Synthesis and?anticancer activity of?lavendustin A derivatives containing arylethenylchromone substituents

Article abstract of DOI:10.1016/j.ejmech.2006.04.008

2-Styrylchromones, which are relatively scarce in nature, have been reported to possess potent cytotoxicities on KB cell line. Lavendustin A, a metabolite of Streptomyces griseolavendus, has been shown to inhibit a growth of A431 cell line. Accordingly, a

Full text of DOI:10.1016/j.ejmech.2006.04.008

European Journal of Medicinal Chemistry 41 (2006) 991–996
http://france.elsevier.com/direct/ejmech
Synthesis and anticancer activity of lavendustin A
derivatives containing arylethenylchromone substituents
Ki Yong Lee a,*, Dong Hyuk Nam a, Chang Sang Moon b, Seon Hee Seo b
Jae Yeol Lee c, Yong Sup Lee a,*
a Kyung Hee East-West Pharmaceutical Research Institute and Department of Pharmaceutical Science,
College of Pharmacy, Kyung Hee University, 1 Hoegi-Dong, Seoul 130-701, South-Korea
b Division of Life Sciences, Korea Institute of Science & Technology, P.O. Box 131 Cheongryang, Seoul 130-650, South-Korea
c Research Institute for Basic Sciences and Department of Chemistry, Kyung Hee University, 1 Hoegi-Dong, Seoul 130-701, South-Korea
Received 18 October 2005; received in revised form 31 March 2006; accepted 3 April 2006
Available online 09 June 2006
Abstract
2-Styrylchromones, which are relatively scarce in nature, have been reported to possess potent cytotoxicities on KB cell line. Lavendustin A, a
metabolite of Streptomyces griseolavendus, has been shown to inhibit a growth of A431 cell line. Accordingly, a series of compounds 3a–g
having structural features of styrylchromones and lavendustin A were synthesized and evaluated for cytotoxicity using SRB assay on four tumor
cell lines. Compounds 3a–g were synthesized by the condensation of 2-methylchromone derivative 7 with several aromatic aldehydes. Among
synthesized, compound 3e showed the significant cytotoxic activity on HCT-15 cell line with IC50 values of 7.17 μg/ml indicating that laven-
dustin A derivatives containing 2-arylethenylchromone ring have a potential in anti-tumor application.
© 2006 Elsevier SAS. All rights reserved.
Keywords: Styrylchromone; Arylethenylchromone; Lavendustin A; Cytotoxicity; HCT-15
1. Introduction
Recently, hybridization of natural products has been pro-
posed as a promising strategy in the development of new leads
for medicinal application. The biological activities of several
new hybrids have been found to exceed those of the parent
compounds [7].
In this study, we synthesized a new structure of compounds
by combining structures of styrylchromone and lavendustin A
to form hybrid 3 and evaluated them for cytotoxicities on tu-
mor cell lines.
2-Arylchromones, also known as flavones, are among the
most ubiquitous classes of natural products occurring in the
plant kingdom. On the other hand, 2-styrylchromones are rela-
tively scarce in nature and only a few including hormotham-
nione (1) have been identified from the blue-green algae species
[1,2]. Consequently, syntheses of 1 have reported due to its un-
ique structure and cytotoxic effects [3]. Regardless of isolation
of 1, the carbon skeleton of 2-styrylchromones has already been
known; however, the synthesis of its derivatives for structure–
activity relationship study has not been accomplished [4].
Lavendustin A (2), a metabolite of Streptomyces griseola-
vendus, has been shown to inhibit protein-tyrosine kinase in
A431 cell line [5]. Some stilbene and benzylaniline derivatives,
which can be considered as the fragments of lavendustin A
have been synthesized to reduce polarity or simplify the struc-
ture of 2, and evaluated for cytotoxicity in cancer cell cultures
[6] (Fig. 1).
2. Results and discussion
2.1. Synthesis
To investigate the influence of styrylchromone rings on cy-
totoxicity, we designed a series of compounds 3, where p-
methoxybenzyl and phenethyl substituents on nitrogen are
fixed, while aromatic substituents on styrylchromone ring were
varied. Compound 4 was selected as a starting material since
amine substituents and arylethenyl group can readily be intro-
duced on C-8 and C-2 positions of chromone ring, respec-
tively, through reductive-amination and aldol-type condensa-
tion reactions (Scheme 1).
