Synthesis and in vitro antitumor activity of novel scopoletin derivatives

Article abstract of DOI:10.1016/j.bmcl.2012.06.014

Twenty scopoletin derivatives were developed by a systematic combinatorial chemical approach and their chemical structures were confirmed by MS, IR, ¹H NMR spectra and elemental analysis. Primary screening against mammary (MCF-7 and MDA-MB 231) and colon (HT-29) carcinoma cells indicated that five compounds (8d, 8g, 8j, 11b and 11g) displayed high antitumor potencies with IC₅₀ values below 20 μM whereas scopoletin showed IC₅₀ values above 100 μM. Moreover, the most promising compound 11g was more active than 5-fluorouracil. These results clearly indicated that the modification of the scopoletin structure could greatly increase its antitumor activity in vitro.

Full text of DOI:10.1016/j.bmcl.2012.06.014

Bioorganic & Medicinal Chemistry Letters 22 (2012) 5008–5012
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and in vitro antitumor activity of novel scopoletin derivatives
Wukun Liu a,b, Jie Hua c, Jinpei Zhou a, , Huibin Zhang a, Haiyang Zhu a, Yanhua Cheng a, Ronald Gust d,
⇑
⇑
a Department of Medicinal Chemistry, China Pharmaceutical University, Tongjia Xiang 24, 210009 Nanjing, PR China
b Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Str 2+4, 14195 Berlin, Germany
c R&D Institute of Jiangsu Jumpcan Pharmaceutical Co. Ltd, 225441 Taixin, PR China
d Institut für Pharmazie, Universität Innsbruck, Innrain 80/82, A-6020 Innsbruck, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
Twenty scopoletin derivatives were developed by a systematic combinatorial chemical approach and
their chemical structures were confirmed by MS, IR, 1H NMR spectra and elemental analysis. Primary
screening against mammary (MCF-7 and MDA-MB 231) and colon (HT-29) carcinoma cells indicated that
five compounds (8d, 8g, 8j, 11b and 11g) displayed high antitumor potencies with IC50 values below
Received 17 April 2012
Revised 4 June 2012
Accepted 7 June 2012
Available online 15 June 2012
20 lM whereas scopoletin showed IC50 values above 100 lM. Moreover, the most promising compound
11g was more active than 5-fluorouracil. These results clearly indicated that the modification of the
scopoletin structure could greatly increase its antitumor activity in vitro.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Scopoletin
Scopoletin derivatives
Synthesis
Antitumor activity
A long-standing way to find new drugs represents the isolation
of the ingredient of plants, fungi, bacteria, and marine organisms.1
After evaluation of their biological activity, the pharmacological
profile often needs optimization by structural modification. Espe-
cially in cancer therapy, such drugs play a significant role.2 Accord-
ing to the National Cancer Institute (NCI), more than 60% of
currently used cancer therapeutics are derived from natural com-
pounds showing often a much better therapeutic profile than pure
synthetic drugs.3
Scopoletin (7-hydroxy-6-methoxy-2H-chromen-2-one 7, Scheme
2) also known as gelseminic acid, chrysatropic acid, and murrayetin
has been isolated from several plant species, such as Erycibe obtusifo-
lia Benth, Aster tataricus and Foeniculum vulgare and belongs to the
class of coumarins.4–26
Studies demonstrated that scopoletin exhibited significant phar-
macological activities. It is an anti-oxidant, acts as spasmolytic, anti-
inflammatory, anti-arthritic, and anti-angiogenetic agent mainly
due to the inhibition of COX-2 expression, nitric oxide synthesis,
endothelial cell migration, pro-inflammatory cytokine production,
tube formation and VEGF receptor 2 autophosphorylation.4–16
Scopoletin displayed only low antitumor activity. But it could
induce cell cycle arrest and increase apoptosis in human prostate
tumor cells and human leukemia cell line via activation of
caspase-3.17–19 It also showed considerable antitumor potentials
cancer in mice in vivo.22 In addition, Khuda-Bukhsh and co-work-
ers. reported that its derivatives and analogues exhibited antitu-
mor effects in vitro and in vivo.23–26
Therefore, our interest now focused on the modification of
scopoletin to increase the cytotoxic potency by using a molecular
hybridization method. In this structure–activity relationship
(SAR) study, all hybrid target compounds were obtained by reac-
tion of scopoletin or 3-acetamido-substituted scopoletin with
N-phenylacetamide derivatives. A systematic combinatorial chem-
ical approach which is recently widespread as tool for the discov-
ery of new therapeutic agents was used.27 All synthesized
compounds were characterized by MS, IR, 1H NMR, elemental anal-
ysis and evaluated for their in vitro cytotoxicities against human
breast (MCF-7, MDA-MB 231) and colon (HT-29) cancer cell lines.
As previously reported scopoletin (7) could be synthesized by
condensation of 2,4-dihydroxy-5-methoxy-benzaldehyde (5) with
(methoxycarbonyl)methylene triphenylphosphorane in N,N-dieth-
ylaniline under reflux in a nitrogen atmosphere.28 However,
(methoxycarbonyl)methylene triphenylphosphorane is less acces-
sible as it needs to be synthesized from triphenylphosphine and
ethyl bromoacetate.
Here we describe a new method to prepare scopoletin by the
Knoevenagel–Doebner reaction, which can effectively produce
scopoletin on a large scale.29 The preparation method is very sim-
ple and all reagents are commercially available.
against 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin
The intermediate 5 was obtained in a one-step reaction from
2,4,5-trimethoxybenzaldehyde (4) by reaction with aluminium(III)
chloride in dichloromethane, followed by acid hydrolysis.30
Treatment of 5 with malonic acid in pyridine for 24 h at room
⇑
Corresponding authors. Tel.: +86 25 83471532; fax: +86 25 83271480 (J.Z.);
tel.: +43 512 507 58200; fax: +43 512 507 58299 (R.G.).
E-mail addresses: jpzhou668@163.com (J. Zhou), ronald.gust@uibk.ac.at (R. Gust).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.06.014

