Synthesis and biological evaluation of 4α/4β-imidazolyl podophyllotoxin analogues as antitumor agents

Article abstract of DOI:10.1002/ardp.201100094

A series of 4α/4β-imidazolyl podophyllotoxin analogues have been designed and synthesized. All of the compounds were evaluated for their anticancer activity against a panel of three human cancer cell lines. Within the cell lines tested, some of the synthe

Full text of DOI:10.1002/ardp.201100094

Arch. Pharm. Chem. Life Sci. 2012, 345, 43–48
43
Full Paper
Synthesis and Biological Evaluation of 4a/4b-Imidazolyl
Podophyllotoxin Analogues as Antitumor Agents
Hai Shang1, Hong Chen2, Dongmei Zhao1, Xiaowei Tang2, Yongfeng Liu2, Li Pan1, and
Maosheng Cheng1
1 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education,
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, P. R.China
2 Tianjin Key Laboratory for Biomarkers of Occupational and Environmental Hazards, Medical College of
Chinese People’s Armed Police Forces, Tianjin, P. R.China
A series of 4a/4b-imidazolyl podophyllotoxin analogues have been designed and synthesized. All of
the compounds were evaluated for their anticancer activity against a panel of three human cancer cell
lines. Within the cell lines tested, some of the synthesized compounds showed promising anticancer
activity. Compound 12, in particular, exhibited remarkable cytotoxicity, demonstrating effects
against all tumor cell lines, including the K562/ADM cell line.
Keywords: Cancer cell lines / Cytotoxicity / Multidrug resistance / Podophyllotoxin
Received: March 15, 2011; Revised: May 29, 2011; Accepted: June 15, 2011
DOI 10.1002/ardp.201100094
Introduction
analogues, which have proven to be capable of overcoming
drug resistance against etoposide. GL-331 (5) [8–10], a 4b-
arylamino derivative, was more active than etoposide in both
in-vitro and in-vivo studies, especially in resistant malignan-
cies. TOP-53 (6) [11–13], a 4b-alkylated etoposide analogue,
exhibited high activity against non-small cell lung cancer in
both tumor cell lines and animal tumor models. Recently,
more complex and diverse modifications to podophyllotoxin
have been achieved. Among them, Wang [14, 15] and Kumar
[16–18] have reported the synthesis of 4b-[(5-substituted)-
1,2,3-triazol-1-yl] and 4b-[(4-substituted)-1,2,3-triazol-1-yl]
podophyllotoxin derivatives as new anticancer compounds,
respectively (Fig. 1). These two series of podophyllotoxin
derivatives showed significant cytotoxic activity against sev-
eral human cancer cell lines. These results attracted our
interest and prompted us to synthesize the C-4 imidazole
substituted analogues as new anticancer compounds. Thus,
we now report the synthesis of a library of 4a/4b-imidazolyl
podophyllotoxin derivatives as antitumor agents.
Podophyllotoxin (1) has been shown to inhibit tubulin assem-
bly during the formation of microtubules via tubulin binding
[1, 2]; however, its high toxicity has limited its application as
a chemotherapeutic. In order to obtain more potent, yet less
toxic, anticancer agents, many derivatives of podophyllo-
toxin have been synthesized. Among them, two semi-
synthetic glycosidic cyclic acetals of podophyllotoxin, etopo-
side (2) and teniposide (3), are widely used as anticancer drugs
and show encouraging clinical efficacy against several types
of neoplasms [3, 4]. This clinical efficacy is due to their ability
to inhibit the ubiquitous DNA-topoisomerase II [5, 6].
However, both drugs have some intrinsic disadvantages such
as developed drug resistance, myelosuppression and poor
oral bioavailability. Another podophyllum glycoside deriva-
tive, NK611 (4), is currently being evaluated in phase I clinical
trials [7]. The main advantage of this compound is its superior
water solubility compared to that of etoposide.
For the last two decades, synthetic studies on podophyllo-
toxin have been focused on C-4 non-sugar substituted
Results and discussion
Chemistry
The synthetic route to the target compound formation is
depicted in Scheme 1. Compounds 10–13 were obtained
Correspondence: Maosheng Cheng, Key Laboratory of Structure-Based
Drugs Design & Discovery of Ministry of Education, School of
Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103
Wenhua Road, Shenhe District, Shenyang, 110016, P. R. China.
