Synthesis and evaluation of substituted dibenzo[c,e]azepine-5-ones as P-glycoprotein-mediated multidrug resistance reversal agents

Article abstract of DOI:10.1016/j.bmcl.2012.03.005

A series of substituted dibenzo[c,e]azepine-5-ones (7a-h) were synthesized and evaluated as P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) reversal agents. The most potent compound 7h could significantly and selectively enhance the chemo-sensit

Full text of DOI:10.1016/j.bmcl.2012.03.005

Bioorganic & Medicinal Chemistry Letters 22 (2012) 2675–2680
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of substituted dibenzo[c,e]azepine-5-ones
as P-glycoprotein-mediated multidrug resistance reversal agents
Xiaobo Tang a,b, , Xiaoke Gu a,b, , Zhiguang Ren c,d, Yuanfang Ma d, Yisheng Lai a,b, Hui Peng c,
,
⇑
Sixun Peng a,b, Yihua Zhang a,b,
⇑
a State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China
b Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China
c Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing 100850, PR China
d Institute of Immunology, Medical School of Henan University, Kaifeng 475001, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of substituted dibenzo[c,e]azepine-5-ones (7a–h) were synthesized and evaluated as P-glycopro-
tein (P-gp)-mediated multidrug resistance (MDR) reversal agents. The most potent compound 7h could
significantly and selectively enhance the chemo-sensitivity of drug-resistant K562/A02 cells to the cyto-
toxic effect of adriamycin (ADR) in a dose-dependent manner. Further studies indicated that 7h could
markedly increase intracellular accumulation of both rhodamine 123 and ADR in K562/A02 cells and
inhibit their efflux from the cells. And 7h had little effect on the levels of P-gp mRNA and protein in
K562/A02 cells. These results suggest that the anti-MDR effect of 7h might be attributed to the inhibition
of drug efflux function of P-gp, leading to the increased drug accumulation in K562/A02 cells, and thus
the compound could be served as a lead for developing P-gp-mediated MDR reversal agents.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 5 January 2012
Revised 20 February 2012
Accepted 5 March 2012
Available online 8 March 2012
Keywords:
Dibenzo[c,e]azepine-5-one
DDB
P-gp inhibitors
Multidrug resistance (MDR)
Multidrug resistance (MDR) of cancer cells impairs efficient
treatment and has now become a major hindrance to successful
cancer chemotherapy.1 The mechanisms underlying MDR are very
complicated, and one of the most recognized mechanisms attri-
butes to the frequent overexpression of ATP-binding cassette
(ABC) transporters on the plasma membrane of cancer cells,
such as P-glycoprotein (P-gp), multidrug resistance-associated
protein 1 (MRP1), and breast cancer resistance protein (BCRP).2
P-gp, a 170-kDa transmembrane protein encoded by the MDR1
gene, is now the best characterized drug transporter which can ac-
tively efflux a wide range of structurally and functionally related or
unrelated anticancer drugs out of cancer cells, thereby decreasing
their intracellular levels to sublethal concentration and reducing
their therapeutic efficacy.3,4 A wide variety of investigations have
suggested that inhibition of the drug efflux function and/or the
overexpression of P-gp is the most important strategy to overcome
P-gp-mediated MDR.5 Thus, considerable attempts have been
made to suppress MDR by developing P-gp inhibitors during past
decades. And several well-known P-gp inhibitors entered clinical
trials, such as Verapamil, Valspoder (PSC 833) and Tariquidar
(XR9576).6 However, up to now, no drug of this class has been mar-
keted for many reasons, such as low selectivity, poor potency,
inherent toxicity and/or unpredictable pharmacokinetic interac-
tions with the co-administered anticancer drugs.6 Therefore, there
is a clear and urgent need to develop safe and effective P-gp
inhibitors.
