Synthesis and anti-HCV entry activity studies of β-cyclodextrin- pentacyclic triterpene conjugates

Article abstract of DOI:10.1002/cmdc.201300545

In our previous studies, oleanolic acid (OA) and echinocystic acid (EA), isolated from Dipsacus asperoides, were found to have anti-HCV entry properties. The major issue for members of this type of triterpene is their low water solubility. In this study, a series of new water-soluble triazole-bridged β-cyclodextrin (CD)-pentacyclic triterpene conjugates were synthesized via click chemistry. Thanks to the attached β-CD moiety, all synthesized conjugates showed lower hydrophobicity (Alog P) than their parent compounds. Several conjugates exhibited moderate anti-HCV entry activity. With the exception of per-O-methylated β-CD-pentacyclic triterpene conjugates, all other conjugates showed no cytotoxicity based on an alamarBlue assay carried out with HeLa, HepG2, MDCK, and 293T cells. More interestingly, the hemolytic activity of these conjugates disappeared upon the introduction of β-CDs. Easy access to such conjugates that combine the properties of β-CD and pentacyclic triterpenes may provide a way to obtain a new class of anti-HCV entry inhibitors. An awesome CD collection: A series of water-soluble triazole-bridged β-cyclodextrin (CD)-pentacyclic triterpene conjugates were synthesized, and their hydrophobicity, anti-HCV entry activities, and toxicity were studied. Easy access to such conjugates may provide a way to obtain a new class of anti-HCV entry inhibitors.

Full text of DOI:10.1002/cmdc.201300545

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DOI: 10.1002/cmdc.201300545
Synthesis and Anti-HCV Entry Activity Studies of b-
Cyclodextrin–Pentacyclic Triterpene Conjugates
[a]
[a, c]
[a]
[a]
[a]
[a]
Sulong Xiao,* Qi Wang,
Longlong Si, Yongying Shi, Han Wang, Fei Yu,
[b]
[a]
[a]
[a]
[a]
Yongmin Zhang, Yingbo Li, Yongxiang Zheng, Chuanling Zhang, Chunguang Wang,
[a]
[a]
Lihe Zhang, and Demin Zhou*
In our previous studies, oleanolic acid (OA) and echinocystic
acid (EA), isolated from Dipsacus asperoides, were found to
have anti-HCV entry properties. The major issue for members
of this type of triterpene is their low water solubility. In this
study, a series of new water-soluble triazole-bridged b-cyclo-
dextrin (CD)–pentacyclic triterpene conjugates were synthe-
sized via click chemistry. Thanks to the attached b-CD moiety,
all synthesized conjugates showed lower hydrophobicity
hibited moderate anti-HCV entry activity. With the exception of
per-O-methylated b-CD–pentacyclic triterpene conjugates, all
other conjugates showed no cytotoxicity based on an ala-
marBlue assay carried out with HeLa, HepG2, MDCK, and 293T
cells. More interestingly, the hemolytic activity of these conju-
gates disappeared upon the introduction of b-CDs. Easy access
to such conjugates that combine the properties of b-CD and
pentacyclic triterpenes may provide a way to obtain a new
class of anti-HCV entry inhibitors.
(AlogP) than their parent compounds. Several conjugates ex-
Introduction
[
6]
Hepatitis C virus (HCV) is the leading cause of chronic hepatitis,
proach for the prevention and reduction of infection. Devel-
opment of HCV entry inhibitors could satisfy the tandem use
with other inhibitors of viral replication, leading to a multifacet-
ed approach to control HCV infection more effectively.
[
1]
cirrhosis, and eventually leads to liver carcinomas. In 2002
there were ~170 million individuals infected worldwide, com-
[
2]
prising ~3% of the global population. Treatment of HCV in-
fection with peginterferon/ribavirin has been used for almost
Natural products play a significant role in the drug discovery
[7]
30 years. In 2011, the US Food and Drug Administration (FDA)
and development process. It has been estimated that over
40% of medicines have their origins in active natural prod-
approved the HCV NS3 protease inhibitors telaprevier (Incivek)
and boceprevir (Victrelis) for targeting HCV replication, repre-
senting the beginning of a new era in the control of HCV infec-
[8]
ucts. Pentacyclic triterpenes are secondary plant metabolites,
[9]
widespread in fruit peels, leaves, and stem bark, with a few
[
3]
tion. However, resistance to individual antiviral drugs is likely
species containing triterpenes up to 30% of their dry
[
4]
[10]
to appear, and a combination of drugs that target different
stages of the HCV life cycle is required. The recently approved
olysio (Simeprevir) is also an HCV protease inhibitor; however,
a decrease in efficacy was observed in patients infected with
HCV genotype 1a with an NS3 protease Q80K polymorphism,
weight.
It has been estimated that there are more than
[11]
20000 triterpenoids in nature.
It is generally believed that the physiological function of tri-
terpenoids is defense (a plant’s acquired resistance) against
[12]
plant pathogens. Plant-derived pentacyclic triterpenoids of
lupine and oleanane families provide a versatile structural plat-
form for the discovery of new biologically active compounds
[5]
a strain of HCV commonly found in the United States. Inhibi-
tion of virus entry into HCV-permissive cells is an emerging ap-
(
Figure 1). Betulinic acid (BA), a lupane-type triterpene, has
been confirmed by many studies to display significant inhibit-
[
a] Dr. S. Xiao, Dr. Q. Wang, L. Si, Y. Shi, H. Wang, F. Yu, Y. Li, Y. Zheng,
C. Zhang, Prof. C. Wang, L. Zhang, D. Zhou
State Key Laboratory of Natural and Biomimetic Drugs
School of Pharmaceutical Sciences
Peking University, Beijing 100191 (China)
E-mail: slxiao@bjmu.edu.cn
[13]
ing activity against HIV entry and virus maturation/release.
One derivative, bevirimat (PA-457), is already in clinical trials.
[14]
Ursolic acid (UA) and moronic acid (MA), two oleanane-type tri-
[15]
terpenes, also display anti-HIV activity in vitro. In our previ-
[16]
ous studies, we found that oleanolic acid (OA) and echino-
cystic acid (EA), two naturally occurring oleanane-type triter-
penes, and their derivatives display substantial activity to in-
hibit HCV entry. The putative mechanism behind EA blocking
of HCV entry is its strong binding to HCV envelope glycopro-
tein E2. Other diverse and promising biological activities of tri-
terpenes, including anti-inflammatory, hepatoprotective, anal-
gesic, antimicrobial, antimycotic, virostatic, immunomodulato-
ry, and tonic effects, warrant further pharmaceutical develop-
deminzhou@bjmu.edu.cn
[
b] Prof. Y. Zhang
Sorbonne Universitꢀs, UPMC Univ Paris 06
LabEx Michem, CNRS, UMR 8232, IPCM, 75005 Paris (France)
[
c] Dr. Q. Wang
Department of Molecular and Cellular Pharmacology
School of Pharmaceutical Sciences
Peking University, Beijing 100191 (China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201300545.
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number of organic and inorganic
[19]
guest molecules.
Thus, CDs
have frequently been applied in
[
19a–d]
pharmacy,
analytical chemis-
[
19b]
[19f]
try,
enzyme mimics,
as well
as agriculture and environmental
[
19h]
engineering,
etc. For instance,
[
19a,e,20]
in the pharmaceutical field,
CDs are versatile excipients used
to enhance the solubility, stabili-
ty, safety, and bioavailability of
drugs. In addition, chemically
modified CD derivatives have
also been widely used in the
design of artificial enzymes and
Figure 1. Structures of pentacyclic triterpenes.
[19b,f,g]
for enantiomeric separation.
As a continuation of our ongo-
[
17]
[16]
ment and even clinical investigation.
In particular, the
ing studies, we describe herein a simple and reliable synthet-
ic protocol involving a copper-catalyzed azide–alkyl cycloaddi-
tion (CuAAC, ’click chemistry’) for the preparation of b-CD–
pentacyclic triterpene conjugates as a new class of anti-HCV
entry inhibitors.
lupane and oleanane triterpenes display no prominent cytotox-
icity, which has been accepted through their long-term use in
complementary medicinal history. However, the low solubility
of triterpenes in biological environments and high hydropho-
bicity (logP) is a drawback for further broad applications, in
particular, for development into a therapeutic medicine. For
example, the solubilities of BA and OA in water are ~0.02 and Results and Discussion
ꢀ
1
[18]
0
.05 mgmL , respectively.
Chemistry
Cyclodextrins (CDs) are cyclic (a-1,4-)-linked water-soluble
A
A
oligosaccharides of a-glucopyranose containing a relatively hy-
drophobic central cavity and hydrophilic outer surface. The
most common cyclodextrins are a-CD, b-CD, and g-CD, which
consist of six, seven, and eight glucopyranose units, respective-
ly. Given their hydrophilic external surface and hydrophobic
inner surface structure, CDs and their derivatives have proven
to be very efficient host molecules for the binding of a large
The synthetic routes for 6 -azide-6 -deoxyper-O-alkylated b-
CDs 4 and 5 are depicted in Scheme 1. Briefly, selective mono-
tosylation of b-CD 1, according to the procedure described by
[21]
Thatcher and colleagues. with minor modifications, afforded
compound 2. This was followed by nucleophilic substitution
with sodium azide in N,N-dimethylformamide (DMF) to provide
A
A
the key intermediate 6 -azide-6 -deoxy-b-CD 3 in quantitative
2 3 3 2
Scheme 1. Reagents and conditions: a) H O, NaOH, TsCl; b) DMF, NaN , 808C, 18 h; c) DMF, NaH, CH I; d) pyridine, DMAP, Ac O.
