 4-fold potency, respectively.
Compound 33 showed higher potency in vitro for anti-
VZV activity than BVDU, which is known to be a potent
and selective anti-VZV agent. Among the tested com-
pounds, BVAU was the most potent compound against
VZV. The synthesized compounds did not show any
toxicity up to 100 µM in CEM cells and also did not show
mitochondrial toxicity, which demonstrates high selec-
tivity (SI > 2300) for compounds 29, 31, and 33.
Mansour and co-workers reported that â-L-dioxolane
nucleoside 31 and (E)-5-(2-bromovinyl)-2′-deoxy-3′-oxa-
â-D-thiouridine showed significant antiviral activity
against HSV-1 (EC50 0.3 µg/mL) and HSV-2 (EC50 2.9
µg/mL).37b However, in our studies, compound 29 (EC50
18 µM) was as active as PCV (EC50 18 µM), whereas 31
(EC50 36 µM) and 33 (EC50 33 µM) were only weakly
active against HSV-1 (ACV and PCV: EC50 13.6 and
18 µM, respectively). Compounds 29, 31, and 33 did not
exhibit any activity against HSV-2. According to Spadari
et al., L-BVDU (2) was found to inhibit HSV-1 thymidine
kinase with an IC50 of 0.26 µM and was fully resistant
to hydrolysis by nucleoside phosphorylase.15 However,
in our in vitro study against HSV-1, L-BVDU did not
display any activity up to 50 µM.
In summary, we demonstrated that L-dioxolane nu-
cleosides bearing the (E)-5-(2-halovinyl)uracil hetero-
cyclic moiety show potent and selective anti-VZV and
anti-EBV activity in vitro, and the anti-VZV activity is
dependent on the size of the halogen atoms. Therefore,
further pharmacological and biochemical studies are
warranted to elucidate their mechanism of action as well

2542 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 13
Choi et al.
Ac2O (20 mL) was added to this and the mixture was stirred
at room temperature for 20 h. Removal of the solvent and
recrystallization from EtOH gave 6 as a white solid (6.8 g, total
41%): UV (MeOH) λmax 257.0 nm; 1H NMR (CDCl3) δ 8.62 (s,
1H, NH, D2O exchangeable), 7.33 (d, 1H, J ) 8.1 Hz, 6-H),
5.72 (dd, 1H, J ) 25.0, 2.0 Hz, 1′-H), 5.70 (d, 1H, J ) 8.1 Hz,
5-H), 5.30 (ddd, 1H, J F-H ) 52.2 Hz, 2′-H), 5.08 (ddd, 1H, J F-H
) 17.9 Hz, 3′-H), 4.31 (m, 3H, 4′-H, 5′-H), 2.07, 2.03 (2s, 6H,
Ac).
1-(2-Deoxy-2-flu or o-â-L-r ibofu r a n osyl)-5-iod ou r a cil (7).
A mixture of 6 (3.3 g, 0.01 mol) and ICl (2.4 g, 0.015 mol) in
CH2Cl2 (100 mL) was stirred at reflux for 5 h. It was then
diluted with CH2Cl2 (150 mL), washed successively with
NaHSO3 (100 mL × 3) and saturated NaHCO3 (50 mL × 2)
and dried (MgSO4). Removal of the solvent gave a white foam
(4.1 g, 90%), which was treated with NaOMe/MeOH. Tritua-
tion in ether followed by recrystallization from water gave 7
as a white solid: mp 217-218 °C; [R]27D +9.41° (c 0.36, MeOH);
UV (H2O) λmax 285.5 nm (ꢀ 8660) (pH 1), 283.5 nm (ꢀ 8090)
(pH 7), 277.0 nm (ꢀ 6450) (pH 11); 1H NMR (DMSO-d6) δ 11.75
(s, 1H, NH, D2O exchangeable), 8.54 (s, 1H, 6-H), 5.86 (bd,
1H, J F-H ) 16.8 Hz, 1′-H), 5.62 (d, 1H, 3′-OH, D2O exchange-
able), 5.41 (t, 1H, 5′-OH, D2O exchangeable), 5.04 (dd, 1H, J F-H
) 53.1 Hz, 2′-H), 4.18 (dm, 1H, J F-H ) 23.4 Hz, 3′-H), 3.90
(m, 1H, 4′-H), 3.72 (m, 2H, 5′-H). Anal. (C9H10FIN2O5) C, H,
N.
(E)-5-(2-Br om ovin yl)-1-(2-d eoxy-2-flu or o-â-L-r ibofu r a -
n osyl)u r a cil (8). A mixture of Ph3P (125 mg, 0.47 mmol), Pd-
(OAc)2 (63 mg, 0.25 mmol), and Et3N (1.25 mL) in 1,4-dioxane
(30 mL) was stirred under reflux for 10 min, then cooled to
just under reflux. To this was added methyl acrylate (1.13 mL,
12.6 mmol), followed by 7 (930 mg, 2.50 mmol) and 1,4-dioxane
(10 mL). The mixture was refluxed for 0.5 h and then filtered
through a Celite pad and washed with dioxane. The combined
filtrates were evaporated to dryness and the residue was
purified by silica gel column chromatography (CHCl3:MeOH,
9:1) to give an off-white foam (630 mg, 76%): UV (MeOH) λmax
299.5, 264.0 nm (sh); 1H NMR (CDCl3) δ 11.73 (s, 1H, NH,
D2O exchangeable), 8.51 (s, 1H, J ) 8.1 Hz, 6-H), 7.29 (d, 1H,
J ) 15.9 Hz, vinylic Ha), 6.79 (d, 1H, J ) 15.9 Hz, vinylic Hb),
5.88 (d, 1H, J F-H ) 16.9 Hz, 1′-H), 5.62 (d, 1H, 3′-OH, D2O
exchangeable), 5.48 (t, 1H, 5′-OH, D2O exchangeable), 5.04 (dd,
1H, J F-H ) 52.8 Hz, 2′-H), 4.16 (dm, 1H, J F-H ) 24.3 Hz, 3′-
H), 3.90 (m, 3H, 4′-H), 3.72 (m, 2H, 5′-H), 3.68 (s, 3H, COOMe).
as to determine the metabolic stability toward pyrimi-
dine nucleoside phosphorylase.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were determined on a
Mel-temp II and are uncorrected. 1H NMR spectra were
recorded on a Bruker 400 AMX spectrometer for 400 MHz,
with Me4Si as the 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 (multiplet),
or br s (broad singlet). Optical rotations were performed on a
J asco DIP-370 digital polarimeter. TLC was 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 spectropho-
tometer. Elemental analyses were performed by Atlantic
Microlab, Inc., Norcross, GA.