Nowadays, researchers have been turning to natural products
and their derivatives to identify novel and effective MDR reversal
agents by virtue of their advantages, for example, low toxicity,
few unfavorable pharmacokinetic interactions and showing anti-
cancer and/or MDR reversal activities, etc.2,6,7 And a wealth of doc-
uments have reported that flavonoids, curcumins, schizandirins
and their derivatives possess MDR reversal effects owing to modu-
lating one or more ABC transporters.8–10 Schizandrins (A, B and C)
(Fig. 1) isolated from Schisandra chinensis Baill (Wuweizi) have at-
tracted much attention for their potential ability to restore the sen-
sitivity of several drug-resistant cancer cells to anticancer drugs
through increasing intracellular accumulation of anticancer drugs,
promoting apoptosis, down-regulating P-gp mRNA and protein
and total protein kinase C (PKC) expression in MDR cells.11–13
Dimethyl-4,40-dimethoxy-5,6,50,60-dimethylenedioxybiphenyl-2,20-
dicarboxylate (DDB), an analogue of schisandrin C, is an effective
liver protective drug, which has been widely used for the treat-
ment of chronic viral hepatitis B for more than 20 years in China
with few side effects.14 It has recently been reported that DDB is
also able to reverse P-gp-mediated MDR in vitro and in vivo by
⇑
Corresponding authors. Tel.: +86 10 66932339; fax: +86 10 68159436 (H.P.);
tel./fax: +86 25 83271015 (Y.H.).
E-mail addresses: p_h2002@hotmail.com (H. Peng), zyhtgd@163.com, zyhtgd@
sohu.com (Y. Zhang).
These two authors contributed equally to this work.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.03.005

2676
X. Tang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2675–2680
nitrogen-containing cyclic moiety was hybridized with such scaf-
fold to form dibenzoazepine compounds I and II, whose biological
activities were improved as compared with DDB, probably attrib-
utable to the variation of ring strain and basicity.16–18 Thus, it is
of interest to examine whether the dibenzoazepine compounds
like I and II possess improved MDR reversal activity relative to
DDB. Additionally, a number of studies have revealed that a ter-
tiary aminoalkyl moiety serves as a basic center which would be
charged at physiological pH and has frequently been considered
to be the hall mark of P-gp inhibitors.6,19 Based on the above inves-
tigations, we synthesized and biologically evaluated substituted
dibenzo[c,e]azepine-5-ones (7a–h) as P-gp-mediated MDR reversal
agents.
The synthetic routes of target compounds 7a–h are outlined in
Scheme 1. The monoester compound 1 was prepared starting from
diester compound DDB by three steps according to literature.20
Treatment of 1 with imidazole in the presence of 1-(3-dimethyl-
aminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and 4-
dimethylaminopyridine (DMAP) in CH2Cl2 afforded amide 2, which
was then selectively reduced by NaBH4 to give benzylalcohol 3.
Compound 3 was treated with SOCl2 to generate benzyl chloride
4, which was nucleophilically substituted by ethanolamine and
then intramolecularly aminolyzed to result in ring closure, yielding
N-substituted aminoethanol 5. Subsequently, the hydroxyl of 5
was chlorinated to chloride 6 which was treated with different sec-
ondary amines to provide 7a–h. Compounds 7a–h were purified
by column chromatography, and their structures were character-
ized by IR, 1H NMR, 13C NMR, MS, and HRMS.
Figure 1. The structures of schiandrins (A, B and C) and their analogs (DDB, I and II).
increasing intracellular accumulation of anticancer drugs and pro-
moting apoptosis through inhibiting P-gp, and more importantly,
there is no pharmacokinetic interaction problem between DDB
and co-administered anticancer drugs, at least adriamycin
(ADR).14 However, the reversal activity of DDB is weaker than
verapamil (VRP), an established P-gp-mediated MDR reversal
agent.14 Therefore, improving reversal activity of DDB by proper
structural modification is of great significance. Previous studies
have revealed that the scaffold of alkoxyl biphenyl moiety in
DDB is crucial for its pharmacological activities,15 and when a
Firstly, the antiproliferative activity of compounds 7a–h and
DDB against human leukemic K562 cells and its drug-resistant
K562/A02 cells was determined in vitro by 3-(4,5-dimethyl-
thiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-
Scheme 1. Synthesis of compounds 7a–h. Reagents and conditions: (a) (i) 10% NaOH, reflux, 5 h, 96%; (ii) (Ac)2O, reflux, 8 h, 90%, (iii) CH3OH, reflux, 3 h, 98%; (b) imidazole,
EDCI, DMAP, CH2Cl2, rt, 2 h, 95%; (c) THF, NaBH4, 0 °C, 1 h, 90%; (d) SOCl2, 1H-benzotriazole, CH2Cl2, 0 °C, 2 h, 98%; (e) ethanolamine, Et3N, KI, CH2Cl2, reflux, 3 h, 86%; (f) SOCl2,
CH2Cl2, 0 °C, 2 h, 93%; (g) secondary amines, KI, CH2Cl2, reflux, 2 h, 84–91%.