* Corresponding authors. Tel.: +82 2 961 0370; fax: +82 2 966 3885.
E-mail address: kyslee@khu.ac.kr (Y.S. Lee).
0223-5234/$ - see front matter © 2006 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2006.04.008

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K.Y. Lee et al. / European Journal of Medicinal Chemistry 41 (2006) 991–996
Scheme 1. Reagents and conditions. a) PMB-Cl, NaI, K2CO3, DMF; b) p-methoxybenzylamine, NaBH4, MeOH; c) phenethyl bromide, NaI, NaH, DMF; d)
phenethylamine, NaBH4, MeOH; e) PMB-chloride, NaI, NaH, DMF.
7 only in 12% yield. Although this reaction was carried out
using weak base, DBU in DMSO, the yield was not improved
resulting in 11% yield of 7. As the low yield was thought to be
due to the decomposition of phenethyl bromide to styrene
through the elimination of HBr by the base, we decided to in-
troduce phenethyl group firstly through reductive-amination
with phenethylamine and then p-methoxybenzyl group. Thus,
compound 5 was again treated with phenethylamine and
NaBH4 in MeOH to afford 8 in 93% yield. As expected, the
aminoalkylation of 8 with PMB-Cl and NaH in the presence of
catalytic amount of NaI provided 7 in improved 57% yield.
Next, for the synthesis of target compounds 3, arylethenyl
group was introduced through aldol-type condensation of 7
with aromatic aldehydes as depicted in Scheme 2. In order to
examine the effects of aromatic substituents on cytotoxicity,
various aromatic and heteroaromatic aldehydes were used.
Compound 7 was treated with aldehydes using KOH in EtOH
to afford 9a–g in 37–92% yields [10]. Finally, PMB-protected
compounds 9a–g were subjected to hydrolysis condition by
treatment of trifluoroacetic acid (TFA) in CH2Cl2 to provide
3a–g in 36–86% yield.
Fig. 1.
C-7 hydroxyl group of 4 [4,8] was protected with the reac-
tion of p-methoxybenzyl chloride (PMB-Cl) to afford 5 in 90%
yield. To introduce amine group in chromone ring using reduc-
tive-amination reaction, compound 5 was reacted with p-meth-
oxybenzylamine in methanol followed by treatment of NaBH4
to provide 6 in 76% yield [9]. Aminoalkylation reaction of 6
with phenethyl bromide using NaH as a base in DMF afforded
2.2. Biological activity
The synthesized compounds 3a–g were evaluated for their
cytotoxic activities against four tumor cell lines, including hu-
Scheme 2. Reagents and conditions. a) Ar-CHO, KOH, EtOH; b) TFA, CH2Cl2.

K.Y. Lee et al. / European Journal of Medicinal Chemistry 41 (2006) 991–996
993
man lung carcinoma (A-549), human colon cancer cells (HCT-
15), human epidermoid carcinoma (KB), and malignant mela-
noma (SK-MEL-2) using SRB assay [11]. The results are
shown as IC50 values in Table 1, which are mean values from
three independent experiments.
gel 60 Art 9385 (230–400 mesh). All solvents used were pur-
ified according to standard procedures.
3.1.1. 7-(4-Methoxybenzyloxy)-2-methyl-8-formylchromone (5)
To a stirred solution of 7-hydroxy-8-formyl-2-methylchro-
mone (4, 100 mg, 0.49 mmol) in DMF (5 ml) was added suc-
cessively K2CO3 (135 mg, 1.21 mmol) and p-methoxybenzyl
chloride (PMB-Cl, 0.13 ml, 0.94 mmol), and catalytic amount
of NaI. The reaction mixture was warmed up to 55 °C and
further stirred for 1 h. The mixture was diluted with EtOAc
and washed with brine. The organic layer was dried over
MgSO4, concentrated, and purified by flash column chromato-
graphy (CH2Cl2/CH3OH = 98:2) to afford 5 (145 mg, 91%) as
Most of compounds synthesized exhibited weak or no cyto-
toxicity under the concentration of 100 μg/ml on KB and SK-
MEL-2 cell lines. However, they showed significant cytotoxi-
city on A-549 and HCT-15 cell lines in the range of 7.17–
83.7 μg/ml of IC50 values. Especially, they showed marked
structure–activity relationships on HCT-15 cell. Compounds
3b and 3c, which have electron releasing methoxy groups on
arylethenylchromone ring showed decreased cytotoxicity when
compared to that of 3a. On the other hand, compounds 3d, 3e,
and 3g, which have electron withdrawing bromide or hetero-
aromatic ring exhibited potent cytotoxicity with IC50 values in
the range of 7.17–11.98 μg/ml on HCT-15 cell. Regarding the
cytotoxicity on A-549 cell line, noticeable structure–activity
relationships were not found. Among the tested compounds,
compounds 3a and 3e showed the most potent cytotoxicity.
