Synthesis, biological evaluation and structure-activity relationships of glycyrrhetinic acid derivatives as novel anti-hepatitis B virus agents

Article abstract of DOI:10.1016/j.bmcl.2012.03.081

Fifty-seven derivatives of glycyrrhetinic acid (GA) were synthesized, and their anti-hepatitis B virus (HBV) activity was evaluated in HepG 2.2.15 cells. Among them, sixteen compounds showed greater anti-HBV activity than GA, especially, compounds 29, 32, 35, 41 exhibited significantly inhibitory activities against HBV DNA replication with IC₅₀ values of 5.71, 5.36, 8.90 and 9.08 μM, respectively. The structure-activity relationships (SARs) of GA derivatives were discussed for exploring novel anti-HBV agents.

Full text of DOI:10.1016/j.bmcl.2012.03.081

Bioorganic & Medicinal Chemistry Letters 22 (2012) 3473–3479
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, biological evaluation and structure–activity relationships of
glycyrrhetinic acid derivatives as novel anti-hepatitis B virus agents
Li-Jun Wang a,b, Chang-An Geng a, Yun-Bao Ma a, Xiao-Yan Huang a, Jie Luo a, Hao Chen a,b
,
Xue-Mei Zhang a, Ji-Jun Chen a,
⇑
a State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, PR China
b Graduate University of the Chinese Academy of Sciences, Beijing 100049, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Fifty-seven derivatives of glycyrrhetinic acid (GA) were synthesized, and their anti-hepatitis B virus
(HBV) activity was evaluated in HepG 2.2.15 cells. Among them, sixteen compounds showed greater
anti-HBV activity than GA, especially, compounds 29, 32, 35, 41 exhibited significantly inhibitory activ-
ities against HBV DNA replication with IC50 values of 5.71, 5.36, 8.90 and 9.08 lM, respectively. The struc-
ture–activity relationships (SARs) of GA derivatives were discussed for exploring novel anti-HBV agents.
Received 24 February 2012
Revised 21 March 2012
Accepted 22 March 2012
Available online 28 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Glycyrrhetinic acid derivatives
Anti-HBV activity
Structure–activity relationships
Hepatitis B virus (HBV) infection can cause liver disease, such as
liver cancer or cirrhosis, which is a significant health problem
throughout the world.1 Currently, therapies for HBV infection
including immuno-modulator, interferons (interferon-alpha and
pegylated interferon) and nucleoside analogues (lamivudine
(3TC), adefovir dipivoxil (ADV), entecavir (ETV), telbivudine (LdT)
and tenofovir-DF (TDF) are less than satisfactory.2 For example,
interferons have limited effectiveness and serious side effects
(influenza-like symptoms, fatigue, myalgia, nausea, headache,
etc.); nucleoside analogues result in drug resistance and high
recurrence for the single target on the viral DNA polymerase.3,4
Thus, researchers are continuing to search for new anti-HBV agents
with novel antiviral targets and mechanisms.
Natural products and their derivatives by simple functional-
group transformations offer many opportunities for finding novel
anti-HBV inhibitors.5–14 Licorice root (Glycyrrhizae glabra) has long
been used widely as a traditional medicine mainly for the treatment
of peptic ulcer, hepatitis C, pulmonary and skin diseases, and
several other useful pharmacological properties (antiinflammatory,
antiviral, antimicrobial, antioxidative, anticancer activities, etc.).15
Glycyrrhizin (Fig. 1) and its metabolite and pharmacologically
active form glycyrrhetinic acid (GA, Fig. 1) are the main effective
constituents of Licorice root.16 Many derivatives of chemical modi-
fied GA were reported, which mainly focused on enhancing the
antiinflammatory and antitumor activity.17–24 Although GA had
been used for the treatment of chronic hepatitis B,25–29 no
investigation of GA derivatives had been conducted for their
anti-HBV activity. Moreover, GA has been used as a ligand for liver
targeting, and GA-modified carriers were shown to be more
efficient for liver- or hepatocyte-targeted delivery.30–32 Therefore,
we synthesized a series of GA derivatives in order to develop novel
anti-HBV agents. Herein, we report the synthesis of several GA
derivatives modified on rings A, C, and E at positions 3, 11, 12, 13
and 30, respectively. Structure–activity relationships (SARs) of
these GA analogs with anti-HBV activity are also discussed in this
letter.
The syntheses of GA derivatives were summarized in Scheme 1.
GA was treated with anhydride and a catalytic amount of 4-dimeth-
ylaminopyridine (DMAP) in dry pyridine to afford compounds 1–3.
Derivative 4 was synthesized by the reaction of 3,4,5-trimethoxy-
cinnamic acid with GA in the presence ofN0,N0-dicyclohexylcarbodi-
imide (DCC) and DMAP.8 Oxidation derivative 5 was successfully
obtained by treatment of GA with pyridinium chlorochromate
(PCC) in CH2Cl2.33 Anhydrous K2CO3 was added to a solution of
GA and alkyl- or benzyl halide in dry DMF to yield the derivatives
6–41.34 11-Deoxo-GA (42) was prepared by treatment of GA in gla-
cial acetic acid with catalytic reduction using PtO2 under the H2
atmosphere.35 In order to further evaluation the function of hydro-
xy at C-3 and carboxyl at C-30 for biological activity, the C-30 esters
(43–46) and C-3, 30 diesters (47–56) of compound 42 were ob-
tained by the method described above for compounds 6–41 and
4, respectively. Epoxidation of compound 42 with m-chloroperoxy-
benzoic acid (m-CPBA) in CH2Cl2 at room temperature gave deriva-
tive 57.14 All of the synthesized derivatives were purified by column
chromatography and their structures were characterized by
⇑
Corresponding author. Tel.: +86 871 5223265; fax: +86 871 5227197.
E-mail address: chenjj@mail.kib.ac.cn (J.-J. Chen).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.03.081

