Synthesis and cytotoxicity of 3-aryl acrylic amide derivatives of the simplified saframycin-ecteinascidin skeleton prepared from l-dopa

Article abstract of DOI:10.1016/j.ejmech.2013.01.033

Twenty four compounds with diversified 3-aryl acrylic amide side chains of the simplified saframycin-ecteinascidin pentacyclic skeleton were synthesized via a 14-step stereospecific route starting from l-dopa. The cytotoxicities of these compounds were tested against eight human tumor cell lines including HCT-8, BEL-7402, BGC-803, A549, A2780, MCF-7, MX-1, and MDA-MB-231. Most of these compounds exhibited potent antitumor activity, and a preliminary structure-activity relationship (SAR) was discussed. Compound 28 with 3-thiophenyl acrylic amide side chain exhibited selective cytotoxicity against MDA-MB-231 cell line with the IC₅₀ value of 50 nM.

Full text of DOI:10.1016/j.ejmech.2013.01.033

European Journal of Medicinal Chemistry 62 (2013) 670e676
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and cytotoxicity of 3-aryl acrylic amide derivatives of
the simplified saframycineecteinascidin skeleton prepared
from -dopa
L
,b,
*
Ju Guo a, Wenfang Dong a, Wei Liu a, Zheng Yan b, Nan Wang b, Zhanzhu Liu a
a State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College
and Chinese Academy of Medical Sciences, Beijing 100050, PR China
b Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College
and Chinese Academy of Medical Sciences, Beijing 100050, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Twenty four compounds with diversified 3-aryl acrylic amide side chains of the simplified saframycin
eecteinascidin pentacyclic skeleton were synthesized via a 14-step stereospecific route starting from
Received 17 December 2012
Received in revised form
9 January 2013
Accepted 25 January 2013
Available online 5 February 2013
L-dopa. The cytotoxicities of these compounds were tested against eight human tumor cell lines
including HCT-8, BEL-7402, BGC-803, A549, A2780, MCF-7, MX-1, and MDA-MB-231. Most of these
compounds exhibited potent antitumor activity, and a preliminary structureeactivity relationship (SAR)
was discussed. Compound 28 with 3-thiophenyl acrylic amide side chain exhibited selective cytotoxicity
against MDA-MB-231 cell line with the IC50 value of 50 nM.
Keywords:
Ó 2013 Elsevier Masson SAS. All rights reserved.
Ecteinascidin
Saframycin
Cytotoxicity
L-dopa
Synthesis
1. Introduction
dopa [16]. Among those analogs, the compound with the 3-phenyl
acrylic acid side chain was found to show promising cytotoxicity.
Bistetrahydroisoquinoline is a large family of natural products
that display a range of biological properties such as antitumor and
antimicrobial activities [1]. Ecteinascidin 743 (Et-743), which is
isolated from the Caribbean tunicate Ecteinascidia turbinate, is the
most potent one of this family and has been launched in Germany
and UK for the treatment of soft tissue sarcoma [2]. The total syn-
thesis of these tetrahydroisoquinoline alkaloids has been studied
by us and many other research groups [3e8]. Since the biste-
trahydroisoquinoline alkaloids are excellent lead compounds for
the search of new antitumor drugs, studies have been reported on
their structural modification [9]. As a result, a few promising novel
antitumor agents have been discovered, such as phthalascidin (Pt-
650) [10e12] and Zalypsis [13e15] (Fig. 1).
Interestingly, Zalypsis, which is being clinically tested, had a similar
(2E)-3-(3-thifluoromethyl-phenyl) acrylic amide side chain. Inspired
both by our results and the structure of Zalypsis, we decide to further
study the structureeactivity relationship of this type of simplified
compounds with the focus on the investigation of the SAR of the aryl
moiety of 3-aryl acrylic amide. All the analogs were evaluated for
their in vitro cytotoxicity against HCT-8, BEL-7402, BGC-823, A549,
A2780, MCF-7 MX-1 and MDA-MB-231 human tumor cell lines.
2. Chemistry
The synthetic route basically follows our previous one with the
sole difference in the final steps of replacing the N-Cbz with N-Boc
protecting group, which avoided the side reactions in the reductive
cyanation step and thus improved the synthetic efficiency. Inter-
mediate 1 was prepared according to the synthetic procedure as we
have reported [16c]. Removal of the N-Cbz group of 1 by catalytic
hydrogenation afforded compound 2, which was then protected by
(Boc)2O to give 3. Partial reduction of the lactam ring of 3 to the
corresponding cyclic hemiaminal was followed by treatment with
KCN to yield compound 4. Cleavage of the Boc group by CF3COOH at
In our previous work, we synthesized a series of analogs of
a simplified bistetrahydroisoquinoline skeleton prepared from L-
* Corresponding author. State Key Laboratory of Bioactive Substances and Func-
tions of Natural Medicines, Institute of Materia Medica, Peking Union Medical
College and Chinese Academy of Medical Sciences, Beijing 100050, PR China.
Tel.: þ86 10 63165253; fax: þ86 10 63017757.
E-mail address: liuzhanzhu@imm.ac.cn (Z. Liu).
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.01.033