1
a yellow solid. H NMR (300 MHz, CDCl3) δ 10.60 (1H, s),
8.32 (1H, d, J = 9.0 Hz), 7.36 (2H, d, J = 8.5 Hz), 7.12 (1H, d,
J = 9.0 Hz), 6.93 (2H, d, J = 8.5 Hz), 6.14 (1H, s), 5.22 (2H,
s), 3.81 (3H, s), 2.40 (3H, s); 13C NMR (75 MHz, CDCl3) δ
187.18, 176.77, 166.63, 164.91, 159.10, 156.48, 133.30,
133.02, 129.15, 128.61, 126.99, 117.58, 114.24, 113.87,
113.21, 110.78, 110.61, 71.34, 64.91, 55.32, 29.69, 20.50.
3.1.2. (7-(4-Methoxybenzyloxy)-8-[(4-metoxybenzylamino)
methyl]-2-methylchromone(6)
3. Experimental section
To a stirred solution of 5 (480 mg, 1.47 mmol) and 4-meth-
oxybenzylamine (0.39 ml, 2.94 mmol) in MeOH (10 ml) was
added portion-wise NaBH4 (111 mg, 2.93 mmol) at 0 °C. After
5 min, the mixture was warmed up to room temperature and
further stirred for 1 h. The reaction mixture was poured into
water and extracted with EtOAc. The organic layer was dried
over MgSO4, concentrated, and purified by flash column chro-
matography (CH2Cl2/CH3OH = 98:2), and further purified by
3.1. Chemistry
1H and 13C NMR spectra were recorded on a Gemini Var-
ian-300 (300 and 75 MHz, respectively). Analytical thin layer
chromatographies (TLC) were carried out by precoated silica
gel (E. Merck Kiesegel 60F254 layer thickness 0.25 mm). Flash
column chromatographies were performed with Merck Kiese-
Table 1
The chemical yields of 9 and 3 and cytotoxicity of 3 on cancer cell lines in vitro
a
b
c
Yield of 9 from 7. Yield of 3 from 9. IC50 value of compound against each cancer cell line, which was defined as a concentration (μg/ml) that caused 50%
inhibition of cell growth in vitro.

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K.Y. Lee et al. / European Journal of Medicinal Chemistry 41 (2006) 991–996
recrystallization with EtOAc and hexane to afford 6 (500 mg,
76%) as a yellow solid. H NMR (300 MHz, CDCl3) δ 8.06
3.1.6. (E)-7-(4-methoxybenzyloxy)-8-{[phenethyl-(4-
1
methoxybenzyl)amino]methyl}-vinylchromone (9a)
1
(1H, d, J = 9.2 Hz), 7.30 (2H, d, J = 8.4 Hz), 7.15 (2H, d,
J = 8.4 Hz), 7.03 (1H, d, J = 9.2 Hz), 6.89 (2H, d, J = 8.8
Hz), 6.78 (2H, d, J = 8.8 Hz), 6.05 (1H, s), 5.09 (2H, s), 4.02
(2H, s), 3.79 (3H, s) 3.75 (3H, s), 3.69 (2H, s), 2.27 (3H, s); 13C
NMR (75 MHz, CDCl3) δ 118.00, 165.77, 160.89, 159.67,
158.57, 155.60, 132.17, 129.24, 127.97, 125.90, 117.60,
116.19, 114.11, 113.67, 109.92, 70.62, 55.27, 55.22, 52.52,
40.72, 20.48.