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Scheme 2. Reagents and conditions: a) H
2
CrO
4
, acetone, 08C!RT, 18 h; b) NaBH
4 2 3
, THF, RT, 2.5 h; c) TBTU, DIPEA, THF; d) propargylamine, K CO , DMF, 1 h;
ONa/CH OH, RT, 8–10 h.
e) THF/H
2
O (1:1, v/v), CuSO
4
, sodium l-ascorbate, 4 or 5; f) CH
3
3
yield, which was used without further purification in the next
step. Methylation of crude 3 with methyl iodide in the pres-
A
A
ence of sodium hydride afforded the 6 -azide-6 -deoxyper-O-
A
A
methylated b-CD 4 in 86% yield. 6 -Azide-6 -deoxyper-O-ace-
tylated b-CD 5 was obtained in 92% yield by treating crude 3
with acetic anhydride in the presence of 4-dimethylaminopyri-
dine (DMAP) and pyridine.
The synthesis of b-CD–BA conjugates 11–13 is illustrated in
Scheme 2. At first, BA was synthesized by a modified method
[
22]
of Kim et al. Oxidation of betulin 6 with Jones reagent in
acetone, followed by reduction with sodium borohydride in
tetrahydrofuran gave betulinic acid 8 in 42% yield (two
[
23]
1
steps). Activation of the carboxyl group of 8 with 2-(1H-ben-
zotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate
TBTU) gave the stable intermediate 9 in excellent yield and
Figure 2. Aromatic region of the 400 MHz H NMR spectra of conjugates
a) 11 (CDCl ), b) 12 (CDCl ), and c) 13 (CD OD) recorded at 258C.
3
3
3
(
purity, which was treated with propargylamine under basic
conditions to afford 10 in 1 h in 92% yield. Compound 10
HSQC. Similarly, the CuAAC reaction for the synthesis of other
triterpene–b-CD conjugates 23–31 were carried out from com-
mercially available pentacyclic triterpenes OA, EA, and UA in
good yields (61–91%; Scheme 3). The aromatic region signals
(triazole-CH and CONH) of conjugates 23–25 are similar to
then underwent a click reaction with 4 or 5 in THF/H O (1:1) in
2
the presence of a catalytic amount of copper sulfate and
sodium ascorbate as reducing agent to yield 11 and 12 in 72
and 79% yields, respectively. The acetyl groups of 12 were re-
moved by Zemplꢁn reaction to afford 13.
those of conjugate 11 (Figure 2). Figure 4 presents the charac-
1
The structures of conjugates 11–13 were identified by 1D
and 2D NMR spectroscopy as well as ESI high-resolution mass
spectrometry (ESI-HRMS). In the aromatic region (Figure 2), the
signal at d=7.58–7.83 ppm referring to 1H, according to its
teristic parts (d=4.2–5.6 ppm) of the H NMR spectra (in CDCl )
3
of conjugates 11 and 23–25. The signals have been fully as-
1
1
1
13
signed with the aid of H– H COSY and H– C HSQC spectra.
1
1
1
13
H– H and H– C correlation spectra, could be assigned to tria-
Calculated ALogP
zole-CH. An additional signal was observed for the amide
proton at 6.31–6.47 ppm for conjugates 11–12 (in CDCl ) and
The logarithm of the 1-octanol/water partition coefficient
3
at d=8.16 ppm for conjugate 13 (in CD OD), indicating that
these conjugates are indeed connected by a triazole linker. As
(logP) is a well-known measure of molecular hydrophobicity
3
[24]
(or lipophilicity).
Lipophilicity governs the interaction of
mono-functionalization of b-CD itself causes loss of C symme-
a given molecule with the intestinal membrane, yet such
a compound must also possess hydrophobic character for pas-
sive transport across intestinal epithelia. In our study, the calcu-
lated AlogP values were determined using Pipeline Pilot soft-
7
try, spectral overlap in the 1D and 2D COSY spectra make as-
1
13
signment of the H and C signals of the glucose moieties ex-
tremely complex. The lower-field regions of these conjugates
were relatively well resolved and fully assigned with the aid of
[25]
ware version 7.5 (Accelrys Corp., San Diego, CA, USA). All the
conjugates 11–13 and 23–31 showed increased hydrophilicity
relative to their parent compound (Table 1). For example, a de-
1
1
1
13
H– H COSY and H– C HSQC spectra (Figure 3), which could
be useful for assignment of the other signals by 2D COSY and
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Table 1. Calculated AlogP values of b-CD–pentacyclic triterpene conjuga-
[
a]
tes.
Compd
AlogP
Compd
AlogP
Compd
AlogP
BA
OA
EA
6.546
6.447
5.345
6.492
2.405
1.817
13
23
24
25
26
27
ꢀ5.765
2.306
1.204
2.352
1.718
28
29
30
31
0.616
ꢀ6.966
1.764
ꢀ5.819
UA
1
1
1
2
ꢀ5.864
[
a] AlogP values (Ghose and Crippen octanol–water partition coefficient
at 258C) were calculated using Pipeline Pilot software, version 7.5 (Accel-
rys Corp., San Diego, CA, USA).
crease in AlogP value in the order BA>11 >12>13 was ob-
served for BA and its conjugates. Similar results were also ob-
served for OA, EA, and UA. Benefiting from the hydrophilic b-
CD moiety, conjugates 13, 27, 29, and 31 showed the lowest
AlogP values.
Anti-HCV entry activity
b-CD has had well-known use in the improvement of certain
[19]
properties of drugs such as bioavailability.
Our previous
studies suggested that pentacyclic triterpenes OA and EA dis-
[16]
play substantial activity in blocking HCV entry. Could b-CD
improve the bioavailability of EA and OA, thereby increasing
their anti-HCV entry activity? With this in mind, a series of b-
CD–triterpene conjugates were designed and synthesized. As
listed in Table 2, we found that: 1) the anti-HCV entry activities
of the four pentacyclic triterpenes increased in the order: EA>
BA@UA>OA, and the potencies of EA and BA are greater
than those of the highly potent compound reported by Mitta-
[26]
palli et al.; 2) except for BA, the introduction of b-CD on the
triterpene resulted in modest (27 vs. OA and 31 vs. UA) or the
largest (29 vs. EA) increases in potency, whereas no inhibition
was observed in for anti-VSV (vesicular stomatitis virus) entry
activity; and 3) all the per-O-me-
Figure 3. Characteristic portions of the 400 MHz a) 2D-COSY and b) HSQC
spectra of conjugate 11 recorded in CDCl
3
at 258C.
thylated b-CD–triterpene conju-
gates (conjugates 11, 23, 24,
and 25) showed more potent
anti-VSV entry activities than
their parent compound, especial-
ly for conjugates 11 and 23, indi-
cating that methylation of b-CD
may impart some degree of cy-
totoxicity.
In vitro cytotoxic activity
The in vitro cytotoxic activity
was evaluated for all of the syn-
thesized conjugates 11–13 and
23–31 against HeLa (cervical
cancer), HepG2 (liver cancer),
MDCK (Madin–Darby canine
kidney), and 293T (human
1
Figure 4. Characteristic portions of the 400 MHz H NMR spectra of conjugates 11, 23, 24, and 25 recorded in
CDCl at 258C
3
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2 3 2 4 3
Scheme 3. Reagents and conditions: a) TBTU, DIPEA, THF; b) propargylamine, K CO , DMF, 1 h; c) THF/H O (1:1, v/v), CuSO , sodium l-ascorbate; d) CH ONa/
CH OH, RT, 10 h.
3
Table 2. Anti-HCV and VSV pseudo-particle (pp) entry activities of b-CD–
pentacyclic triterpene conjugates.
relative to positive control (paclitaxel, PTX), whereas almost no
cytotoxic activity was observed for EA, OA, and other b-CD
conjugates (Figure 5). Similar results were also observed for
the HepG2, 293T, and MDCK cell lines, except for BA, which
showed no cytotoxic activity toward MDCK cells. In all experi-
ments, four per-O-methylated b-CD–triterpene conjugates
showed some cytotoxicity at 5 mm and strong cytotoxicity at
[
a]
[b]
Compd
Inhibition [%]
HCVpp Entry
mm 5 mm
CC50/EC50
VSVpp Entry
1
1 mm
5 mm
[
c]
Ctrl
EA
21.2ꢁ1.1 34.0ꢁ0.9
27.5ꢁ2.1 77.7ꢁ3.3
22.4ꢁ1.4 26.4ꢁ0.9
13.8ꢁ3.2 35.1ꢁ3.7
11.7ꢁ2.2
7.2ꢁ1.7
10.6ꢁ2.0
2.8ꢁ0.7
12.8ꢁ1.8
9.0ꢁ0.8
23.6ꢁ2.2
3.9ꢁ0.4
1.9ꢁ2.1
98.6ꢁ0.3
10.3ꢁ3.1
3.8ꢁ1.6
99.5ꢁ0.8
49.8ꢁ0.9
24.9ꢁ1.7
7.6ꢁ2.0
18.5ꢁ3.2
19.6ꢁ1.4
9.3ꢁ0.3
–
–
–
–
–
~1
–
–
~1
–
–
–
–
–
–
–
–
OA
UA
BA
50 mm, indicating per-O-methylated b-CD may have some cyto-
toxicity in vitro.
