Synthesis and anti-BVDV activity of novel δ-sultones in vitro: Implications for HCV therapies

Article abstract of DOI:10.1016/j.bmcl.2014.03.012

In this study we report the synthesis and activity against bovine viral diarrhea virus (BVDV) of a novel series of bicycle δ-sultones containing γ-lactones. BVDV is responsible for major losses in cattle. Some of the synthesized δ-sultones showed pronounced anti-BVDV activity with EC ₅₀ values of 0.12-1.0 μM and no significant cytotoxicity. Among them, the ortho bromosubstituted derivative 4f (EC₅₀ = 0.12 μM) showed better antiviral activity than other derivatives and was 10 fold more that of than positive control ribavirin (EC₅₀ = 1.3 μM). BVDV is also considered to be a valuable surrogate for the hepatitis C virus (HCV) in antiviral drug studies. The above results provided a novel candidate for the development of anti-HCV agents.

Full text of DOI:10.1016/j.bmcl.2014.03.012

Accepted Manuscript
Synthesis and Anti-BVDV Activity of Novel δ-Sultones in Vitro: Implications
for HCV Therapies
Hai-Wei Xu, Ling-Jie Zhao, Huan-Fei Liu, Dan Zhao, Jiao Luo, Xiao-Ping Xie,
Wen-Sheng Liu, Jia-Xin Zheng, Gui-Fu Dai, Hong-Min Liu, Long-Hua Liu, Yi-
Bo Liang
PII:
S0960-894X(14)00228-5
DOI:
http://dx.doi.org/10.1016/j.bmcl.2014.03.012
BMCL 21405
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 November 2013
9 February 2014
5 March 2014
Please cite this article as: Xu, H-W., Zhao, L-J., Liu, H-F., Zhao, D., Luo, J., Xie, X-P., Liu, W-S., Zheng, J-X.,
Dai, G-F., Liu, H-M., Liu, L-H., Liang, Y-B., Synthesis and Anti-BVDV Activity of Novel δ-Sultones in Vitro:
Implications for HCV Therapies, Bioorganic & Medicinal Chemistry Letters (2014), doi: http://dx.doi.org/10.1016/
j.bmcl.2014.03.012
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Graphical Abstract
Synthesis and Anti-BVDV Activity of Novel δ-Sultones in
Leave this area blank for abstract info.
Vitro: Implications for HCV Therapies
Hai-Wei Xua*, Ling-Jie Zhaoa, Huan-Fei Liub, Dan Zhaob, Jiao Luoa, Xiao-Ping Xiea,
Wen-Sheng Liua, Jia-Xin Zhenga, Gui-Fu Daib*, Hong-Min Liua*, Long-Hua Liuc，Yi-
Bo Lianga
R
R
O
O
S
NaOH, DMF, 80-85
OMs
O
O
O
O
O
O
4
7
Aanti-BVDV : EC50 0.12~1.0 μM
1