X. Tang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2675–2680
2677
Table 1
rhodamine 123 (Rh123), a fluorescent substrate of P-gp, accumula-
tion in P-gp overexpressed K562/A02 cells. The fluorescence activ-
ity ratio (FAR) values, which are the ratios of the mean fluorescent
intensities of Rh123 in treated and untreated K562/A02 cells, are
positively related with their MDR reversal activity. Since P-gp-
mediated MDR is due to the increased efflux of its substrate or a
drug from tumor cells, a FAR value larger than 1 represents that
the reversal of MDR has taken place and the higher FAR value indi-
cates stronger reversal activity.24 All compounds 7a–h were as-
The antiproliferative activities of compounds 7a–h and DDB against K562 and K562/
A02 cells in vitro by MTS assay
a,b
a,b
Compound
IC50
K562
(
l
M)
Compound
IC50
K562
(lM)
K562/A02
K562/A02
ADRc
DDB
7a
7b
7c
0.43
46.69
>200
>100
94.78
>100
7d
7e
7f
7g
7h
>100
89.99
>100
>100
49.19
>100
91.08
>100
>100
56.28
>200
>100
62.44
>100
sayed at 10 lM, a concentration could result in less than 10%
a
The IC50 values represent the concentration which results in a 50% decrease in
inhibition in cell growth after 72 h incubation, and the results
are presented in Table 2. As we can see, 7a–h displayed varying
levels of MDR reversal activity and their FAR values ranged from
1.03 to 14.11. The activity of 7e and 7f is comparable to the estab-
lished MDR reversal agent verapamil (VRP) (FAR = 3.46, 3.23, 4.16,
respectively), and 7h (FAR = 14.11) is more active than VRP. And all
tested compounds except 7g (FAR = 1.03) showed stronger MDR
reversal activity than parental compound DDB, suggesting that
the structural modification of DDB is beneficial for enhancing its
MDR reversal activity.
The analysis of structure–activity reveals that different R sub-
stituents in 7a–h (Scheme 1) could affect Rh123 accumulation in
K562/A02 cells: (a) The longer N-alkyl chain in R might be benifi-
cial for the MDR revesal activity. For example, the FAR values of
dimethylamino (7a), diethylamino (7b) and dipropylamino (7c)
are 1.44, 2.57 and 2.84, respectively; (b) The size of one nitro-
gen-containing hetercycle in R is likely to affect MDR reversal
activity since the FAR value of 7d containing a five-membered
pyrrolidino ring is less than 7e with a six-membered piperidino
ring (1.65 vs 3.46); and (c) The different type of six-membered het-
ercyclic rings in R could have different MDR reversal activity. For
example, 7f (FAR = 3.23) containing a morpholino ring in R was
more active than 7g (FAR = 1.03) with a 4-methylpiperidine moi-
ety. However, when the 4-methylpiperazin was changed to benzyl-
piperazine, the corresponding compound 7h showed the strongest
activity (FAR = 14.11), suggesting that introducion of an additonal
benzene ring to the molecule of 7g could dramatically strengthen
its binding affinity with P-gp, leading to more Rh123 accumulation
in K562/A02 cells.
cell growth after 72 h incubation.
b
Values are the mean values of three experiments.
Adriamycin (ADR) was used as a positive control.
c
Table 2
The effect of compounds 7a–h on the intracellular Rh123 accumulation in K562/A02
cells at 10 lM
Compound
FAR valuea
Compound
FAR valuea
7a
7b
7c
7d
7e
1.44
2.57
2.84
1.65
3.46
7f
7 g
7h
3.23
1.03
14.11
1.15
4.16
DDB
VRPb
a
The fluorescence activity ratio (FAR) values are the ratios of the mean fluores-
cent intensities of Rh123 in treated and untreated K562/A02 cells.
b
VRP was used as a positive control.
tetrazolium (MTS) assay.21 A well-known anticaner drug adriamy-
cin (ADR) was used as a positive control. It can be seen from Table
1 that K562/A02 cells used in the present experiment displayed
much serious drug resistance to ADR than parental K562 cells
(IC50: 46.69 vs 0.43 lM), with a resistant fold of about 108, which
is reportedly caused by overexpressing P-gp in K562/A02 cells
leading to drug-resistance.22 DDB had little cytotoxicity (IC50
>200
with previous reports.14,23 Compounds 7a–h had little (IC50
100 M) or somewhat (IC50 = 49.19–94.78 M) antiproliferative
lM) to both K562/A02 and K562 cells, which is consistent
>
l
l
activity to both K562/A02 and K562 cells, suggesting these com-
pounds are suitable candidates for the research and development
of MDR reversal agents.