4.2ꢁ0.8 65.2ꢁ3.2 ꢀ2.0ꢁ4.3
1
1
88.2ꢁ3.6 98.2ꢁ2.5
70.3ꢁ5.6 81.7ꢁ4.7
4.5ꢁ0.8
8.7ꢁ1.5
1
1
2
2
2
2
2
2
2
3
3
2
3
3
4
5
6
7
8
9
0
1
37.1ꢁ2.3 42.7ꢁ1.9 ꢀ1.7ꢁ3.5
82.7ꢁ3.8 98.2ꢁ5.1
59.5ꢁ3.5 74.5ꢁ2.1
10.1ꢁ1.0 37.7ꢁ2.6
24.9ꢁ1.7
11.5ꢁ1.1
21.6ꢁ1.3
56.7ꢁ3.5 89.7ꢁ4.3 ꢀ9.2ꢁ3.6
25.2ꢁ0.8 67.1ꢁ3.9 ꢀ1.4ꢁ4.8
ꢀ4.0ꢁ2.0 37.3ꢁ0.7
86.5ꢁ4.4 95.9ꢁ0.7
5.6ꢁ0.8
3.4ꢁ1.2
62.6ꢁ4.6 80.7ꢁ3.5 ꢀ1.8ꢁ2.3 ꢀ2.0ꢁ3.7
13.6ꢁ1.8 48.9ꢁ2.7 ꢀ2.8ꢁ2.6 ꢀ2.4ꢁ3.1
[
a] Percent inhibition=(100%)ꢀ(DMSO negative control%) for each
tested compound; data represent the mean ꢁSEM of three independent
experiments performed in triplicate. [b] Except for compounds 11 and 23,
no significant toxicity was observed at 100 mm. [c] Positive control:
methyl
9-(3-(4,6-dimethoxypyrimidin-2-yloxy)propyl)-2,3,4,9-tetrahydro-
[
26]
1H-carbazole-6-carboxylate.
Figure 5. In vitro activity of conjugates 11–13 and 23–31 against HeLa cells.
4
The cells were seeded at a density of 1ꢂ10 cells per well in 96-well plates.
The plates were left for 16 h to allow the cells to adhere to the well surface.
Conjugates were added at 5 or 50 mm in triplicate, and the cells were left for
another 48 h. Control wells contained the equivalent volume of culture
medium with 1% DMSO. An alamarBlue assay was performed to determine
the level of anti-proliferation. Error bars represent standard deviations.
kidney) cell lines, by using an alamarBlue assay. The results
showed that BA, UA, and four per-O-methylated b-CD–triter-
pene conjugates showed significant activity against HeLa cells
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13
Hemolytic assays
of MeOD). C NMR chemical shifts are referenced to the solvent
signal (d =77.00 ppm for the central line of CDCl , d =49.00 ppm
C
3
C
for the central line of MeOD). Reactions were monitored by thin-
layer chromatography (TLC) on pre-coated silica gel 60 F254 plates
A series of studies have demonstrated that the aglycons of tri-
terpenoids exert a significant influence on hemolytic proper-
(
layer thickness: 0.2 mm, E. Merck, Darmstadt, Germany) and de-
tected by staining with a yellow solution containing Ce(NH ) (NO )
3 6
[27]
ties, one of the well-known characteristics of saponins. In
our previous studies, the substantial hemolytic property of tri-
terpenes disappeared upon biotransformation or modification
4
2
(
0.5 g) and (NH ) Mo O ·4H O (24.0 g) in 6% H SO (500 mL) fol-
4 6 7 24 2 2 4
lowed by heating. Flash column chromatography was performed
on silica gel 60 (200–300 mesh, Qingdao Haiyang Chemical Co.
Ltd.). The calculated AlogP and water solubility values were deter-
mined using Pipeline Pilot software v.7.5 (Accelrys Corp., San
Diego, CA, USA).
[
16]
at the C28 carboxyl group. In this study we also found that
all the b-CD–pentacyclic triterpene conjugates were depleted
of hemolytic activity upon the introduction of b-CD or its de-
rivatives at the C28 carboxyl group (Figure 6).
General procedure A for the synthesis of 1-benzotriazolyl triter-
pene ester: To a solution of triterpene BA, OA, EA, or UA
(0.22 mmol) in THF (10 mL) was added TBTU (106 mg, 0.33 mmol)
and DIPEA (0.12 mL, 0.66 mmol) at room temperature. The reaction
mixture was stirred for 5 h under nitrogen. The solvent was re-
moved in vacuo. The residue was dissolved with CH Cl (15 mL),
2
2
washed with brine (3ꢂ5 mL), dried with Na SO , filtered, and the
2
4
solvent was removed in vacuo. The crude product was purified by
flash chromatography.
General procedure B for the synthesis of N-propargyl triterpene
amide: To
a solution of 1-benzotriazolyl triterpene ester
(
0.74 mmol) in DMF (10 mL) was added K CO (153 mg, 1.11 mmol)
2
3
and 2-propargylamine (33 mL, 0.89 mmol) at room temperature.
The reaction mixture was stirred for 1 h under nitrogen. The sol-
vent was removed in vacuo. The residue was dissolved with 25 mL
CH Cl , washed with brine (3ꢂ5 mL), dried with Na SO , filtered,
Figure 6. Hemolysis assay of EA and its b-CD conjugates.
2
2
2
4
and the solvent was removed in vacuo. The crude product was pu-
rified by flash chromatography.
General procedure C for the click reaction: To a solution of
Conclusions
alkyne (0.09 mmol) and azide (0.06 mmol) in THF/H O (1:1 v/v,
2
We have shown the synthesis, anti-HCV entry activity, and cyto-
toxicity, including hemolytic exploration of new b-CD–pentacy-
clic triterpene conjugates. As expected, all the new conjugates
showed lower hydrophobicity (AlogP) than their respective
parent compounds. Several conjugates exhibited moderate
anti-HCV entry activity in an HCV pseudo-particle (HCVpp)
entry assay. Except these per-O-methylated b-CD–pentacyclic
triterpene conjugates, other conjugates showed no apparent
cytotoxicity in an alamarBlue assay using four cell lines. In ad-
dition, the hemolytic toxicity of these new conjugates disap-
peared upon coupling with b-CD. Easy access to such conju-
gates that combine the properties of b-CD and pentacyclic tri-
terpenes may provide a way to obtain a new class of anti-HCV
entry inhibitors.
5 mL) was added CuSO (9.5 mg, 0.06 mmol) and sodium ascorbate
4
(24 mg, 0.12 mmol). The resulting solution was stirred vigorously
for 12 h at room temperature. The reaction mixture was extracted
with CH Cl (3ꢂ10 mL). The combined organic layer was dried over
2
2
Na SO , filtered, and concentrated. The residue was purified by
2
4
column chromatography.
General procedure D for the deacetylation reaction: The per-O-
acetylated b-CD–triterpene conjugate was dissolved in dry CH OH
3
(
~5 mL per 100 mg compound) and a solution of NaOCH (30% in
3
3
ꢀ
1
CH OH, 0.1 equiv[mol acetate] ) was added. The solution was
stirred at room temperature for 4–6 h. After completion (TLC) the
+
reaction mixture was neutralized with Amberlite IR-120 (H ) ion-
exchange resin, then filtered and concentrated. The crude product
was purified by RP column chromatography (eluted by CH OH).
3
1
-Benzotriazolyl 3b-hydroxylup-20(29)-en-28-oate (9): According
to general procedure A, the residue was purified by flash chroma-
tography (eluent: petroleum ether (PE)/EtOAc=4:1) to afford 9 as
Experimental Section
1
a white solid in 93% yield. R =0.43 (PE/EtOAc=2:1); H NMR
f
(
7
400 MHz, CDCl ): d=8.08 (d, 1H, J=8.4 Hz), 7.55 (t, 1H, J=7.4 Hz),
.42 (t, 1H, J=7.6 Hz), 7.37 (d, 1H, J=8.3 Hz), 4.73 (s, 1H), 4.64 (s,
3
Chemistry
The syntheses of 2–5, 7–8, 18, and 21 were performed as previous-
1H), 3.19 (dd, 1H, J=4.9, 11.1 Hz), 2.95 (td, 1H, J=4.9, 11.1 Hz),
2.64 (m, 1H), 2.41 (dd, 1H, J=7.8, 13.0 Hz), 2.22 (td, 1H, J=3.6,
12.4 Hz), 2.04–2.15 (m, 1H), 0.78–1.82 (m, other aliphatic ring pro-
tons), 1.71, 1.05, 0.99, 0.98, 0.81, 0.76 (s, each 3H), 0.70 ppm (d, 1H,
[16b,21,22]
ly reported (Supporting Information).
IR spectra were re-
corded on a Nicolet Nexus 470 spectrometer (American Thermo
ꢀ
1
Nicolet Co.) in the range 400–4000 cm using KBr pellets. ESI-
HRMS data were obtained with an APEX IV FT_MS (7.0 T) spectrom-
eter (Bruker) in positive ESI mode. NMR spectra were recorded on
13
J=10.6 Hz); C NMR (100 MHz, CDCl ): d=171.80, 149.20, 143.59,
3
128.87, 128.61, 124.65, 120.59, 107.90, 110.34, 78.90, 57.00, 55.37,
50.55, 49.95, 46.55, 42.46, 40.78, 38.84, 38.73, 38.49, 37.18, 36.75,
34.36, 31.39, 30.28, 30.10, 27.97, 27.36, 25.41, 20.79, 19.37, 18.26,
16.12, 16.07, 15.33, 14.81 ppm; IR (KBr): n˜ =3434, 2944, 2871, 1808,
1
a Bruker DRX 400 spectrometer at room temperature. H NMR
chemical shifts are referenced to the internal standard TMS (d =
H
0
.00 ppm) or the solvent signal (d =3.31 ppm for the central line
H
ꢀ
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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&
6
&
ÞÞ
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ꢀ
1
1
643, 1452, 1020, 741 cm ; ESI-HRMS calcd for C H N O [M+
15.33, 14.59 ppm; IR (KBr): IR (KBr): n˜ =3468, 2949, 1751, 1658,
36
52
3
3
+
ꢀ1
H] : 574.4003, found: 574.4003.