(E)-5-(2-Br om ovin yl)-2′-d eoxy-L-u r id in e (2). L-BVDU (2)
was synthesized in three steps as described for the correspond-
ing D-enantiomer,22 starting from â-L-IUdR (1):21 mp 156 °C
dec; [R]27 -19.4° (c 0.20, MeOH); UV (H2O) λmax 249.5 (ꢀ
D
10900), 249.5 nm (ꢀ 8040) (pH 7), 249 (ꢀ 10800), 293.5 nm (ꢀ
8040) (pH 2), 254.0 nm (ꢀ 10800), 283.5 nm (ꢀ 6850) (pH 11);
1H NMR (DMSO-d6) δ 11.00 (s, 1H, NH), 8.00 (s, 1H, 6-H),
7.17 (d, 1H, J ) 13.6 Hz, vinylic Ha), 6.77 (d, 1H, J ) 13.6
Hz, vinylic Hb), 6.05 (t, 1H, J ) 6.5 Hz, 1′-H), 5.19 (d, 1H,
3′-OH), 5.04 (t, 1H, 5′-OH), 4.17 (m, 1H, 3′-H), 3.71 (m, 1H,
4′-H), 3.52 (m, 2H, 5′-H), 2.06 (m, 2H, 2′-H). Anal. (C11H13
-
BrN2O5) C, H, Br, N.
1-(â-L-Ar abin ofu r an osyl)-(E)-5-(2-br om ovin yl)u r acil (4).
L-BVAU (4) was also synthesized by the same procedure as
for the synthesis of L-BVDU from â-L-I-ara-U (3), which was
prepared from l-arabinose:21 mp 178-180 °C; [R]26 -18.1° (c
D
0.16, EtOH); UV (H2O) λmax 250.5 (ꢀ 13300), 293.0 nm (ꢀ 9850)
(pH 7), 251.0 (ꢀ 13300), 293.0 nm (ꢀ 10300) (pH 2), 256.0 (ꢀ
13500), 284.5 nm (ꢀ 8470) (pH 11); 1H NMR (DMSO-d6) δ 9.69
(br s, 1H, NH), 7.90 (s, 1H, 6-H), 7.24 (d, 1H, J ) 13.9 Hz,
vinylic Ha), 6.87 (d, 1H, J ) 13.9 Hz, vinylic Hb), 5.99 (t, 1H,
J ) 4.4 Hz, 1′-H), 5.59 (d, 1H, 2′-OH), 5.49 (d, 1H, 3′-OH),
5.14 (t, 1H, 5′-OH), 4.05 (m, 1H, 2′-H), 3.91 (m, 1H, 3′-H), 3.75
(m, 1H, 4′-H), 3.65 (m, 2H, 5′-H). Anal. (C11H13BrN2O6‚
0.3EtOH) C, H, N.
The ester derivative (560 mg, 1.70 mmol) was stirred in a
NaOH solution (2 N, 5 mL) at room temperature for 1.5 h,
then diluted with water (20 mL) and neutralized with Dowex
50w × 8 (H+) resin. The mixture was filtered and washed with
water and acetone. The combined filtrate was evaporated to
dryness to give a pale-white solid, which was triturated with
Et2O to give a free acid derivative as an off-white solid (450
mg, 84%): UV (MeOH) λmax 298.0, 267.0 nm (sh); 1H NMR
(CDCl3) δ 11.70 (s, 1H, NH, D2O exchangeable), 8.49 (s, 1H, J
) 8.1 Hz, 6-H), 7.22 (d, 1H, J ) 15.9 Hz, vinylic Ha), 6.73 (d,
1H, J ) 15.9 Hz, vinylic Hb), 5.89 (d, 1H, J F-H ) 16.8 Hz,
1′-H), 5.86 (d, 1H, 3′-OH, D2O exchangeable), 5.62 (bs, 1H, 5′-
OH, D2O exchangeable), 5.05 (dd, 1H, J F-H ) 52.9 Hz, 2′-H),
4.18 (dm, 1H, J F-H ) 24.1 Hz, 3′-H), 3.89 (m, 3H, 4′-H), 3.74
(m, 2H, 5′-H).
1-(3,5-Di-O-a cetyl-2-d eoxy-2-flu or o-â-L-r ibofu r a n osyl)-
u r a cil (6). To a suspension of 2,2′-anhydro-L-uridine (17.0 g,
0.075 mol)21 in DMF (300 mL) and 3,4-dihydropyran (180 mL)
was added p-toluenesulfonic acid (14.0 g) at 0 °C and the
mixture was stirred at 0 °C for 4 h, at which time a clear
solution was obtained. This was neutralized with Et3N (30 mL)
and then evaporated to dryness. The residue was redissolved
in EtOAc, washed with saturated NaHCO3 and dried (MgSO4).
Removal of the solvent gave a residue which was triturated
with hexanes and filtered. The filter cake was washed with
hexanes and dried to give protected 2,2′-anhydro-L-uridine as
a white solid (27.5 g, 93%), whose suspension (23.0 g, 58.5
mmol) in MeOH (300 mL) and 1 N NaOH (100 mL) was stirred
at room temperature for 2 h, then neutralized with dilute
acetic acid. The mixture was evaporated to dryness and the
residue was loaded to a silica gel pad, eluted with EtOAc to
give 5 as a white solid (22.6 g, 94%): UV (MeOH) λmax 263.0
nm.
To a stirred mixture of 5 (20.6 g, 0.05 mol) in CH2Cl2 (300
mL) and pyridine (50 mL) was added DAST (25.0 g, 0.155 mol)
at -60 °C under N2. This resulting mixture was slowly warmed
to room temperature and then refluxed for 4 H. The reaction
was quenched with saturated NaHCO3 and ice-water, then
extracted with CH2Cl2 (100 mL × 3), washed with saturated
NaHCO3 and dried (MgSO4). Removal of the solvent gave a
dark-brown syrup (18.9 g), which was redissolved in MeOH
(300 mL). p-Toluenesulfonic acid (6 g) was added to this and
the mixture was stirred at room temperature for 3 h. It was
then neutralized with pyridine (50 mL), coevaporated with
pyridine (2 × 50 mL), then redissolved in pyridine (100 mL).