Bioorganic & Medicinal Chemistry Letters
jour nal homepage: ww w.elsevier. com
Synthesis and Anti-BVDV Activity of Novel δ-Sultones in Vitro:
Implications for HCV Therapies
Hai-Wei Xua*, Ling-Jie Zhaoa, Huan-Fei Liub, Dan Zhaob, Jiao Luoa, Xiao-Ping Xiea, Wen-Sheng Liua,
﹡
Jia-Xin Zhenga, Gui-Fu Daib*, Hong-Min Liua , Long-Hua Liuc，Yi-Bo Lianga
aNew Drug Research & Development Center, School of Pharmaceutical Sciences, Zhengzhou University, No.100, KeXue DaDao, Zheng zhou, Henan Province,
450001, P.R. China
bSchool of life Sciences, Zhengzhou University, No.100, KeXue DaDao, Zheng zhou, Henan Province, 450001, P.R. China
cCollege of Chemistry and Molecular Engineering, Zhengzhou University, No.100, KeXue DaDao, Zheng zhou, Henan Province, 450001, P.R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
In this study we report the synthesis and activity against bovine viral diarrhea virus (BVDV)
of a novel series of bicycle δ-sultones containing γ-lactones. BVDV is responsible for major
losses in cattle. Some of the synthesized δ-sultones showed pronounced anti-BVDV activity
with EC50 values of 0.12 ~ 1.0 μM and no significant cytotoxicity. Among them, the ortho
bromosubstituted derivative 4f (EC50 = 0.12 μM) showed better antiviral activity than other
derivatives and was 10 fold more that of than positive control ribavirin (EC50 = 1.3 μM). BVDV
is also considered to be a valuable surrogate for the hepatitis C virus (HCV) in antiviral drug
studies. The above results provided a novel candidate for the development of anti-HCV agents.
Keywords:
Sultone
Lactone
Synthesis
CSIC reaction
Anti-BVDV;
Anti-HCV
Figure 1 Representative non-nucleoside inhibitor of HCV.
Sultones are the internal esters of hydroxy sulfonic acids
and are, as such, sulfur analogues of lactones. Sultones are also
demanded scaffold in medicinal chemistry research. The
biological activities of sultones are mainly concerned with skin
sensitization and toxicological1. Synthesis and bioactivities of
them continue to be of interest2. Recently a new family of non-
nucleoside anti - HCMV and anti - VZV agents, 4 - and 5-
substituted -5H- 1, 2 - oxathiole - 2, 2 - dioxide derivatives (1)
were reported (Figure 1)3. Lactone derivatives such as
parthenolide (2), dehydrocostus lactone (3)4 have been reported
as a new family of non-nucleoside anti - HCV agents5.
The hepatitis C virus (HCV) belongs to the Flaviviridae
family. It is the most common cause of chronic hepatitis
throughout the world and is the major risk factor involved in the
development of liver cirrhosis and hepatocellular carcinoma.
Nearly 3% of the world’s population is infected with hepatitis C
virus (HCV), and more than 80% of them will progress into
chronic hepatitis6. An optimal therapy for HCV consists of
weekly subcutaneous injections of pegylated interferon-R (PEG-
IFN) in combination with twice daily oral doses of ribavirin
(RBV)7. The inadequacies of this treatment regimen are evident
in the low response rates for genotype 1-infected patients and the
significant incidence of side effects. Highly effective and
selective inhibitors of HCV replication are urgently needed.2, 3, 6b-
R
O
d, 8,
O
O
O
.
S
O
O
Like HCV, bovine viral diarrhea virus (BVDV) also belongs
to the Flaviviridae family. It is the prototype of the Pestivirus
O
2
1 a R=H; b R= Cl; c R= CF3
genus of the Flaviviridae family. BVDV causes a range of
clinical manifestations including early embryonic death, abortion,
teratogenesis, respiratory problems, chronic wasting syndrome,
and immune system disorder which resulted in a mortality rate of
R
O
H
O
S
H
O
O
O
17-32%9 in cattle throughout the world. BVDV is considered to
be a valuable surrogate virus model for identifying and
characterizing antiviral agents for use against HCV.9 ,12
O
O
3
4
———
﹡ Tel./ Fax: 86-371-67781739, E-mail: liuhm@zzu.edu.cn; Tel./ Fax:86-371-67767604, E-mail: daiguifu@zzu.edu.cn;
2