1373, 1238, 1045, 603 cm
;
ESI-HRMS (m/z) calcd for
+
C115H161N NaO [M+Na+H]/2 : 1258.4875, found: 1258.4836;
4
56
N-propargyl 3b-hydroxylup-20(29)-en-28-amide (10): According
to general procedure B, the residue was purified by flash chroma-
tography (eluent: PE/EtOAc=4:1) to afford 10 as a white solid in
0% yield. R =0.43 (PE/EtOAc=2:1); H NMR (400 MHz, CDCl ): d=
+
C115H161KN O [M+K+H]/2 : 1266.4744, found: 1266.4754.
4
56
A
N-[1-(6 -deoxy-b-CD-6-yl)-1H-1,2,3-triazol-4-yl]methyl 3b-hydrox-
ylup-20(29)-en-28-amide (13): Prepared from 12 according to
general procedure D, the residue was purified by RP flash chroma-
1
9
5
f
3
.81 (t, 1H, J=4.8 Hz), 3.94–4.10 (m, 2H), 3.10–3.20 (m, 2H), 2.42
(
td, 1H, J=3.3, 12.7 Hz), 2.21 (t, 1H, J=2.4 Hz), 0.74–1.96 (m, other
tography (eluent: CH OH) to afford 13 as a white solid in 91%
3
1
aliphatic ring protons), 1.68, 0.97, 0.96, 0.94, 0.82, 0.75 (s, each 3H),
yield. H NMR (400 MHz, CD OD): d=8.16 (brs, 1H), 7.83 (brs, 1H),
3
13
0
1
4
2
1
6
4
.67 ppm (d, 1H, J=8.8 Hz); C NMR (100 MHz, CDCl ): d=175.83,
5.13 (d, 1H, J1,2 =2.4 Hz), 4.97–5.02 (m, 7H, overlap with H O), 4.72
3
2
50.77, 109.36, 80.14, 78.91, 71.06, 55.62, 55.35, 50.59, 50.13, 46.66,
2.41, 40.75, 38.81, 38.69, 38.06, 37.71, 37.16, 34.35, 33.55, 30.76,
9.35, 28.94, 27.95, 27.37, 25.56, 22.62, 20.86, 19.45, 18.26, 16.10,
5.32, 14.61 ppm; IR (KBr): n˜ =3368, 3312, 2946, 2869, 1643, 1453,
(s, 1H), 4.58 (s, 1H), 4.33–4.55 (m, 3H), 4.06 (t, 1H), 3.68–3.96 (m,
22H), 3.42–3.60 (m, 12H), 3.57 (m, 1H), 3.35–3.40 (m, 2H, overlap
with CH OH), 3.05–3.16 (m, 2H), 2.55 (t, 1H, J=10.5 Hz), 2.15 (d,
3
1H, J=11.6 Hz), 1.82–1.92 (m, 2H), 0.85–1.75 (m, other aliphatic
ꢀ1
+
26 cm ; ESI-HRMS calcd for C H NO [M+H] : 494.3993, found:
ring protons), 1.69, 1.01, 0.95, 0.93, 0.87, 0.76 (6ꢂCH ), 0.71 ppm
33
52
2
3
13
94.3991.
(d, 1H, J=8.6 Hz); C NMR (100 MHz, CD OD): d=179.40, 152.27,
3
1
1
7
6
4
2
47.21, 126.25, 110.10, 103.99, 103.90 (2C), 103.87, 103.83, 103.79,
03.55, 84.85, 83.11, 83.06, 83.01, 82.94, 82.82, 79.65, 74.79, 74.70,
4.59, 74.42, 74.21, 74.12, 74.07, 73.88, 73.66, 73.21, 72.11, 70.59,
1.83, 61.34, 57.01, 56.92, 52.29, 52.12, 49.85, 48.04, 43.51, 42.04,
0.07, 39.96, 39.32, 39.01, 38.33, 35.92, 35.63, 34.00, 31.99, 30.63,
A
N-[1-(6 -deoxyper-O-methyl-b-CD-6-yl)-1H-1,2,3-triazol-4-yl]-
methyl 3b-hydroxylup-20(29)-en-28-amide (11): Prepared from 4
and 10 according to general procedure C, the residue was purified
by flash chromatography (eluent: PE/EtOAc/acetone=1:1:1) to
afford 11 as a white solid in 62% yield. R =0.30 (CH Cl /CH OH=
f
2
2
3
8.69, 28.06, 27.03, 22.21, 19.71, 19.56, 16.91, 16.25, 15.10 ppm; IR
1
1
(
5
(
(
(
0
5:1); H NMR (400 MHz, CDCl ): d=7.65 (s, 1H), 6.31 (t, 1H), 5.30
ꢀ1
3
(KBr): 3400, 2926, 1641, 1453, 1155, 1031, 581 cm ; ESI-HRMS calcd
d, 1H, J1,2 =3.2 Hz, overlap with CH Cl ), 5.16–5.18 (m, 3H), 5.11–
.14 (m, 4H), 4.78–4.91 (m, 2H), 4.72 (brs, 1H), 4.58 (brs, 1H), 4.48
d, 2H, J=4.8 Hz), 4.04–4.08 (m, 1H), 3.32–3.99 (m, 92H), 3.16–3.26
m, 7H), 3.07–3.14 (m, 1H), 3.02 (dd, 1H, J=3.4, 9.8 Hz), 2.37–2.44
m, 1H), 0.88–2.04 (m, other aliphatic ring protons), 1.67, 0.96, 0.95,
+
2
2
for C H N O
36
C H N NaO [M+Na] : 1675.7574, found: 1675.7494.
[M+H] : 1653.7755, found: 1653.7821;
75
121
4
+
75
120
4
36
1
-Benzotriazolyl 3b-hydroxyolean-12-en-28-oate (17): According
to general procedure A, the residue was purified by flash chroma-
tography (eluent: PE/EtOAc=4:1) to afford 17 as a white solid in
13
.84, 0.81, 0.75 (6ꢂCH ), 0.67 ppm (d, 1H, J=8.8 Hz); C NMR
3
(
100 MHz, CDCl ): d=176.24, 150.79, 144.33, 124.45, 109.43, 99.19,
3
93% yield. R =0.42 (PE/EtOAc=2:1); d=8.05 (d, 1H, J=8.4 Hz),
f
9
8
7
6
5
5
3
1
1
1
8.93, 98.90, 98.85, 98.75, 98.23, 82.70, 82.14, 82.02, 82.01, 81.96,
1.88, 81.78, 81.76, 81.51, 81.08, 80.39, 80.27, 80.18, 79.79, 79.02,
8.90, 71.57, 71.32, 71.25, 71.04, 70.96, 70.92, 70.76, 70.56, 70.20,
1.77, 61.48, 61.45, 61.34, 61.32, 61.28, 59.20, 59.06, 58.99, 58.93,
8.70, 58.63, 58.58, 58.43, 58.32, 58.29, 55.62, 55.33, 51.21, 50.56,
0.08, 46.76, 42.43, 40.73, 38.83, 38.67, 38.20, 37.76, 37.18, 34.65,
4.29, 33.54, 30.82, 29.40, 27.96, 27.38, 25.56, 20.88, 19.37, 18.28,
6.11, 15.95, 15.35, 14.61 ppm; IR (KBr): n˜ =3436, 2930, 1660, 1460,
7
8
.52 (t, 1H, J=7.4 Hz), 7.39 (t, 1H, J=8.0 Hz), 7.37 (d, 1H, J=
.2 Hz), 5.38 (t, 1H, J=3.4 Hz), 3.22 (dd, 1H, J=4.2, 11.4 Hz), 2.98
(dd, 1H, J=4.1, 13.6 Hz), 2.26 (td, 1H, J=5.4, 14.9 Hz), 2.14 (td, 1H,
J=4.6, 13.5 Hz), 0.78–2.05 (m, other aliphatic ring protons), 1.22,
1
.00, 0.97, 0.91, 0.85, 0.77 (6ꢂCH ), 0.75 ppm (d, 1H, J=11.6 Hz);
3
13
C NMR (100 MHz, CDCl ): d=173.57, 143.51, 142.06, 128.73,
3
1
4
28.40, 124.56, 123.87, 120.46, 108.11, 78.91, 55.21, 47.57, 47.53,
5.44, 41.87, 41.56, 39.44, 38.92, 38.72, 38.48, 36.98, 34.07, 33.64,
ꢀ
1
+
038, 554 cm
;
ESI-HRMS calcd for C H N O
[M+H] :
95
161
4
36
32.88, 32.81, 32.39, 30.60, 29.44, 28.09, 28.02, 27.14, 25.70, 23.48,
934.0885, found: 1934.0836.
