Anti-HBV agents. Part 3: Preliminary structure-activity relationships of tetra-acylalisol A derivatives as potent hepatitis B virus inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.10.006

Thirty-two tetra-acylated derivatives of alisol A were synthesized and evaluated for their anti-hepatitis B virus (HBV) activities and cytotoxicities in vitro. Among the series of alisol A derivatives examined, five analogues were active against HBV surfa

Full text of DOI:10.1016/j.bmcl.2009.10.006

Bioorganic & Medicinal Chemistry Letters 19 (2009) 6659–6665
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Anti-HBV agents. Part 3: Preliminary structure–activity relationships
of tetra-acylalisol A derivatives as potent hepatitis B virus inhibitors
Quan Zhang a, Zhi-Yong Jiang a, Jie Luo a, Yun-Bao Ma a, Ji-Feng Liu a, Rui-Hua Guo a, Xue-Mei Zhang a,
Jun Zhou a, Wei Niu b, Fei-Fei Du b, Li Li b, Chuan Li b, 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 650204, PR China
b Shanghai Center for DMPK Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Thirty-two tetra-acylated derivatives of alisol A were synthesized and evaluated for their anti-hepatitis B
virus (HBV) activities and cytotoxicities in vitro. Among the series of alisol A derivatives examined, five
analogues were active against HBV surface antigen (HBsAg) and HBV e antigen (HBeAg) secretion in HepG
2.2.15 cells. These results also provide interesting structure–activity relationships of tetra-acylalisol A
derivatives. Compounds tetra-acetyl alisol A (A1), tetra-methoxyacetyl alisol A (A23), and tetra-ethoxy-
acetyl alisol A (A24) exhibited high activities against secretion of HBsAg with IC50 values of 0.0048,
0.0044, and 0.014 mM, respectively, HBeAg with IC50 values of 0.011, 0.012, and 0.018 mM, respectively,
and remarkable selective index values SIHBsAg >333, SIHBeAg >145; SIHBsAg = 209, SIHBeAg = 77; and SIHBsAg
>200, SIHBeAg >156, respectively. Additional studies in rats showed that compound A1 has favorable phar-
macokinetic prosperities for further development purpose, with elimination half-time (t1/2) of 1.63 h and
oral bioavailability (F) of 40.9%.
Received 25 May 2009
Revised 16 September 2009
Accepted 2 October 2009
Available online 7 October 2009
Keywords:
Anti-HBV activity
Protostane-type triterpene
Alisol A
Derivatives
Chemical modification
Ó 2009 Elsevier Ltd. All rights reserved.
Hepatitis B virus (HBV), a member of the hepadnavirus (hepato-
tropic DNA viruses) family, causes acute and chronic infection of
the liver.1 HBV infection is the world’s ninth leading cause of death.2
Chronic HBV infection can lead to cirrhosis, liver failure, and hepato-
cellular carcinoma. An estimated 350–400 million people are chron-
ically infected by HBV throughout the world with 0.5–1.2 million
global deaths per year.3,4 Rates of new HBV infections in developing
countries continue to climb at an alarming rate. Currently, only two
interferons and five nucleoside inhibitors (lamivudine, adefovir
dipivoxil, entecavir, telbivudine,tenofovirdisoproxilfumarate)have
received FDA approval as single-agent treatments for HBV infection.
pharmacological, and medicinal activities including antiviral activ-
ity.12–22 As a part of our continuous search for active anti-HBV
leads from natural sources and synthetic compound,23–25 we first
reported that protostane-type triterpenes exhibit significant
in vitro antiviral activity against HBV.26 With alisol A (1, Fig. 1), a
naturally occurring protostane-type triterpene, as the starting
point, we began bioassay-directed design and synthesized a series
of alisol A analogues,27,28 which led us to discover tetra-acylated
alisol A derivatives 11,23,24,25-tetra-O-20-methoxyacetylalisol A
(2) and 11,23,24,25-tetra-O-20-ethoxyacetylalisol A (3) with high
inhibition activity against the secretion of HBV surface antigen
(HBsAg) and HBV e antigen (HBeAg), and revealed that acylation
of C-25 hydroxyl enhanced anti-HBV potency.28 As a continuation
of this work, we synthesized a series of tetra-acylated alisol A ana-
logues and evaluated their HBV inhibitory activities in HepG 2.2.15
cells. The preliminary structure–activity relationships of these pro-
tostane-type triterpenes were also discussed.
