Synthesis, in vitro and in vivo evaluation of 3-arylisoquinolinamines as potent antitumor agents

Article abstract of DOI:10.1016/j.bmcl.2010.06.132

In the search for potent water-soluble 3-arylisoquinolines, several 3-arylisoquinolinamines were designed and synthesized. Various substituted 3-arylisoquinolinamines exhibited strong cytotoxic activity against eight different human cancer cell lines. In

Full text of DOI:10.1016/j.bmcl.2010.06.132

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5277–5281
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, in vitro and in vivo evaluation of 3-arylisoquinolinamines
as potent antitumor agents
Su Hui Yang a, Hue Thi My Van a, Thanh Nguyen Le a, Daulat Bikram Khadka a, Suk Hee Cho a,
a,
Kyung-Tae Lee b, Hwa-Jin Chung c, Sang Kook Lee c, Chang-Ho Ahn d, Young Bok Lee d, , Won-Jea Cho
*
*
a College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea
b College of Pharmacy, Kyung-Hee University, Seoul 130-701, Republic of Korea
c College of Pharmacy, Seoul National University, Seoul, Republic of Korea
d Rexahn Pharmaceuticals, Inc., Rockville, MD 20850, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
In the search for potent water-soluble 3-arylisoquinolines, several 3-arylisoquinolinamines were
designed and synthesized. Various substituted 3-arylisoquinolinamines exhibited strong cytotoxic activ-
ity against eight different human cancer cell lines. In particular, C-6 or C-7 dimethylamino-substituted 3-
arylisoquinolinamines displayed stronger potency than the lead compound 7a. Interestingly, compounds
7b and 7c showed more effective activity against paclitaxel-resistant HCT-15 human colorectal cancer
cell lines when compared to the original cytotoxic cancer drug, paclitaxel. We analyzed the cell cycle
dynamics by flow cytometry and found that treatment of human HCT-15 cells with 3-arylisoquinolin-
amine 7b blocked or delayed the progression of cells from G0/G1 phase into S phase, and induced cell
death. Treatment with compound 7b also significantly inhibited the growth of tumors and enhanced
tumor regression in a paclitaxel-resistant HCT-15 xenograft model.
Received 3 May 2010
Revised 23 June 2010
Accepted 28 June 2010
Available online 3 July 2010
Keywords:
3-Arylisoquinolinamines
Antitumor agents
In vivo evaluation
Cytotoxicity
Ó 2010 Elsevier Ltd. All rights reserved.
Synthesis
Qsar
Cancer is a complex disease that depends on the tissue and
original cell types along with many causal factors. Among various
targets for the development of antitumor agents, protein kinases,1,2
and topoisomerases I and II3–6 have emerged as promising targets
for the treatment of tumors. With these targets in mind, it is antic-
ipated that current advances in our understanding of the molecular
and structural biology of the cell cycle7,8 will lead to the discovery
of small-molecule inhibitors that target proteins whose improper
expression or action has been linked to tumor progression. The cell
cycle is considered an attractive target for the development of
small-molecule inhibitors for use as both new chemotherapeutics
and research probes.9
Since the potent antitumor activity of 7,8-dimethoxy-2-methyl-
3-(4,5-methylenedioxy-2-vinylphenyl)isoquinolin-1(2H)-one (1)
was first described,10 we have investigated the structure–activity
relationships of 3-arylisoquinolines against human tumor cell
lines. Diverse modifications of the 3-arylisoquinoline skeleton pro-
vided the indeno[1,2-c]isoquinolines 2,11,12 isoindolo[2,1-b]iso-
quinolinones 3,13 12-oxobenzo[c]phenanthridinones 4, and
benz[b]oxepines 514 as the constrained forms of the 3-aryl rings
as shown in Figure 1. Most of these arylisoquinoline derivatives
exhibited micromolar cytotoxicities with topoisomerase I inhibi-
tory activities. The rigidification of the flexible 3-aryl ring flattened
the molecule so that it could work as a DNA intercalator in the
topoisomerase I–DNA ternary complex. However, we could not
find any compounds that exceeded the cytotoxicity of the original
hit compound 1, even in the SAR study of 3-arylisoquinolines 6.