Yield: 51%; H NMR (300 MHz, CDCl3) δ 8.11 (1H, d,
J = 8.9 Hz), 7.59 (1H, d, J = 16.0 Hz), 7.49–7.46 (2H, m),
7.40–7.35 (5H, m), 7.18–7.10 (5H, m) 7.04 (1H, d, J = 8.9
Hz), 6.97 (2H, m), 6.91 (2H, d, J = 8.6 Hz), 6.77 (1H, d,
J = 16.0 Hz) 6.72 (2H, d, J = 8.6 Hz), 6.29 (1H, s), 5.14 (2H,
s), 4.13 (2H, s), 3.82 (3H, s), 3.76 (2H, s), 3.72 (3H, s), 2.84–
2.78 (4H, m); 13C NMR (75 MHz, CDCl3) δ 178.30, 161.66,
161.51, 159.62, 158.43, 155.87, 140.72, 136.68, 135.07,
131.55, 129.66, 129.27, 128.98, 128.60, 128.17, 127.67,
126.11, 125.71, 120.71, 118.16, 115.80, 114.07, 113.42,
110.07, 70.69, 57.91, 55.30, 55.20, 47.18, 33.10.
3.1.3. 7-(4-Methoxybenzyloxy)-8-[(phenethylamino)methyl]-2-
methylchromone (8)
Compound 8 was obtained from 5 with phenethylamine by
using the similar procedure for 6. Yield: 93%; 1H NMR
(300 MHz, CDCl3) δ 8.07 (1H, d, J = 9.0 Hz), 7.30–7.08
(7H, m), 7.03 (1H, d, J = 9.0 Hz), 6.92–6.88 (2H, m), 6.07
(1H, s), 5.06 (2H, s), 4.07 (2H, s), 3.82 (3H, s), 2.87–2.74
(4H, m), 2.28 (3H, s); 13C NMR (75 MHz, CDCl3) 178.26,
166.01, 161.05, 159.90, 155.90, 140.05, 129.37, 128.86,
128.68, 128.22, 126.43, 126.23, 117.79, 116.07, 114.35,
110.17, 70.82, 55.56, 50.21, 41.42, 36.31, 20.77.
3.1.7. (E)-7-(4-methoxybenzyloxy)-8-{[phenethyl-(4-
methoxybenzyl)amino]methyl}-2-(4-methoxybenzyl)
vinylchromone (9b)
1
Yield: 31%; H NMR (300 MHz, CDCl3) δ 8.09 (1H, d,
J = 9.0 Hz), 7.53 (1H, d, J = 15.9 Hz), 7.38 (2H, d, J = 8.7
Hz), 7.34 (2H, d, J = 8.4 Hz), 7.16–7.11 (6H, m), 7.01 (1H,
d, J = 9.0 Hz), 6.95–6.87 (5H, m), 6.70 (2H, d, J = 8.7 Hz),
6.60 (1H, d, J = 15.9 Hz), 6.25 (1H, s), 5.20 (2H, s), 4.10
(2H, s), 3.82 (3H, s), 3.79 (3H, s), 3.73 (2H, s), 3.70 (3H, s),
2.79–2.77 (4H, m); 13C NMR (75 MHz, CDCl3) δ 178.54,
162.27, 161.82, 161.23, 159.86, 158.68, 156.12, 140.99,
136.62, 131.86, 129.91, 129.50, 128.84, 128.54, 128.41,
128.11, 126.31, 125.94, 118.55, 118.42, 116.01, 114.68,
114.31, 113.67, 110.23, 109.58, 70.94, 58.17, 55.53, 47.44,
33.35, 29.98.
3.1.4. 7-(4-Methoxybenzyloxy)-8-{[phenethyl-(4-
methoxybenzyl)amino]methyl}-2-methylchromone (7)
To a solution of 8 (103 mg, 0.22 mmol) in DMF (1.3 ml)
was added NaH (60% in oil, 9.6 mg, 0.24 mmol) at 0 °C and
stirred for 15 min. The mixture was treated with a solution of
PMB-Cl (0.03 ml, 0.24 mmol) and catalytic amount of NaI in
DMF (1.0 ml) and warmed up to room temperature. After
further stirring for 2 h, the reaction mixture was poured into
water and extracted with EtOAc. The organic layer was dried
over MgSO4, concentrated, and purified by flash column chro-
matography (CH2Cl2/CH3OH = 98:2) to afford 7 (75 mg,
3.1.8. (E)-7-(4-methoxybenzyloxy)-8-{[phenethyl-(4-
methoxybenzyl)amino]methyl}-2-(3′,4′-dimethoxybenzyl)
vinylchromone (9c)
1
Yield: 76%; H NMR (300 MHz, CDCl3) δ 8.13 (1H, d,
J = 9.0 Hz), 7.59 (1H, d, J = 15.9 Hz), 7.40–6.66 (24H, m),
6.29 (1H, s), 5.21–5.17 (2H, m), 4.17–4.14 (2H, m), 3.95–
3.74 (17H, m), 2.82–2.80 (4H, m); 13C NMR (75 MHz,
CDCl3) δ 178.54, 162.17, 161.81, 159.87, 158.69, 156.17,
150.94, 149.55, 140.92, 136.91, 131.86, 129.87, 129.50,
128.84, 128.43, 126.34, 125.97, 122.03, 118.76, 118.45,
115.94, 114.32, 113.68, 111.44, 110.23, 109.68, 70.96,
58.11, 56.25, 56.04, 55.53, 55.43, 47.41, 33.19, 24.99, 24.85.