To a suspension of the free acid (190 mg, 0.6 mmol) and
KHCO3 (240 mg, 2.4 mmol) in DMF (10 mL), was added
N-bromosuccinimide (130 mg, 0.72 mmol). The mixture was
stirred at room temperature for 5 h and then evaporated to
dryness. The residue was purified on a silica gel column (9:1
CHCl3:MeOH) followed by preparative TLC (CHCl3:MeOH,
9:1). Coevaporation of the product with Et2O gave a white solid
of 90 mg (43%): mp 80-83 °C; [R]28 +14.4° (c 0.20, MeOH);
D
UV (H2O) λmax 249.5 (ꢀ 11500), 292.5 nm (ꢀ 8810) (pH 7), 249.0
(ꢀ 13100), 290.0 nm (ꢀ 9660) (pH 2), 249.0 (ꢀ 13800), 290.0 nm
(sh) (pH 11); 1H NMR (DMSO-d6) δ 11.66 (s, 1H, NH), 8.19 (s,
1H, 6-H), 7.20 (d, 1H, J ) 13.7 Hz, vinylic Ha), 6.75 (d, 1H, J
) 13.7 Hz, vinylic Hb), 5.87 (dd, 1H, J F-H ) 16.9 Hz, 1′-H),
5.62 (d, 1H, 3′-OH, D2O exchangeable), 5.37 (t, 1H, 5′-OH, D2O
exchangeable), 5.04 (dd, 1H, J F-H ) 52.3 Hz, 2′-H), 4.16 (dm,

SAR of (E)-5-(2-Bromovinyl)uracil
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 13 2543
1H, J F-H ) 23.7 Hz, 3′-H), 3.88 (m, 1H, 4′-H), 3.70 (m, 2H,
5′-H). Anal. (C11H12BrFN2O5‚0.5H2O) C, H, N.
(2S,5R)-(E)-5-(2-Br om ovin yl)-1-[2-(h yd r oxym eth yl)-1,3-
oxa th iola n -5-yl]u r a cil (13). To a solution of 12 (153 mg,
0.313 mmol) in 10 mL of EtOH was added NaBH4 (24 mg,
0.626 mmol) portionwise at 0 °C and the mixture was stirred
at room temperature for 6 h. The reaction mixture was
neutralized with AcOH and extracted with CH2Cl2 (2 × 10
mL). The organic layer was dried (MgSO4), filtered, and
concentrated. The residue was purified by silica gel column
chromatography (CHCl3:MeOH, 30:1) to give 13 (73 mg, 70%)
as a white solid which was recrystallized from hexanes-CH2-
Cl2-MeOH: mp 155 °C dec; [R]D +62.4° (c 0.21, MeOH); UV
(MeOH) λmax 251.0 nm (ꢀ 15400), 291.5 (ꢀ 13100) (pH 7), 249.0
(ꢀ 16600), 292.0 nm (ꢀ 12600) (pH 2), 254.0 (ꢀ 16600), 284.5
(E)-5-(2-Br om ovin yl)-1-(2-d eoxy-2-flu or o-â-L-a r a bin o-
fu r a n osyl)u r a cil (10). A mixture of Ph3P (40 mg, 0.15 mmol),
Pd(OAc)2 (20 mg, 0.08 mmol), and Et3N (0.4 mL, 2.8 mmol) in
1,4-dioxane (15 mL) was refluxed to form a dark-red solution
and then cooled to just below reflux. To this was added methyl
acrylate (0.36 mL, 4.0 mmol), followed by 9 (300 mg, 0.8 mmol)
with dioxane (10 mL) and Et3N (0.15 mL). The mixture was
refluxed for 0.5 h and then filtered through a Celite pad and
washed with dioxane. The combined filtrates were evaporated
to dryness and purified on a silica gel column (CHCl3:MeOH,
9:1) to give an ester as a white foam (145 mg, 54%): UV
(MeOH) λmax 299.0 nm; 1H NMR (DMSO-d6) δ 11.79 (s, 1H,
NH, D2O exchangeable), 8.35 (s, 1H, 6-H), 7.41 (d, 1H, J )
15.9 Hz, vinylic Ha), 6.90 (d, 1H, J ) 15.8 Hz, vinylic Hb),
6.14 (dd, 1H, J F-H ) 14.2 Hz, 1′-H), 5.81 (d, 1H, 3′-OH, D2O
exchangeable), 5.25 (t, 1H, D2O exchangeable 5′-OH), 5.10 (dt,
1H, J F-H ) 52.6 Hz, 2′-H), 4.26 (dt, 1H, J F-H ) 19.8 Hz, 3′-H),
3.84 (m, 1H, 4′-H), 3.69 (dm, 2H, 5′-H).
1
nm (sh, ꢀ 10800) (pH 11); H NMR (DMSO-d6) δ 11.7 (s, 1H,
NH), 8.22 (s, 1H, 6-H), 7.25 (d, 1H, J ) 13.6 Hz, vinylic Ha),
6.85 (d, 1H, J ) 13.6 Hz, vinylic Hb), 6.18 (ps t, 1H, J ) 5.1,
4.5 Hz, 1′-H), 5.46 (t, 1H, 5′-OH), 5.21 (ps t, 1H, J ) 4.1, 3.9
Hz, 4′-H), 3.80-3.75 (m, 2H, 2′-H), 3.45 (dd, 1H,J ) 11.9, 5.5
Hz, 5-Ha), 3.26 (dd, 1H, J ) 11.9, 4.2 Hz, 5′-Hb). Anal. (C10H11
BrN2O3S) C, H, Br, N, S.
-
(2R,5S)-(E)-5-(2-Br om ovin yl)-1-[2-[(1R,2S,5R)-m en t h -
yloxyca r bon yl]-1,3-oxa th iola n -5-yl]u r a cil (15). To a sus-
pension of (E)-5-bromovinyluracil (250 mg, 1.15 mmol) in CH2-
Cl2 (2 mL) were added TBDMSOTf (0.7 mL, 2.53 mmol) and
2,4,6-collidine (0.4 mL, 2.27 mmol) at room temperature. The
reaction mixture was stirred for 30 min. To the resulting
solution was added a solution of 14 (380 mg, 1.15 mmol) in
CH2Cl2 (5 mL) slowly, followed by TMSI (0.18 mL, 1.27 mmol).
The mixture was stirred at room temperature for 3 h and then
quenched with saturated Na2S2O3 solution. The organic layer
was washed with brine, dried (MgSO4), filtered, and concen-
trated. The residue was chromatographed on silica gel (hex-
anes:EtOAc, 3:1) to give a white solid as anomeric mixture
(â:R ) 27:1 by 1H NMR), which was recrystallized from EtOAc
and hexanes to give 15 (456 mg, 81%) as a white solid: mp
A solution of the ester (135 mg, 0.41 mmol) in a 2 N NaOH
solution (5 mL) was stirred at room temperature for 1.5 h and
then cooled in an ice bath. pH was carefully adjusted with 12
N HCl to ca. 1 and the mixture was stirred for 10 min. The
white precipitate was collected by filtration and washed with
water and acetone to give an acid as a white powder (96 mg,
74%): mp 284 °C dec; UV (MeOH) λmax 298.0, 268.0 nm (sh);
1H NMR (DMSO-d6) δ 11.80 (s, 1H, NH, D2O exchangeable),
8.28 (s, 1H, 6-H), 7.31 (d, 1H, J ) 15.8 Hz, vinylic Ha), 6.79
(d, 1H, J ) 15.9 Hz, vinylic Hb), 6.12 (dd, 1H, J 1′,F ) 14.0 Hz,
1′-H), 5.90 (d, 1H, 3′-OH, D2O exchangeable), 5.23 (t, 1H, 5′-
OH, D2O exchangeable), 5.08 (dt, 1H, J F-H ) 52.7 Hz, 2′-H),
4.27 (dt, 1H, J F-H ) 19.6 Hz, 3′-H), 3.81 (m, 1H, 4′-H), 3.65
(dm, 2H, 5′-H).