J. Guo et al. / European Journal of Medicinal Chemistry 62 (2013) 670e676
671
OCH3
CH3
HO
OMe
HO
Me
HO
OAc
NH
AcO
O
OMe
MeO
H3C
Me
N
CH3
HO
H
N
Me
O
Me
N
N
N
S
O
O
AcO
O
H
N
OH
O
Me
O
CN
O
NH
N
Me
O
CF3
O
H
O
H
OH
Zalypssis
Ecteinascidin 743
Phthalascidin
Fig. 1. Structures of Et-743, phthalascidin and Zalypsis.
room temperature provided precursor 5, which was acylated with
various 3-aryl acrylic acids to afford the corresponding target am-
ides 6e29 (Scheme 1). All the structures of the compounds were
confirmed by 1H, 13C NMR, and FAB-MS.
values at the level of 10ꢀ6 M or 10ꢀ7 M. Compound 28 showed the
most potent cytotoxicity of all these compounds. This study con-
firmed that the 3-aryl acrylic amide side chain played an important
role for the antitumor activity of this type of analogs.
3. Cytotoxicity
6. Experimental protocols
Cytotoxicity of this series of simplified tetrahydroisoquinoline
analogs was evaluated against eight human cell lines: HCT-8 (hu-
man colon cancer cell line), BEL-7402 (human hepatic carcinoma
cell line), BGC-823 (human gastric adenocarcinoma cell line), A549
(human lung adenocarcinoma epithelial cell line), A2780 (human
ovarian cancer cell line), MX-1 (human breast cancer cell line),
MDA-MB-231 (human breast cancer cell line), and MCF-7 (human
breast cancer cell line) by the standard MTT assay. The results are
shown in Table 1.
6.1. General
Melting points were obtained on Yanaco MP-500D melting
point apparatus and were uncorrected. Optical rotations were
measured on a PerkinElmer Polarimeter 341LC using 10 cm cells
and the sodium D line (589 nm) at 20 ꢁC and concentration indi-
cated. HRMS were carried out by Agilent LC/MSD TOF. 1H and 13C
NMR spectra were recorded on a Varian Mercury 400 spectrometer
(400 MHz, 1H; 100 MHz, 13C) or Varian Mercury 300 spectrometer
(300 MHz, 1H; 75 MHz, 13C) in CDCl3, using tetramethylsilane (TMS)
as an internal standard. Chemical shifts (d) are expressed in parts
4. Results and discussion
per million (ppm), and the following abbreviations are used: singlet
(s), doublet (d), triplet (t), doubled doublet (dd), multiplet (m), etc.
All common reagents and solvents were purchased from com-
mercial suppliers and purified before use.
As shown in Table 1, most of the compounds exhibited consid-
erable cytotoxicities to these eight cell lines. Notably, most of these
compounds showed selective inhibition against the two breast
tumor cell lines of MDA-MB-231 and MX-1 with the IC50 values at
the level of 10ꢀ7 M regardless of the structural changes of the amide
side chain (for example, compounds 8, 20, 25, and 28 with different
3-aromatic rings of the acrylic amide moiety). It is also apparent