Next our interest was focused on finding potent water-soluble 3-
arylisoquinolines. The designed 3-arylisoquinolinamines 7 were
expected to maintain the cytotoxicity of the 3-arylisoquinolines
because the nitrogen atom is considered the bioisostere of the oxy-
gen of the amide carbonyl group.15 In this work, we synthesized
various 3-arylisoquinolinamines based on the previously reported
3-arylisoquinolinamine 7a, which exhibited sub-micromolar cyto-
toxicities against several cancer cell lines.16 One feasible mecha-
nism of these compounds was suggested to be inhibition of
topoisomerase I. However, the precise mechanism of action of
these analogs remains unclear. In order to understand the mode
of action of 3-arylisoquinolinamines, as well as their SAR, we syn-
thesized diverse substituents of the lead compound 7a (Table 1).
For the synthesis of 3-arylisoquinoliamines 7, we used the pre-
viously reported lithiated toluamide–benzonitrile cycloaddition
method.17 N-Diethyl-o-toluamides 8 were treated with n-BuLi to
give the anions, which were then reacted with benzonitrile 9 to af-
ford the 3-arylisoquinolines 6 in moderate yield. Treatment of 6
with POCl3 provided the corresponding imine chloride 10, which
was then reacted with p-methoxybenzylamine and K2CO3 in DMF
* Corresponding authors. Tel.: +82 62 530 2933; fax: +82 62 530 2911 (W.-J.C.).
E-mail address: wjcho@jnu.ac.kr (W.-J. Cho).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.06.132

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S. H. Yang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5277–5281
R2
O
R2
O
R1
R1
N
NMe
N
MeO
Me
OMe O
O
O
2
3
1
O
N
O
Me
N
R2
Me
R1
R1
N
R
R
NH2
O
O
7a
4
5
R2
R2
R1
R1
NH
N
O
NH2
6
7
Figure 1. Structure of potent antitumor agent
1
constrained structures of 3-arylisoquinolines; indeno[1,2-b]isoquinoline 2, isoindolo[2,1-b]isoquinoline 3, 12-
oxobenzo[c]phenanthridine 4, and benz[b]oxepine 5. Structural modification of 6 to 3-arylisoquinolinamines 7.
Table 1
Chemical yield and melting points of the 3-arylisoquinolinamines 7a–s
No.
Compound
R1
R2
R3
Yieldb
Mp (°C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
7s
–CH3
H
H
H
H
–N(CH3)2
–CH3
–CH3
–CH3
–CH3
–CH3
H
H
2-Methyl
3-Methoxy
3-Methyl
3,4-Dimethoxy
3,5-Dimethoxy
3-Methoxy
2-Methoxy
3-Methoxy
4-Methoxy
3,5-Dimethoxy
2-Fluoro
2-Methoxy
2-Fluoro
2,6-Dimethyl
3,4-Methylenedioxide
3-Methyl
5-Methoxy-2-methyl
2,6-Dimethyl
3-Methyl
68
62
63
76
35
67
64
68
60
90
69
75
79
68
70
97
77
82
78
269–270
–N(CH3)2
–N(CH3)2
–N(CH3)2
–N(CH3)2
H
H
H
H
H
202–206 (dec)
223–227 (dec)
249–260 (dec)
251–252 (dec)
265–276 (dec)
226–232
147–148
134–139
248–257 (dec)
127–128
195–211 (dec)
114–121
H
–CH3
–CH3
–CH3
–CH3
–CH3
–CH3
–OCH3
–OCH3
H
H
H
H
166–167 (dec)
172–175
75–85a
H
148–159
262–273 (dec)
259–266 (dec)
–OCH3
–OCH3
a
Not HCl salt.
Yield calculated from compound 11.
b
to yield the PMB-protected isoquinolinamine 11 in good yield. In
the previous work,16 we introduced benzylamine at the C-1 posi-
tion, followed by catalytic hydrogenation to obtain the amine in
moderate yield. However, deprotection of the benzyl group by cat-
alytic hydrogenation reaction did not work on some substituted
analogs. After several attempts under various conditions, deprotec-
tion of PMB of 11 was successfully accomplished with trifluoroace-
tic acid to afford the desired isoquinolinamines 7 in moderate yield
as shown in Scheme 1. The free amines were then treated with c-
HCl in acetone to provide the HCl salt forms of the amines.