Based on the important roles of sultone1 and lactone10，and
the high interest of developing novel anti - HCV chemical
candidates, the synthesis and the antiviral activity of 4- and 5 -
substituted - 1, 2 - oxathin - 2, 2 – dioxide derivative (4) were
investigated.
After obtaining key intermediates 7a, we aimed to investigate
whether the intramolecular nucleophilic substitution reaction
could take place in the polar aprotic solvents in the presence of
base. Initially, the reaction was researched in DMF in the
presence of various bases including pyridine, triethylanmine,
DBU, Na2CO3, NaOH. However, the methyl removal reaction of
4-methoxyl in 7a was observed in the presence of organic bases
and Na2CO3. In surprise, an unknown compound was discovered
in the presence of NaOH. Is it our target compound? By analysis
of NMR, IR, MS, its structure was identified to be 3 - (3, 4 -
difluoro) - phrnyl - 7a - methyl - 7, 7a - dihydrofuro [3, 2 -d] [1,
2] oxathin -5, 5 - dioxide - 2(4H) - one (4a). The structure of 4a
was finally confirmed by single crystal X - ray diffraction
analysis (Crystallographic data for 4a have been deposited with
the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 953265.) ( Figure 2).
The Carbanion-mediated Sulfonate (Sulfonamide) Intramole-
cular Cyclization reaction (CSIC reaction) is an intramolecular
cyclization brought about by the treatment of either cyanohydrins
or aminonitrile alkylsulfonates to synthesize sultone with non-
nucleophilic bases such as DBU or NaH11. Ketones and
aldehydes as sources of the cyanohydrins and aminonitrile
intermediates required for the study of this cyclization have been
looked into. In our groups, the basic hydrolysis of 3- (3, 4-
difluoro) - 4 - methoxy butenolide (5) was found to take place
smoothly, leading to 3 - (3, 4 - difluoro) - 4 - hydroxyl butenolide
(6) (Scheme 1). This let us realize that the alkylsulfonate 7 may
be as the sources of CSIC reaction to prepare the bicycle δ-
sultones containing γ-lactones (4).
F
F
F
F
Na2CO3
O
OH
Methanol,H2O
O
O
O
O
6
5
R
Figure 2 Structure of compound 4a
R
With the above similar conditions, we extended substrates to
a series of methane sulfonate derivatives 7b - 7k with electron-
withdrawing or -donating groups, which were prepared and
submitted to the reaction system. In all cases, complete
conversion of 7 was observed. A significant difference in the
isolated yields of the title compounds 4a - 4k (32~70 % in
respect to 13a), most probable, was due to crystallization from
mixture of DMF and water (Table 1). All bicycle δ - sultone
containing γ - lactone derivatives 4 were fully characterized by
NMR, MS, IR Spectra.
O
O
S
O
O
O
S O
O
O
O
O
O
4
7
Scheme 1 Synthetic design of bicycleδ-Sultone
O
O
F
O
F
F
OH
Br
O
a
+
O
O
O
F
F
9
10a
8a
F
F
F
Table 2 Anti-BVDV activity of δ-sultone derivatives 4a-4k
O
d
Compounds
R
m,p-diF
o-F
m-F
p-F
EC50 (μM)
>1.2
0.5
1.0
>1.2
0.5
0.12
1.0
>1.2
>1.2
>1.2
0.5
CC50 (μM)
Noa
>20
>20
--- b
>20
>20
No.
---
b
c
OH
4a
4b
4c
4d
4e
4f
4g
4h
4i
O
O
O
O
11a
12a
F
F
F
F
F
F
H
O
S
O
O
O
f
e
o-Br
p-Br
p-CH3O
p-CF3
p-CH3
p-Cl
_
O
OMs
O
OH
O
O
O
O
O
4a
7a
13a
No
No
No
5
4j
4k
Scheme 2 Reagents and conditions: (a) (Et)3N, THF, reflux; (b) t-BuOK,
DMF, 0 ℃, 96%( a, b two steps) ; (c) Me2SO4/K2CO3, CH3COCH3, 92%; (d)
(CH2O)n, CH3ONa, CH3OH, reflux, 91%; (e) MsCl, (Et)3N,CH2Cl2, 0℃; (f)
NaOH, DMF, 85 ℃, 52%( e, f two steps).
Ribavirin
1.3
a No cytotoxicity was observed in 20 μM.
b the cytotoxicity wasn`t tested.
In order to prepare the key intermediate 7, a series of
Compounds 4a - 4k were evaluated for their antiviral
activity against BVDV (a pestivirus, bovine viral diarrhea virus)
in MDBK (Madin-Darby bovine kidney) cells and for their
cytotoxicity by MTT. As shown in Table 2, compounds 4b, 4c,
4e, 4f, 4g and 4k showed pronounced antiviral activity with an
EC50 value of 0.12~1.0 μM and no significant cytotoxicity. Their
antiviral activities were better than that of positive control
ribavirin (Table 2). Preliminary SAR showed that single halogen
substitution at the phenyl group retained or enhanced the antiviral
activity. Interestingly, the ortho fluoro derivative 4b (EC50 = 0.5
μM) showed better antiviral activity than meta fluoro derivative
4c (EC50 = 1.0 μM) followed by para fluoro derivative 4d (EC50 >
1.2 μM), which meaned that the ortho substitution benefited the
antiviral activity. The ortho bromosubstituted derivative 4f with
EC50 of 0.12 μM showed better antiviral activity than other
derivatives and was 10 fold more that of than positive control
ribavirin (EC50 = 1.3 μM), which was another proof of the above
reactions were carried out from phenyl acetic acid. The
preparation of the 3 - (3, 4 - difluoro - ) - phenyl - 7a - methyl - 7,
7a - dihydrofuran [3, 2-d] [1, 2] oxathin - 5, 5 - dioxide -2(4H) -
one (4a) from 3 - methoxy - 2 - methyl - 5 - oxo - 2, 5 - dihydro
furan - 2 - yl) methyl methanesulfonate (7a) was outlined as a
representative example in Scheme 2. Firstly, the 3, 4 -
difluorophenyl acetic acid (8a) was treated with ethyl 2 -
bromopropionate to afford the acyclic ester (10a), which then
underwent an intramolecular cyclization to afford the 3 - (3, 4 -
difluorophenyl) - 4 - hydroxy - 5-methylfuran - 2(5H) - one
(11a). Compound 11a was then converted to its 4 - methoxy
derivative 12a via a methylation reaction. Compound 12a was
used to prepare 3 - (3, 4 - difluorophenyl) - 5 - (hydroxymethyl) -
4-methoxy furan - 2(5H) - one (13a) through aldol condensation
with paraformaldehyde. The key intermediate 7a could be
obtained by methyl sulfonylation reaction of compound 13a.
3