The syntheses of alisol A derivatives are summarized in Scheme 1
and Scheme 2. Treatment of compound 1 with an excess of acetic
anhydride and a catalytic amount of 4-dimethylaminopyridine
(DMAP) in triethylamine afforded ester A1 (78%) as the major prod-
uct, togetherwithcompoundD(6%)asa minorproduct. Compound1
was converted to tetra-acylated derivatives A2–A21 (Table 1) by
refluxing with carboxylic acids in thepresence of N0,N0-dicyclohexyl-
carbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) in
CH2Cl2. Compound A22 was obtained by treatment of compound 1
Unfortunately, clinical response rates to interferon-
a and peginter-
feron-
a
tend to be low (20–30%).5 On the other hand, the required
prolonged regimen of nucleoside analogues almost invariably leads
to drug-resistance problems.6–9 Although the combination therapy
of lamivudine with adefovir dipivoxil, or antiviral drugs together
with immunomodulators such as interferon-a might be more effec-
tive and safer in the therapeutic process,10 it is still limited.11 There-
fore, there is an urgent need for the development of novel classes of
anti-HBV agents with new structures and mechanisms of action.
Triterpenoids are natural products with 30 carbon atoms, bio-
synthetically derived from the cyclization of squalene. Many trit-
erpenoids are reported to have various interesting biological,
* Corresponding author. Tel./fax: + 86 871 5223265.
E-mail address: chenjj@mail.kib.ac.cn (J.-J. Chen).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.10.006

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Q. Zhang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6659–6665
Figure 1. Structures of compounds 1–3
with chlorotrimethylsilane. Acetylation of compound 1 with acetic
anhydride afforded tri-acetyl derivative B1, which was further
converted to compoundsA23, A24 by reaction of compound B1 with
appropriate carboxylic acids in the presence of DCC and DMAP. Sim-
ilarly, compounds A25–A27 were synthesized via tri-acyl analogues
B2–B4 from compound 1. Epoxidation of compound 1 with m-chlo-
roperoxybenzoic acid (mCPBA) in CH2Cl2 at room temperature gave
compound E. Treatment of compound E with acetic anhydride or
with carboxylic acids in the presence of DCC and DMAP afforded
compounds C1–C4.
namely the abilities to inhibit the secretion of HBsAg and HBeAg in
HepG 2.2.15 cells using lamivudine (3TC, a clinically popular anti-
HBV agent) as a positive control. The evaluated compounds and
previously assayed compounds 1–3, B1–B4, and E are divided into
five categories: tetra-acylated derivatives (A); tri-acylated deriva-
tives (B); combination of epoxided at C-13(17) and tetra-acylated
derivatives (C); combination of A-ring modified and tetra-acylated
derivatives (D); epoxided at C-13(17) derivatives (E). Among the
tested analogues, five analogues exhibited inhibitory activity
against the secretion of HBsAg and HBeAg (Table 1).
The synthesized alisol A analogues A1–A27, C1–C4, and D were
evaluated for their cytotoxicities and potential anti-HBV activities,
As previously assayed, the parent compound 1 showed
inhibitory potency to the secretion of HBsAg (IC50 = 0.039 mM),
OAc
OH
OAc
OR
AcO
H
AcO
H
OAc
OAc
c
H
H
O
O
R
B1
MeO
A23
A24
O
EtO
b
O
OH
OAc
OR
OH
O
OAc
OR
HO
H
AcO
H
OH
RO
H
OAc
OR
a
+
H
H
H
O
AcO
1
D
A1-A22
d
OR
OR
OAc
OH
e
RO
H
OR
RO
H
OR
H
H
O
O
A25-A27
B2-B4
R
R
A25
B2
B3
B4
O
O
O
O
A26
A27
O
O
Scheme 1. Reagents and conditions: (a) for A1 and D: (CH3CO)2O, DMAP, triethylamine, rt, 78% (A1), 6% (D), for A2–A21: RCOOH, DCC, DMAP, CH2Cl2, reflux, 56–92%; for A22:
Me3SiCl, Et3N, CH2Cl2, rt, 92%; (b) (CH3CO)2O, pyridine, rt, 86%; (c) RCOOH, DCC, DMAP, CH2Cl2, rt, for A23: 92%, for A24: 87%; (d) RCOOH, DCC, DMAP, CH2Cl2, rt, 68–83%; (e)
(CH3CO)2O, DMAP, triethylamine, rt, 55–82%.