W. Liu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5008–5012
5009
H3CO
H3CO
CHO
HOOC
O
OCH3
OH
H3CO
HO
CHO
OH
a
b
OCH3
O
6
5
4
OCH3
O
OCH3
OH
c
H
N
d
6
O
O
O
O
R
O
8a-j
7
(Scopoletin)
Scheme 1. Reagents and conditions: (a) AlCl3 CH2Cl2, rt, 24 h; (b) malonic acid, phenylamine, pyridine, rt, 24 h; (c) pyridine: ethylene glycol (1:1.1); (d) 3a–j, K2CO3, acetone,
reflux, 2 h.
H3CO
HO
CHO
OH
AcHN
O
OCH3
OAc
AcHN
O
OCH3
OH
a
b
O
O
5
9
10
AcHN
O
OCH3
O
c
H
N
10
O
R
O
11a-j
Scheme 2. Reagents and conditions: (a) N-acetylglycine, AcONa, Ac2O, reflux, 4 h; (b) K2CO3, methanol, reflux, 0.5 h; (c) 3a–j, K2CO3, acetone, reflux, 2 h.
temperature (rt) using phenylamine as catalysts afforded 7-hydro-
xy-6-methoxy-2-oxo-2H-chromene-3-carboxylic acid (6) in 86%
NHs and OHs) and not more than 10 H-bond acceptors (expressed
as the number of Ns and Os) are present (see Table 1).
yield. Then heating
6
in
a
pyridine/ethylene glycol mixture
All target compounds and scopoletin were evaluated for growth
inhibitory activities against breast (MCF-7 and MDA-MB 231) and
colon cancer (HT-29) cell lines (Fig. 1, Table 2) according to a pre-
vious published method.35,36 A known number of cells were ex-
posed to increasing concentrations of compounds on a 96-well
tissue culture plate and incubated for a given period of time. In
addition, the established cytostatic agent 5-fluorouracil (5-FU)
was used as reference. Growth-inhibitory effects (T/Ccorr (%)) in
(1:1.1) to reflux for 3 h gave scopoletin (7, Scheme 1).
The synthetic route to obtain [N-(7-hydroxy-6-methoxy-2-oxo-
2H-chromen-3-yl)acetamide] (10) also started from 5 which was
treated with 2 equiv. of N-acetylglycine in acetic anhydride using
4 equiv. of sodium acetate as base. After heating to reflux for 4 h,
3-acetamido-6-methoxy-2-oxo-2H-chromen-7-yl acetate (9) could
be isolated and selectively hydrolyzed by K2CO3 in methanol to
give 10 (Scheme 2).
The substituted 2-iodo-N-phenylacetamides 3a-j used as syn-
thons were obtained by using the Finkelstein reaction.31,32 Treat-
ment of substituted 2-chloro-N-phenylacetamides 2a–j, which
were prepared by reacting 2-chloroacetyl chloride with substituted
anilines 1a–j with an equimolar amount of KI in acetone under re-
flux for 2 h afforded 3a–j in about 90% yields (Scheme 3). Finally,
treatment of 7 or 10 with 3a–j in acetone using K2CO3 as base
yielded the target compounds 8a–j and 11a–j, respectively
(Schemes 1 and 2).
all cell lines at 10 and 20
presented in Figure 1.
lM after an incubation time of 72 h are
It is obvious that 8d, 8g, 8j, 11b, 11f, 11g and 11i were more ac-
tive than the other compounds at 20 M causing T/Ccorr <50%.
l
Compound 8g with a 4-standing tert-butyl residue was cytocidal
(T/Ccorr <0%) against MCF-7 and MDA-MB 231 cells and 8j as most
active compound (R = 3-Cl, 4-F) even showed cytocidal effects at
10
l
M at all cell lines.
The 3-acetamido-substituted scopoletin derivatives were not as
active. For instance the tert-butyl analog 11g showed only cytoto-
static potency with T/Ccorr = 0–10% at 20 M. A distinctly greater
All of the synthetic compounds gave satisfactory analytical and
spectral data, which were in full accordance with their predicted
structures.
l
influence had the 3-acetamido group on the growth inhibitory ef-
fects of 8j. The high activity was completely terminated.
In addition, based on Lipinski’s rule of five33 derived from an
analysis of drug-like compounds from the World Drug Index data-
base,34 all novel molecules (expect for compounds 11h and 11i) pos-
sess the parameters important for the favorable oral bioavailability:
the determined logP values are less than 5, the molecular weight is
<500 Da, not more than 5 H-bond donors (expressed as the sum of
For a better comparison, IC50 values were determined and pre-
sented in Table 2. The most active compounds 8j and 11g were at
least 12-fold more active than 7 (IC50 >100
rably effective against the breast and colon carcinoma cells with
IC50 values of 6.3–7.6 M (8j) and 3.9–4.5 M (11g), respectively.
lM). They were compa-
l
l
11g was even more active than 5-FU (IC50 = 4.7–9.6 lM).
H
N
H
N
NH2
a
Cl
b
I
R
R
R
O
O
1a-j
2a-j
3a-j
Scheme 3. Reagents and conditions: (a) ClCH2COCl, AcOH, 0 °C, then rt, 4 h; (b) KI, acetone, reflux, 2 h.