2
1
7
3.43, 23.09, 22.91, 22.62, 20.11, 19.13, 18.28, 17.25, 15.56, 15.33,
4.37, 11.35 ppm; IR (KBr): n˜ =3433, 2945, 1810, 1632, 1381, 1048,
A
N-[1-(6 -deoxyper-O-acetyl-b-CD-6-yl)-1H-1,2,3-triazol-4-yl]meth-
yl 3b-hydroxylup-20(29)-en-28-amide (12): Prepared from 5 and
ꢀ1
+
43 cm
; ESI-HRMS calcd for C H N O [M+H] : 574.4033,
36 52 3 3
found: 574.4014.
1
0 according to general procedure C, the residue was purified by
flash chromatography (eluent: PE/EtOAc/acetone=1:1:1) to afford
2 as a white solid in 73% yield. R =0.34 (CH Cl /CH OH=15:1);
1
-Benzotriazolyl 3b-dihydroxyurs-12-en-28-oate (19): According
1
f
2
2
3
to general procedure A, the residue was purified by flash chroma-
tography (eluent: PE/EtOAc=4:1) to afford 19 as a white solid in
93% yield. R =0.42 (PE/EtOAc=2:1); H NMR (400 MHz, CDCl ): d=
1
H NMR (400 MHz, CDCl ): d=7.58 (s, 1H), 6.47 (t, 1H), 5.54 (d, 1H,
3
J1,2 =3.2 Hz), 5.25–5.38 (m, 6H), 5.13–5.19 (m, 2H), 5.00–5.13 (m,
1
f
3
6
4
4
8
3
H), 5.05 (m, 1H), 4.94 (dd, 1H, J=4.0, 8.3 Hz), 4.66–4.87 (m, 7H),
.73 (m, 2H), 4.69 (m, 1H), 4.52–4.61 (m, 5H), 4.58 (m, 1H), 4.01–
.39 (m, 13H), 4.35(m, 1H), 3.69–3.77 (m, 5H), 3.62 (t, 1H, J=
.3 Hz), 3.54 (t, 1H, J=8.9 Hz), 3.18 (dd, 1H, J=4.6, 11.2 Hz), 3.09–
.13 (m, 1H), 2.48 (t, 1H, J=9.7 Hz), 2.03–2.18 (m, 60H), 0.86–1.90
8
7
2
6
0
.04 (d, 1H, J=8.4 Hz), 7.51 (t, 1H, J=7.4 Hz), 7.39 (t, 1H, J=
.5 Hz), 7.35 (d, 1H, J=8.3 Hz), 5.38 (t, 1H, J=3.5 Hz), 3.23 (m, 1H),
.39 (d, 1H, J=1.2 Hz), 2.29 (td, 1H, J=4.0, 13.4 Hz), 1.93–2.21 (m,
H), 0.85–1.71 (m, other aliphatic ring protons), 1.12, 1.01, 1.00,
.94, 0.92, 0.91, 0.80 (6ꢂCH ), 0.75 ppm (d, 1H, J=11.6 Hz);
3
(
(
m, other aliphatic ring protons), 1.67, 1.26, 0.96, 0.91, 0.82, 0.75
6ꢂCH ), 0.67 ppm (d, 1H, J=8.4 Hz); C NMR (100 MHz, CDCl3):
13
C NMR (100 MHz, CDCl ): d=173.25, 143.45, 136.76, 128.68,
3
13
3
128.30, 127.04, 124.49, 120.37, 108.12, 78.84, 55.21, 52.94, 49.04,
d=176.29, 170.82, 170.72, 170.67, 170.57, 170.51, 170.46, 170.36,
4
2
1
7
7.47, 42.22, 39.63, 38.96, 38.69, 38.64, 36.90, 36.62, 33.14, 30.42,
8.31, 28.10, 27.14, 24.28, 23.29, 20.95, 18.23, 17.45, 16.81, 15.59,
5.46 ppm; IR (KBr): n˜ =3433, 2927, 1806, 1620, 1458, 1047,
1
1
7
7
6
5
3
2
70.25, 169.51, 169.39, 169.34, 169.29, 169.13, 150.93, 144.89,
24.73, 109.34, 97.06, 96.92, 96.84, 96.80, 96.71, 96.60, 96.41, 78.95,
7.87, 77.20, 77.02, 76.84, 76.69, 76.55, 75.95, 71.50, 71.34, 71.28,
1.12, 70.98, 70.82, 70.46, 70.39, 70.18, 70.04, 69.98, 69.87, 69.66,
9.54, 69.49, 69.37, 69.29, 62.77, 62.69, 62.59, 62.46, 62.25, 55.63,
5.36, 50.62, 50.08, 49.55, 46.66, 42.45, 40.72, 38.83, 38.70, 38.16,
7.66, 37.40, 37.18, 34.71, 34.36, 33.49, 30.84, 29.44, 29.24, 27.95,
7.40, 25.60, 20.87, 20.77, 20.72, 20.63, 19.40, 18.29, 16.10, 16.07,
ꢀ1
+
42 cm
; ESI-HRMS calcd for C H N O [M+H] : 574.4003,
36 52 3 3
found: 574.4005.
N-propargyl 3b-hydroxyolean-12-en-28-amide (20): According to
general procedure B, the residue was purified by flash chromatog-
raphy (eluent: PE/EtOAc=4:1–3:1) to afford 20 as a white solid in
ꢀ
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 0000, 00, 1 – 12
&
7
&
ÞÞ
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CHEMMEDCHEM
FULL PAPERS
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1
9
6
3
1
0
5% yield. R =0.40 (PE/EtOAc=2:1); H NMR (400 MHz, CDCl ): d=
3H), 3.39 (2ꢂs, 6H), 3.38 (s, 3H), 3.34 (s, 3H), 3.33 (s, 3H), 3.00 (dd,
1H, J=2.4, 10.8 Hz), 2.74 (dd, 1H, J=3.3, 13.4 Hz), 2.22 (t, 1H, J=
13.3 Hz), 0.86–2.02 (m, other aliphatic ring protons), 1.35, 0.99,
f
3
.12 (t, 1H, J=4.5 Hz), 5.42 (t, 1H, J=3.1 Hz), 3.87–4.09 (m, 2H),
.22 (dd, 1H, J=4.3, 11.1 Hz), 2.54 (dd, 1H, J=3.3, 12.6 Hz), 2.21 (t,
H, J=2.4 Hz), 0.81–2.03 (m, other aliphatic ring protons), 1.17,
.99, 0.91, 0.80, 0.79 (7ꢂCH ), 0.73 ppm (d, 1H, J=11.2 Hz);
C NMR (100 MHz, CDCl ): d=177.95, 144.62, 123.10, 79.58, 78.77,
1.52, 55.02, 47.44, 46.56, 46.20, 42.02, 41.92, 39.30, 38.67, 38.43,
6.85, 33.98, 32.90, 32.24, 32.14, 30.62, 29.25, 28.01, 27.16, 27.05,
5.67, 23.78, 23.50, 23.44, 18.19, 16.87, 15.50, 15.29 ppm; IR (KBr):
n˜ =3436, 2942, 2876, 1658, 1509, 1045 cm ; ESI-HRMS calcd for
C H NO [M+NH ] : 494.3993, found: 494.3991.
13
0.91, 0.90, 0.78, 0.65 ppm (7ꢂCH3); C NMR (100 MHz, CDCl ): d=
3
177.70, 144.13, 143.38, 124.42, 123.55, 99.16, 98.92, 98.81, 98.73,
98.59, 98.18, 82.16, 82.12, 81.98, 81.96, 81.84, 81.74, 81.70, 81.39,
81.13, 80.39, 80.30, 80.24, 79.78, 79.64, 78.82, 78.70, 75.37, 71.57,
71.32, 71.22, 71.03, 70.96, 70.94, 70.88, 70.79, 70.58, 70.14, 61.71,
61.48, 61.44, 61.33, 61.29, 59.21, 59.06, 58.98, 58.92, 58.65, 58.63,
58.61, 58.44, 58.34, 58.30, 55.14, 50.97, 48.94, 46.77, 46.68, 41.74,
41.50, 39.56, 38.72, 38.50, 36.90, 35.24, 35.22, 35.11, 32.54, 32.48,
3
1
3
3
7
3
2
ꢀ
1
+
3
3
52
3
4
3
1
9
1
0.53, 30.19, 28.01, 27.13, 26.85, 25.12, 23.33, 18.18, 16.81,
N-propargyl 3b-dihydroxyurs-12-en-28-amide (22): According to
general procedure B, the residue was purified by flash chromatog-
raphy (eluent: PE/EtOAc=4:1) to afford 22 as a white solid in 93%
5.56 ppm; IR (KBr): n˜ =3434, 2929, 1730, 1658, 1462, 1368, 1038,
ꢀ1
+
71, 554 cm ; ESI-HRMS (m/z) calcd for C H N O Na [M+Na] :
95
160
4
37
972.0654, found: 1972.0618.