E-mail: mscheng@syphu.edu.cn
The author contributed equally: Hong Chen,
chenhongtian06@yahoo.com.cn
Fax: þ86-24-23995043
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44
H. Shang et al.
Arch. Pharm. Chem. Life Sci. 2012, 345, 43–48
Figure 1. Structures of podophyllotoxin, etoposide and other analogues.
through the coupling of podophyllotoxin (1) or 4’-O-demeth-
ylepipodophyllotoxin (9) with substituted imidazoles and by
employing anhydrous FeCl3 in CH3NO2 under 50–608C with
good yields [19]. However, the above reaction condition was
only suitable for imidazoles with electron-withdrawing
groups. The attempt to obtain the derivatives of imidazoles
with electron-donating groups was unsuccessful. Therefore,
compounds 15–17 were prepared from compound 1 through
mesylation [20] with mesyl chloride in the presence of tri-
ethylamine, followed by nucleophilic substitution with imi-
dazole or imidazoles with electron donor groups. The
reaction of mesylate 14 with the corresponding substituted
imidazoles yielded two major products. We speculated that
they were a pair of configurational isomers (C4-a and C4-b
imidazolyl podophyllotoxin derivatives), presumably formed
via an SN1 mechanism. Purification of these configurational
isomers was extremely difficult owing to their similar polar-
ities. Compounds 15–17 were obtained by recycling prepara-
tive HPLC, but their C-4 isomers were not. The structures of all
target compounds were identified by 1H-NMR, 13C-NMR, IR
and HRMS.
During synthesis of the target compounds 10–13, the C-4b
isomers were obtained as the major products, and in
some cases, C-4a isomers were also observed in trace
amounts. The reaction was found to be highly stereoselective.
We presumed that one of the reasons for this stereoselectivity
was that the bulky C-4a pendant aromatic ring E directed the
substituent to bind in the opposite plane and yield a C-4b
isomer as the major product. Another possible reason was
that imidazole could coordinate to FeCl3. The subsequent
bulky complex led to a greater spatial hindrance and thus
led to greater stereoselectivity. The complex might also affect
reactivity, which is why this reaction condition was only
suitable for imidazoles with electron-withdrawing groups
but not for imidazoles with electron-donating groups.
Further study of this reaction is currently underway in our
group, and the corresponding research will be reported
separately in due course.
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Arch. Pharm. Chem. Life Sci. 2012, 345, 43–48
4a/4b-Imidazolyl Podophyllotoxin Analogues
45
Scheme 1. Synthesis of compounds 10–13 and 15–17. Reaction conditions: (a) Anhydrous FeCl3, CH3NO2, and 4-nitro-1H-
imidazole or 2-methyl-5-nitro-1H-imidazole; (b) MsCl, Et3N, CH2Cl2; (c) CH3CN, 1H-imidazole or 2-methyl-1H-imidazole or 4-methyl-
1H-imidazole.
The assignment of the configuration at the C-4 position for
target podophyllotoxin derivatives was based on J3,4 coupling
constants or NOESY. Compound 15 has a value of 11.0 Hz for
and H-20, 60 as H-3 is cis to H-4. The C-4 configuration of the
other compounds was confirmed by the same method.
J
3,4, and the NOESY spectra reveal that an obvious coupling
Cytotoxic activity
between H-4 and H-1 is observed due to a trans-relationship
between H-3 and H-4. On the other hand, compound 10 has a
value of 5.0 Hz for J3,4, and there is a correlation between H-4
The biological activities of 4a/4b-imidazolyl podophyllotoxin
derivatives were evaluated by their cytotoxic activitiy against
three tumour cell lines, which comprised the following:
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46
H. Shang et al.
Arch. Pharm. Chem. Life Sci. 2012, 345, 43–48
Table 1. In vitro cytotoxicity of compounds 10–13 and 15–17
against a panel of human tumor cell lines (IC50, mM).
compounds on tubulin and human DNA topoisomerase II.
Other syntheses and in-vivo antitumor activity studies are also
currently in progress.
