Design, synthesis and antitumor activity of a series of novel coumarin-stilbenes hybrids, the 3-arylcoumarins

Article abstract of DOI:10.1016/j.cclet.2010.04.034

A series of novel coumarin-stilbenes hybrids called 3-arylcoumarins were synthesized via Perkin reaction and evaluated as potential antitumor agents. The results showed that some compounds exhibited in vitro activity against KB, KV, MCF-7, MCF-7/ADR cell

Full text of DOI:10.1016/j.cclet.2010.04.034

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 1295–1298
www.elsevier.com/locate/cclet
Design, synthesis and antitumor activity of a series of novel
coumarin–stilbenes hybrids, the 3-arylcoumarins
Chun Fen Xiao a,b, Li Yang Tao c, Hong Yi Sun a,b, Wen Wei a, Yu Chen a,b,
Li Wu Fu c, Yong Zou a,
*
a Guangzhou Institute of Chemistry, Chinese Academy of Sciences, Guangzhou 510650, China
b Graduated School of Chinese Academy of Sciences, Beijing 100049, China
c Oncology Research Department of Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
Received 9 March 2010
Abstract
A series of novel coumarin–stilbenes hybrids called 3-arylcoumarins were synthesized via Perkin reaction and evaluated as
potential antitumor agents. The results showed that some compounds exhibited in vitro activity against KB, KV, MCF-7, MCF-7/
ADR cell lines to some extent. Compound 3a showed remarkable effect against KB tumor cells with an IC50 value of 5.18 mmol/L.
# 2010 Yong Zou. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Perkin reaction; 3-Arylcoumarin; Trans-stilbene; Antitumor activity
Trans-stilbenes are an important family of plant secondary metabolites derived from the phenylpropanoid pathway,
and have been found in a number of plant species [1]. Many trans-stilbenes, including resveratrol, oxyresveratrol,
pterostilbene, piceatannol and isorhapotigenin exhibit high levels of biological activities and are renowned for
protection properties against cancer, heart diseases, stroke, Alzheimer’s disease, inflammations, infections and so on
[2–4]. Studies also proved that stilbenes like resveratrol can activate SIRT1 and resulting in anti-aging effects in
numerous organisms [5]. Although the skeleton of trans-stilbenes bear the resemblance to isoflavones, flavones and
coumarins, which are related with each other in biosynthesis, implying a good opportunity for crosswise structure
modification of these compounds (Fig. 1), few compounds have been documented concerning about the medicinal
chemistry until recently. Vilar et al. reported the synthesis of a series of coumarin–resveratrol hybrids by Pechmann
and Perkin reaction with yields of 27.3–42%. Pharmacological tests showed the new hybrids possess more potent
vasorelaxant and platelet antiaggregatory activity than that of resveratrol [6]. The results indicated that further
chemical and biological studies of coumarin–stilbenes hybrids would be worthy to do in the future.
As a continuation of our work on the chemistry of stilbene derivatives, we herein report the design and synthesis of a
series of novel coumarin–stilbenes hybrids 4, namely 3-arylcoumarins, which the trans double bond of the stilbenes
were locked by a six-membered benzopyrone ring, with satisfactory yields (74–93%). Structurally, these 3-
arylcoumarins bear close resemblance to the distinguished parent trans-stilbenes such as resveratrol, oxyresveratrol,
* Corresponding author.
E-mail address: zou_jinan@163.com (Y. Zou).
1001-8417/$ – see front matter # 2010 Yong Zou. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.04.034