Subsequently, flow cytometric analysis (FACS Calibur, Becton-
Dickinson, USA) was employed to evaluate the effect of compounds
7a–h and DDB on the function of P-gp by testing their effect on
Based on the results of above experiments, the most active com-
pound 7h was selected to test for P-gp-mediated MDR reversal
activity. Chemosensitizing effect of 7h on drug-resistant K562/
A02 cells to ADR was assayed according to previous report with
minor modifications.25 As shown in Figure 2A, 7h could signifi-
cantly enhance the chemo-sensitivity of K562/A02 cells to the
Figure 2. The effect of compound 7h on the chemo-sensitivity of drug-resistant K562/A02 cells toward ADR. K562/A02 and K562 cells were treated with 2 and 0.04
respectively, combined with three concentrations (cl: 2.5 M; cm: 5 M; ch: 10 M) of 7h or VRP for 72 h. The survival rates of the cells were determined by MTS assay. The
VRP was used as a positive control. ⁄P <0.05, #P <0.01 versus ADR treatment alone group.
lM ADR,
l
l
l

2678
X. Tang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2675–2680
Figure 3. The dose–response effect of 7h on the intracellular Rh123 (A and B) and ADR (C) accumulation in K562/A02 cells. K562/A02 cells were incubated with 0.5
lM Rh123
or 0.5 M ADR in the presence or absence of 0.33, 3.3 or 10 M of 7h or VRP at 37 °C for 30 min. The K562 cells were treated with 0.5 M Rh123 or ADR only. After treatment,
l
l
l
the cells were washed twice with PBS and resuspended in medium, and then incubated at 37 °C for an additional 60 min to allow efflux of the dye. The cells were then
observed and photographed under a fluorescence microscope (A), and the amount of Rh123 and ADR accumulated in the tumor cells was determined by measuring the cell-
associated fluorescence. The fluorescence detection was operated at excitation and emission wavelengths of 488 and 520 nm for Rh123 (B), and of 488 and 570 nm for ADR
(C), respectively, using flow cytometry. VRP was used as a positive control and 0.1% DMSO was used as vehicle control.
cytotoxic effect of ADR in a dose-dependent manner when com-
pared with VRP, a well-known P-gp inhibitor. Interestingly, it
was observed that the survival rate of K562/A02 cells was about
little P-gp. These results suggest that the selective chemosensitiz-
ing effect of compound 7h could be due to the inhibition of drug
efflux function of P-gp, leading to the increased intracellular accu-
mulation of ADR in K562/A02 cells.
To validate our assumption, the dose–response effect of 7h on
inhibiting the drug efflux function of P-gp was assayed by evaluat-
ing the Rh123 accumulation in K562/A02 and K562 cells using
fluorescence microscope ( Fig. 3A) and flow cytometry ( Fig. 3B
and C). The results in Figure 3A show that K562 cells retained
89.1% when treated with 2
K562/A02 cells with a combination of 2
concentrations (cl: 2.5 M, cm: 5 M or ch: 10 l
l
M ADR alone, however, when treated
M ADR and 7h at three
M), the survival
l
l
l
rate was markedly decreased to 33.9%, 19.9% and 7.5%,
respectively. Nevertheless, such chemosensitizing effect of 7h
was not observed in sensitive K562 cells (Fig. 2B), which expresses

X. Tang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2675–2680
2679
Figure 4. The effect of 7h on P-gp mRNA level (A) and protein expression (B) in K562/A02 cells at 10
treated with 0.1% DMSO or 10 M compound 7h for 72 h. The total RNA was extracted and reverse transcripted from mRNA to cDNA using the RT-PCR (Promega, WI, USA),
and the data was analyzed with Bio-Rad iQ5 software.Western blot analysis: after incubation, the cells were harvested and lyzed. The cell lysates (30 g) were separated by
lM for 72 h treatment. K562/A02 cells with P-gp overexpression were
l
l
SDS–PAGE (12% gel) and transferred onto a PVDF membrane. After blocked in TBST containing 5% non-fat milk, the target proteins were probed with anti-P-gp, anti-GAPDH.
