Inhibitory effects of polyphenols toward HCV from the mangrove plant Excoecaria agallocha L.

Article abstract of DOI:10.1016/j.bmcl.2011.11.109

Four new polyphenols namely excoecariphenols A-D (1-4) were isolated from the Chinese mangrove plant Excoecaria agallocha L. together with 23 known phenolic compounds. The structures of new compounds were elucidated on the basis of extensive spectroscopic analyses including IR, MS, NMR, and CD data. Excoecariphenols A and B presented as the unusual flavane-based 1-thioglycosides. Part of the isolated polyphenols were tested against hepatitis C NS3-4A protease and HCV RNA in huh 7.5 cells. Excoecariphenol D, corilagin, geraniin, and chebulagic acid showed potential inhibition toward HCV NS3-4A protease with IC₅₀ values in a range of 3.45-9.03 μM, while excoecariphenol D and corilagin inhibited HCV RNA in huh 7.5 cells significantly. A primary structure-activity relationship (SAR) is discussed.

Full text of DOI:10.1016/j.bmcl.2011.11.109

Bioorganic & Medicinal Chemistry Letters 22 (2012) 1099–1102
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Inhibitory effects of polyphenols toward HCV from the mangrove plant
Excoecaria agallocha L.
Yongxin Li a, Shanjiang Yu b, Dong Liu a, Peter Proksch c, Wenhan Lin a,
⇑
a State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, PR China
b China National Center for Biotechnology Development, Beijing 100036, PR China
c Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine University, Duesseldorf D-40225, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Four new polyphenols namely excoecariphenols A–D (1–4) were isolated from the Chinese mangrove plant
Excoecaria agallocha L. together with 23 known phenolic compounds. The structures of new compounds
were elucidated on the basis of extensive spectroscopic analyses including IR, MS, NMR, and CD data. Excoe-
cariphenols A and B presented as the unusual flavane-based 1-thioglycosides. Part of the isolated polyphe-
nols were tested against hepatitis C NS3-4A protease and HCV RNA in huh 7.5 cells. Excoecariphenol D,
corilagin, geraniin, and chebulagic acid showed potential inhibition toward HCV NS3-4A protease with
Received 4 October 2011
Revised 25 November 2011
Accepted 28 November 2011
Available online 4 December 2011
Keywords:
Mangrove plant
IC50 values in a range of 3.45–9.03
lM, while excoecariphenol D and corilagin inhibited HCV RNA in huh
7.5 cells significantly. A primary structure–activity relationship (SAR) is discussed.
Excoecaria agallocha L.
Excoecariphenols A–D
NS3-4A protein kinase inhibition
HCV RNA inhibition
Huh 7.5 cells
Ó 2011 Elsevier Ltd. All rights reserved.
Hepatitis C virus (HCV) infection caused a serious health prob-
lem, and distributed worldwide with 3–4 million new cases
reported each year.1–3 Chronic HCV infection affects 170 million
people at risk of developing liver cirrhosis and hepatocellular
carcinoma.4,5 Unfortunately, there is no HCV vaccine, and current
limited therapies are often poorly tolerated and frequently ineffec-
tive. The standard therapy for chronic hepatitis C patients in hospi-
as clinical proof-of-concept for HCV NS3-4A protease inhibitors
BILN 2061 and VX-950,11,12 indicating that viral proteases, such
as the HCV NS3-4A protease, could be excellent targets for a struc-
ture-based drug design approach. Discovery of a potent, small-
molecule, and orally available drug candidate from natural prod-
ucts would be an enormously challenging task.
The mangrove plant Excoecaria agallocha L. (Euphorbiaceae)13 is
a herb medicine traditionally used for the treatment of ulcers,
rheumatism, leprosy, and paralysis in the coast regions of South
China.14–17 Its leaves and latex were used as a dart poison and fish
poison in some Asian countries, while the latex was used as a pur-
gative and abortifacient. A bioassay guiding fractionation revealed
the BuOH extract of E. agallocha possessing inhibitory activity
against HCV NS3-4A protease. Chromatographic separation of this
fraction resulted in the isolation of 27 polyphenols, including four
new compounds namely excoecariphenols A–D (1–4). This Letter
intends to report the structural elucidation of the new compounds
and anti-HCV effects of polyphenols.