Compound
HeLa
K562
K562/ADM
10
11
12
13
15
16
17
2
>10
>10
>10
>10
>10
>10
Experimental
8.12 ꢂ 1.03
7.43 ꢂ 0.62
4.16 ꢂ 0.54
Chemistry
>10
>10
>10
>10
7.46 ꢂ 2.19
4.48 ꢂ 1.67
5.22 ꢂ 0.96
2.99 ꢂ 0.87
8.85 ꢂ 2.56
8.08 ꢂ 0.90
2.88 ꢂ 1.36
6.0 ꢂ 1.84
All commercially available reagents and solvents were employed
without further purification. Melting points were determined in
a Bu¨chi Melting Point B-540 apparatus and were uncorrected.
Infrared spectra were recorded in a Bruker IFS-55 spectropho-
tometer. Optical rotations were measured on a Perkin Elmer
241MC spectrometer. 1H-NMR and 13C-NMR spectra were
recorded in Bruker ARX 300 MHz or 600 MHz, using TMS as
the internal standard. Chemical shift values were reported in
d (ppm) and coupling constants in Hz. High resolution mass
spectrometry (HRMS) was obtained using a Bruker MicroTOF
QII Time of Flight mass spectrometer. Recycling preparative
HPLC was obtained from a reverse phase column (JAIGEL ODS-
AP-L SP-120-15), using JAI LC-9103. Column chromatography was
performed on silica gel H and analytical TLC data on silica gel
>10
>10
76.55 ꢂ 8.36
HeLa (cervix, human), K562 (leukemia, human) and K562/
ADM (adriamycin resistant), with etoposide serving as the
reference compound. The screening procedure was based on
the standard MTT method. The IC50 values are shown in
Table 1.
Some of the compounds exhibited promising antitumor
potency against one or more cell lines. For the HeLa cell line,
compounds 12, 15, 16 and 17 demonstrated cytotoxicity at a
concentration below 10 mM. Compounds 10, 11 and 13 were
less potent, requiring concentrations above 10 mM to initiate
cytotoxicity. For the K562 cell line, compound 17 was found
to be more potent than etoposide, while compounds 12, 15
and 16 were as effective as etoposide. The other three com-
pounds showed limited effects. For the K562/ADM cell line,
compound 12 displayed remarkable anticancer activity,
which was at least one order of magnitude more potent than
etoposide. However, the other compounds were less cyto-
toxic, requiring concentrations above 10 mM.
HF254
.
General procedure for preparation of compounds 10–13
To a stirred solution of podophyllotoxin 1 (1 mmol) or 40-O-
demethylepipodophyllotoxin 9 (1 mmol) and corresponding imi-
dazole (1 mmol) in dry nitromethane (3 mL) was added anhy-
drous FeCl3 (0.1 mmol). The reaction mixture was stirred under
608C until the starting material had been completely converted.
The reaction mixture was then concentrated under reduced
pressure and the residue was purified by column chromatog-
raphy on silica gel with CH2Cl2/AcOEt to give compounds 10–13.
4b-(4-Nitro-1H-imidazol-1-yl)-4-desoxypodophyllotoxin 10
25
Pale yellow solid; yield: 79.4%; mp: 235.4–237.08C; ½aꢀD ꢁ70.4
1
(c 0.5, CH2Cl2); H-NMR (600 MHz, CDCl3) d: 2.94 (dd, 1H,
For compounds 15 and 16, the only difference was the
position of methyl in the imidazole group. It was demon-
strated that pharmacologically, the different positions of
methyl in the imidazole group did not affect the overall
cytotoxicity. Compounds 10 and 12 shared very similar struc-
tures, with the exception of the 40-methoxy moiety. There was
a distinction between the activity of compounds 10 and 12,
indicating that demethylation of the 40-methoxy moiety
markedly affected the overall activity profile. For the 40-O-
methyl-4b-imidazolyl analogues of podophyllotoxin (com-
pounds 10 and 11), pharmacological results showed that
nitro and methyl substituents on the imidazole ring reduced
the overall activity.
J ¼ 5.0, 14.5 Hz), 3.19–3.25 (m, 1H), 3.39 (dd, 1H, J ¼ 9.0,
10.8 Hz), 3.77 (s, 6H), 3.82 (s, 3H), 4.42 (t, 1H, J ¼ 8.0 Hz),
4.78 (d, 1H, J ¼ 5.0 Hz), 5.70 (d, 1H, J ¼ 5.0 Hz), 6.04 (s, 2H),
6.31 (s, 2H), 6.62 (s, 1H), 6.66 (s, 1H), 7.36 (s, 1H), 7.55 (s, 1H);
13C-NMR (150 MHz, CDCl3) d: 36.9, 41.2, 43.5, 56.4, 57.0,
60.8, 66.8, 102.2, 108.3, 108.6, 110.5, 119.0, 123.7, 133.4,
133.8, 135.8, 137.8, 148.3, 148.6, 149.9, 152.9, 172.2; IR
(KBr): 3435.8, 2904.5, 1783.6, 1589.4, 1507.6, 1486.0,
1237.8, 1125.5, 1093.2, 1036.8, 1002.3 cmꢁ1; ESI-HRMS:
Calcd. for C25H23N3O9Na, 532.1327; found, 532.1326
[MþNa]þ.