A suspension of the acid (80 mg, 0.25 mmol) and KHCO3
(100 mg, 1.0 mmol) in DMF (1.5 mL) was stirred at room
temperature for 20 min. To this was added N-bromosuccun-
imide (53 mg, 0.3 mmol) in DMF (1.0 mL). The mixture was
stirred at room temperature for 1.5 h then filtered and washed
with methanol. The filtrate was evaporated to dryness and
purified on preparative TLC (CHCl3:MeOH, 6:1). After co-
evaporation with ether, 11 was obtained as a white foam (47
mg, 53%): mp 190-192 dec; [R]28D -59.4° (c 0.17, MeOH); UV
(H2O) λmax 250 0 nm (ꢀ 14600) (pH 7), 250.0 nm (ꢀ 15800) (pH
124-126 °C; [R]28 -97.2° (c 0.34, CHCl3); UV (MeOH) λmax
D
248.5, 292.0 nm; 1H NMR (CDCl3) δ 8.47 (s, 1H, 6-H), 8.27 (s,
NH), 7.42 (d, 1H, J ) 13.7 Hz, vinylic Ha), 6.78 (d, 1H, J )
13.7 Hz, vinylic Hb), 5.46 (s, 1H, 4′-H), 4.84-4.78 (m, 1H,1′-
H), 3.44 (dd, 1H, J ) 12.1, 4.7 Hz, 2′-Ha), 3.18 (dd, 1H, J )
12.1, 7.1 Hz, 2′-Hb), 2.08-1.41 (m, 7H), 1.13-0.86 (m, 8H),
0.78 (d, 3H, J ) 6.9 Hz). Anal. (C20H27BrN2O4S) C, H, Br, N,
S.
(2R,5S)-(E)-5-(2-Br om ovin yl)-1-[2-(h yd r oxym eth yl)-1,3-
oxa th iola n -5-yl]u r a cil (16). To a solution of 15 (124 mg,
0.254 mmol) in 8 mL of EtOH was added NaBH4 (19 mg, 0.508
mmol) portionwise at 0 °C and the mixture was stirred at room
temperature for 6 h. The reaction mixture was neutralized
with AcOH and extracted with CH2Cl2 (10 mL × 2). The
combined organic layers were dried (MgSO4), filtered, and
concentrated. The residue was purified by silica gel column
chromatography (CHCl3:MeOH, 30:1) to give 16 (54 mg, 64%)
as a white solid, which was recrystallized from hexanes-CH2-
Cl2-MeOH: mp 154 °C dec; [R]26D -60.2° (c 0.56, MeOH); UV
(MeOH) λmax 250.5 (ꢀ 12700), 293.0 nm (ꢀ 10700) (pH 7), 249.5
(ꢀ 14100), 292.5 nm (ꢀ 10800) (pH 2), 254.0 (ꢀ 14100), 285.0
1
2), 254.0 nm (ꢀ 15900) (pH 11); H NMR (DMSO-d6) δ 11.70
(s, 1H, NH), 7.97 (s, 1H, 6-H), 7.26 (d, 1H, J ) 13.6 Hz, vinylic
Ha), 6.88 (d, 1H, J ) 13.7 Hz, vinylic Hb), 6.10 (d, 1H, J F-H
)
14.7 Hz, 1′-H), 5.86 (d, 1H, 3′-OH), 5.12 (t, 1H, 5′-OH), 5.04
(dt, 1H, J F-H ) 52.6 Hz, 2′-H), 4.23 (dt, 1H, J F-H ) 19.9 Hz,
3′-H), 3.80 (m, 1H, 4′-H), 3.63 (m, 2H, 5′-H). Anal. (C11H12
-
BrFN2O5) C, H, N.
(2S,5R)-(E)-5-(2-Br om ovin yl)-1-[2-[(1R,2S,5R)-m en t h -
yloxyca r bon yl]-1,3-oxa th iola n -5-yl]u r a cil (12). To a sus-
pension of (E)-5-(2-bromovinyl)uracil (257 mg, 1.18 mmol) in
CH2Cl2 (3 mL) were added TBDMSOTf (0.72 mL, 3.13 mmol)
and 2,4,6-collidine (0.42 mL, 3.11 mmol) at room temperature.
The reaction mixture was stirred for 30 min. To the resulting
solution was added a solution of 11 (362 mg, 1.15 mmol) in
CH2Cl2 (8 mL) slowly, followed by TMSI (0.19 mL, 1.3 mmol).
The mixture was stirred at room temperature for 3 h and then
quenched with saturated Na2S2O3 solution. The organic layer
was washed with brine, dried (MgSO4), filtered, and concen-
trated. The residue was chromatographed on a silica gel
(hexanes:EtOAc, 3:1) to give a white solid as anomeric mixture
(â:R ) 30:1 by 1H NMR), which was recrystallized from EtOAc
and hexanes to give 12 (500 mg, 87%) as a white solid: mp
128-129 °C; [R]D +6.6° (c 0.28, CHCl3); UV (MeOH) λmax 248.5,
292.0 nm; 1H NMR (CDCl3) δ 8.47 (s, 1H, 6-H), 7.41 (d, 1H, J
) 13.7 Hz, vinylic Ha), 6.78 (d, 1H, J ) 13.7 Hz, vinylic Hb),
5.46 (s, 1H, 4′-H), 4.85-4.78 (m, 1H, 1′-H), 3.43 (dd, 1H, J )
12.1, 4.7 Hz, 2′-Ha), 3.16 (dd, 1H, J ) 12.1, 7.5 Hz, 2′-Hb),
2.06-1.40 (m, 7H), 1.15-1.00 (m, 2H), 0.96-0.91 (m, 6H), 0.81
(d, 3H, J ) 6.8 Hz). Anal. (C20H27BrN2O4S‚0.1C6H14) C, H, Br,
N, S.