1
yield. R =0.41 (PE/EtOAc=2:1); H NMR (400 MHz, CDCl ): d=6.12
f
3
(
1
1
1
7
3
2
1
brs, 1H), 5.36 (brs, 1H), 3.87–4.06 (m, 2H), 3.21 (dd, 1H, J=3.6,
1.2 Hz), 2.22 (brt, 1H), 0.87–2.02 (m, other aliphatic ring protons),
.10, 0.99, 0.95, 0.92, 0.87, 0.80, 0.78 (7ꢂCH ), 0.72 ppm (d, 1H, J=
A
[
3
1-(6 -deoxyper-O-methyl-b-CD-6-yl)-1H-1,2,3-triazol-4-yl]methyl
b-dihydroxyurs-12-en-28-amide (25): Prepared from 4 and 22
according to general procedure C, the residue was purified by
flash chromatography (eluent: PE/EtOAc/acetone=1:2:1) to afford
5 as a white solid in 73% yield. R =0.53 (PE/EtOAc/acetone=
3
1
3
1.0 Hz); C NMR (100 MHz, CDCl ): d=177.80, 139.60, 125.97,
3
9.63, 78.77, 71.51, 55.04, 53.59, 47.63, 47.43, 42.33, 39.60, 39.45,
2
1
5
1
1
1
f
8.93, 38.65, 38.57, 36.81, 36.76, 32.60, 30.73, 29.26, 28.04, 27.71,
7.08, 24.83, 23.29, 23.18, 21.12, 18.16, 17.13, 16.82, 15.54,
5.42 ppm; IR (KBr): n˜ =3421, 2936, 2870, 1649, 1516, 1456, 1045,
1
:2:3); H NMR (400 MHz, CDCl ): d=7.62 (s, 1H), 6.57 (brs, 1H),
3
.36 (d, 1H, J1,2 =3.2 Hz), 5.33 (brs, 1H), 5.14–5.18 (m, 5H), 5.11 (d,
H, J1,2 =3.3 Hz), 5.08 (dd, 1H, J=4.8, 14.4 Hz), 4.70 (d, 1H, J=
2.9 Hz), 4.56 (dd, 1H, J=5.6, 14.9 Hz), 4.27 (dd, 1H, J=4.9,
4.7 Hz), 4.01–4.05 (m, 1H), 3.15–3.94 (m, 40H), 3.65 (s, 12H), 3.63
ꢀ1
+
7
23 cm ; ESI-HRMS calcd for C H NO [M+NH ] : 494.3993,
33 52 3 4
found: 494.3989.
A
(s, 9H), 3.52 (s, 6H), 3.51 (s, 6H), 3.50 (2ꢂs, 6H), 3.48 (s, 3H), 3.39
2ꢂs, 12H), 3.35 (s, 3H), 3.34 (s, 3H), 2.98 (dd, 1H, J=3.1, 9.8 Hz),
N-[1-(6 -deoxyper-O-methyl-b-CD-6-yl)-1H-1,2,3-triazol-4-yl]-
methyl 3b-hydroxyolean-12-en-28-amide (23): Prepared from 4
and 20 according to general procedure C, the residue was purified
by flash chromatography (eluent: PE/EtOAc/acetone=1:2:1) to
(
0
0
0
.85–2.02 (m, other aliphatic ring protons), 2.02 (m, 1H), 1.08, 0.98,
.93, 0.89, 0.85, 0.86, 0.77 (6ꢂCH ), 0.71 (d, 1H, J=11.4 Hz),
3
13
.64 ppm (CH3); C NMR (100 MHz, CDCl ): d=178.07, 144.11,
3
afford 23 as a white solid in 73% yield. R =0.53 (PE/EtOAc/ace-
tone=1:2:3); H NMR (400 MHz, CDCl ): d=7.64 (s, 1H), 6.59 (brs,
f
1
139.21, 126.08, 124.71, 99.20, 98.95, 98.85, 98.77, 98.52, 98.16,
3
8
8
7
6
5
3
2
2.14, 82.10, 82.01, 81.98, 81.89, 81.88, 81.77, 81.71, 81.40, 81.11,
0.48, 80.36, 80.29, 79.76, 79.68, 78.90, 78.67, 71.69, 71.33, 71.24,
1.08, 70.99, 70.89, 70.80, 70.60, 70.15, 61.76, 61.51, 61.47, 61.33,
1.29, 61.27, 61.20, 59.26, 59.07, 58.99, 58.94, 58.68, 58.63, 58.42,
8.30, 58.28, 55.08, 53.57, 50.97, 47.64, 47.51, 42.33, 39.68, 39.49,
8.98, 38.72, 38.56, 37.01, 36.91, 34.78, 32.67, 30.81, 28.08, 27.82,
7.17, 24.85, 23.29, 21.16, 18.23, 17.15, 16.62, 15.59, 15.44 ppm; IR
1
H), 5.38 (t, 1H, J=4.0 Hz), 5.33 (d, 1H, J1,2 =3.5 Hz), 5.16 (d, 2H,
J1,2 =3.3 Hz), 5.12–5.13 (m, 3H), 5.10 (d, 1H, J1,2 =3.6 Hz), 4.94 (dd,
1H, J=5.0, 14.0 Hz), 4.75 (brd, 1H, J=12.4 Hz), 4.58 (dd, 1H, J=
5.7, 15.0 Hz), 4.28 (dd, 1H, J=4.4, 15.2 Hz), 4.03–4.05 (m, 1H), 3.47–
3.96 (m, 72H), 3.26–4.43 (m, 18H), 3.38 (m, 1H), 3.29 (m, 1H), 3.24
(
9
dd, 1H, J=3.5, 9.44 Hz), 3.16–3.22 (m, 6H), 2.98 (dd, 1H, J=3.4,
.8 Hz), 2.53 (brd, 1H, J=9.2 Hz), 0.85–2.01 (m, other aliphatic ring
protons), 1.14, 0.97, 0.88, 0.87, 0.86, 0.77 (6ꢂCH ), 0.70–0.72 (m,
ꢀ
1
(KBr): n˜ =3436, 2929, 1659, 1459, 1369, 1040, 972, 554 cm ; ESI-
3
+
1
3
HRMS calcd for C H N O
36
[M+H] : 1934.0885, found:
95
161
4
1
1
8
8
7
6
5
3
2
H), 0.61 ppm (CH3); C NMR (100 MHz, CDCl ): d=178.21, 144.30,
3
1
934.0854.
44.17, 124.79, 123.17, 99.22, 98.97, 98.86, 98.79, 98.60, 98.20,
2.27, 82.13, 82.03, 81.99, 81.89, 81.80, 81.76, 81.70, 81.42, 81.11,
0.47, 80.40, 80.27, 79.76, 79.70, 78.88, 78.78, 71.67, 71.32, 71.22,
1.03, 70.98, 70.89, 70.78, 70.60, 70.15, 69.47, 61.74, 61.51, 61.49,
1.33, 61.29, 59.24, 59.07, 58.99, 58.94, 58.69, 58.64, 58.42, 58.31,
8.26, 55.06, 51.07, 47.52, 46.57, 46.21, 42.00, 41.90, 39.31, 38.72,
8.41, 36.93, 34.82, 34.05, 32.96, 32.46, 32.31, 30.68, 28.05, 27.28,
7.13, 25.77, 23.76, 23.62, 23.43, 18.25, 16.60, 15.54, 15.32 ppm; IR
A
[1-(6 -deoxyper-O-acetyl-b-CD-6-yl)-1H-1,2,3-triazol-4-yl]methyl
3
b-hydroxyolean-12-en-28-amide (26): Prepared from 5 and 20
according to general procedure C, the residue was purified by
flash chromatography (eluent: PE/EtOAc/acetone=1:1:1) to afford
2
6 as a white solid in 61% yield. R =0.38 (CH Cl /CH OH=15:1);
f 2 2 3
1
H NMR (400 MHz, CDCl ): d=7.58 (s, 1H), 6.63 (t, 1H, J=5.3 Hz),
3
ꢀ
1
5.62 (d, 1H, J1,2 =3.8 Hz), 5.40 (brs, 1H), 5.26–5.36 (m, 6H, overlap
with CH Cl ), 5.16–5.20 (m, 3H), 5.08–5.13 (m, 3H), 5.07 (d, 1H, J=
(
KBr): n˜ =3429, 2929, 1659, 1461, 1367, 1040, 972, 556 cm ; ESI-
+
2
2
HRMS calcd for C H N NaO [M+Na] : 1956.0704, found:
9
5
160
4
36
3
.7 Hz), 5.03 (d, 1H, J=3.6), 4.95 (dd, 1H, J=3.9, 8.6 Hz), 4.74–4.88
1
956.0713.
(m, 6H), 4.12–4.70 (m, 22H), 3.69–3.77 (m, 5H), 3.65 (t, 1H, J=
A
[1-(6 -deoxyper-O-methyl-b-CD-6-yl)-1H-1,2,3-triazol-4-yl]methyl
8.2 Hz), 3.51 (t, 1H, J=9.5 Hz), 3.20 (dd, 1H, J=4.2, 11.2 Hz), 2.60–
3b,16a-dihydroxyolean-12-en-28-amide (24): Prepared from 4
2.62 (m, 1H), 2.02–2.18 (m, 60H), 0.75–1.90 (m, other aliphatic ring
and 21 according to general procedure C, the residue was purified
by flash chromatography (eluent: PE/EtOAc/acetone=1:2:1) to
protons), 1.26, 1.15, 0.98, 0.89, 0.88, 0.77, 0.59 (7ꢂCH ), 0.73 ppm
3
13
(t, 1H, J=11.6 Hz); C NMR (100 MHz, CDCl ): d=178.13, 170.78,
3
afford 24 as a white solid in 65% yield. R =0.38 (PE/EtOAc/ace-
170.74, 170.71, 170.66, 170.58, 170.54, 170.48, 170.42, 170.35,
170.33, 170.28, 170.22, 169.54, 169.40, 169.37, 169.36, 169.28,
169.15, 144.36, 144.22, 125.14, 123.05, 97.08, 96.98, 96.85, 96.66,
96.61, 96.54, 96.37, 78.89, 77.36, 77.20, 76.92, 76.85, 76.66, 75.91,
71.63, 71.23, 71.17, 70.89, 70.79, 70.68, 70.41, 70.34, 70.12, 69.97,
69.82, 69.73, 69.66, 69.60, 69.51, 69.47, 69.42, 69.29, 62.80, 62.57,
62.42, 62.35, 62.22, 55.07, 49.17, 47.51, 46.53, 46.17, 41.92, 41.87,
f
1
tone=1:2:3); H NMR (400 MHz, CDCl ): d=7.60 (brs, 1H), 6.86 (t,
3
1
2
H, J=5.1 Hz), 5.52 (brs, 1H), 5.34 (d, 1H, J=3.6 Hz), 5.17–5.18 (m,
H), 5.11–5.14 (m, 4H), 4.92 (dd, 1H, J=5.3, 14.4 Hz), 4.76 (dd, 1H,
J=2.2, 14.3 Hz), 4.54 (dd, 1H, J=5.4, 15.1 Hz), 4.39 (brs, 1H), 4.27
dd, 1H, J=4.7, 15.0 Hz), 4.02–4.06 (m, 1H), 3.17–3.96 (m, 39H),
.65 (s, 9H), 3.63 (s, 12H), 3.52, 3.51, 3.50, 3.48 (4ꢂs, 21H), 3.40 (s,
(
3
ꢀ
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 0000, 00, 1 – 12
&
8
&
ÞÞ
These are not the final page numbers!