1
57%). H NMR (300 MHz, CDCl3) δ 8.06 (1H, d, J = 8.3
Hz), 7.30 (2H, d, J = 8.7 Hz), 7.17–7.08 (7H, m), 7.01(1H, d,
J = 8.3 Hz), 6.92 (2H, d, J = 9.0 Hz), 6.75 (2H, d, J = 8.7 Hz),
6.06 (1H, s), 5.08 (2H, s), 3.90 (2H, s), 3.78 (3H, s), 3.75 (3H,
s), 3.63 (2H, s), 2.74–2.68 (4H, m), 2.22 (3H, s); 13C NMR
(75 MHz, CDCl3) δ 178.46, 166.09, 161.56, 159.88, 158.73,
156.72, 141.10, 132.26, 130.10, 129.54, 128.83, 128.47,
128.34, 126.23, 125.94, 117.88, 115.89, 114.32, 113.67,
110.25, 70.93, 58.62, 55.53, 55.21, 46.35, 33.70, 20.82.
3.1.9. (E)-7-(4-methoxybenzyloxy)-8-{[phenethyl-(4-
methoxybenzyl)amino]methyl}-2-bromovinylchromone (9d)
1
3.1.5. General procedure for 9a–g by the condensation
reaction of 9 with aromatic aldehydes
Yield: 42%; H NMR (300 MHz, CDCl3) δ 8.06 (1H, d,
J = 8.7 Hz), 8.01 (1H, d, J = 15.9 Hz), 7.64 (1H, d, J = 7.5
Hz), 7.59 (1H, d, J = 8.4 Hz), 7.34 (2H, d, J = 8.1 Hz), 7.20
(1H, d, J = 7.5 Hz), 7.17–7.00 (7H, m), 6.68–6.51 (3H, m),
6.28 (1H, s), 5.12 (2H, s), 4.10 (2H, br s), 3.78 (3H, s), 3.74
(2H, s), 3.70 (3H, s), 2.80–2.72 (4H, m); 13C NMR (75 MHz,
CDCl3) δ 178.55, 162.20, 161.11, 159.86, 158.61, 155.92,
141.08, 135.22, 133.71, 132.00, 130.99, 129.97, 129.53,
128.87, 128.53, 128.35, 128.11, 127.52, 126.33, 125.88,
125.61, 123.46, 118.19, 116.26, 114.30, 113.57, 110.97,
110.54, 70.9, 58.31, 55.72, 55.53, 55.45, 47.32, 33.42.
To a solution of 9 (0.2 mmol, 1 eq.) in EtOH was added
powdered KOH (10 eq.) and stirred for 5 min. The mixture
was treated with aromatic aldehydes (3 eq.) and warmed up to
55 °C. After stirring for 1–2 h, the reaction mixture was cooled
to 0 °C diluted with water, and neutralized with 3 N HCl. The
mixture was extracted with EtOAc and the organic layer was
dried over MgSO4, concentrated, and purified by flash column
chromatography (CH2Cl2/CH3OH = 98:2) to afford 9a–g as
yellow solids

K.Y. Lee et al. / European Journal of Medicinal Chemistry 41 (2006) 991–996
995
3.1.10. (E)-7-(4-methoxybenzyloxy)-8-{[phenethyl-(4-
methoxybenzyl)amino]methyl}-2-(pyrdin-2-yl)vinylchromone
(9e)
116.88, 115,24, 114.08, 110.52, 107.86, 56.85, 55.15, 54.73,
49.50, 33.15.