Excoecariphenol A (1) has a molecular formula of C21H24O11S as
determined by HRESIMS (m/z 507.0941 [M+Na]+, calcd 507.0937),
indicating 10° of unsaturation and containing a sulfur atom. The
IR absorptions at 3420 and 1640 cmꢀ1 in association with 13C
NMR data ascertained the presence of hydroxy and aromatic
groups. The 1H NMR spectrum exhibited four aromatic protons
for a singlet at dH 6.13 (1H, br s, H-6) and an ABX spin system at
dH 6.81 (1H, d, J = 9.0 Hz, H-50), 6.77 (1H, br d, J = 9.0 Hz, H-60)
and 6.91 (1H, br s, H-20), while COSY correlated oxymethine dH
tal is a combination of pegylated interferon (IFN)-a and ribavirin,
which inhibit viral indirectly due to no specific target upon HCV
protein or RNA element.6 In addition, this therapy is associated
with considerable adverse effects, including depression, fatigue,
and ‘flu-like’ symptoms caused by IFN-a, and hemolytic anemia
by ribavirin.7 Thus, there is an urgent medical need for orally
available, small-molecule, direct anti-HCV drugs to treat hepatitis
C patients with more effective and fewer side effects. HCV encodes
four viral enzymes in its nonstructural protein region including
autoprotease NS2-3, serine protease NS3-4A, helicase NS3, and
RNA-dependent RNA polymerase NS5B.8–10 Among them, NS3-4A
serine protease is responsible for the proteolytic cleavage at four
junctions of the HCV polyprotein precursors, and has been
subjected to intense efforts on the discovery of potent, selective
inhibitors as potential new therapies for the hepatitis C patients.
Significant progress has been made in recent years to identify
potent small-molecule inhibitors against the HCV protease, such
⇑
Corresponding author.
E-mail address: whlin@bjmu.edu.cn (W. Lin).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.11.109

1100
Y. Li et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1099–1102
4.13 (1H, ddd, J = 5.0, 7.5, 8.0 Hz, H-3) to an oxymethine (dH 4.68, d,
J = 7.5 Hz, H-2) and the methylene protons at dH 2.56 (1H, dd,
J = 5.0, 16.3 Hz, H-4a) and 2.89 (1H, dd, J = 8.0, 16.3 Hz, H-4b) to
Excoecariphenol C (3) has a molecular formula of C37H30O24, as
determined by HRESIMS (m/z 881.1022 [M+Na]ꢀ, calcd 881.1019),
containing 23° of unsaturation. The 13C NMR and DEPT displayed a
total of 37 carbon resonances, including 24 aromatic carbons for
four phenyl rings. Based on 2D NMR data analysis, this molecule
was consisted of four building blocks. The duplicated aromatic pro-
tons at dH 6.98 (2H, s) together with their HMBC interactions were
characteristic of a galloyl group (unit A). Unit B was assigned to a
hexahydroxydiphenic acidic (HHDP) moiety, based on the presence
of 12 aromatic carbons whose NMR data were compatible to those
of macabarterin,21 in association with the HMBC relationships
from H-300 (dH 6.48, s) and H-3000 (dH 6.68) to C-100 (dC 116.4), C-1000
(dC 116.5), C-500 (dC 135.9), C-5000 (dC 136.3), C-400 (dC 144.4), C-4000
(dC 144.2), and two acetyl carbons at dC 167.7 (C-700) and 166.7
(C-7000), respectively. The COSY correlations connected the protons
of a glucosyl moiety, whose protonated carbons were assigned by
HMQC. The NMR data (Supplementary data) of the glucosyl unit
exhibited the signals for H-1 (dH 6.46, d, J = 7.5 Hz), H-2 (dH 5.17,
br d, J = 7.5 Hz), H-3 (dH 4.64 br s), H-4 (dH 4.30 br s), H-5 (dH
4.49, dd, J = 7.0, 8.0 Hz), and H2-6 (dH 3.98, 4.38, dd), which fea-
tured a skew-boat conformation, the same as the reported data
for phyllanemblinin B.22 The final moiety (unit C) was established
as a galloyl-20000-methylacetate, which was evident from the pres-
ence an aromatic singlet (dH 7.01, s), a methoxy group (dH 3.46,
s), and the geminal protons at dH 3.85 (1H, d, J = 17.0 Hz) and
3.92 (1H, d, J = 17.0 Hz), in combination with their HMBC relation-
ships. The connectivity of each moiety was achieved by the HMBC
interactions from H-20 and H-1 to C-70, H-2 and H-60000 to C-70000, H2-6
and H-600 to C-700, and H-3 and H-6000 to C-7000, respectively, indicat-
ing the formation of ester bonds of HHDP to C-3 and C-6, galloyl
group to C-1, and the esterification of galloyl-20000-methylacetate
with the hydroxy group at C-2 (Fig. 1).
establish a 1,2-dioxypropyl unit. In addition, the proton signals
for a sugar moiety including the hydroxymethylene at dH 3.55
(1H, dd, J = 6.2, 12.3 Hz, Ha-600) and 3.79 (1H, dd, J = 1.8, 12.3 Hz,
Hb-600) and an anomeric proton at dH 4.22 (1H, d, J = 9.4 Hz, H-100)
were connected by COSY correlations, while their corresponding
carbons were assigned by HMQC. The 13C NMR and DEPT spectra
displayed 21 carbon resonances including twelve aromatic carbons
for two aromatic rings, two methylenes and seven oxymethines.