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3
2
2
1
6
9.28, 38.71, 38.42, 36.89, 35.01, 34.03, 32.97, 32.48, 32.34, 30.66,
8.03, 27.27, 27.13, 25.74, 23.72, 23.57, 23.41, 20.84, 20.81, 20.76,
0.74, 20.71, 20.68, 20.65, 20.62, 20.57, 18.23, 16.58, 15.51,
5.28 ppm; IR (KBr): n˜ =3433, 1932, 1750, 1651, 1372, 1238, 1045,
1H), 4.57 (dd, 1H, J=6.9, 14.3 Hz), 4.49 (d, 1H, J=15.3 Hz), 4.27–
4.33 (m, 2H), 4.03–4.09 (m, 1H), 3.71–3.93 (m, 23H), 3.41–3.59 (m,
13H), 3.38 (brs, 1H), 3.23 (t, 1H, J=9.4 Hz), 3.16 (t, 1H, J=5.0 Hz),
3.10–3.15 (m, 1H), 2.88–2.91 (m, 1H), 2.28 (t, 1H, J=13.3 Hz), 1.92–
1.96 (m, 3H), 1.80–1.85 (m, 1H), 0.70–1.67 (m, other aliphatic ring
ꢀ1
2+
03 cm ; ESI-HRMS (m/z) calcd for C115H160N Na O [M+2Na]
4
2
56
1
3
:
1269.4796, found: 1269.4846.
protons), 1.35, 0.97, 0.94, 0.89, 0.77, 0.71 ppm (7ꢂCH3); C NMR
(
100 MHz, CDCl /CD OD 5:1): d=180.04, 145.79, 144.43, 126.01,
3 3
A
[
1-(6 -deoxy-b-CD-6-yl)-1H-1,2,3-triazol-4-yl]methyl 3b-hydroxyo-
1
8
7
4
3
1
5
1
1
24.03, 103.84, 103.71, 103.70, 103.63, 103.26, 84.63, 82.86, 82.81,
2.67, 79.43, 75.11, 74.45, 74.41, 74.38, 74.23, 74.13, 73.96, 73.79,
3.61, 73.36, 73.31, 72.92, 71.70, 61.55, 61.05, 56.48, 52.01, 49.99,
7.90, 47.59, 42.67, 42.13, 40.61, 39.71, 39.62, 37.87, 35.88, 33.66,
3.12, 30.95, 30.79, 28.59, 27.62, 27.32, 25.75, 24.27, 19.21, 17.72,
6.23, 16.16 ppm; IR (KBr): n˜ =3399, 2929, 1639, 1155, 1081, 1032,
lean-12-en-28-amide (27): Prepared from 26 according to general
procedure D, the residue was purified by RP flash chromatography
eluent: CH OH) to afford 27 as a white solid in 92% yield. H NMR
400 MHz, CDCl /CD OD 5:1): d=7.79 (s, 1H), 5.36 (brs, 1H), 5.07
1
(
(
(
1
1
3
2
3
3
3
d, 1H, J1,2 =3.4 Hz), 4.93–4.96 (m, 7H, overlap with H O), 4.56 (dd,
2
H, J=7.4, 14.3 Hz), 4.48 (d, 1H, J=15.2 Hz), 4.34 (d, 1H, J=
5.2 Hz), 4.05–4.09 (m, 1H), 3.70–3.91 (m, 23H), 3.37–3.57 (m, 14H),
.25 (t, 1H, J=9.4 Hz), 3.14–3.15 (m, 2H), 2.76–2.80 (m, 1H), 2.03–
.10 (m, 1H), 1.90–1.92 (m, 1H), 1.77 (t, 1H, J=13.4 Hz), 0.90–1.62
ꢀ1
+
81 cm
;
ESI-HRMS (m/z) calcd for C H N O
37
[M+H] :
75
121
4
+
669.7704, found: 1669.7677; calcd for C H N NaO [M+Na] :
75
120
4
37
691.7524, found: 1691.7489.
(
m, other aliphatic ring protons), 1.16, 0.97, 0.93, 0.91, 0.77 (6ꢂ
A
13
[
1-(6 -deoxyper-O-acetyl-b-CD-6-yl)-1H-1,2,3-triazol-4-yl]methyl
CH ), 0.75 (d, 1H, J=12.0 Hz), 0.66 ppm (CH ); C NMR (100 MHz,
3
3
3b-dihydroxyurs-12-en-28-amide (30): Prepared from 5 and 22
CDCl /CD OD 5:1): d=180.25, 146.12, 144.87, 126.14, 124.03,
3
3
according to general procedure D, the residue was purified by
flash chromatography (eluent: PE/EtOAc/acetone=1:1:1) to afford
1
7
6
3
2
1
6
03.92, 103.78, 103.73, 103.32, 84.69, 82.87, 82.80, 82.67, 79.50,
8.94, 74.51, 74.30, 74.22, 74.03, 73.86, 73.67, 73.39, 73.01, 71.80,
1.59, 61.07, 56.44, 51.94, 49.85, 47.39, 47.33, 42.72, 42.42, 40.43,
9.67, 39.62, 37.95, 35.84, 34.93, 33.97, 33.60, 33.52, 31.49, 28.65,
8.31, 27.64, 26.45, 24.38, 24.06, 23.95, 19.30, 17.61, 16.27,
5.91 ppm; IR (KBr): n˜ =3435, 2946, 1750, 1651, 1372, 1238, 1045,
3
0 as a white solid in 61% yield. R =0.38 (CH Cl /CH OH=15:1);
f 2 2 3
1
H NMR (400 MHz, CDCl ): d=7.57 (s, 1H), 6.63 (t, 1H, J=5.0 Hz),
3
5
.62 (d, 1H, J1,2 =3.8 Hz), 5.26–5.38 (m, 6H), 5.35 (m, 1H), 5.16–5.23
(m, 3H), 5.12 (d, 1H, J=4.0 Hz), 5.08–5.11 (m, 2H), 5.07 (d, 1H, J=
ꢀ1
+
3.6 Hz), 5.01 (d, 1H, J=3.7 Hz), 4.95 (dd, 1H, J=3.8, 8.7 Hz), 4.75–
4.88 (m, 6H), 4.69 (d, 1H, J=11.4 Hz), 4.63 (m, 1H), 4.08–4.60 (m,
27H), 3.69–3.78 (m, 5H), 3.65 (t, 1H, J=8.4 Hz), 3.52 (t, 1H, J=
9.1 Hz), 3.20 (dd, 1H, J=4.0, 11.4 Hz), 2.02–2.18 (m, 60H), 0.90–2.10
03 cm
;
ESI-HRMS (m/z) calcd for C H N O
36
[M+H]
75
121
4
+
:
:
1653.7755, found: 1653.7673, calcd for C H N NaO [M+Na]
75 120 4 36
1675.7574, found: 1675.7566.