3474
L.-J. Wang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3473–3479
COOH
COOH
30
H
H
E
12
O
O
13
C
11
D
HOOC
HO
H
O
A
H
B
O
3
HO
HO
H
H
HOOC
HO
O
O
HO
Glycyrrhetinic acid (GA)
Glycyrrhizin
OH
Figure 1. Chemical structure of glycyrrhizin and glycyrrhetinic acid (GA).
COOH
COOH
COOH
H
H
H
O
H
O
H
O
H
H
H
O
RO
HO
H
1-4
57
5
COOR
a or b
O
f
COOH
COOH
c
H
H
H
O
e
d
H
H
H
HO
HO
HO
H
H
H
42
GA
6-41
COOR
d
COOR
b
H
H
H
H
R1O
HO
H
H
47-56
43-46
Scheme 1. Synthesis of compounds 1–57. Reagents and conditions: (a) (RCO)2O, DMAP, anhydrous pyridine, reflux; (b) DMAP, DCC, carboxylic acid, CH2Cl2, rt; (c) PCC,
CH2Cl2, rt; (d) RX, K2CO3, DMF, rt; (e) H2, PtO2, CH3COOH; (f) m-CPBA, CH2Cl2, rt.
spectroscopic means (1H, 13C NMR, MS and HRMS), which had a de-
gree of purity >90%, based on the TLC method in three different sol-
vent systems (all compounds exhibited one spot both under UV
radiation and when sprayed with H2SO4) and NMR spectra (the
baseline was smooth without impurity peaks).
GA and its derivatives were tested for their cytotoxicities and
potential anti-HBV activities, namely inhibiting the secretion of
hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg),
and HBV DNA replication in HepG 2.2.15 cells using tenofovir as a
positive control.36 The results of their anti-HBV activity and cyto-
toxicity were listed in Tables 1 and 2.
to GA. Oxidation of the hydroxy at C-3 of GA produced the ketone
5, which exhibited low anti-HBV activity relative to that of GA.
Thus, it could be concluded that the hydroxy group of the C-3
was important for the anti-HBV activity.
Derivatives (6–12) with aliphatic groups lost their anti-HBV
activity, except that compound 10 (the alkyl chain was six carbon
atoms) was observed to possess activity against the HBV DNA rep-
lication with the IC50 value of 66.15 lM. This result indicated that
the chain length could affect the anti-HBV activity of these deriva-
tives. Compounds 13 and 14 with cyclopropyl and cyclobutyl
groups exhibited inhibitory activity on HBV DNA replication.
Otherwise, derivative 15 lost its anti-HBV activity when the (tetra-
hydro-2H-pyran-4-yl) methyl group was incorporated. Most of the
C-30 esters (16–25) with substituted alkyl moiety (bromo, hydro-
xyl, ethoxycarbonyl, etc.) showed potent activity against the HBV
DNA replication. The derivatives (26–37) yielded from the reaction
of GA with various substituted benzylbromide could greatly reduce
the cytotoxicity and enhance the anti-HBV activity. Among them,
compounds 29, 32 and 35 exhibited significant efficacy on sup-
pressing the HBV DNA replication with the IC50 values of
As shown in Table 1, GA showed inhibitory potency to the
secretion of HBsAg and HBV DNA replication with the IC50 value
of 20.86
l
M and 39.28
l
M, but displayed cytotoxicity (CC50
=
=
55.15 M), resulting in relatively low selectivity index (SIHBsAg
l
2.6, SIHBV DNA = 1.4). Tenofovir, the positive control drug, showed
significant inhibitory of HBV DNA replication with the IC50 value
of 0.89 lM (SI > 1973.4) but weak activity of against the secretion
of HBsAg and HBeAg. The cytotoxicity of derivatives (1–4) de-
creased with acylation of the hydroxy at C-3 of GA. Among them,
compounds 2 and 3 exhibited inhibitory to the secretion of HBeAg
and HBV DNA replication, without obvious advantage comparing
5.71
lM, 5.36 lM, 8.90 lM, along with the high SI values of more
than 172.6, 255.9, 149.2, respectively. Interestingly, the positions