5010
W. Liu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5008–5012
Table 1
Structure, mp (°C), yield (%) and drug-likeness of target compounds
a
Compd.
R
Formula
18H15NO5
C19H17NO6
C20H17NO6
mp (°C)
Yield (%)
LogP (<5)
H-bond donorsb (<5)
H-bond acceptorsc (<10)
MWT (<500)
8a
8b
8c
8d
8e
8f
8g
8h
H
C
224–226
192–194
217–219
220–221
224–226
210–213
203–204
196–198
205–207
212–214
236–238
226–227
240–242
250–251
240–242
239–241
230–231
232–233
210–212
236–238
94.5
57.7
79.8
78.3
79.8
54.7
52.1
88.1
78.5
90.3
99.4
81.6
77.8
97.1
96.5
99.0
34.1
90.1
95.8
94.6
2.09
1.96
1.4
2.64
2.24
2.57
3.79
1.83
1.83
2.8
0.47
0.35
À0.21
1.03
0.63
0.96
2.18
0.22
0.22
1.19
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
6
7
7
6
6
6
6
8
8
6
8
9
9
8
8
8
8
325.32
355.34
367.35
359.76
343.31
339.34
381.42
385.37
385.37
377.75
382.37
412.39
424.40
416.81
400.36
396.39
438.47
442.42
442.42
434.80
2-OCH3
3-COCH3
4-Cl
4-F
4-CH3
4-C(CH3)3
2,4-OCH3
3,4-OCH3
3-Cl,4-F
H
2-OCH3
3-COCH3
4-Cl
4-F
4-CH3
4-C(CH3)3
2,4-OCH3
3,4-OCH3
3-Cl,4-F
C18H14ClNO5
C18H14FNO5
C19H17NO5
C22H23NO5
C20H19NO7
C20H19NO7
8i
8j
C
C
18H13ClFNO5
20H18N2O6
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
C21H20N2O7
C22H20N2O7
C
C
20H17ClN2O6
20H17FN2O6
C21H20N2O6
C24H26N2O6
C22H22N2O8
C22H22N2O8
10
10
8
C20H16ClFN2O6
a
b
c
Indicated that the values of logP for all compounds were calculated through ChemDraw.
H-bond donors expressed as the sum of NHs and OHs.
H-bond acceptors expressed as the sum of Ns and Os.
10 µM, MCF-7
20 µM, MCF-7
10 µM, MDA-MB 231
20 µM, MDA-MB 231
10 µM, HT-29
140
120
100
80
20 µM, HT-29
60
40
20
0
-20
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
-40
10 µM, MCF-7
20 µM, MCF-7
140
120
100
80
10 µM, MDA-MB 231
20 µM, MDA-MB 231
10 µM, HT-29
20 µM, HT-29
60
40
20
0
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
-20
-40
Figure 1. Growth-inhibitory effects (Treated/Controlcorr (%)) on MCF-7, MDA-MB 231 and HT-29 cancer cells at 10 and 20 lM after 72 h of incubation.