The in vitro cytotoxicity experiments were performed with the
synthesized compounds against various human cancer cell lines
such as MDA-MB-231 (breast), PC3 (prostate), HCT-15 (colon),
HCT 116 (colon), OVCAR-3 (ovary), Caki-1 (kidney), PANC-1
(pancreas), SNB-19 (glioblastoma), and SK-MEL-28 (melanoma)
cells from the American Type Culture Collection (ATCC) (Manassas,
VA).
The growth inhibition assay of representative 3-arylisoquino-
linamine derivatives against human cancer cell lines was per-
formed using the sulforhodamine B method.18 Absorbance was
measured at 530 nm using Benchmark Plus Microplate reader
(Bio-Rad Laboratories, Hercules, CA). The drug concentration which
inhibited the cell growth by 50% (IC50) was calculated using Kale-
dia Graph software program (Synergy software, Reading, PA).

S. H. Yang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5277–5281
5279
R1
R2
Me
NEt2
R3
R1
POCl3
n-BuLi
R3
+
THF
NH
NC
R2
O
O
8
9
6
R3
R3
R3
PMBNH2
K2CO3
R1
R2
R1
R2
R1
R2
1) TFA/ CH2Cl2
N
N
2) c-HCl, acetone
N
DMF
Cl
.
NH2
NHPMB
HCl
10
7
11
Scheme 1. The synthesis of 3-arylisoquinolinamines 7a–s. (a) R1 = Me, R2 = H, R3 = 2-Me; (b) R1 = H, R2 = NMe2, R3 = 3-MeO; (c) R1 = H, R2 = NMe2, R3 = 3-Me; (d) R1 = H,
R2 = NMe2, R3 = 3,4-(OMe)2; (e) R1 = H, R2 = NMe2, R3 = 3,5-(OMe)2; (f) R1 = NMe2, R2 = H, R4 = 3-MeO; (g) R1 = Me, R2 = H, R3 = 2-MeO; (h) R1 = Me, R2 = H, R3 = 3-MeO; (i)
R1 = Me, R2 = H, R3 = 4-MeO; (j) R1 = Me, R2 = H, R3 = 3,5-(OMe)2; (k) R1 = Me, R2 = H, R3 = 2-F; (l) R1 = H, R2 = Me, R3 = 2-MeO; (m) R1 = H, R2 = Me, R3 = 2-F; (n) R1 = H, R2 = Me,
R3 = 2,6-(Me)2; (o) R1 = H, R2 = Me, R3 = 3,4-(OCH2O); (p) R1 = H, R2 = Me, R3 = 3-Me; (q) R1 = H, R2 = Me, R3 = 5-MeO-2-Me; (r) R1 = OMe, R2 = OMe, R3 = 2,6-(Me)2; (s)
R
1 = OMe, R2 = OMe, R3 = 3-Me.
Table 3
Surprisingly, most 3-arylisoquinolinamine derivatives exhibited
IC50 of compounds 7b, 7c, and paclitaxel in HCT-15 and HCT 116 cells
potent cytotoxicities in dose-dependent manner, as shown in Table
2, against eight cancer cell lines, suggesting that the potency of
these compounds was not highly dependent on the substitution
pattern of the modified phenyl ring. Among these compounds,
eight compounds, 7b, 7c, 7d, 7e, 7f, 7h, 7n, and 7q, showed equal
or better growth inhibitory activity against human cancer cells
compared to 7a. In particular, compounds 7b and 7c inhibited
the cell growth at IC50 values ranged from 14 nM to 32 nM in the
human cancer cells tested, which are 5–13 times more active than
compound 7a.
From the viewpoint of structure–activity relationships, the gen-
eral features could be summarized as follows. The dimethylamino
group on C-6 or C-7 position of the A ring contributed to significant
increases in cytotoxic potency with the preference at C-7. But
methyl-substituted compounds on C-6 or C-7 of the A ring did
not show the relationship between substitution and activity.