1
3.1.15. (E)-7-hydroxy-8-{[phenethyl-(4-methoxybenzyl)amino]
Yield: 38%; H NMR (300 MHz, CDCl3) δ 8.65 (1H, d,
methyl}-2-(4-methoxy-benzyl)vinylchromone (3b)
J = 4.2 Hz), 8.09 (1H, d, J = 9.3 Hz), 7.67–6.88 (19H, m),
6.72–6.68 (2H, m), 6.36 (1H, s), 5.13 (2H, s), 4.12 (2H, s),
3.80 (3H, s), 3.75 (2H, s), 3.70 (3H, s), 2.79–2.76 (4H, m);
13C NMR (75 MHz, CDCl3) δ 177.86, 164.20, 159.94,
159.30, 159.09, 138.64, 136.82, 134.50, 131.01, 128.59,
128.55, 127.05, 126.51, 126.13, 124.80, 123.73, 123.55,
116.85, 115.32, 114.03, 111.77, 107.92, 57.09, 55.12, 54.75,
49.58, 33.12, 29.65, 24.52, 24.46, 24.41.
1
Yield: 30%; H NMR (300 MHz, CDCl3) δ 8.02 (1H, d,
J = 8.7 Hz), 7.48 (2H, d, J = 8.7 Hz), 7.32–7.14 (12H, m),
6.95 (2H, d, J = 8.7 Hz), 6.87–6.84 (3H, m), 6.64 (1H, d,
J = 15.9 Hz), 6.22 (1H, s), 4.18 (2H, s), 3.86 (3H, s), 3.79
(2H, s), 3.71 (3H, s), 2.96–2.82 (4H, m); 13C NMR (75 MHz,
CDCl3) δ 177.94, 164.78, 163.36, 159.58, 155.58, 136.08,
131.06, 129.78, 128.87, 128.14, 127.85, 126.20, 115.14,
114.25, 110.30, 107.97, 58.16, 57.58, 55.38, 48.76, 20.49.
3.1.11. (E)-7-(4-methoxybenzyloxy)-8-{[phenethyl-(4-
3.1.16. (E)-7-hydroxy-8-{[phenethyl-(4-methoxybenzyl)amino]
methoxybenzyl)amino]methyl}-2-(furan-3yl)vinylchromone (9f)
1
methyl}-2-(3′,4′-dimethoxy-benzyl)vinylchromone (3c)
Yield: 92%; H NMR (300 MHz, CDCl3) δ 8.12 (1H, d,
1
Yield: 86%; H NMR (300 MHz, CDCl3) δ 8.04 (1H, d,
J = 8.7 Hz), 7.50–7.45 (3H, m), 7.38 (2H, d, J = 8.4 Hz),
7.21–7.14 (6H, m), 7.06 (1H, d, J = 9.0 Hz), 6.99–6.92 (5H,
m), 6.76 (2H, d, J = 8.7 Hz), 6.66 (2H, s), 6.51 (1H, d, J = 15.9
Hz), 6.25 (1H, s), 5.15 (2H, s), 3.83 (2H, s), 3.75 (6H, s),
2.80–2.78 (4H, m); 13C NMR (75 MHz, CDCl3) δ 178.54,
161.86, 159.88, 158.69, 156.11, 144.68, 144.07, 140.91,
131.81, 129.87, 129.54, 128.81, 128.44, 126.98, 126.35,
125.99, 123.51, 120.64, 118.37, 115.92, 114.32, 113.69,
110.28, 109.63, 107.49, 70.95, 60.64, 58.20, 55.53, 55.43,
47.40, 33.40, 21.29, 14.46.
J = 8.7 Hz), 7.33–7.09 (14H, m), 6.94–6.81 (5H, m), 6.65
(1H, d, J = 15.9 Hz), 6.27 (1H, s), 4.22 (2H, s), 4.00 (2H, s),
3.96 (3H, s), 3.82 (3H, s), 3.72 (3H, s), 2.99–2.96 (4H, m); 13
C
NMR (75 MHz, CDCl3) δ 212.25, 169.10, 164.30, 161.16,
159.60, 149.69, 138.97, 136.11, 131.41, 128.91, 128.84,
128.30, 127.00, 126.84, 126.39, 122.43, 188.75, 117.09,
155.39, 144.29, 111.42, 110.07, 109.43, 108.12, 89.33,
86.28, 74.15, 56.95, 56.28, 55.37, 55.02, 49.72, 33.44, 29.91,
25.00, 24.65, 21.67, 19.56.