[(Fig._1)TD$FIG]
1296
C.F. Xiao et al. / Chinese Chemical Letters 21 (2010) 1295–1298
Fig. 1. Structure similarities between trans-stilbenes, (iso) flavones and 3-arylcoumarins.
pterostilbene, piceatannol and isorhapotigenin in terms of skeleton and hydroxyl substitution pattern. Cytotoxicities of
the compounds were evaluated against four human cancer cell lines (KB, KV, MCF-7, MCF-7/ADR) by MTT assays,
and compound 3a was found to be a promising candidate with potent anticancer activity.
Preparation of the compounds 3 and 4 was shown in Scheme 1. Treatment of substituted phenyl acetic acid 1 and
ortho-hydroxylbenzaldehyde 2 in the presence of acetic anhydride and triethylamine for 8–12 h at 110 8C resulted in
acetylated 3-arylcoumarin 3 in 74–93% isolated yields. Compounds 4 were obtained by hydrolysis of 3 in the presence
of 10% hydrochloric acid in ethanol at 80 8C in 90–95% yields. The Structures of these compounds were conformed
1
by H NMR, 13C NMR, EI/ESI-MS, IR spectra (Table 1).
The synthesized compounds were evaluated for their inhibitory effects on the proliferation of tumor cells in vitro by
MTT assays (Table 2). The concentrations required to inhibit growth by 50% (IC50) were calculated from survival
curves using the Bliss method [8]. Among the prepared compounds, compound 3a, 3d and 4a which were
characterized by a 7, 8-dihydroxy group or 7, 8-diacetyloxy group exhibited apparent activity. Especially, compound
3a was found to possess the most potent activity with an IC50 value of 5.18 mmol/L against KB cell lines. It is worth
mentioning that compound 3a and 4a showed more potent inhibitory effects against MCF-7/ADR cell lines
(IC50 = 11.94, 11.11 mmol/L, respectively) than normal MCF-7 cell lines (IC50 = 21.43, 22.94 mmol/L, respectively),
implying a remarkable anti-MDR properties endowed with these compounds.
In conclusion, a series of novel 3-arylcoumarins were synthesized and their anticancer activities were evaluated for
four types cell lines. Among them, 3a, 3d and 4a exhibited remarkable cytotoxic activity invitro. Particularly, compound
3a showed the most potent activity with an IC50 value of 5.18 mmol/L against KB cell lines. The results suggested that 3-
arylcoumarins which possessing 7, 8-dihydroxy group or 7, 8-diacetyloxy group may be beneficial to cytotoxicities.
Further structural modification aiming at discovering more potent compounds is under way in our laboratory.
[(Scheme_1)TD$FIG]
Scheme 1. Synthesis of 3-arylcoumarins.

C.F. Xiao et al. / Chinese Chemical Letters 21 (2010) 1295–1298
1297
Table 1
The substituents, melting points and yields of compound 3 and 4.
Entry1
R6
R7
R8
R9
R10
Yielda (%)
Mp (8C)
3a
3b
3c
3d
3e
3f
OCH3
OCH3
OCH3
OAc
OCH3
OCH3
OCH3
OAc
OAc
OAc
H
OAc
OCH3
OAc
OAc
OCH3
OAc
OAc
H
77
93
91
75
76
74
88
155–156
159–161
162–164
168–170
204–206
189–191
236–238
H
H
OAc
OAc
H
H
OAc
OAc
H
OAc
OAc
H
3g
OAc
OAc
H
OAc
Entry2
R11
R12
R13
R14
R15
Yielda (%)
Mp (8C)
4a
4b
4c
4d
4e
4f
4g
a
OCH3
OCH3
OCH3
OH
OCH3
OCH3
OCH3
OH
OH
OH
H
OH
H
90
128–130 (lit. [7]:128–130)
OCH3
OH
H
93
165–167
221–223
>280
H
95
OH
OH
H
OH
H
91
OH
OH
OCH3
OH
H
90.5
90
249–251
>280
>280
OH
OH
H
OH
OH
H
OH
OH
94
Isolated yield.
Table 2
In vitro cytotoxic activity of tested compounds against KB, KV, MCF-7, MCF-7/ADR cell lines.
Compounds
Cell lines IC50 (mmol/L)
KB
KV
MCF-7
MCF-7/ADR
3a
3b
3c
3d
3e
3f
5.18
13.96
>100
>100
33.85
>100
>100
ND
21.43
>100
>100
30.77
>100
>100
>50
11.94
>100
>100
39.23
>100
>100
ND
>100
>100
29.15
>100
>100
>50
3g
4a
4b
4c
4d
4e
4f
9.747
>100
>100
>100
>100
>50
17.20
>100
>100
>100
>100
ND
22.94
>100
>100
>100
>100
>50
11.11
>100
>100
>100
>100
ND
4g
>50
ND
>50
ND
ND: not determined.
1. Experimental
All melting points were determined on SGW X-4 melting-point apparatus and uncorrected. IR spectra were
1
recorded on an Analect RFX-65A IR spectrometer. H NMR and 13C NMR were obtained from a Brucker DRX-
400 MHz spectrometer with TMS as an internal standard. MS analyses were performed using a Shimadzu GCMS-
QP5050A and Thermo GCMS-MAT95XP mass spectrometer.
1.1. Preparation of acetoxylated 3-arylcoumarins 3a–g
To a solution of ortho-hydroxybenzaldehyde 2 (10 mmol) and substituted phenyl acetic acid 1 (10 mmol) in acetic
anhydride (70 mmol), triethylamine (50 mmol) was added. The mixture was heated at 110 8C and stirred for 8–12 h.
After cooling, it was poured into ice-water, stirred and stored for several hours. A yellow solid was precipitated,
filtrated and washed with water, dried in air, then recrystalized from ethyl acetate.