Next, the in vitro antitumor effects of compounds 7b and 7c
were tested against paclitaxel-resistant HCT-15 human colorectal
cancer cells and HCT 116 colon cancer cells, and their antitumor
activities were compared with those of paclitaxel (TaxolÒ). As
shown in Table 3, compounds 7b and 7c showed potent antiprolif-
7b
7c
Paclitaxel
HCT-15
15 nM
17 nM
0.88
21 nM
23 nM
0.91
140 nM
2 nM
70
HCT 116
Resistant indicesa
a
The resistant indices are defined by IC50 (HCT-15)/IC50 (HCT 116).
erative activities in vitro with IC50 values in the low nanomolar
range in both cell types and higher antitumor activities than that
of paclitaxel against paclitaxel-resistant HCT-15 colorectal cancer
cells. When IC50 values were compared in both colon cancer cell
lines, the activity of paclitaxel was decreased by 70-fold in HCT-
15 cells but both compounds 7b and 7c displayed still the strong
growth inhibition of these cells.
Although some 3-arylisoquinoline derivatives showed moder-
ate topoisomerase I inhibitory activities in a previous study,16 no
confirmed cytotoxic mechanism were clarified. To better under-
stand the cytotoxic mechanism of the compounds, cell cycle
dynamics were analyzed by flow cytometry. Briefly, HCT-15 cells
were plated at a density of 1 Â 106 cells per 100-mm culture dish
Table 2
Inhibition of cell growth (IC50, lM) by 3-arylisoquinolinamine compounds 7a–s against human cancer cell lines
Compound MDA-MB-231
(breast)
PANC-1
(pancreas)
HCT 116
(colon)
PC3
(prostate)
OVCAR-3
(ovary)
SK-MEL-28
(melanoma)
Caki-1
(kidney)
SNB19
(glioblastoma)
7aa
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
0.15
0.021
0.021
0.15
0.027
0.059
0.44
0.14
0.93
0.18
0.55
0.32
0.72
0.051
0.15
0.21
0.030
0.25
0.79
0.24
0.019
0.018
0.19
0.026
0.11
0.93
0.31
2.27
0.38
1.59
0.68
2.14
0.079
0.37
0.69
0.058
0.54
2.27
0.19
0.017
0.023
0.18
0.029
0.064
0.67
0.19
1.36
0.24
0.70
0.47
1.22
0.074
0.18
0.28
0.042
0.79
2.32
0.24
0.019
0.024
0.23
0.048
0.19
>3.0
0.25
2.98
0.43
1.84
1.01
2.76
0.12
0.25
0.71
0.070
0.68
2.50
0.15
0.014
0.016
0.14
0.025
0.071
0.49
0.18
0.79
0.18
0.57
0.51
0.91
0.075
0.23
0.29
0.042
0.16
0.58
0.35
0.032
0.032
0.33
0.045
0.11
0.80
0.34
1.80
0.41
1.07
0.67
1.62
0.12
0.42
0.50
0.051
0.63
1.12
0.12
0.022
0.023
0.17
0.038
0.068
0.35
0.13
0.75
0.16
0.46
0.22
0.59
0.048
0.13
0.44
0.047
0.53
1.78
0.26
0.032
0.028
0.25
0.057
0.094
1.13
0.29
2.23
0.47
1.51
0.78
2.20
0.12
0.38
0.53
0.052
0.42
1.56
7s
a
Compound 7a was previously reported16 and was therefore used as a reference molecule for cytotoxicity comparison in this Letter.

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S. H. Yang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5277–5281
and incubated for 24 h. Fresh media containing test samples were
added to the culture dishes. After 24 h and 48 h, the cells were har-
vested (trypsinization and centrifugation), fixed with 70% ethanol,
and incubated with a staining solution containing 0.2% NP-40,
2000
1800
1600
Control
Paclitaxel, 10 mg/kg
Compound 7b, 10 mg/kg
1400
1200
1000
800
RNase A (30 lg/ml), and propidium iodide (50 lg/ml) in phos-
phate–citrate buffer (pH 7.2). Cellular DNA content was analyzed
by flow cytometry using a Becton Dickinson laser-based flow
cytometer. At least 20,000 cells were used for each analysis, and
the results were displayed as histograms. In cell cycle analysis
using HCT-15 cells (see Fig. 2), treatment of 1 nM of compound
7b displayed a significant increase in G0/G1 phase at 24 h with a
decrease in G2/M phase, but the increase of G0/G1 phase at 48 h
was not significant. At higher concentration of compound 7b
(10 nM), there were a significant increase in G0/G1 phase and de-
crease in G2/M phase, and an emergence of sub-G1phase, at both
24 h and 48 h. These data indicated that compound 7b blocked
or delayed the progression of cells from G0/G1 phase into S phase,
and induced cell death.