1
nm (sh, ꢀ 9100) (pH 11); H NMR (DMSO-d6) δ 11.7 (s, 1H,
NH), 8.23 (s, 1H, 6-H), 7.25 (d, 1H, J ) 13.6 Hz, vinylic Ha),
6.85 (d, 1H, J ) 13.6 Hz, vinylic Hb), 6.19 (ps t, 1H, J ) 5.1,
4.5 Hz, 1′-H), 5.46 (t, 1H, 5′-OH), 5.21 (ps t, 1H, J ) 4.1, 3.8
Hz, 4′-H), 3.82-3.78 (m, 2H, 2′-H), 3.45 (dd, 1H, J ) 11.9, 5.4
Hz, 5-Ha), 3.27 (dd, 1H, J ) 12.1, 4.2 Hz, 5′-Hb). Anal. (C10H11
BrN2O3S) C, H, Br, N, S.
-
(2R ,5R )-(E )-5-(2-B r o m o v in y l)-1-[2-[[(t er t -b u t y ld i-
p h en ylsilyl)oxy]m eth yl]-1,3-d ioxola n -5-yl]u r a cil (18) a n d
(2R,5S)-(E)-5-(2-Br om ovin yl)-1-[2-[[(ter t-b u t yld ip h en yl-
silyl)oxy]m eth yl]-1,3-d ioxola n -5-yl]u r a cil (19). To a sus-
pension of (E)-5-bromovinyluracil (420 mg, 1.94 mmol) in
CH2Cl2 (20 mL) were added TBDMSOTf (1.2 mL, 5.13 mmol)
and 2,4,6-collidine (0.67 mL, 5.10 mmol) at room temperature.
The reaction mixture was stirred for 30 min. To the resulting
solution was added a solution of 17 (775 mg, 1.94 mmol) in
CH2Cl2 (20 mL) slowly dropwise, followed by TMSI (0.31 mL,
2.14 mmol). The mixture was stirred at room temperature for

2544 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 13
Choi et al.
3 h and then quenched with saturated Na2S2O3 solution. The
organic layer was washed with brine, dried (MgSO4), filtered,
and concentrated. The residue was chromatographed on silica
gel (hexanes:EtOAc, 4:1) to give R-isomer 19 (164 mg, 15%)
as a white solid and â-isomer 18 (519 mg, 48%) as a white
foam, which was crystallized from CH2Cl2 and hexanes. 18:
2′-Hb), 3.74 (dd, 1H, J ) 11.6, 2.7 Hz, 5′-Ha), 3.70 (dd, 1H, J
t
) 11.7, 3.4 Hz, 5′-Hb), 1.07 (s, 9H, Bu). Anal. (C26H29ClN2O5-
Si‚0.2H2O) C, H, N.
(2S,5S)-(E)-5-(2-Br om ovin yl)-1-[2-[[(ter t-bu tyld ip h en yl-
silyl)oxy]m eth yl]-1,3-dioxolan -5-yl]u r acil (25) an d (2S,5R)-
(E)-5-(2-Br om ovin yl)-1-[2-[[(ter t-bu tyld ip h en ylsilyl)oxy]-
m eth yl]-1,3-d ioxola n -5-yl]u r a cil (26). 25 (58%): mp 62-
mp 64-66 °C; [R]25 +22.6° (c 0.46, CHCl3); UV (MeOH) λmax
D
1
249.5, 293.0 nm; H NMR (CDCl3) δ 8.24 (s, NH), 7.70-7.30
65 °C; [R]29 -19.0° (c 0.8, CHCl3); UV (MeOH) λmax 249.5,
D
(m, 11H, Ph-H, 6-H), 7.32 (d, 1H, J ) 13.6 Hz, vinylic Ha),
6.30 (ps t, 1H, J ) 2.9, 1.6 Hz, 1′-H), 6.29 (d, 1H, J ) 13.6 Hz,
vinylic Hb), 5.10 (ps t, 1H, J ) 3.4, 3.3 Hz 4′-H), 4.20-4.15
292.5 nm; 1H NMR (CDCl3) δ 8.24 (s, NH), 7.70-7.30 (m, 11H,
Ph-H, 6-H), 7.32 (d, 1H, J ) 13.6 Hz, vinylic Ha), 6.30 (ps t,
2H, J ) 2.9, 1.6 Hz, 1′-H), 6.29 (d, 1H, J ) 13.6 Hz, vinylic
Hb), 5.10 (ps t, 1H, J ) 3.4, 3.3 Hz, 4′-H), 4.20-4.15 (m, 2H,
2′-H), 3.95 (dd, 1H, J ) 11.7, 3.2 Hz, 5′-Ha), 3.89 (dd, 1H, J )
(m, 2H, 2′-H), 3.95 (dd, 1H, J ) 11.7, 3.2 Hz, 5′-Ha), 3.89 (dd,
t
1H, J ) 11.7, 3.5 Hz, 5′-Hb), 1.09 (s, 9H, Bu). Anal. (C26H29
-
BrN2O5Si) C, H, Br, N. 19: mp 148-150 °C; [R]D -1.7° (c 1.29,
CHCl3); UV (MeOH) λmax 249.5, 293.0 nm; 1H NMR (CDCl3) δ
8.17 (s, NH), 7.69-7.39 (m, 11H, Ph-H, 6-H), 7.28 (d, 1H, J )
13.6 Hz, vinylic Ha), 6.68 (d, 1H, J ) 13.6 Hz, vinylic Hb),
6.28 (dd, 1H, J ) 5.2, 2.0 Hz, 1′-H), 5.55 (ps t, 1H, J ) 3.1, 2.9
Hz, 4′-H), 4.41 (dd, 1H, J ) 9.7, 5.2 Hz, 2′-Ha), 4.04 (dd, 1H,
J ) 9.7, 2.0 Hz, 2′-Hb), 3.74 (dd, 1H, J ) 11.7, 2.8 Hz, 5′-Ha),
t
11.7, 3.5 Hz, 5′-Hb), 1.09 (s, 9H, Bu). Anal. (C26H29BrN2O5Si)
C, H, Br, N. 26 (20%): mp 147-149 °C; [R]28 +1.4° (c 0.76,
D
CHCl3); UV (MeOH) λmax 249.5, 293.0 nm; 1H NMR (CDCl3) δ
8.21 (s, NH), 7.69-7.39 (m, 10H, Ph-H), 7.28 (d, 1H, J ) 13.6
Hz, vinylic Ha), 6.68 (d, 1H, J ) 13.6 Hz, vinylic Hb), 6.28 (dd,
1H, J ) 5.2, 2.0 Hz, 1′-H), 5.55 (ps t, 1H, J ) 3.1, 2.9 Hz, 4′-
H), 4.41 (dd, 1H, J ) 9.7, 5.2 Hz, 2′-Ha), 4.04 (dd, 1H, J ) 9.7,
t
3.70 (dd, 1H, J ) 11.7, 3.4 Hz, 5′-Hb), 1.07 (s, 9H, Bu). Anal.