that this type of bistetrahydroisoquinoline compounds seems to be
less sensitive toward the human lung adenocarcinoma epithelial
cell line A549. In addition, it is noteworthy that compounds 16, 18,
19 and 27 exhibited rather weak cytotoxicity against most of the
cell lines in spite of the fact that great differences of the 3-aromatic
rings exist among these four compounds. Finally, compound 28,
which had a 3-thiophenyl acrylic amide side chain exhibited broad
and potent cytotoxic activity with the strongest selective inhibition
activity of 50 nM against MDA-MB-231.
6.2. Synthetic procedures for the key intermediate compounds 3
and 4
Compound 1 was synthesized from L-dopa through a multi-step
stereospecific synthetic route we had built previously [16c].
6.2.1. Preparation of intermediate compound 3
To a solution of compound 1 (60 mg, 0.105 mmol) in CH3OH
(10 mL) were added Pd(OH)2 (moist, Pd content 20%, 20 mg) and
acetic acid (2 drops). Then the mixture was hydrogenated in a Parr
apparatus (40 psi H2) for 2 h at room temperature. The reaction
mixture was filtered and concentrated under reduced pressure. The
residue was dissolved in EtOAc (50 mL), washed with saturated
aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, and
concentrated under reduced pressure to give the crude product 2
(39 mg) as a yellow oil (83% yield).
Although a general structureeactivity relationship of this type
of simplified tetrahydroisoquinoline compounds could not be
summarized from these data, it still can be concluded that the
structure of the acrylic amide side chain had a certain influence on
both the potency and selectivity of their cytotoxicity.
To a solution of compound 2 (31 mg, 0.068 mmol) and Et3N
(0.035 mL, 0.17 mmol) in CH2Cl2 (10 mL) was added Boc2O (18 mg in
CH2Cl2, 5 mL) dropwise at 0 ꢁC, and the mixture was stirred at room
temperature for 4.5 h. The reaction mixture was washed with brine,
dried over anhydrous Na2SO4, and concentrated under reduced
pressure to give the crude product. Purification by column chroma-
tography (CH2Cl2/MeOH ¼ 80:1) afforded the N-Boc product 3
5. Conclusions
Twenty-four simplified tetrahydroisoquinoline analogs were
prepared from L-dopa through a fourteen-step stereospecific pro-
cedure. The cytotoxicities of these compounds were tested against
HCT-8, BEL-7402, BGC-823, A549, A2780, MCF-7 MX-1 and MDA-
MB-231 human tumor cell lines by standard MTT assay. Most of
the compounds showed potent antitumor activity with the IC50
(33 mg, 89%) as a yellow solid. Mp: 122e124 ꢁC. [
a]
D
20: ꢀ52.6 (c 0.10,
CDCl3). HRMS calcd. for C30H40N3O7 [M þ H]þ 554.2867, found
554.2861. 1H NMR (400 MHz, CHCl3):
d 6.71 (s, 1H), 6.64 (s, 2H), 6.57