Analysis of HMBC relationships allowed to establish a nucleus of
5,8,30,40-tetrahydroxyfavan-3-ol and a glucosyl unit in the mole-
cule, closely related to catechin-8-C-b-D
-glucopyranoside.18 How-
ever, the quaternary carbon C-8 of 1 shifted extremely to upfield
at dC 93.2, and the anomeric carbon of sugar presented at dC 89.6
which shifted to downfield with 13.3 ppm more than that of
C-glucosides.18 These findings declared 1 to be a 1-thioglycoside.
The HMBC interaction between H-100 and C-8 further confirmed
the glucosyl unit to linked to C-8 through a thioether bond. Thus,
the structure of 1 was determined as catechin-8-S-glucopyrano-
side. The coupling constant of JH-2/H-3 (7.5 Hz) was indicative of a
trans axial-orientation of H-2 and H-3. Based on the revised
Snatzke’s helicity rule for the assessment of absolute configuration
of flavan-3-ols,19,20 the negative CE280 (ꢀ3.42) nm (1Lb transition)
and the positive CE240 (+4.02) nm (1La transition) in the CD spec-
trum of 1 was in accordance with 2R. Therefore, C-3 was assumed
to be S configuration. The b-configuration of the glucosyl unit was
00
00
evident from the coupling constant (JH-1 /H-2 = 7.7 Hz). Since the
structure of co-existing (+)-catechin-3-O-b- -glucopyranoside
D
was established to be identical to the synthesized product in
respect to the physical and chemical properties, the configuration
of glucose unit in 1 and also in 2–4 was biogenetically assumed
The molecular formula (C46H36O31) of excoecariphenol D (4)
was determined on the basis of HRESIMS data (m/z 1083.1171
to be in D-form.
OH
HO
HO
O
OH HO
OH
HO
OH
HO
HO
OH
H
6''
OH
OH
OH
OH
2"'
2"
H
OH
1"
1"'
H
O
OH
O
O
1" 1"'
H
O
6
1'
7"
O
O
OH
OH
O
1
7"
O
HO
O
4'
O
O
O
H
H
H
OH
6
O
1''
H
O
1
7'
S
4'
OH
1'
1'
8
3
O
8a
2
3
HO
O
4
O
O
O
R
7"" 6""
H
1""
OH
OH
OH
O
O
7""
18""
14""
O
8""
O
4a
OH
1""
5
19""
8""
HO
OH
1 R = H
OH
HO
H
O
H
O
4""
13""
O
H
OH
OH
OH
3
2
HO
O
4
R = OH
OH
HO
OH
The NMR data of excoecariphenol B (2) were closely resembled
those of 1, except for the presence of two overlapped aromatic pro-
tons at dH 6.46 (2H, s) in ring B instead of an ABX spin system, sug-
gesting ring B of 2 to be symmetrical substitution and C-50 to be
positioned by a hydroxy group. This assignment was supported
by the molecular formula C21H24O12S of 2 showing one oxygen
atom more than that of 1. The stereogenic centers of 2 were as-
signed to be the same as that of 1 based on the similar CD data
and the biogenetic consideration.
[MꢀH]ꢀ, calcd 1083.1168), indicating 29° of unsaturation. The
13C NMR and DEPT spectra displayed 24 aromatic signals for four
aromatic rings and five ester carbonyl carbons (dC 164.6, 165.3,
165.9, 168.0, 170.8), which were attributed to a galloyl group (unit
A), a dibenzofurandicarboxyl group (unit B), and a penta-substi-
tuted aromatic ring (unit C). These assignments were inferred from
the comparison of NMR data with the structurally similar ellagit-
annins such as phyllanemblinin A22 and macabarterin,21 together
with the HMBC data of aromatic protons. A glucosyl moiety was

Y. Li et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1099–1102
1101
7"'
O
OHHO
H
6
HO
OH
H
OH
O
7""
H
O
3
H
2"'
2"
O
O
1""
7"
OH
OH
4'
OH
HO
O 7'
O
1
H
O
8""
6"'
H
6''
H
H
1'
7"
H
1"'
7"'
HO
O
7'
H
O
1'
O
O
H
O
O
4""
COSY
HMBC
OH
sugar
O
H
HO
O
OH
unit C
7""
unit A
unit B
Figure 1. Key HMBC and COSY relationships of 3.