conjecture. Other substitution derivatives (4a, 4h, 4i, 4j with
EC50 > 1.2 μM) led to a marked decrease in antiviral activity.
.
Table 1 NaOH catalyzed cyclization of mesylsalicyl derivatives
R
R
O
O
S
NaOH, DMF, 80-85
OMs
O
O
O
O
O
O
4
7
Entry
1
Substrate
R
Product
Yieldsa (%)
56
Mp (℃)
7a
m,p-diF
o-F
4a
4b
130-131
2
3
7b
7c
60
59
165-167
179-180
m-F
4c
4
5
6
7
7d
7e
7f
p-F
H
4d
4e
4f
62
48
39
38
182-183
215-216
163-164
226-227
o-Br
p-Br
7g
4g
8
9
7h
7i
p-CH3O
p-CF3
4h
4i
70
59
186-188
196-197
10
11
7j
p-CH3
p-Cl
4j
67
32
186-188
218-219
7k
4k
aIsolated yields after crystallization from DMF and Water. Yields are given with respect to 13.
BVDV is often used as a model for HCV infection. Both
viruses are flaviviruses and have similar genomic structures and
likely share similar replication strategies. Antiviral agents that
target host enzymes important for BVDV replication would
likely inhibit replication of HCV9, 12. Thus the novel bicycle δ-
sultones containing γ-lactones may serve as novel antiviral agents
against HCV infection.
them showed excellent antirival activity against BVDV with no
significant cytotoxicity. They may be useful as therapy for the
treatment of HCV infection. Design and synthesis of much more
new δ-Sultone analogous are currently in progress. After the
synthesis of them was completed, the anti-HCV activity, NS5B
inhibitory activity and QSAR will be researched and reported in a
successive paper.
In summary, series of novel bicycle δ-sultones containing γ-
lactones can be prepared using a new CSIC reaction. Most of
Acknowledgments
4

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This work was supported by National Natural Science
Foundation of China (Project No. 81172937).
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Experiment details for synthetic procedures and associated
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5

Graphical Abstract
Synthesis and Anti-BVDV Activity of Novel δ-Sultones in
Leave this area blank for abstract info.
Vitro: Implications for HCV Therapies
Hai-Wei Xua*, Ling-Jie Zhaoa, Huan-Fei Liub, Dan Zhaob, Jiao Luoa, Xiao-Ping Xiea,
Wen-Sheng Liua, Jia-Xin Zhenga, Gui-Fu Daib*, Hong-Min Liua*, Long-Hua Liuc，Yi-
Bo Lianga
R
R
O
O
S
NaOH, DMF, 80-85
OMs
O
O
O
O
O
O
4
7
Aanti-BVDV : EC50 0.12~1.0 μM
6