2.0 Hz, 2′-Hb), 3.74 (dd, 1H, J ) 11.7, 2.8 Hz, 5′-Ha), 3.70 (dd,
(C26H29BrN2O5Si) C, H, Br, N.
t
1H, J ) 11.7, 3.4 Hz, 5′-Hb), 1.07 (s, 9H, Bu). Anal. (C26H29
-
(2R,5R)-(E)-5-(2-Br om ovin yl)-1-[2-(h ydr oxym eth yl)-1,3-
d ioxola n -5-yl]u r a cil (20). A solution of 18 (278 mg, 0.499
mmol) in CH3CN (15 mL) was treated with tetra-n-butylam-
monium fluoride (1 M solution in THF) (0.6 mL, 0.6 mmol) at
room temperature for 1 h. After concentration of the mixture,
the residue was purified by silica gel column chromatography
(CHCl3:MeOH, 20:1) to give 20 (151 mg, 95%) as a white
BrN2O5Si) C, H, Br, N.
(2S,5S)-1-[2-[[(ter t-Bu tyld ip h en ylsilyl)oxy]m eth yl]-1,3-
d ioxola n -5-yl]-(E)-5-(2-iod ovin yl)u r a cil (27) a n d (2S,5R)-
1-[2-[[(ter t-Bu tyld ip h en ylsilyl)oxy]m eth yl]-1,3-d ioxola n -
5-yl]-(E)-5-(2-iod ovin yl)u r a cil (28). 27 (56%): mp 74-76 °C;
[R]26 -24.0° (c 0.23, CHCl3); UV (MeOH) λmax 254.0, 298.5
D
1
solid: mp 176-177 °C; [R]27 +6.5° (c 0.47, MeOH); UV
nm; H NMR (CDCl3) δ 8.10 (s, NH), 7.71-7.37 (m, 11H, Ph-
D
H, 6-H), 7.33 (d, 1H, J ) 14.6 Hz, vinylic Ha), 6.64 (d, 1H, J
) 14.6 Hz, vinylic Hb), 6.29 (dd, 1H, J ) 4.3, 3.0 Hz, 1′-H),
5.10 (ps t, 1H, J ) 3.41, 3.35 Hz, 4′-H), 4.18 (s, 1H, 2′-H), 4.17
(d, 1H, J ) 1.7 Hz, 2′-H), 3.95 (dd, 1H, J ) 11.8, 3.2 Hz, 5′-H),
(MeOH) λmax 249.5 (ꢀ 15600), 291.0 nm (ꢀ 11700) (pH 7), 248.5
(ꢀ 16300), 291.5 nm (ꢀ 11800) (pH 2), 253.5 (ꢀ 16500), 284.5
1
nm (sh, ꢀ 9870) (pH 11); H NMR (DMSO-d6) δ 11.6 (s, 1H,
NH), 8.16 (s, 1H, 6-H), 7.21 (d, 1H, J ) 13.6 Hz, vinylic Ha),
6.82 (d, 1H, J ) 13.6 Hz, vinylic Hb), 6.21 (d, 1H, J ) 4.9 Hz,
1′-H), 5.32 (t, 1H, 5′-OH), 4.94 (s, 1H, 4′-H), 4.31 (d, 1H, J )
10.0 Hz, 2′-Ha), 4.08 (dd, 1H, J ) 9.9, 5.5 Hz, 2′-Hb), 3.72-
3.66 (m, 2H, 5′-H). Anal. (C10H11BrN2O5) C, H, Br, N.
t
3.89 (dd, 1H, J ) 11.7, 3.6 Hz, 5′-H), 1.09 (s, 9H, Bu). Anal.
(C26H29IN2O5Si) C, H, N. 28 (28%): mp 146-147 °C; [R]27
D
+2.3° (c 0.42, CHCl3); UV (MeOH) λmax 254.0, 297.5 nm; 1H
NMR (CDCl3) δ 8.15 (s, NH), 7.69-7.40 (m, 11H, Ph-H, 6-H),
7.28 (d, 1H, J ) 14.6 Hz, vinylic Ha), 7.02 (d, 1H, J ) 14.6
Hz, vinylic Hb), 6.27 (dd, 1H, J ) 5.1, 1.9 Hz, 1′-H), 5.55 (ps
t, 1H, J ) 3.04, 2.99 Hz, 4′-H), 4.40 (dd, 1H, J ) 9.7, 5.2 Hz,
2′-Ha), 4.04 (dd, 1H, J ) 9.7, 1.9 Hz, 2′-Hb), 3.76-3.71 (m,
(2R,5S)-(E)-5-(2-Br om ovin yl)-1-[2-(h yd r oxym eth yl)-1,3-
d ioxola n -5-yl]u r a cil (21). A solution of 19 (140 mg, 0.251
mmol) in CH3CN (10 mL) was treated with tetra-n-butylam-
monium fluoride (1 M solution in THF) (0.3 mL, 0.3 mmol) at
room temperature for 1 h. After concentration of the mixture,
the residue was purified by silica gel column chromatography
(CHCl3:MeOH, 20:1) to give 21 (72 mg, 90%) as a white solid:
t
2H, 5′-H), 1.07 (s, 9H, Bu). Anal. (C26H29BrN2O5Si) C, H, N.
(2S,5S)-(E)-5-(2-Ch lor ovin yl)-1-[2-(h yd r oxym eth yl)-1,3-
d ioxola n -5-yl]u r a cil (29): mp 193-194 °C; [R]28 -4.0° (c
D
mp 75-78 °C; [R]28 -2.8° (c 0.40, MeOH); UV (MeOH) λmax
D
0.37, MeOH); UV (MeOH) λmax 246.5 (ꢀ 17800), 291.0 nm (ꢀ
12500) (pH 7), 246.0 (ꢀ 18400), 290.5 nm (ꢀ 12500) (pH 2), 250.5
250.0 (ꢀ 13900), 292.0 nm (ꢀ 10600) (pH 7), 249.5 (ꢀ 14400),
291.5 nm (ꢀ 10800) (pH 2), 254.0 (ꢀ 14100), 284.0 nm (sh, ꢀ
1
(ꢀ 18100), 284.5 nm (sh, ꢀ 10100) (pH 11); H NMR (DMSO-
1
9090) (pH 11); H NMR (DMSO-d6) δ 11.7 (s, 1H, NH), 7.82
d6) δ 11.6 (s, 1H, NH), 8.14 (s, 1H, 6-H), 7.14 (d, 1H, J ) 13.3
Hz, vinylic Ha), 6.56 (d, 1H, J ) 13.3 Hz, vinylic Hb), 6.21 (d,
1H, J ) 4.6 Hz, 1′-H), 5.32 (t, 1H, 5′-OH), 4.94 (ps t, 1H, J )
2.1, 2.0 Hz, 4′-H), 4.31 (d, 1H, J ) 9.9 Hz, 2′-Ha), 4.08 (dd,
1H, J ) 9.9, 5.6 Hz, 2′-Hb), 3.74-3.65 (m, 2H, 5′-H). Anal.