L.-J. Wang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3473–3479
3475
Table 1
Structure, anti-HBV activity and cytotoxicity of GA derivatives 1–41a
COOH
COOR
COOH
H
H
H
O
O
H
O
H
H
H
H
O
HO
RO
H
6-41
1-4
5
HBsAgc
M)
20.86
HBeAgd
M)
130.49
DNA replication
b
Compd
R
CC50
(
l
M)
SIf
2.6
IC50
(
l
SIf
IC50
(
lM)
SIf
e
e
e
IC50
(l
g
GA
55.15
—
39.28
1.4
O
O
1
517.87
1001.50
1357.83
369.65
—
—
—
>517.87
49.20
—
121.14
4.3
2.2
2.5
Me
2
3
99.58
2.0
44.40
48.22
O
118.80
37.03
3.2
5.0
O
MeO
MeO
MeO
4
>1164.43
>1164.43
—
232.16
120.10
189.31
>9.7
5
6
467.14
432.54
1.1
>467.14
—
2.5
—
Me
>1744.29
>1744.29
—
—
—
—
>1744.29
—
—
—
—
>443.57
>577.64
>246.58
332.04
7
8
9
>2310.55
>986.33
>2310.55
>986.33
>2310.55
>986.33
—
—
>1754.39
>1754.39
>1754.39
>5.3
10
11
12
13
H3C
H3C
H3C
175.04
>1446.71
>1027.76
695.92
>1696.43
>1446.71
>1027.76
678.43
—
—
—
—
>1696.43
>1446.71
>1027.76
>1102.40
—
—
—
—
66.15
>361.67
>256.94
67.02
2.6
—
4
6
8
—
10.4
14
742.35
810.05
—
>1813.46
—
89.53
8.3
15
16
17
18
O
>1914.57
160.10
101.19
540.86
>1914.57
>1392.04
57.38
—
—
>1914.57
>1392.04
>1179.00
>1717.14
—
—
—
—
>478.64
28.59
—
5.6
7.1
2.7
Br
O
1.8
14.17
835.27
—
198.16
O
H2N
HO
19
55.33
40.00
1.4
>1115.36
—
28.76
1.9
O
20
21
380.11
67.28
1010.98
129.06
—
—
>1924.57
>1254.70
—
—
297.86
47.68
1.3
1.4
HO
HO
5
22
23
157.28
145.46
1.1
>1392.36
>1203.30
—
—
13.23
11.9
>8.7
7
O
>1203.30
>1203.30
—
138.54
O
O
O
C2H5
2
24
53.34
38.22
1.4
56.77
—
30.87
1.7
O
C2H5
4
25
26
54.74
208.96
—
—
>1747.22
>2007.88
—
—
47.16
1.2
O
2007.88
>2007.88
153.08
13.1
F
27
>1313.97
587.62
>2.2
>1313.97
—
19.54
>67.2
(continued on next page)