4b-(2-Methyl-5-nitro-1H-imidazol-1-yl)-4-
desoxypodophyllotoxin 11
In conclusion, seven podophyllotoxin derivatives were syn-
thesized and screened for anticancer activities against three
human cancer cell lines. Some compounds exhibited in-vitro
cytotoxic activitiy, particularly compound 12. Thus, the
results obtained with the newly synthesized podophyllotoxin
derivatives demonstrate that some derivatives warrant the
pursuit of additional research. Additional studies are cur-
rently being conducted to determine the actions of these
25
Pale yellow solid; yield: 69.2%; mp: 272.2–273.68C; ½aꢀD ꢁ59.8
(c 0.5, CH2Cl2); 1H-NMR (300 MHz, CDCl3) d: 2.53 (s, 3H),
3.00 (dd, 1H, J ¼ 4.9, 14.0 Hz), 3.16–3.36 (m, 2H), 3.77 (s, 6H),
3.82 (s, 3H), 4.42 (t, 1H, J ¼ 7.3 Hz), 4.78 (d, 1H, J ¼ 4.9 Hz),
5.55 (d, 1H, J ¼ 4.8 Hz), 6.05 (s, 2H), 6.31 (s, 2H), 6.52 (s, 1H),
6.67 (s, 1H), 7.22 (s, 1H); 13C-NMR (75 MHz, CDCl3) d: 13.9,
37.4, 41.3, 43.7, 55.5, 56.7, 61.1, 66.9, 102.5, 108.6, 108.8,
110.8, 119.1, 124.7, 133.5, 134.0, 138.2, 144.9, 147.2, 148.9,
150.1, 153.2, 172.4; IR (KBr): 3441.3, 2901.5, 1788.4, 1590.1,
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Arch. Pharm. Chem. Life Sci. 2012, 345, 43–48
4a/4b-Imidazolyl Podophyllotoxin Analogues
47
1505.9, 1485.0, 1235.8, 1124.9, 1095.2, 1038.5, 1000.7 cmꢁ1
ESI-HRMS: Calcd. for C26H25N3O9Na, 546.1483; found,
;
128.5, 129.2, 130.8, 137.3, 139.3, 146.1, 147.4, 147.7, 153.8,
176.6; IR (KBr): 3426.0, 2935.8, 1778.0, 1591.3, 1504.6, 1482.5,
546.1483 [MþNa]þ.
1239.1, 1126.9, 1037.4, 1004.1 cmꢁ1
; ESI-HRMS: Calcd.
for C26H27N2O7, 479.1813; found, 479.1813 [MþH]þ.
40-O-Demethyl-4b-(4-nitro-1H-imidazol-1-yl)-4-
desoxypodophyllotoxin 12
4a-(4-Methyl-1H-imidazol-1-yl)-4-desoxypodophyllotoxin
16
25
White solid; yield: 76.0%; mp: 233.1–235.08C; ½aꢀD ꢁ81.2 (c 0.5,
25
CH2Cl2); 1H-NMR (300 MHz, DMSO-d6) d: 3.06–3.19 (m, 1H),
3.21–3.26 (m, 1H), 3.33–3.36 (m, 1H), 3.65 (s, 6H), 4.41 (t, 1H,
J ¼ 7.5 Hz), 4.65 (d, 1H, J ¼ 4.8 Hz), 5.94 (d, 1H, J ¼ 4.3 Hz),
6.04 (s, 2H), 6.25 (s, 2H), 6.67 (s, 1H), 6.87 (s, 1H), 7.76 (s, 1H),
8.19 (s, 1H), 8.32 (s, 1H); 13C-NMR (75 MHz, DMSO-d6) d: 36.9,
40.8, 43.3, 56.2, 56.5, 67.7, 102.1, 108.9, 109.2, 110.3, 122.1,
125.9, 130.1, 134.4, 135.4, 137.9, 147.5, 147.6, 147.7, 148.8,
174.0; IR (KBr): 3422.3, 2902.3, 1770.6, 1612.6, 1506.7, 1483.9,
1230.7, 1113.8, 1095.5, 1031.7, 1003.2 cmꢁ1; ESI-HRMS: Calcd.
for C24H21N3O9Na, 518.1170; found, 518.1169 [MþNa]þ.