A
[1-(6 -deoxyper-O-acetyl-b-CD-6-yl)-1H-1,2,3-triazol-4-yl]methyl
(
0
m, other aliphatic ring protons), 1.26, 1.09, 0.98, 0.89, 0.86, 0.77,
.62 (7ꢂCH ), 0.71 ppm (d, 1H, J=11.6 Hz); C NMR (100 MHz,
3
13
3
b,16a-dihydroxyolean-12-en-28-amide (28): Prepared from 5
and 21 according to general procedure D, the residue was purified
by flash chromatography (eluent: PE/EtOAc/acetone=1:1:1) to
CDCl ): d=178.04, 170.79, 170.74, 170.72, 170.67, 170.63, 170.57,
3
1
70.55, 170.50, 170.43, 170.35, 170.29, 170.24, 169.56, 169.41,
afford 28 as a white solid in 68% yield. R =0.25 (eluent: PE/EtOAc/
f
169.39, 169.37, 169.35, 169.29, 169.16, 144.25, 139.04, 126.03,
125.16, 97.10, 97.00, 96.85, 96.67, 96.61, 96.59, 96.38, 78.93, 77.36,
76.94, 76.89, 76.69, 76.62, 75.90, 71.62, 71.25, 71.22, 70.91, 70.79,
70.65, 70.40, 70.35, 70.12, 70.05, 70.02, 69.96, 69.75, 69.66, 69.61,
69.52, 69.46, 69.28, 62.80, 62.61, 62.57, 62.43, 62.38, 62.22, 55.10,
53.47, 49.18, 47.60, 47.51, 42.28, 39.64, 39.48, 38.88, 38.71, 38.58,
36.99, 36.87, 34.92, 32.71, 30.81, 29.22, 28.07, 27.81, 27.17, 24.77,
1
acetone=1:2:3); H NMR (400 MHz, CDCl ): d=7.52 (brs, 1H), 6.90
3
(
brs, 1H), 5.58 (d, 1H, J1,2 =3.3 Hz), 5.52 (brs, 1H), 5.24–5.37 (m,
6
5
3
1
4
H), 5.19 (t, 1H, J=8.4 Hz), 5.17 (d, 1H, J1,2 =3.7 Hz), 5.15 (m, 1H),
.10 (d, 1H, J1,2 =4.0 Hz), 5.08 (d, 1H, J1,2 =4.0 Hz), 5.06 (d, 1H, J1,2
=
.7 Hz), 5.04 (d, 1H, J1,2 =3.7 Hz), 4.99 (d, 1H, J1,2 =3.6 Hz), 4.92 (dd,
H, J1,2 =3.7 Hz, J2,3 =8.7 Hz), 4.78–4.84 (m, 3H), 4.73–4.76 (m, 2H),
.09–4.68 (m, 23H), 3.67–377 (m, 5H), 3.62 (m, 1H, J=8.3 Hz), 348
2
1
3.29, 21.17, 20.86, 20.83, 20.77, 20.74, 20.69, 20.66, 20.63, 20.58,
(
m, 1H, J=9.0 Hz), 3.18 (dd, 1H, J=4.6, 10.7 Hz), 3.18 (dd, 1H, J=
.5, 13.5 Hz), 2.01–2.13 (m, 60H), 1.32, 0.97, 0.91, 0.88, 0.87, 0.75,
8.22, 17.12, 16.61, 15.56, 15.40 ppm; IR (KBr): n˜ =3419, 2930, 1640,
ꢀ1
2
0
1
1
1
9
7
7
6
4
3
2
1155, 1081, 1033, 582 cm ; HRMS calcd for C115H160N NaO [M+
4 56
1
3
+
.62 ppm (7ꢂCH3); C NMR (100 MHz, CDCl ): d=177.64, 170.77,
3
Na] : 2515.9687, found: 2515.9626.
70.70, 170.68, 170.60, 170.54, 170.47, 170.44, 170.34, 170.32,
70.27, 170.22, 169.52, 169.38, 169.36, 169.34, 169.27, 169.14,
A
[
1-(6 -deoxy-b-CD-6-yl)-1H-1,2,3-triazol-4-yl]methyl 3b-dihydrox-
44.41, 143.19, 124.82 (triazole-CH ), 123.42, 97.03 (2C), 96.81,
2
yurs-12-en-28-amide (31): Prepared from 30 according to general
6.65, 96.60, 96.56, 96.41, 78.84, 77.31, 77.20, 76.97, 76.75, 76.67,
6.56, 75.88, 75.15, 71.57, 71.27, 71.22, 70.91, 70.57, 70.41, 70.29,
0.17, 70.06, 69.98, 69.83, 69.67, 69.63, 69.53, 69.47, 69.32, 62.78,
2.62, 62.58, 62.47, 62.41, 62.24, 55.21, 49.27, 49.07, 46.77, 46.68,
1.78, 41.46, 39.63, 38.73, 38.56, 36.90, 35.32, 35.21, 35.07, 32.55,
0.13, 29.03, 28.01, 27.17, 26.89, 25.37, 23.33, 20.82, 20.78, 20.76,
0.73, 20.70, 20.69, 20.65, 20.61, 20.57, 18.21, 16.85, 15.54 ppm; IR
procedure D, the residue was purified by RP flash chromatography
1
(
eluent: CH OH) to afford 31 as a white solid in 91% yield. H NMR
3
(
400 MHz, CDCl ): d=7.89 (brs, 1H), 5.11 (d, 1H, J =3.7 Hz), 4.95–
3
1,2
4
1
1
.99 (m, 6H, 5ꢂCD-H ), 4.93 (m, 1H, overlap with H O), 4.65 (dd,
1 2
H, J=7.6, 14.4 Hz), 4.43 (d, 1H, J=15.3 Hz), 4.37 (d, 1H, J=
5.3 Hz), 4.06–4.10 (m, 1H), 3.42–3.93 (m, 36H), 3.37 (m, 1H), 3.31
ꢀ1
(m, 1H, overlap with CH OH), 3.12–3.17 (m, 2H), 2.15 (d, 1H, J=
3
(
KBr): n˜ =3435, 2960, 1750, 1656, 1372, 1237, 1045, 603 cm ; ESI-
+
10.8 Hz), 2.05–2.13 (m, 1H), 0.80–1.95 (m, other aliphatic ring pro-
HRMS calcd for C115H160N NaO [M+NH ] : 2531.9637, found:
4
57
4
tons), 1.13, 0.98, 0.91, 0.93, 0.79, 0.67 (7ꢂCH ), 0.75 ppm (d, 1H, J=
3
2
531.9640.
13
1
1.5 Hz); C NMR (100 MHz, CDCl ): d=180.35, 145.96, 139.83,
3
A
[
1-(6 -deoxy-b-CD-6-yl)-1H-1,2,3-triazol-4-yl]methyl 3b,16a-dihy-
127.31, 126.73, 104.01, 103.99, 103.88, 103.79, 103.48, 84.78, 83.08,
droxyolean-12-en-28-amide (29): Prepared from 28 according to
general procedure D, the residue was purified by RP flash chroma-
83.05, 83.02, 82.95, 82.86, 79.67, 74.80, 74.73, 74.59, 74.40, 74.23,
74.20, 74.08, 73.97, 73.87, 73.68, 73.30, 71.89, 61.92, 61.84, 61.35,
56.68, 54.14, 52.43, 49.85, 48.92, 43.26, 40.84, 40.27, 39.93, 39.84,
38.59, 38.09, 35.72, 34.14, 31.88, 29.54, 28.93, 28.78, 27.89, 25.22,
24.38, 24.09, 21.62, 19.46, 17.79, 17.71, 16.45, 16.13 ppm; IR (KBr):
tography (eluent: CH OH) to afford 29 as a white solid in 89%
3
1
yield. H NMR (400 MHz, CDCl /CD OD 5:1): d=7.78 (s, 1H), 5.48
3
3
(
brs, 1H), 5.06 (d, 1H, J1,2 =3.6 Hz), 4.93–4.97 (m, 6H), 4.91 (brs,
ꢀ
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 0000, 00, 1 – 12
&
9
&
ÞÞ
These are not the final page numbers!

CHEMMEDCHEM
FULL PAPERS
www.chemmedchem.org
ꢀ
1
n˜ =3422, 2927, 1635, 1155, 1081, 1033, 581 cm ; ESI-HRMS calcd
Acknowledgements
+
for C H N O [M+H] : 1653.7755, found: 1653.7767.
7
5
121
4
36
This work was supported by the National Basic Research Pro-
gram of China (973 Program; grant no. 2010CB12304) and the
National Natural Science Foundation of China (grant nos.
8
1101239, 20932001,81361168002, and 81373271). The authors
Bioassays
gratefully acknowledge Dr. Lingxiao Zeng (State Key Laboratory
of Natural and Biomimetic Drugs, Peking University) for carrying
out the AlogP determinations.
HCV and VSV pseudovirus entry assays: All compounds were
tested using the HCV and VSV pseudo-particle (HCVpp and VSVpp)
entry assay as described previously.
[6a,16]
Pseudotyped viruses were
produced by co-transfecting plasmid expressing HCV E1E2 or vesic-
ular stromatis G protein (VSVG) with pNL4–3 HIV proviral DNA
Keywords: antiviral agents · click chemistry · echinocystic
(
AIDS Reagent Program, NIH, Bethesda, MD, USA), the envelope-
acid
· HCV entry inhibitors · pentacyclic triterpenes ·
and Vpr-deficient HIV vector carrying a luciferase reporter gene in-
serted into the Nef position in 293T producer cells. For compound
library screening, Huh-7 cells (5ꢂ10 cells per well) were seeded
cyclodextrins
3
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0
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8
ꢀ1
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[
Received: December 20, 2013
Revised: February 19, 2014
Published online on && &&, 0000
ꢀ
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 0000, 00, 1 – 12
&
11
&
ÞÞ
These are not the final page numbers!

FULL PAPERS
S. Xiao,* Q. Wang, L. Si, Y. Shi, H. Wang,
F. Yu, Y. Zhang, Y. Li, Y. Zheng, C. Zhang,
C. Wang, L. Zhang, D. Zhou*
An awesome CD collection: A series of
water-soluble triazole-bridged b-cyclo-
dextrin (CD)–pentacyclic triterpene con-
jugates were synthesized, and their hy-
drophobicity, anti-HCV entry activities,
and toxicity were studied. Easy access
to such conjugates may provide a way
to obtain a new class of anti-HCV entry
inhibitors.
&& – &&
Synthesis and Anti-HCV Entry Activity
Studies of b-Cyclodextrin–Pentacyclic
Triterpene Conjugates
ꢀ
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 0000, 00, 1 – 12
&12
&
ÞÞ
These are not the final page numbers!