Q. Zhang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6659–6665
6661
OH
OH
OR
OH
O
OH
O
OR
O
O
HO
H
HO
H
RO
H
OH
OH
OR
b
a
H
H
H
O
1
E
C1-C4
C1
O
O
C2
O
C3
O
C4
Scheme 2. Reagents and conditions: (a) mCPBA, CH2Cl2, rt, 88%; (b) for C1: (CH3CO)2O, triethylamine, DMAP, rt, 72%, for C2–C4: R1COOH, DCC, DMAP, CH2Cl2, reflux, 65–77%.
Table 1
Structures, anti-HBV activity, cytotoxicity and selectivity index of alisol A derivativesa
OH
OR
OR
OAc
OAc
OH
OR
O
OR
O
HO
H
OH
RO
H
RO
H
OR
OR
AcO
H
OAc
H
H
H
H
O
O
1
2, 3, A1–A22
A23–A24
A25–A27
OR
OH
OR
OAc
OH
OH
OR
O
O
OAc
O
RO
H
HO
H
OR
RO
OH
OR
AcO
OAc
H
H
H
H
H
H
O
O
AcO
B1–B4
C1–C4
D
E
Compounds
R
CC50b (mM)
0.062
HBsAgc
HBeAgd
SIf
1.6
IC50 (mM)
>2.4
SI
e
IC50 (mM)
1g
/
0.039
<0.030
2h
3h
>2.5
>2.3
0.028
>90
>11
0.027
0.26
>93
MeO
O
EtO
O
0.20
>8.7
O
A129
A2
>1.6
>1.9
>1.8
0.0048
0.90
>333
>2.1
—
0.011
>1.9
1.8
>145
—
O
O
A3
>1.8
—
O
A4
>1.4
>1.4
—
>1.4
—
(continued on next page)

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Q. Zhang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6659–6665
Table 1 (continued)
Compounds
R
CC50b (mM)
HBsAgc
HBeAgd
e
IC50 (mM)
SIf
—
IC50 (mM)
>2.0
SI
—
O
A5
A6
>2.0
>1.6
>2.0
>1.6
O
—
—
>1.6
>1.7
—
—
O
A7
A8
>1.7
>2.1
>1.7
>2.1
O
—
—
>2.1
>1.4
—
—
O
O
A9
>1.4
>1.4
>1.4
>1.4
>1.4
0.48
I
A10
A11
—
>1.4
>1.4
—
—
O
O
>2.9
Cl
Cl
Cl
A12
A13
>1.0
>1.1
>1.0
>1.1
—
—
>1.0
>1.1
—
—
O
O2N
O2N
O
A14
>0.99
>0.99
—
>0.99
—
NO2
O
A15
A16
>1.2
>1.4
>1.2
>1.4
—
—
>1.2
>1.4
—
—
Cl
O
O2N
A17
A18
>1.2
>1.4
>1.2
>1.4
—
—
>1.2
>1.4
—
—
O
O
O
Cl
O
O
A19
A20
Cl
>1.2
>1.3
>1.2
>1.3
—
—
>1.2
>1.3
—
—
Cl
O
O
N
O

Q. Zhang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6659–6665
6663
Table 1 (continued)
Compounds
R
CC50b (mM)
HBsAgc
HBeAgd
IC50 (mM)
SIf
—
IC50 (mM)
>1.6
SI
—
e
O
A21
>1.6
>1.6
O
O
A22
A23
Me3Si
MeO
0.051
0.92
0.020
2.5
>0.051
0.012
<1.0
77
0.0044
209
O
EtO
A24
A25
A26
>2.8
>1.7
>1.9
0.014
0.46
>1.9
>200
>3.7
—
0.018
0.086
1.5
>156
>20
O
O
O
>1.3
O
A27
>1.7
>1.7
—
>1.7
—
O
B1g
B2g
>2.0
>1.4
>2.0
>1.4
—
—
>2.0
>1.4
—
—
O
O
B3g
B4g
>2.2
>1.5
1.7
>1.3
—
0.9
>2.4
—
O
>1.5
>1.5
O
C1
C2
>4.0
>2.2
0.046
>2.2
>87
—
0.061
1.3
>66
O
>1.7
O
O
C3
C4
>1.9
>1.7
>1.9
>1.7
—
—
>1.9
1.1
—
>1.5
D
/
/
/
>2.1
0.43
35
>2.1
0.045
13
—
0.28
1.1
22
>7.5
0.39
1.6
Eg
9.6
2.7
3TCi
a
All values are the mean of two independent experiments.