3.1.17. (E)-7-hydroxy-8-{[phenethyl-(4-methoxybenzyl)amino]
3.1.12. (E)-7-(4-methoxybenzyloxy)-8-{[phenethyl-(4-
methoxybenzyl)amino]methyl}-2-(thiophen-2-yl)vinylchromone
(9g)
methyl}-2-bromovinylchromone (3d)
1
Yield: 48%; H NMR (300 MHz, CDCl3) δ 7.99 (1H, d,
1
Yield: 76%; H NMR (300 MHz, CDCl3) δ 8.12 (1H, d,
J = 9.0 Hz), 7.90 (1H, d, J = 16.2 Hz), 7.71 (1H, dd, J = 1.5,
8.1 Hz), 7.65 (1H, dd, J = 1.2, 7.8 Hz), 7.37–7.09 (10H, m),
6.85 (2H, dd, J = 1.5, 9.0 Hz), 6.75 (1H, d, J = 16.2 Hz), 6.27
(1H, s), 4.25 (2H, s), 3.76 (2H, s), 3.73 (3H, s), 2.96–2.89 (4H,
m); 13C NMR (75 MHz, CDCl3) δ 178.00, 159.96, 159.62,
154.91, 138.68, 134.71, 134.56, 133.60, 131.08, 130.95,
128.76, 128.69, 128.09, 127.19, 126.69, 125.49, 122.81,
114.32, 57.76, 55.29, 49.84, 32.56, 30.99.
J = 8.4 Hz), 7.72 (1H, d, J = 15.6 Hz), 7.38 (3H, d, J = 9.8
Hz), 7.19–6.99 (11H, m), 6.96 (1H, d, J = 8.4 Hz), 6.80 (1H,
d, J = 8.7 Hz), 6.69 (1H, d, J = 15.6 Hz), 6.26 (1H, s), 5.16
(2H, s), 4.13 (2H, s), 3.84 (3H, s), 3.75 (6H, s), 2.81–2.79
(4H, m); 13C NMR (75 MHz, CDCl3) δ 178.42, 161.09,
161.46, 159.90, 158.71, 156.10, 140.96, 140.76, 131.83,
130.10, 129.90, 129.69, 129.54, 128.87, 128.44, 128.01,
126.38, 125.99, 119.91, 118.42, 115.94, 114.35, 113.71,
110.31, 110.00, 70.97, 58.18, 55.55, 55.46, 47.46, 33.42.
3.1.18. (E)-7-hydroxy-8-{[phenethyl-(4-methoxybenzyl)amino]
methyl}-2-(2-pyrdin-2-yl)vinylchromone (3e)
1
3.1.13. General procedure for PMB-deprotection
Yield: 65%; H NMR (300 MHz, CDCl3) δ 8.71–8.68 (1H,
A solution of 9a–f (0.2 mmol) in CH2Cl2 (5.0 ml) was trea-
ted with TFA (5.0 ml) and stirred at room temperature for
30 min. The reaction mixture was extracted with CH2Cl2 and
the organic layer was dried over MgSO4, concentrated, and
purified by flash column chromatography (CH2Cl2/CH3OH
= 98:2) to afford 3a–g as yellow solids.
d, J = 4.2 Hz), 8.04 (1H, d, J = 8.8 Hz), 7.81–7.72 (1H, m),
7.48–7.13 (11H, m), 6.91–6.86 (3H, m), 6.36 (1H, s), 4.23
(2H, s), 3.81 (2H, s), 3.74 (3H, s), 2.97–2.90 (4H, m); 13C
NMR (75 MHz, CDCl3) δ 178.58, 161.99, 161.26, 159.87,
158.65, 156.15, 153.46, 150.35, 140.97, 137.07, 135.33,
131.87, 129.92, 129.85, 129.51, 128.84, 128.39, 126.39,
125.93, 125.00, 124.59, 123.96, 118.44, 116.09, 114.32,
113.66, 111.72, 110.41, 70.96, 58.21, 55.63, 55.54, 55.43,
47.44, 33.43.