carbons were assigned by HMQC. The COSY cross-peaks from
H-170000 to H2-180000 and H-160000 together with the HMBC relationship
between H2-180000 and C-150000 led to the formation of a tetrahydro-
furan ring, which was fused to perhydropyran ring. The chemical
shift of C-150000 was in accordance with an acetal carbon. Therefore,
the structure of unit C was established to be identical to that of
macabarterin. The connectivity of units A–C to glucosyl unit was
accomplished by the interpretation of HMBC interactions from glu-
cosyl protons to ester carbonyl carbons (Fig. 2). The relative config-
urations of the stereogenic centers in unit C were assigned by the
NOE relationship and J value. The observation of NOE cross-peak
between Hb-140000 (dH 2.48) and Hb-180000 (dH 3.69) ascertained a
cis-fusion of tetrahydrofuran ring and perhydropyran ring. Addi-
tional NOE interactions from H-130000 to H-160000 and H-90000 indicated
the same face of these protons, while H-130000 and H-90000 should be
axial-oriented. Thus, a cis-fusion of cyclohexane ring with dihydro-
OH
O
H
O
OH
7""
O 1""
14""
HO
18""
9""
9""
O
OH
OH
OH
16""
H
H
H18""
O
13""
H
H
HO
COSY
HMBC
OH
HO
NOE
Figure 2. Key COSY, HMBC, and NOESY interactions of unit C in 4.
recognized by the consecutive COSY cross-peaks from H-1 (dH 6.24,
d, J = 3.5 Hz) to H2-6 (dH 4.17, 4.55). It is noted that the J values of
the glucosyl protons presented as JH-1/H-2 = 3.5 Hz, JH-2/H-3 = 0 Hz,
JH-3/H-4 = 3.8 Hz, and JH-4/H-5 = 0 Hz, indicating the equatorial orien-
tation of H-1 to H-4 when the glucosyl ring adopt a chair-form. In
regard to unit C, the uncommon moiety is consist of an aromatic
ring, two ester carbonyl carbons (C-70000 and C-190000), five aliphatic
quaternary carbons, four methines, and two methylenes. A pen-
ta-substituted phenyl ring was recognized by the presence of an
aromatic singlet at dH 7.18 (s, H-60000). The HMBC relationships of
H-60000 with C-10000 (dC 111.4), C-20000 (dC 117.7), C-40000 (dC 145.4), C-
50000 (dC 138.6) and C-70000 (dC 165.3) indicated C-10000 to be positioned
benzofuran ring was supposed. If H-160000 was arbitrarily assigned
0000
H-160000/H-17
to
a-face, the J
value (0 Hz) reflected their dihedral an-
gle to be approached to 90o, indicating b-face of H-160000. These
assignments indicated the acyl group of 4 to be the same as that
of macabarterin.21
Basis on 1D and 2D NMR, and MS spectroscopic data and compar-
ison of spectroscopic data with the reported data in literature, the
structures of 23 known phenolic compounds were identified. These
included ten flavonoids (2R,3S)-gallocatechin,23 (+)-catechin,24
(+)-catechin-3-O-b-
D
-glucopyranoside,25 (+)-catechin-7-O-b-
D
-gluco-
pyranoside,26 (+)-catechin-3-O-
a-L
-rhamnose,27 quercetin-3-O-b-
by an ester carbonyl carbon. A methine proton at dH 4.50 (s, H-90000
correlated to the carbon at dC 51.6 (C-90000) in HMQC, and it showed
key HMBC interactions (Fig. 2) with aromatic carbons C-10000, C-20000
)
glucopyranoside, myricetin-3-O-(6-O-galloyl)-b-glucopyranoside,28
quercetin-3-O-(6-O-galloyl)-b-glucopyranoside, quercetin-3-O-b-ga-
lactopyranoside, quercetin-3-O-(6-O-galloyl)-b-gallcopyranoside.29
,
and C-30000 (dC 145.2), two acetal carbons at dC 98.7 (C-100000) and 97.8
(C-110000), a methylene at dC 32.2 (C-140000), a quaternary carbon at dC
52.3 (C-80000), and a carbonyl carbon at dC 170.8 (C-190000), indicating
the presence of a dihydrobenzofuran ring. In addition, the correla-
Nine tannins were identical to 1,3,4,6-tetra-O-galloyl-b-
1,2,6-tri-O-galloyl-b-
-glucose,31 1,2,3,4,6-penta-O-galloyl-b-
cose,32 corilagin,33 tercatain,34 1,2-di-O-galloyl-3,6-(R)-HHDP-b-
D
-glucose,30
-glu-
D
D