CC50: 50% cytotoxic concentration.
HBsAg: HBV surface antigen.
HBeAg: HBV e antigen.
IC50: 50% effective concentration.
b
c
d
e
f
SI (selective index) = CC50/IC50
Data from Ref. 27.
.
g
h
i
Data from Ref. 28.
3TC: lamivudine, an antiviral agent used as positive control.

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Q. Zhang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6659–6665
Table 2
but appeared toxic (CC50 = 0.062 mM), which led to a relative low
selectivity index (1.6).27 Initially, tetra-acetyl derivative A1 was
synthesized. Surprisingly, this modification resulted in an eightfold
increase in inhibition to the secretion of HBsAg compared to com-
pound 1 (IC50 = 0.0048 mM vs IC50 = 0.039 mM). Meanwhile it had
lower cytotoxicity (CC50 >1.6 mM vs CC50 = 0.062 mM), resulting a
higher selective index (SI >333 vs SI = 1.6). In addition, compound
A1 also showed highly inhibitory activity on HBeAg secretion with
a SI value of >145 (IC50 = 0.011 mM). A-ring modified compound D
(IC50 = 0.28 mM, SI >7.5) exhibited reduced inhibition effect on
HBeAg secretion compared to compound A1 and lost suppressant
property on the secretion of HBsAg, which indicated that A-ring
of alisol A derivatives is essential for potent anti-HBV activity.
However, we have only one example, we can not conclude that this
will be a general relationship. To further explore the role of acyl-
oxyl at C-11,23,24,25, we performed additional structural modifi-
cations. The addition of methene groups (compound A2) reduced
activity 187-fold of the inhibition to HBsAg secretion compared
to compound A1 (IC50 = 0.90 mM vs IC50 = 0.0048 mM). In addition,
this change produced a loss of property on the secretion of HBeAg.
More bulky tetra-acyl derivatives A3–A21 showed loss of anti-HBV
activity, except that compound A11 was observed to possess mod-
erate activity against the secretion of HBsAg (IC50 = 0.48 mM,
SI >2.9). In an effort to gain more information as to the struc-
ture–activity relationships of alisol A derivatives, we probed addi-
tional structure change. Bioisosteric replacement of the acetyl
groups with trimethylsilyl groups (A22) resulted in 4-fold decrease
in inhibition to the secretion of HBsAg compared to compound A1
(IC50 = 0.020 mM vs IC50 = 0.0048 mM), whereas compound A22
was found toxic (CC50 = 0.051 mM), resulting relative low SI value
(2.5).