W. Liu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5008–5012
5011
Table 2
cially the C-4 position of the aryl ring is important. Lipophilic
groups such as a tert-butyl group or a chlorine are favored against
methoxy or acetyl groups. Furthermore, the effects seem to be not
independent on substituents at the chromene-2-one ring. The 3-
acetamido group lowered the activity of 11g and 11j, but caused
higher activity in the case of 11b, 11f, and 11i. From another point
of view it can be deduced that in most of the 3-acetamido substi-
tuted scopoletin derivatives strong electron-donating groups such
as methyl (11f), methoxy (11b and 11i) and especially tert-butyl
groups (11g) are more cytotoxic than those with electron-absorb-
ing groups (11c–e, 11h, and 11j).
Cytotoxicity (IC50, lM) of compounds against MCF-7 and MDA-MB 231 and HT-29
cancer cells after 72 h of incubation
Compd.
MCF-7
MDA-MB 231
HT-29
Scopoletin (7)
8d
8g
8j
11b
11f
11g
11i
5-FU
>100
>100
>100
19.5 0.6
10.1 1.4
6.5 0.2
17.9 1.1
19.0 0.4
3.9 0.9
14.9 0.2
4.7 0.4
19.3 2.1
8.1 0.3
6.3 0.1
14.7 0.7
13.9 1.4
4.5 0.4
8.4 1.3
9.6 0.3
18.1 1.8
19.6 0.1
7.6 1.0
19.1 1.3
>20
4.3 0.3
>20
7.3 1.0
Because of these findings we tried to correlate the LogP value
(P = partition coefficient in an octanol-water system) as parameter
for hydrophobicity of a molecule with its biological data. The logP
values of the new compounds (Table 1) calculated by ChemDraw
are in the range from À0.21 to 3.79. Although a correlation of logP
and growth inhibitory activity is not observable it is worthy to note
that compound 11g with the high logP value of 2.18 showed the
highest growth inhibitory effects in the series of 3-acetamido
substituted scopoletin derivatives. The scopoletin derivatives 8d,
8j and 8g with high logP values (2.64, 3.79 and 2.8, respectively)
exhibited higher activity than other compounds in the series.
Finally, as scopoletin could induce cell cycle arrest and increase
apoptosis in tumor cells via activation of caspase-3, we investi-
gated if its derivatives have the same effects.17 Unfortunately, the
most promising compound 11g did not activate caspase-3 in
MDA-MB 231 and U2-OS cell lines at a cytostatic concentration
120
100
80
60
40
20
0
(10 lM), so it was renounced on further experiments.
In summary, a new method to prepare scopoletin was devel-
oped and two series of scopoletin derivatives were synthesized.
Preliminary in vitro cytotoxicity studies indicated that one third
of the synthesized compounds displayed significant growth inhib-
itory activities against breast and colon cancer cell lines. Moreover,
compounds 8j and 11g demonstrated equal or higher antitumor ef-
fects than 5-FU. Modification of the scopoletin structure could
greatly increase its antitumor potency. The introduction of hydro-
phobic residues at C-4 position of the aryl ring was associated with
enhanced cytotoxic activities. Furthermore, the data indicated that
the use of strong electron-donating substituents at the arylamido
moiety of the 3-acetamido-substituted scopoletin 11a generally in-
creased the activities. To confirm this finding and to get an insight
into the mode of action an enlarged SARs study is in progress and
will be part of a forthcoming paper.
-20
0
20
40
60
80
100
120
140
Incubation time (h)
1.25 µM
2.5 µM
5 µM
10 µM
20 µM
120
100
80
60
40
20
0
Acknowledgments
The authors are grateful for the financial supports of Jiangsu
Enterprise-Academics-Research Innovation Found-Prospective
Joint Research Project (No. BY2011158), the China Scholarship
Council (CSC) and the Deutsche Forschungsgemeinschaft (DFG)
within FOR 630 ‘Biological function of organometallic compounds’.
-20
0
20
40
60
80
100
120
140
20 µM
Incubation time (h)
1.25 µM
2.5 µM
5 µM
10 µM
Figure 2. Time activity curves of 11g on MCF-7 (above) and HT-29 (below) cell
lines. Error bars are hidden behind the symbols in some cases.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012
.06.014.
Furthermore, the time over activity correlations of 11g depicted
in Figure 2 are nearly identical for MCF-7 and HT-29 cells. The T/
Ccorr values remain nearly constant until the end of the experiment.
This is an indication that the cells will not become resistance
against the drug during the time of incubation. Furthermore, it is
obvious that only 8j and 11g caused high growth inhibitory effects
at HT-29 cells. The IC50 values of all other compounds were
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