3476
L.-J. Wang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3473–3479
Table 1 (continued)
b
Compd
R
CC50
(l
M)
HBsAgc
M)
HBeAgd
M)
DNA replication
e
e
e
IC50
(
l
SIf
—
IC50
(l
SIf
—
IC50
(
lM)
SIf
Cl
28
29
>1850.92
>985.68
>1850.92
>985.68
>1850.92
>985.68
529.31
5.71
>3.5
I
—
—
>172.6
—
F
30
>1233.09
>1233.09
—
>1233.09
—
>307.43
F
Br
31
32
>1431.23
>1373.13
>805.06
—
—
>805.06
—
—
18.12
5.36
>79.0
F
F3C
F3C
>1373.13
>1373.13
>255.9
33
34
>1702.45
1025.29
>1702.45
54.40
—
>1702.45
>1212.24
—
—
>425.60
21.24
—
F3C
H3C
O
S
18.8
48.3
O
35
36
>1327.92
>1132.84
606.49
>2.2
—
>1327.92
>1132.84
—
—
8.90
>149.2
>7.1
O2N
>1132.84
159.71
F3CO
CN
37
38
>1537.41
>1698.35
>1537.41
>1698.35
—
—
>1537.41
>1698.35
—
—
195.17
15.30
>7.9
>111.0
N
39
40
320.99
1071.55
926.80
—
>1356.43
>2064.32
—
—
171.30
23.74
1.9
N
N
1985.79
2.1
83.6
N
N
41
37.17
36.34
1.0
>1483.90
1248.76
—
9.08
0.89
4.1
H3C
S
h
TF
>1756.36
1442.23
>1.2
>1.4
>1973.4
a
Values are means of two independent experiments.
CC50 is 50% cytotoxicity concentration in HepG2 2.2.15 cells.
HBsAg: hepatitis B surface antigen.
HBeAg: hepatitis B e antigen.
IC50 is 50% inhibitory concentration.
b
c
d
e
f
SI (selectivity index) = CC50/IC50
.
g
h
No SI can be obtained.
Tenofovir as the positive control.
and number of substitution on the benzyl moiety could influence
the anti-HBV activity of the C-30 derivatives. Compounds 27 with
3-fluorobenyl moiety and 32 with 4-(trifluoromethyl)benzyl moi-
ety showed potent anti-HBV activity, however, compounds 30 with
3,5-difluorobenzyl moiety and 33 with 3,5-di(triflurometh-
yl)benzyl moiety lost the anti-HBV activity completely, which
may be due to the influence of electron-withdrawing substituents
on the aromatic moiety to have a higher activity while much of
these groups have a deleterious effect. The derivatives of GA with
medium-sized hydrocarbon chains or benzyl on C-30 had potent
anti-HBV activity, suggesting that the steric hindrance may also af-
fect their activity. Four derivatives (38–41) were synthesized based
on the fact that many active anti-HBV agents with nitrogen hetero-
cyclic ring possessed effective anti-HBV activity. The IC50 values of
compounds 38, 40, 41 inhibiting HBV DNA replication were
respectively. From the above results, it suggested that the carboxyl
group at C-30 of GA might be a good target for further optimization
by introducing the suitable substitutions.
In an effort to gain more information of the SARs of GA deriva-
tives, we probed additional structural change. As shown in Table 2,
the anti-HBV activity of 11-deoxo-GA (42) was equivalent to GA,
whereas compound 42 had less cytotoxicity than GA, indicating
that elimination of the carbonyl on C-11 of GA is an important fea-
ture in the conferring relatively low cytotoxicity. The importance
of the functional group at the position of C-11 for maintaining
anti-HBV activity was further demonstrated through comparing
the activity of compounds (43 vs 32, 44 vs 31, 45 vs 24, 46 vs
19). Most of derivatives (43–56) lost the cytotoxicity. But unfortu-
nately, their anti-HBV activity also disappeared except that com-
pound 46 maintained suppressant properties on the HBV DNA
15.30
l
M (SI > 111.0), 23.74
l
M (SI = 83.6), 9.08
lM (SI = 4.1),
replication with IC50 value of 64.91 lM. These results further