White solid; yield: 29.2%; mp: 225.8–227.38C; ½aꢀD ꢁ63.6 (c 0.5,
CH2Cl2); 1H-NMR (300 MHz, CDCl3) d: 2.23 (s, 3H), 3.14–
3.22 (m, 1H), 3.29 (dd, 1H, J ¼ 4.9, 8.3 Hz), 3.85 (s, 6H), 3.87
(s, 3H), 4.13 (d, 1H, J ¼ 10.0 Hz), 4.24 (d, 1H, J ¼ 4.7 Hz), 4.32
(dd, 1H, J ¼ 5.0, 10.0 Hz), 4.87 (d, 1H, J ¼ 11.2 Hz), 5.84
(s, 1H), 5.90 (s, 2H), 6.38 (s, 1H), 6.48 (s, 2H), 6.99 (s, 1H),
7.60 (s, 1H); 13C-NMR (75 MHz, CDCl3) d: 10.0, 40.4, 43.4,
46.6, 54.3, 56.2, 60.9, 68.7, 101.4, 104.5, 105.7, 109.3, 127.9,
128.1, 128.6, 130.6, 135.7, 137.3, 139.5, 147.5, 147.8, 153.8,
176.5; IR (KBr): 3422.4, 2938.5, 1779.3, 1588.0, 1505.2, 1484.0,
1235.0, 1127.0, 1092.7, 1035.9, 1002.4 cmꢁ1; ESI-HRMS:
Calcd. for C26H27N2O7, 479.1812; found, 479.1814 [MþH]þ.
40-O-Demethyl-4b-(2-methyl-5-nitro-1H-imidazol-1-yl)-4-
desoxypodophyllotoxin 13
25
4b-(1H-Imidazol-1-yl)-4-desoxypodophyllotoxin 17
Pale pink solid; yield: 57.8%; mp: 290.4–291.58C; ½aꢀD ꢁ54.2
25
(c 0.5, CH2Cl2); 1H-NMR (300 MHz, CDCl3) d: 2.53 (s, 3H),
2.98 (dd, 1H, J ¼ 5.2, 14.0 Hz), 3.17–3.36 (m, 2H), 3.81 (s, 6H),
4.40 (t, 1H, J ¼ 7.6 Hz), 4.78 (d, 1H, J ¼ 4.8 Hz), 5.47 (s, 1H),
5.54 (d, 1H, J ¼ 4.6 Hz), 6.05 (s, 2H), 6.32 (s, 2H), 6.51 (s, 1H),
6.67 (s, 1H), 7.21 (s, 1H); 13C-NMR (75 MHz, DMSO-d6) d:
13.7, 37.0, 43.3, 54.6, 55.4, 56.5, 67.5, 102.1, 109.0, 109.5,
110.2, 121.6, 126.4, 130.1, 134.4, 135.4, 146.1, 146.3, 147.5,
147.7, 148.7, 174.0; IR (KBr): 3538.1, 3153.3, 2902.2, 1789.2,
1618.0, 1503.2, 1485.2, 1228.1, 1109.0, 1095.1, 1034.0,
White solid; yield: 43.0%; mp: 244.1–245.48C; ½aꢀD ꢁ70.4 (c 0.5,
CH2Cl2); 1H-NMR (300 MHz, CDCl3) d: 3.02 (dd, 1H, J ¼ 4.7,
14.2 Hz), 3.06–3.19 (m, 1H), 3.31 (t, 1H, J ¼ 9.6 Hz), 3.76
(s, 6H), 3.82 (s, 3H), 4.35 (t, 1H, J ¼ 7.0 Hz), 4.75 (d, 1H,
J ¼ 4.7 Hz), 5.60 (d, 1H, J ¼ 4.8 Hz), 6.01 (s, 2H), 6.32
(s, 2H), 6.63 (s, 2H), 6.76 (s, 1H), 7.14 (s, 1H), 7.45 (s, 1H);
13C-NMR (150 MHz, CDCl3) d: 37.5, 41.8, 43.6, 55.4, 56.3,
60.7, 67.3, 101.9, 108.2, 109.0, 110.1, 119.1, 125.7, 130.2,
132.8, 134.3, 137.0, 137.6, 148.1, 149.1, 152.8, 173.1;
IR (KBr): 3457.5, 2909.1, 1778.9, 1588.2, 1505.6, 1484.9,
1000.0 cmꢁ1
;
ESI-HRMS: Calcd. for C25H23N3O9Na,
1237.7, 1126.1, 1036.1, 1005.4 cmꢁ1
; ESI-HRMS: Calcd.