(C10H11ClN2O5) C, H, N.
(s, 1H, 6-H), 7.31 (d, 1H, J ) 13.5 Hz, vinylic Ha), 6.99 (d, 1H,
J ) 13.5 Hz, vinylic Hb), 6.14 (dd, 1H, J ) 5.1, 2.9 Hz, 1′-H),
5.54 (ps t, 1H, J ) 3.7, 3.6 Hz, 4′-H), 5.04 (t, 1H, 5′-OH), 4.29
(dd, 1H, J ) 9.5, 5.4 Hz, 2′-Ha), 4.08 (dd, 1H, J ) 9.5, 2.8 Hz,
2′-Hb), 3.44-3.41 (m, 2H, 5′-H). Anal. (C10H11BrN2O5) C, H,
Br, N.
(2S,5R)-(E)-5-(2-Ch lor ovin yl)-1-[2-(h yd r oxym eth yl)-1,3-
The synthetic methods of the following compounds 29-34
were similar to the synthesis of compounds 21 and 22.
d ioxola n -5-yl]u r a cil (30): mp 101-102 °C; [R]28 +2.4° (c
D
0.28, MeOH); UV (MeOH) λmax 247.0 (ꢀ 13300), 291.5 nm (ꢀ
9550) (pH 7), 246.5 (ꢀ 13700), 291.5 nm (ꢀ 9670) (pH 2), 252.0
(ꢀ 13900), 283.0 nm (sh, ꢀ 8170) (pH 11); 1H NMR (DMSO-d6)
δ 11.7 (s, 1H, NH), 7.79 (s, 1H, 6-H), 7.24 (d, 1H, J ) 13.2 Hz,
vinylic Ha), 6.73 (d, 1H, J ) 13.2 Hz, vinylic Hb), 6.15 (dd,
1H, J ) 5.4, 2.9 Hz, 1′-H), 5.54 (ps t, 1H, J ) 3.7, 3.6 Hz, 4′-
H), 5.05 (t, 1H, 5′-OH), 4.29 (dd, 1H, J ) 9.5, 5.5 Hz, 2′-Ha),
4.08 (dd, 1H, J ) 9.5, 3.0 Hz, 2′-Hb), 3.49-3.43 (m, 2H, 5′-H).
Anal. (C10H11ClN2O5) C, H, N.
(2S,5S)-1-[2-[[(ter t-Bu tyld ip h en ylsilyl)oxy]m eth yl]-1,3-
dioxolan -5-yl]-(E)-5-(2-ch lor ovin yl)u r acil (23) an d (2S,5R)-
1-[2-[[(ter t-Bu tyld ip h en ylsilyl)oxy]m eth yl]-1,3-d ioxola n -
5-yl]-(E)-5-(2-ch lor ovin yl)u r a cil (24). 23 (50%): white foam;
1
[R]28 -12.2° (c 0.29, CHCl3); UV (MeOH) λmax 292.0 nm; H
D
NMR (CDCl3) δ 8.2 (s, NH), 7.70-7.35 (m, 11H, Ph-H, 6-H),
7.20 (d, 1H, J ) 13.3 Hz, vinylic Ha), 6.30 (dd, 1H, J ) 4.5,
2.8 Hz, 1′-H), 6.00 (d, 1H, vinylic Hb, J ) 13.3 Hz), 5.10 (ps t,
1H, J ) 3.41, 3.36 Hz, 4′-H), 4.20-4.15 (m, 2H, 2′-H), 3.95
(dd, 1H, J ) 11.7, 3.3 Hz, 5′-Ha), 3.90 (dd, 1H, J ) 11.8, 3.5
(2S,5S)-(E)-5-(2-Br om ovin yl)-1-[2-(h yd r oxym eth yl)-1,3-
d ioxola n -5-yl]u r a cil (31): mp 176-178 °C; [R]27 -6.5° (c
t
D
Hz, 5′-Hb), 1.08 (s, 9H, Bu). Anal. (C26H29ClN2O5Si) C, H, N.
24 (26%): mp 62-63 °C; [R]27 +3.9° (c 0.31, CHCl3); UV
0.27, MeOH); UV (MeOH) λmax 249.0 (ꢀ 17000), 291.0 nm (ꢀ
13000) (pH 7), 249.0 (ꢀ 17200), 290.5 nm (ꢀ 12300) (pH 2), 253.0
D
(MeOH) λmax 292.0 nm; 1H NMR (CDCl3) δ 8.18 (s, NH), 7.69-
7.27 (m, 11H, Ph-H, 6-H), 7.32 (d, 1H, J ) 13.3 Hz, vinylic
Ha), 6.40 (d, 1H, J ) 13.3 Hz, vinylic Hb), 6.28 (dd, 1H, J )
5.2, 2.0 Hz, 1′-H), 5.55 (ps t, 1H, J ) 3.1, 2.9 Hz, 4′-H), 4.41
(dd, 1H, J ) 9.7, 5.3 Hz, 2′-Ha), 4.05 (dd, 1H, J ) 9.7, 2.1 Hz,
1
(ꢀ 16700), 285.0 nm (sh, ꢀ 10200) (pH 11); H NMR (DMSO-
d6) δ 11.6 (s, 1H, NH), 8.15 (s, 1H, 6-H), 7.21 (d, 1H, J ) 13.6
Hz, vinylic Ha), 6.82 (d, 1H, J ) 13.6 Hz, vinylic Hb), 6.21 (d,
1H, J ) 4.9 Hz, 1′-H), 5.32 (t, 1H, 5′-OH), 4.94 (s, 1H, 4′-H),

SAR of (E)-5-(2-Bromovinyl)uracil
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 13 2545
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infections. J . Infect. Dis. 1992, 166 (Suppl. 1), 51-57.
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4.31 (d, 1H, J ) 10.0 Hz, 2′-Ha), 4.08 (dd, 1H, J ) 9.9, 5.5 Hz,
2′-Hb), 3.72-3.66 (m, 2H, 5′-H). Anal. (C10H11BrN2O5) C, H,
Br, N.