3.1.14. (E)-7-hydroxy-8-{[phenethyl-(4-methoxybenzyl)amino]
methyl}-vinylchromone (3a)
1
Yield: 62%. H NMR (300 MHz, CDCl3) δ 8.05 (1H, s,
J = 8.7 Hz), 7.57–7.16 (15H, m), 6.90–6.78 (4H, m), 6.28
(1H, s), 4.22 (1H, s), 3.83 (2H, s), 3.73 (3H, s), 3.04–2.93
(4H, m); 13C NMR (75 MHz, CDCl3) δ 177.94, 164.11.
160.48, 159.39, 154.80, 138.69, 135.95, 134.99, 131.15,
129.02, 128.68, 128.61, 127.63, 126.60, 126.21, 120.69,
3.1.19. (E)-7-hydroxy-8-{[phenethyl-(4-methoxybenzyl)amino]
methyl}-2-(2-furan-3-yl)vinylchromone (3f)
1
Yield: 37%; H NMR (300 MHz, CDCl3) δ 8.01 (1H, d,
J = 9.0 Hz), 7.32–7.05 (10H, m), 6.88–6.78 (4H, m), 6.43
(1H, d, J = 16.2 Hz), 6.19 (1H, s), 4.10 (2H, s), 3.99 (2H, s),

996
K.Y. Lee et al. / European Journal of Medicinal Chemistry 41 (2006) 991–996
3.71 (3H, s), 2.95–2.83 (4H, m); 13C NMR (75 MHz, CDCl3) δ
177.99, 163.89, 160.89, 159.38, 158.48, 155.39, 144.56,
142.54, 138.59, 131.19, 131.06, 129.85, 129.19, 128.68,
128.59, 126.60, 126.22, 123.26, 119.22, 118.38, 116.79,
115.12, 114.23, 114.09, 109.82, 109.30, 107.75, 107.25,
56.97, 55.17, 54.86, 49.40, 33.17, 32.76, 31.66, 29.71.
five times with 1% acetic acid before air drying. Bound SRB
was solubilized with 100 µl 10 mM unbuffered Tris-base solu-
tion (Sigma) and plates were left on a plate shaker for at least
10 min. The optical density was measured using a microplate
reader (Versamax, Molecular Devices) with a 520 nm wave-
length and the anticancer effective concentration was expressed
as an IC50.
3.1.20. (E)-7-hydroxy-8-{[phenethyl-(4-methoxybenzyl)amino]
methyl}-2-(2-thiophen-2-yl)vinylchromone (3g)
4. Conclusion
1
Yield: 80%; H NMR (300 MHz, CDCl3) δ 8.01 (1H, d,
J = 9.0 Hz), 7.45–6.83 (16H, m), 6.55 (1H, d, J = 15.6 Hz),
6.21 (1H, s), 4.16 (2H, s), 3.78 (2H, s), 3.71 (3H, s), 2.97–
2.89 (4H, m); 13C NMR (75 MHz, CDCl3) δ 182.17, 166.92,
165.77, 164.87, 159.84, 144.34, 140.215, 136.36, 135.12,
134.65, 133.08, 132.68, 132.54, 131.41, 125.22, 122.46,
120.89, 118.69, 113.43, 108.36, 61.80, 59.30, 58.38, 53.817,
53.53, 53.25, 52.86, 52.68, 52.40, 52.11, 35.21.
A series of compounds 3a–g having structural features of
styrylchromones and lavendustin A were synthesized through
reductive-amination, aminoalkylation, and aldol-type conden-
sation reactions from 4. Synthesized compounds were evalu-
ated for their cytotoxicities on four tumor cell lines. Among
tested, compound 3e showed the most potent cytotoxic activity
on HCT-15 cell line with IC50 values of 7.17 μg/ml indicating
that lavendustin A derivatives containing 2-arylethenylchro-
mone ring have a potential in anti-tumor application.
3.2. Biological test
RPMI 1640 medium, fetal bovine serum (FBS), penicillin,
and streptomycin were purchased from Life Technologies Inc.
(Grand Island, NY, USA). Sulforhodamine B, dimethyl sulfox-
ide (DMSO) and cisplatin were purchased from Sigma Chemi-
cal Co. (MO, U.S.A.). Human lung cancer (A549), human epi-
dermoid carcinoma (KB), human colon (HCT-15), and human
melanoma (SK-MEL2) cancer cell limes were supplied from
the Korean Cell Line Bank, Seoul National University.
Acknowledgements
This research was supported by the Vision 21 Program from
Korea Institute of Science and Technology.
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