The protein–antibody complex were visualized by the enhanced Phototope TM-HRP Detection Kit (Cell Signaling, USA) and exposed to Kodak medical X-ray processor (Kodak,
USA). 0.1% DMSO was used as vehicle control. GAPDH was used as a loading control.
the most amount of Rh123, while K562/A02 cells has substantially
pumped the Rh123 out of the cells and there was little fluorescence
could be observed after 60-min incubation. When K562/A02 cells
were treated with 7h, the retained amount of Rh123 was signifi-
cantly increased in a dose-dependent manner. These results sug-
gest that 7h might effectively block the drug efflux function of P-
gp. And the potency of 7h is much greater than that of VRP under
the same conditions. Flow cytometry results showed similar effect
of 7h on Rh123 accumulation in K562/A02 cells. As shown in Fig-
ure 3B, the retained Rh123 level in K562 cells (purple curve) is
much higher than that in K562/A02 cells treated with 0.1% DMSO,
a vehicle control (black background), however, the retained Rh123
levels in K562/A02 cells elevated rapidly after treatment with 7h,
and the Rh123 retained curve shift dramatically from left to right,
fect of adriamycin (ADR) in a dose-dependent manner. And 7h
could markedly increase intracellular accumulation of both rhoda-
mine 123 and ADR in K562/A02 cells, and inhibit their efflux out of
these cells. Additionally, 7h had little effect on the levels of P-gp
mRNA and protein in K562/A02 cells, suggesting that the anti-
MDR effect of 7h might be implicated in the inhibition of drug ef-
flux function of P-gp, leading to the increased drug accumulation in
K562/A02 cells. Therefore, 7h could be served as a promising lead
for developing P-gp-mediated MDR reversal agents.
Acknowledgments
The work was financially supported by the Innovative Program
for Postgraduate Students of Jiangsu province (No. CX10B-372Z)
and National Natural Science Foundation of China Grant No.
30873083 and 81173082, respectively. We thank Professor Don-
gsheng Xiong (Institute of Hematology & Blood Diseases Hospital,
CAMS & PUMC, China) for providing K562 and K562/A02 cell lines.
almost completely overlap with that from K562 cells at 10 lM. And
the Rh123 accumulative effect of 7h is much greater than that of
VRP at the same dose (Fig. 3B). In addition, the effect of 7h on
ADR accumulation in K562/A02 cells was also evaluated by flow
cytometry (Fig. 3C). As we can see, the accumulation amount of
ADR in K562 cells (purple curve) is much larger than that in
K562/A02 cells treated with 0.1% DMSO (black background). When
K562/A02 cells were treated with 7h, the ADR levels in the cells
significantly increased in a dose-dependent manner. In comparison
of 7h with VRP on ADR accumulation, it was observed that the ADR
retaining curve shifted from left to right markedly at the same con-
centration, suggesting that the effect of 7h on ADR accumulation is
much stronger than that of VRP, resulting in greater chemosensi-
tizing effect than VRP in K562/A02 cells. Expectedly, 7h had little
effect on Rh123 or ADR accumulation in sensitive K562 cells (data
not shown). All these results revealed that the MDR reversal effect
of 7h could be due to the inhibition of drug efflux function of P-gp,
leading to the increased ADR accumulation in K562/A02 cells.
In order to further investigate whether the increased Rh123 and
ADR accumulation in K562/A02 cells is caused by decreased P-gp
expression induced by 7h, RT-PCR and western blot experiments
were carried out on the levels of P-gp mRNA and protein. The re-
sults in Figure 4 clearly show that 7h had little affect on the levels
of P-gp mRNA and protein expression in the cells.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2012.03.005. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
References and notes
1. Eckford, P. D.; Sharom, F. J. Chem. Rev. 2009, 109, 2989.
2. Wu, C. P.; Calcagno, A. M.; Ambudkar, S. V. Curr. Mol. Pharmacol. 2008, 1, 93.
3. Callaghan, R.; Ford, R. C.; Kerr, I. D. FEBS Lett. 2006, 1056, 580.
4. Pauwels, E. K.; Erba, P.; Mariani, G.; Gomes, C. M. Drug News Perspect. 2007, 20,
371.