-glucose,35 furosin,36 geraniin,37 chebulagic acid,38 ellagic acid
tions of methine proton H-130000 (dH 4.79, s) to C-90000, C-140000, C-190000
,
D
4-O-xylopyranoside,39 gallic acid, 3,4-dihydroxybenzoic acid, and
C-80000, an acetal carbon C-120000 (dC 98.5), and C-110000 conducted to
establish a 4,5,6-triacetalcyclohexane ring, which fused to the
dihydrobenzofuran ring at the positions of C-90000 and C-100000. In
addition, an ester carbonyl group was located at C-80000. Subse-
quently, the HMBC cross-peaks from H2-140000 (dH 1.32, 2.48) to
C-150000 (dC 108.8, s) and C-160000 (dC 81.9, d), and from H-160000 to
C-130000 revealed a perhydropyran ring fusing to the cyclohexane
ring at the positions of C-80000 and C-130000. The remaining protons in-
cluded oxymethylene H2-180000 (dH 3.69, 4.09) and two oxymethines
H-160000 (dH 3.90, br s) and H-170000 (dH 3.94), and their corresponding
3,4,5-trihydroxybenzoic acid ethyl ester.40
Apart from minor phenols, 22 isolated phenolic compounds
were evaluated for the inhibition against HCV NS3-4A serine pro-
tease by FRET method.41 Four compounds including 4, corilagin,
geraniin, and chebulagic acid showed potential inhibition with
IC50 values in a range of 3.45–9.03 lM. Subsequently, the four ac-
tive compounds were evaluated for anti-HCV activity in the HCV
RNA replicon assay in huh 7.5 cells using real-time qRT-PCR meth-
od. As shown in Table 1, 4 and corilagin possessed significant inhi-
Table 1
Inhibitory activities of polyphenols toward HCV NS3-4A protease and HCV DNA in huh 7.5 cells
NS3-4A protease
Huh 7.5 cells (MTT)
CC50 M)
Huh 7.5 cells (qRT-PCR)
EC50 M)
SI
IC50
(l
M)
(
l
(l
Corilagin
4
Geraniin
Chebulagic acid
BILN2061
3.45
6.93
8.91
9.03
1.54
96.65 4.41
56.25 0.55
63.40 0.76
104.91 3.86
13.59 1.90
12.61 1.43
33.19 8.20
22.25 8.70
7.1
4.5
1.9
4.7
Note: inhibiting HCV RNA replication activity by 50% (EC50), decreasing cell viability by 50% (CC50), and the selective index (SI).

1102
Y. Li et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1099–1102
7. Zeuzem, S. Nat. Clin. Pract. 2008, 5, 610.
bition against HCV RNA replication in huh 7.5 cells, whereas gera-
niin, and chebulagic acid showed moderate inhibition. Thus, HCV
NS3-4A serine protease is regarded to be a possible pathway for
the polyphenols to inhibit HCV.
Primary discussion of structure–activity relationship revealed
that flavonoids and falvanes, as well as the glucosides linked by dif-
ferent numbers of galloyl group, are weakly reacted with HCV NS3-
4A serine protease (Supplementary data).
8. Chen, K. X.; Njoroge, F. G. Curr. Opin. Investig. Drugs 2009, 10, 821.
9. Pereira, A. A.; Jacobson, I. M. Nat. Rev. Gastro. Hepat. 2009, 6, 403.
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Hsiao, H. M.; Ma, S.; Maxwell, J. P.; Cottrell, K. M.; Perni, R. B.; Gates, C. A.;
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In summary, natural products provided a rich bank to assay for
anti-HCV promising compounds for progressing molecules into the
clinic and to improve therapies. The HCV nonstructural protein 3/
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This work was supported by grants from NSFC (No. 30672607),
the National Hi-Tech 863-projects (2006AA09Z446, 2006D
FA31100, 2007AA09Z448, 2006AA09Z405, 2007AA09Z435), and
International Cooperation Projects of BMBF-MOST (2010DFA
31610).
Supplementary data
Supplementary data (experimental section, Tables of 1H and 13
C
NMR data, spectroscopic copies (IR, UV, MS, 1H and 13C NMR, COSY,
HMQC, HMBC, NOESY, and CD) of new compounds) associated with
this article can be found, in the online version, at doi:10.1016/
j.bmcl.2011.11.109.
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