Tri-acetyl derivative B1 is much less potent than tetra-acetyl
analogue A1, indicating that acetylation of the free hydroxyl at
C-25 is important for potent anti-HBV activity of alisol A deriva-
tives. To further explore this phenomenon, tri-acyl derivatives
B2–B4 were acetylated to give A25–A27. Of them, compound
A25 exhibited moderate activity against HBsAg secretion
(IC50 = 0.46 mM, SI >3.7) and high potency on the secretion of
HBeAg (IC50 = 0.086 mM, SI >20). More bulky acyls at C-11,23,24
derivatives A26, A27 were inactive in inhibiting the secretion of
HBsAg and HBeAg, suggesting that for C-25 acetyl alisol A deriva-
tives, small acyloxy substituents at C-11,23,24 may be preferred
for anti-HBV activity. Highly potent anti-HBV activity of com-
pounds 2 (IC50HBsAg = 0.028 mM, SI HBsAg >90; IC50HBeAg = 0.027 mM,
Pharmacokinetic profile of compound A1 in ratsa
Rat PK
2 mg/kg (iv)
10 mg/kg (ig)
C0 (ng/mL)
Cmax (ng/mL)
Tpeak (h)
567 95.6
—
—
1.63 0.30
510 46.7
3.87 0.41
5.73 0.39
—
—
383 88.7
1.00 0.00
—
1045 166
—
—
40.9
t1/2 (h)
AUC (ngꢀh/mL)
CL (L/h/kg)
Vss (L/kg)
F (%)
a
Results are expressed as mean SD of n = 3.
cytotoxicities, and nine tested compounds were active against
HBV in HepG 2.2.15 cells. These results provide the following inter-
esting structure–activity relationships: (1) acetyloxyl, methoxy-
acetyloxyl, and ethoxyacetyloxyl groups at C-25 of alisol
A
derivatives enhance potency; (2) for C-25 acetyloxyl alisol A deriv-
atives, small acyloxyl groups at C-11,23,24 may be preferred for
anti-HBV activity; (3) A-ring of alisol A derivatives might be essen-
tial for potent anti-HBV activity; (4) for tetra-acetyl analogue A1,
epoxide functionality at C-13(17) leads to the decrease of suppres-
sant property on the secretion of HBsAg and HBeAg. Furthermore,
Compound A1 possesses favorable pharmacokinetic properties in
rats.
Acknowledgements
This work was supported by National Natural Science Founda-
tion of China (NSFC No. 30672522), the major project of New
Drug Development, Ministry of Science and Technology (No.
2009ZX09103-108), Xibu Zhiguang Joint-Scholarship of Chinese
Academy of Sciences, the External Cooperation Program of Chinese
Academy of Sciences (No. GJHZ200818), and CAS–Croucher Foun-
dation (CAS-CF07/08.SC03). The authors are grateful to the staff
of the analytical group of the State Key Laboratory of Phytochem-
istry and Plant Resources in West China, Kunming Institute of Bot-
any, Chinese Academy of Sciences, for measurements of all spectra.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.10.006.
SIHBeAg >93) and 3 (IC50HBsAg = 0.20 mM, SIHBsAg >11; IC50HBeAg
=
References and notes
0.26 mM, SIHBeAg >8.7) led us to prepare compounds A23, A24
which suppressed the secretion of HBsAg (IC50 = 0.0044 mM,
SI = 209; IC50 = 0.014 mM, SI >200, respectively) and HBeAg
(IC50 = 0.012 mM, SI = 77; IC50 = 0.018 mM, SI >156, respectively).
For derivatives C1–C4 resulted from tetra-acylation of compound
E, compound C1 showed decreased inhibition to the secretion of
HBsAg (IC50 = 0.046 mM, SI >87) and HBeAg (IC50 = 0.061 mM,
SI >66) compared to compound A1, which indicated that, for tetra-
acyl analogues, epoxide group at C-13(17) led to the decrease of sup-
pressant property on the secretion of HBsAg and HBeAg.
Further study was carried out in male Sprague-Dawley rats to
characterize the pharmacokinetic properties of compound A1. As
shown in Table 2, following ig administration, compound A1 was
rapidly absorbed from the gastrointestinal tract demonstrating
the mean time taken to attain peak concentration (Tpeak) being
1 h, and oral bioavailability (F) was 40.9%. The mean plasma clear-
ance (CL) of compound A1 was 3.87 L/h/kg and steady-state distri-
bution volume (Vss) was 5.73 L/kg resulting in a reasonable
elimination half-life (t1/2) of 1.63 h after an iv administration.
In summary, a series of tetra-acylalisol A analogues were syn-
thesized and examined for their in vitro anti-HBV activities and
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