L.-J. Wang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3473–3479
3477
proved that the functional groups at C-3 and C-30 of GA were the
with IC50 value of 18.37
l
M, whereas an increase in cytotoxicity
factors not only for the anti-HBV activity, but also for generating
cytotoxicity. Compound 57, the epoxide of C-12(13) double bond
of compound 42, enhanced the inhibiting HBV DNA replication
was also noted (CC50 = 35.71 lM) which may be due to an alkylat-
ing effect of the epoxide. The HBsAg and HBeAg, playing the role in
HBV infection, seroconversion was suggested that was an impor-
Table 2
Structure, anti-HBV activity and cytotoxicity of GA derivatives 42–57a
COOR
COOH
COOR
COOH
H
H
H
H
O
H
H
H
H
HO
R1O
HO
HO
H
H
H
H
42
57
43-46
47-56
R1
CC50
(lM)
HBsAgc
HBeAgd
M)
DNA replication
b
Compd
R
SIf
e
e
e
IC50
(
l
M)
SIf
3.3
IC50
(l
SIf
IC50
(
lM)
g
42
43
161.68
48.66
>1374.78
>1499.93
—
47.00
3.4
F3C
Br
>1499.93
>1499.93
—
—
>374.98
—
44
45
46
1152.16
>1526.37
—
>1526.37
>1168.76
>1107.56
—
—
—
>381.60
>292.18
64.91
—
—
F
O
O
C2H5
H2N
2
530.03
471.74
637.80
346.51
—
O
1.4
7.3
O
MeO
MeO
F3C
47
48
>986.85
>898.86
>986.85
>898.86
—
—
>986.85
>898.86
—
—
>246.71
>224.72
—
—
MeO
MeO
O
F3C
F3C
O
49
>1171.87
>1171.87
—
>1171.87
—
>292.97
—
O
O
O
MeO
MeO
Br
50
51
935.05
>1034.51
>1001.89
—
—
>1034.51
>1001.89
—
—
>258.63
>250.47
—
—
F
MeO
MeO
O
Br
Br
>1001.89
F
F
O
O
52
53
54
55
>1083.57
>1227.81
>1175.31
>481.17
>1083.57
>1227.81
>1175.31
229.67
—
—
—
>1083.57
>1227.81
>1175.31
251.59
—
—
>270.88
>306.94
>293.83
>120.31
—
—
—
—
O
O
O
O
MeO
MeO
C2H5
C2H5
H2N
2
2
O
MeO
O
O
—
O
O
O
MeO
MeO
>2.1
>1.9
O
MeO
(continued on next page)

3478
L.-J. Wang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3473–3479
Table 2 (continued)
b
Compd
R
R1
CC50
(
lM)
HBsAgc
M)
HBeAgd
M)
DNA replication
e
e
e
IC50
(l
SIf
—
IC50
(l
SIf
—
IC50
(
lM)
SIf
O
O
H2N
O
56
57
>944.06
>944.06
>944.06
>236.04
—
O
35.71
>1756.36
43.31
1442.23
—
>1.2
>1805.55
1248.76
—
>1.4
18.37
0.89
1.9
>1973.4
h
TF
a
b
c
Values are means of two independent experiments.
CC50 is 50% cytotoxicity concentration in HepG2 2.2.15 cells.
HBsAg: hepatitis B surface antigen.
HBeAg: hepatitis B e antigen.
IC50 is 50% inhibitory concentration.
d
e
f
SI (selectivity index) = CC50/IC50
.
g
h
No SI can be obtained.
Tenofovir as the positive control.
tant end point in the treatment of chronic hepatitis B.37–39 Some of
derivatives had greater activity against the secretion of HBsAg or
HBeAg than that of the tenofovir (positive control, nucleoside
drug), which suggested that they might had different mechanisms
from the nucleoside analogs. The pharmacokinetic properties
(Tmax, Cmax, t1/2, etc.) of GA has been extensively investigated in
the previous reports,40,41 which might be useful for GA derivatives
to be explored and developed as novel anti-HBV agents.
3. Locarnini, S.; Mason, W. S. J. Hepatol. 2006, 44, 422.
4. Zoulim, F.; Locarnini, S. Gastroenterology 2009, 137, 1593.
5. Cheng, Y. C.; Ying, C. X.; Leung, C. H.; Li, Y. J. Clin. Virol. 2005, 34, S147.
6. Ying, C. X.; Li, Y.; Leung, C. H.; Robek, M. D.; Cheng, Y. C. Proc. Natl. Acad. Sci.
U.S.A. 2007, 104, 8526.
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Bioorg. Med. Chem. Lett. 2008, 18, 3787.
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In summary, fifty-seven derivatives of GA were designed, syn-
thesized, and evaluated for their anti-HBV activity in vitro. The pre-
liminary SAR analysis reveals that (i) the free hydroxy (C-3),
carbonyl (C-11) and carboxyl (C-30) group of GA could affect the
anti-HBV activity and cytotoxicity; (ii) esterification of the hydroxy
on C-3 or carboxyl group on C-30 could decrease the cytotoxicity,
but esterifying at both the position C-3 and C-30 would make the
anti-HBV activity disappear; (iii) introduction of suitable substitu-
ent at the 30-position could significantly enhance the activity; (iv)
epoxide functionality at C-12(13) would cause the enhancement of
suppressant properties on anti-HBV activity. Among the synthe-
sized analogs, sixteen compounds showed greater anti-HBV activ-
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The work was supported by the National Natural Science Foun-
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State Key Laboratory of Phytochemistry and Plant Resources in
West China, Kunming Institute of Botany, Chinese Academy of Sci-
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Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.bmcl.
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