532.1327; found, 532.1327 [MþNa]þ.
for C25H25N2O7, 465.1656; found, 465.1651 [MþH]þ.
General procedure for preparation of compounds 15–17
To a solution of podophyllotoxin 1 (1 mmol) in CH2Cl2 (10 mL)
was added triethylamine (1.2 mmol) and mesyl chloride
(1.2 mmol) at 08C. Then the mixture was stirred for 0.5 h at
room temperature. After washing with water and brine, the
organic layer was dried over Na2SO4, concentrated under
reduced pressure, and used for the next reaction without further
purification. To the above crude intermediate 14 dissolved in dry
CH3CN (8 mL) was added corresponding imidazole (2 mmol) and
the mixture was refluxed. While TLC analysis showed that the
starting material had been completely converted, the reaction
was stopped. The reaction mixture was diluted with CH2Cl2 and
washed with water. The organic layers were dried over Na2SO4,
concentrated under reduced pressure, and the residue purified
by column chromatography on silica gel with AcOEt and further
purified by recycling preparative HPLC to give compounds 15–17.
In-vitro evaluation of cytotoxic activity
The antiproliferative activity of these podophyllotoxin deriva-
tives against HeLa, K562 and K562/ADM cell lines was measured
by the standard MTT assay. Cells were seeded in 96-well micro-
titer plates at a density of 4000 cells/well, grown in 5% CO2 at
378C for 24 h, and then exposed to different concentrations of
target compounds (0.01–10 mmol/L), etoposide (0.01–100 mmol/L)
and 0.5% DMSO (as control) for 48 hours. Read the OD values at
570 nm on a microplate reader (BIORAD Model 680, America)
and get the inhibition ratio:
½Inhibition ratio ¼ ðOD of control ꢁ OD of treatmentÞ=
ðOD of controlꢁOD of blankÞ ꢃ 100ꢀ
(1)
Data were analyzed in Excel and the IC50 values (mmol/L) were
determined graphically from cell survival curves. All assays were
done in triplicate.
4a-(2-Methyl-1H-imidazol-1-yl)-4-desoxypodophyllotoxin
15
25
White solid; yield: 37.5%; mp: 242.7–243.78C; ½aꢀD 5.4 (c 0.5,
CH2Cl2); 1H-NMR (300 MHz, CDCl3) d: 2.47 (s, 3H), 3.03–
3.12 (m, 1H), 3.28 (dd, 1H, J ¼ 5.2, 8.5 Hz), 3.86 (s, 6H), 3.88
(s, 3H), 4.08 (d, 1H, J ¼ 9.9 Hz), 4.22 (d, 1H, J ¼ 5.1 Hz), 4.30
(dd, 1H, J ¼ 5.2, 10.0 Hz), 4.92 (d, 1H, J ¼ 11.0 Hz), 5.88
(s, 2H), 5.91 (s, 1H), 6.38 (s, 1H), 6.48 (s, 2H), 6.85 (s, 1H),
7.14 (s, 1H); 13C-NMR (150 MHz, CDCl3) d: 13.6, 40.8, 43.5,
46.5, 55.1, 56.3, 60.9, 68.7, 101.4, 104.6, 105.7, 109.3, 116.2,
We gratefully thank the National Natural Science Foundation of China
(grant No. 30873363), the Program of the Science Foundation of Tianjin
(grant No. 08JCYBJC070000) and the Major Program of the Science
Foundation of Tianjin (grant No. 09ZCKFSH01700).
The authors have declared no conflict of interest.
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48
H. Shang et al.
Arch. Pharm. Chem. Life Sci. 2012, 345, 43–48
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