5. Thomas, H.; Coley, H. M. Cancer Control 2003, 10, 159.
6. Crowley, E.; McDevitt, C. A.; Callaghan, R. Methods Mol. Biol. 2010, 596, 405.
7. Wu, C. P.; Ohnuma, S.; Ambudkar, S. V. Curr. Pharm. Biotechnol. 2011, 12, 609.
8. Um, Y.; Cho, S.; Woo, H. B.; Kim, Y. K.; Kim, H.; Ham, J.; Kim, S. N.; Ahn, C. M.;
Lee, S. Bioorg. Med. Chem. 2008, 16, 3608.
9. Hadjeri, M.; Barbier, M.; Ronot, X.; Mariotte, A. M.; Boumendjel, A.; Boutonnat,
J. J. Med. Chem. 2003, 46, 2125.
10. Liang, X. X.; Liu, G. T.; Chen, Q. H.; Sun, H.; Chen, D. L.; Wang, F. P. J. Asian Nat.
Prod. Res. 2010, 12, 549.
11. Yoo, H. H.; Lee, M.; Lee, M. W.; Lim, S. Y.; Shin, J.; Kim, D. H. Planta Med. 2007,
73, 444.
12. Fong, W. F.; Wan, C. K.; Zhu, G. Y.; Chattopadhyay, A.; Dey, S.; Zhao, Z.; Shen, X.
L. Planta Med. 2007, 73, 212.
In conclusion, eight substituted dibenzo[c,e]azepine-5-ones
(7a–h) were synthesized based on the structural modifications of
DDB and evaluated in vitro as P-gp-mediated MDR reversal agents.
Compound 7h could significantly and selectively enhance the che-
mo-sensitivity of drug-resistant K562/A02 cells to the cytotoxic ef-
13. Huang, M.; Jin, J.; Sun, H.; Liu, G. T. Cancer Chemother. Pharmacol. 2008, 1015, 62.

2680
X. Tang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2675–2680
14. Jin, J.; Sun, H.; Wei, H.; Liu, G. Invest. New Drugs 2007, 25, 95.
15. Chang, J. B.; Chen, R. F.; Guo, R. Y.; Dong, C. H.; Zhao, K. Helv. Chim. Acta 2003,
86, 2239.
16. Buttner, F.; Bergemann, S.; Guenard, D.; Gust, R.; Seitz, G.; Thoret, S. Bioorg.
Med. Chem. 2005, 13, 3497.
20. Kong, X. W.; Zhang, Y. H.; Wang, T.; Lai, Y. S.; Peng, S. X. Chem. Biodivers. 2008,
5, 1743.
21. Patel, M. I.; Tuckerman, R.; Dong, Q. Biotechnol. Lett. 2005, 27, 805.
22. Yang, C. Z.; Luan, F. J.; Xiong, D. S.; Liu, B. R.; Xu, Y. F.; Gu, K. S. Zhongguo Yao Li
Xue Bao 1995, 16, 333.
17. Bergemann, S.; Brecht, R.; Buttner, F.; Guenard, D.; Gust, R.; Seitz, G.; Stubbs, M.
T.; Thoret, S. Bioorg. Med. Chem. 2003, 11, 1269.
18. Wu, W. L.; Chen, S. E.; Chang, W. L.; Lee, A. R. Eur. J. Med. Chem. 1992, 27,
353.
23. Liu, Z.; Liu, G.; Zhang, S. Cancer Lett. 1996, 108, 67.
24. Das, U.; Molnar, J.; Barath, Z.; Bata, Z.; Dimmock, J. R. Bioorg. Med. Chem. Lett.
2008, 18, 3484.
25. Shi, Y. Q.; Qu, X. J.; Liao, Y. X.; Xie, C. F.; Cheng, Y. N.; Li, S.; Lou, H. X. Eur. J.
Pharmacol. 2008, 584, 66.
19. Ecker, G.; Huber, M.; Schmid, D.; Chiba, P. Mol. Pharmacol. 1999, 56, 791.