In order to observe the inhibition of tumor growth in an animal
model, an ex vivo xenograft study of nude mice was conducted uti-
lizing compound 7b. Paclitaxel-resistant HCT-15 cell suspension
(1 Â 106 cells in 0.2 ml of RPMI) was injected subcutaneously into
the right flank of six-week-old female athymic mice (BALB/c nu/
nu) on day 0. Animals with tumors in the proper size range were
assigned to various treatment groups. Paclitaxel was used as a po-
sitive control. Compound 7b and paclitaxel were dissolved in 5%
Cremophor and 5% ethanol in PBS, and solvent alone served as a
vehicle control. All study medications (vehicle control; paclitaxel:
10 mg/kg/day; compound 7b: 10 mg/kg/day) were given by intra-
peritoneal injection three times per week starting on day 10 and
ending on day 29 after inoculation of HCT-15 cells. To quantify tu-
mor growth, three perpendicular diameters of the tumors were
measured with calipers every 3–5 days, and the body weights of
the mice were monitored to assess toxicity. Tumor volume
(mean SEM) in each group of animals is presented in Figure 3,
which shows the measurement of tumor volume as an indicator
of the efficacy of compound 7b against HCT-15 human colon carci-
noma xenografts. Compound 7b treatment was well tolerated with
no deaths and body weight fluctuations of <1 g observed. As a re-
600
400
200
0
10
15
20
25
30
Days after Injection
Figure 3. Antitumor activity of compound 7b against HCT-15 human colon
carcinoma xenografts. Paclitaxel-resistant HCT-15 cell suspension (1 Â 106 cells in
0.2 ml of RPMI) was injected subcutaneously into the right flank of six-week-old
female athymic mice (BALB/c nu/nu) on day 0. Animals with tumors in the proper
size range were assigned to various treatment groups. Palcitaxel was used as a
positive control. Compound 7b and paclitaxel dissolved in 5% Cremophor and 5%
ethanol in PBS were given by intraperitoneal injections three times per week
starting from day 10 and ending on day 29 after inoculation of HCT-15 cells. The
tumor volume (mean SEM) was calculated using the formula: tumor volume
(mm3) = (width) Â (length) Â (height) Â
p/6.
sult of the measurement of antitumor activity against HCT-15 hu-
man colorectal cancer in nude mice at day 29, 7b was found to
have higher antitumor efficacy (69.2% inhibition) than the control
drug, paclitaxel (48.8% inhibition), as shown in Figure 3.
In conclusion, we synthesized various C-6 or C-7 substituted 3-
arylisoquinolinamines based on the lead compound 7a, which
exhibited 0.17 l
M cytotoxicity against A549,16 and their antitumor
activity was examined in eight different human cancer cell lines
using SBR assay. Among them, eight compounds including C-6 or
C-7 dimethylamino-substituted 3-arylisoquinolinamines displayed
stronger potency than the lead compound 7a. Our further in vitro
studies showed that compounds 7b and 7c are potent antiprolifer-
ative agents with low nanomolar range of IC50 against paclitaxel-
resistant HCT-15 cells, and this cell growth inhibition by com-
Figure 2. The effect of 7b on cell cycle progression in HCT-15 cells. Cells were treated with 7b (10 nM) for 24 h or 48 h and then the cell cycle was analyzed by flow cytometry
analysis.

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5281
5. Galvez-Peralta, M.; Hackbarth, J. S.; Flatten, K. S.; Kaufmann, S. H.; Hiasa, H.;
Xing, C. G.; Ferguson, D. M. Bioorg. Med. Chem. Lett. 2009, 19, 4459.