1298
C.F. Xiao et al. / Chinese Chemical Letters 21 (2010) 1295–1298
7, 8-Diacetoxy-3-(30, 50-dimethoxyphenyl)coumarin 3a: IR(KBr): 3006, 2965, 2935, 2838, 1783, 1725, 1594, 1494,
1
1457, 1425, 1365, 1344, 1309, 1259, 1203, 1157, 1105, 1064, 1039, 1010, 923, 885, 835, 771, 744, 715; H NMR
(400 MHz, CDCl3): d 2.32(s, 3H, 7-OAc), 2.40(s, 3H, 8-OAc), 3.80(s, 6H, 30, 50-OCH3), 6.49(t, 1H, J = 2.0 Hz, 40-
ArH), 6.77(d, 2H, J = 2.0 Hz, 20,60-ArH), 7.10(d, 1H, J = 8.4 Hz, 5-H), 7.38(d, 1H, J = 8.4 Hz, 6-H), 7.75(s, 1H, 4-H);
EI-MS m/z: 398(M+), 356(M+-Ac), 314(M+-2Ac).
1.2. Preparation of hydroxylated 3-arylcoumarins 4a–g
Compound 3 (1.25 mmol) was added to a solution of 10% HCl(15 mL) and ethanol(5 mL). The mixture was heated
at 80 8C and stirred for 8–12 h. After cooling, it was poured into ice-water, a light yellow solid was precipitated,
filtrated, washed with cold distilled water, and dried under vacuum, then recrystallized from ethanol and water.
7, 8-Dihydroxy-3-(30, 50-dimethoxyphenyl)coumarin 4a: IR(KBr): 3426, 3345, 2964, 2836, 1691, 1598, 1511, 1459,
1
1425, 1346, 1299, 1257, 1203, 1153, 1114, 1066, 1031, 966, 923, 854, 819, 773, 734, 703; H NMR (400 MHz,
CD3COCD3-d6): d 3.80(s, 6H, 30, 50-OCH3), 6.49(t, 1H, J = 2.0 Hz, 40-ArH), 6.87(d, 1H, J = 8.4 Hz, 6-H), 6.89(d, 2H,
J = 2.0 Hz, 20, 60-ArH), 7.10(d, 1H, J = 8.4 Hz, 5-H), 8.04(s, 1H, 4-H); 13C NMR(400 MHz, CD3COCD3-d6):d 55.6,
100.7, 107.5, 113.4, 114.1, 120.3, 123.8, 132.4, 138.2, 142.1, 143.9, 149.9, 160.3, 161.5; EI-MS m/z: 314(M+), 286,
256.
Acknowledgments
We thank the National Key Technology R&D Program, Science and Technology Program of Guangdong Province
and Strategic Cooperation Program between Guangdong Province and Chinese Academy of Sciences, PR China (Nos.
2007BAD82B02, 2006B35604002, and 2009B091300125) for financial support.
References
[1] J. Chong, A. Poutaraud, P. Hugueney, Plant Sci. 177 (2009) 143.
[2] M. Tolomeo, S. Grimaudo, A.D. Cristina, et al. Int. J. Biochem. Cell Biol. 37 (2005) 1709.
[3] K.A. Roupe, C.M. Remsberg, J.A. Yanez, et al. Curr. Clin. Pharm. 1 (2006) 81.
`
[4] C. Riviere, T. Richard, L. Quentin, et al. Bioorg. Med. Chem. 15 (2007) 1160.
[5] J.C. Milne, P.D. Lambert, S. Schenk, et al. Nature 450 (2007) 712.
[6] S. Vilar, E. Quezada, L. Santana, et al. Bioorg. Med. Chem. Lett. 16 (2006) 257.
¨
¨
[7] C. Gu¨ndu¨z, U. Salan, N. Ozkul, et al. Dyes Pigments 71 (2006) 161.
[8] X. Zhai, J. Li, L. He, et al. Chin. Chem. Lett. 19 (2008) 29.