(2S,5R)-(E)-5-(2-Br om ovin yl)-1-[2-(h yd r oxym eth yl)-1,3-
d ioxola n -5-yl]u r a cil (32): mp 76-78 °C; [R]26D +2.5° (c 0.20,
MeOH); UV (MeOH) λmax 250.5 (ꢀ 16000), 290.0 nm (ꢀ 12400)
(pH 7), 250.0 (ꢀ 16500), 290.0 nm (ꢀ 12200) (pH 2), 254.5 (ꢀ
1
16800) (pH 11); H NMR (DMSO-d6) δ 11.7 (s, 1H, NH), 7.82
(s, 1H, 6-H), 7.31 (d, 1H, J ) 13.5 Hz, vinylic Ha), 6.99 (d, 1H,
J ) 13.5 Hz, vinylic Hb), 6.14 (dd, 1H, J ) 5.1, 2.9 Hz, 1′-H),
5.54 (ps t, 1H, J ) 3.7, 3.6 Hz, 4′-H), 5.04 (t, 1H, 5′-OH), 4.29
(dd, 1H, J ) 9.5, 5.4 Hz, 2′-Ha), 4.08 (dd, 1H, J ) 9.5, 2.8 Hz,
2′-Hb), 3.44-3.41 (m, 2H, 5′-H). Anal. (C10H11BrN2O5) C, H,
Br, N.
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pharmacological properties and therapeutic efficacy in herpes
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(2S,5S)-1-[2-(Hyd r oxym eth yl)-1,3-d ioxola n -5-yl]-(E)-5-
(2-iod ovin yl)u r a cil (33: mp 162 °C dec; [R]28 -6.1° (c 0.52,
D
Faulds, D. Valaciclovir:
a review of its antiviral activity,
MeOH); UV (MeOH) λmax 253.0 (ꢀ 16000), 296.5 nm (ꢀ 11900)
(pH 1), 255.0 (ꢀ 20700) (pH 2), 255.5 (ꢀ 16600) (pH 11); 1H NMR
(DMSO-d6) δ 11.6 (s, 1H, NH), 8.15 (s, 1H, 6-H), 7.17 (d, 1H,
J ) 14.7 Hz, vinylic Ha), 7.10 (d, 1H, J ) 14.7 Hz, vinylic Hb),
6.21 (d, 1H, J ) 5.4 Hz, 1′-H), 5.33 (t, 1H, 5′-OH), 4.93 (d, 1H,
J ) 1.9 Hz, 4′-H), 4.31 (d, 1H, J ) 9.9 Hz, 2′-Ha), 4.08 (dd,
pharmacokinetic properties and therapeutic efficacy in herpes
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J .; De Clercq, E. Phospholysis of (E)-5-(2-bromovinyl)-2′-deoxy-
uridine (BVDU) and other 5-substituted-2′-deoxyuridines by
purified human thymidine phosphorylase and intact blood-
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antiviral activity of some 4′-thio-2′-deoxy nucleoside analogues.
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deoxycytidines. J . Med. Chem. 1985, 28, 550-555.
1H, J ) 9.8, 5.5 Hz, 2′-Hb), 3.69 (m, 2H, 5′-H). Anal. (C10H11
IN2O5) C, H, N.
-
(2S,5R)-1-[2-(Hyd r oxym eth yl)-1,3-d ioxola n -5-yl]-(E)-5-
(2-iod ovin yl)u r a cil (34): mp 60 °C dec; [R]28 +2.3° (c 0.53,
D
MeOH); UV (MeOH) λmax 255.5 (ꢀ 15400), 297.0 nm (ꢀ 12400)
(pH 7), 256.5 (ꢀ 22400) (pH 2), 257.5 (ꢀ 16200) (pH 11); 1H NMR
(DMSO-d6) δ 11.6 (s, 1H, NH), 7.80 (s, 1H, 6-H), 7.26 (s,2H,
vinylic H), 6.14 (dd, 1H, J ) 5.3, 2.9 Hz, 1′-H), 5.55 (ps t, 1H,
J ) 3.6, 3.5 Hz, 4′-H), 4.29 (dd, 1H, J ) 9.4, 5.4 Hz, 2′-Ha),
4.08 (dd, 1H, J ) 9.4, 2.9 Hz, 2′-Hb), 3.44-3.43 (m, 2H, 5′-H).
Anal. (C10H11IN2O5‚0.3MeOH) C, H, N.
Biologica l Eva lu a tion . 1. Cells a n d Vir u s. Human
embryonic lung cells (HEL 299) were grown and maintained
in Eagle’s minimal essential medium supplemented with 10%
fetal bovine serum. Vero cells and EBV-producing H-1 cells
were used for HSV-1, HSV-2, and EBV growth. These cells
were maintained in RPMI 1640 plus 10% FBS. VZV (Ellen
strain), HSV-1 (KOS strain), HSV-2 (333), and EBV were used
in the biological assays.
2. An tivir a l Assa y. Assays used for biological evaluation
of L-BVDU and its analogues were described in detail
previously.38-41 For HSV-1 and HSV-2, plaque reduction assay
was performed in Vero cells. For VZV and EBV, the inhibition
of the viral growth was tested by measuring viral DNA
synthesis as described previously.
3. Mitoch on d r ia l DNA (MtDNA) Con ten t. The mito-
chondrial DNA was analyzed as described previously.39 Briefly,
human T-lymphoid CEM cells were incubated with the drug
at various concentrations for 4 continuous days. The cells were
then replaced with fresh medium and drugs at the same
concentration on days 4 and 6. On day 8, the cells were
harvested and the cellular DNA was extracted by TE buffer
(25 mM Tris, pH 8.0, and 1 mM EDTA) followed by treatment
of RNAse A and protease K. The DNA was then subjected to
“slot-blot”, and the mitochondrial DNA was detected by
MtDNA specific probe.
4. Cytotoxicity. Cytotoxicity was assayed as described
previously.38 Briefly, CEM cells in the logarithmic growth were
treated with the drugs with various dilutions. The cells were
then maintained for three generations and then counted by
Coulter counter. ID50 is defined as the dosage that inhibited
50% cell growth compared with untreated control.
(15) Spadari, S.; Ciarrocchi, G.; Focher, F.; Verri, A.; Maga, G.;
Arcamone, F.; Iafrate, E.; Manzini, S.; Garbesi, A.; Tondelli, L.
5-Iodo-2′-deoxy-L-uridine and (E)-5-(2-bromovinyl)-2′-deoxy-L-
uridine: selective phosphorylation by herpes simplex virus type
1 thymidine kinase, antiherpetic activity, and cytotoxicity stud-
ies. Mol. Pharmacol. 1995, 47, 1231-1238.
(16) 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 Immuno-
deficiency Virus Type I in Human Lymphocytes. Antimicrob.
Agents Chemother. 1992, 36, 672-676.
(17) Schinazi, R. F.; MaMillan, 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 Enantiomers of cis-5-Fluoro-1-[2-(Hydroxymethyl)1,3-Oxa-
thiolan-5-yl]Cytosine. Antimicrob. Agents Chemother. 1992, 36,
2423-2431.
Ack n ow led gm en t. This work was supported by
U.S. Public Health Service Research grants (AI 33655
and AI 32351) from the National Institute of Allergy
and Infectious Diseases.
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