6. Kik, K.; Studzian, K.; Wasowska-Lukawska, M.; Oszczapwicz, I.; Szmigiero, L.
Acta Biochim. Pol. 2009, 56, 135.
7. Bader, Y.; Madlener, S.; Strasser, S.; Maier, S.; Saiko, P.; Stark, N.; Popescu, R.;
Huber, D.; Gollinger, M.; Erker, T.; Handler, N.; Szakmary, A.; Jager, W.; Kopp,
B.; Tentess, I.; Fritzer-Szekeres, M.; Krupitza, G.; Szekeres, T. Oncol. Rep. 2008,
19, 801.
pound 7b results from G0/G1-phase arrest. Moreover, in vivo study
demonstrated that compound 7b inhibited the tumor formation in
paclitaxel-resistant HCT-15 xenograft model to suggest a potential
use of compound 7b in drug-resistant tumor treatment. Thus high-
er antitumor efficacy of 3-arylisoquinolineamine 7b and related
analogs could provide a new research area for the development
of novel antitumor chemotherapeutic candidates.
8. Fortin, J. S.; Cote, M. F.; Lacroix, J.; Patenaude, A.; Petitclerc, E.; C-Gaudreault, R.
Bioorg. Med. Chem. Lett. 2008, 18, 3526.
9. Gauduchon, J.; Seguin, A.; Marsaud, V.; Clay, D.; Renoir, J. M.; Solal, B. Int. J.
Cancer 2008, 122, 2130.
10. Cho, W. J.; Yoo, S. J.; Park, M. J.; Chung, B. H.; Lee, C. O. Arch. Pharm. Res. 1997,
20, 264.
11. Cho, W. J.; Le, Q. M.; Van, H. T. M.; Lee, K. Y.; Kang, B. Y.; Lee, E. S.; Lee, S. K.;
Kwon, Y. Bioorg. Med. Chem. Lett. 2007, 17, 3531.
12. Van, H. T. M.; Le, Q. M.; Lee, K. Y.; Lee, E. S.; Kwon, Y.; Kim, T. S.; Le, T. N.; Lee, S.
H.; Cho, W. J. Bioorg. Med. Chem. Lett. 2007, 17, 5763.
13. Van, H. T. M.; Cho, W. J. Bioorg. Med. Chem. Lett. 2009, 19, 2551.
14. Lee, S. H.; Van, H. T. M.; Yang, S. H.; Lee, K. T.; Kwon, Y.; Cho, W. J. Bioorg. Med.
Chem. Lett. 2009, 19, 2444.
15. Volle, J. N.; Filippini, D.; Krawczy, B.; Kaloyanov, N.; Van der Lee, A.; Maurice,
T.; Pirat, J. L.; Virieux, D. Org. Biomol. Chem. 2010, 8, 1438.
16. Cho, W. J.; Min, S. Y.; Le, T. N.; Kim, T. S. Bioorg. Med. Chem. Lett. 2003, 13, 4451.
17. Le, T. N.; Gang, S. G.; Cho, W. J. J. Org. Chem. 2004, 69, 2768.
18. Rubinstein, L. V.; Shoemaker, R. H.; Paull, K. D.; Simon, R. M.; Tosini, S.; Skehan,
P.; Scudiero, D. A.; Monks, A.; Boyd, M. R. J. Natl. Cancer Inst. 1990, 82, 1113.
Acknowledgment
This work was supported by Korea Research Foundation Grant
(NRF-2009-0071379) and Rexahn Pharmaceuticals, Inc.
References and notes
1. Chang, H. L.; Wu, Y. C.; Su, J. H.; Yeh, Y. T.; Yuan, S. S. F. J. Pharmacol. Exp. Ther.
2008, 325, 841.
2. Chen, Y. J.; Kuo, C. D.; Tsai, Y. M.; Yu, C. C.; Wang, G. S.; Liao, H. F. Anti-Cancer
Drug 2008, 19, 55.
3. Basili, S.; Moro, S. Expert Opin. Ther. Pat. 2009, 19, 555.
4. Feng, W.; Satyanarayana, M.; Tsai, Y. C.; Liu, A. A.; Liu, L. F.; LaVoie, E. J. Bioorg.
Med. Chem. 2009, 17, 2877.