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J. Guo et al. / European Journal of Medicinal Chemistry 62 (2013) 670e676
Scheme 1. Synthesis of the simplified bistetrahydroisoquinoline compounds.
(s,1H), 5.16(t,1H), 4.38(d, J¼12Hz,1H), 4.03(d, J¼ 12Hz,1H), 3.90(s,
3H), 3.87 (s, 6H), 3.84 (s, 3H), 3.76 (d, J ¼ 4 Hz, 1H), 3.71 (d, J ¼ 4 Hz,
1H), 3.27 (dd, J ¼ 4, 12 Hz, 1H), 2.96 (t, 1H), 2.87 (t, 1H), 2.84 (d,
J ¼ 12 Hz,1H), 2.72 (dd, J ¼ 4,12 Hz,1H), 2.64 (t,1H), 2.48 (s, 3H),1.27
(s, 9H).
concentrated in vacuo to give 34 mg of a crude product, which was
purified by column chromatography (CH2Cl2/CH3OH ¼ 30:1) to
afford compound 4 (30 mg) as yellow solid (81% yield). Mp: 152e
154 ꢁC. [
a
]
D
20: ꢀ61.7 (c 0.10, CHCl3). HRMS calcd. for C31H41N4O6
[M þ H]þ 565.3389, found 565.3388. 1H NMR (300 MHz, CDCl3):
d
6.59 (d, J ¼ 9 Hz, 2H), 6.52 (d, J ¼ 9 Hz, 2H), 4.25 (t, 1H), 4.01(d,
6.2.2. Preparation of intermediate compound 4
J ¼ 6 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 3.82 (s, 3H), 3.80
(d, J ¼ 6 Hz, 1H), 3.56 (t, 1H), 3.36 (d, J ¼ 6 Hz, 1H), 3.27 (d, J ¼ 12 Hz,
1H), 3.11e3.19 (dd, J ¼ 6, 12 Hz, 1H), 3.03 (t, 1H), 2.82 (t, 1H), 2.59 (d,
J ¼ 6 Hz, 1H), 2.53 (d, J ¼ 6 Hz, 1H), 2.38 (s, 3H), 1.34 (s, 9H).
Compound 3 (31 mg, 0.056 mmol) in dry THF (5 mL) was added
to a solution of LiAlH4 (16 mg 0.448 mmol) in THF, and the mixture
was stirred for 3 h at 0 ꢁC. Then AcOH (0.06 mL 1.12 mmol) and
a solution of 4.8 M KCN in H2O (0.84 mmol) were added. After
stirring at room temperature for 14 h, the reaction mixture was
quenched with aqueous 10% NaHCO3 (15 mL) and extracted with
CH2Cl2 (3 ꢂ 10 mL). The combined organic layers were washed with
H2O and brine, dried over anhydrous Na2SO4, filtered, and
6.3. General procedure for the synthesis of compounds 6e29
A mixture of compound 4 (57 mg, 0.101 mmol) in trifluoroacetic
acid (1 mL) was stirred at room temperature for 2 h, and then the

J. Guo et al. / European Journal of Medicinal Chemistry 62 (2013) 670e676
673
Table 1
Cytotoxicity of simplified tetrahydroisoquinoline compounds against eight cell lines.
Compound
IC50
(
m
M)a
HCT-8
BEL-7402
BGC-823
A549
A2780
MX-1
MDA-MB-231
MCF-7
6
7
8
9
6.82
2.13
2.04
2.25
1.97
3.24
0.37
4.87
3.06
1.74
>10
2.12
>10
>10
1.97
4.64
3.42
5.18
2.88
1.62
3.03
>10
0.43
3.29
3.10
0.22
1.18
1.40
1.66
2.13
1.16
3.36
0.87
0.68
>10
1.14
>10
7.51
2.13
4.21
2.56
4.93
1.98
1.03
2.28
>10
0.27
2.16
5.83
0.59
2.12
1.97
1.10
3.60
1.42
5.31
2.60
1.71
>10
1.79
>10
>10
2.52
5.86
2.06
5.17
3.71
1.73
3.03
>10
0.25
3.29
>10
9.24
1.20
1.73
1.70
2.81
2.03
3.10
1.73
4.90
2.24
1.64
>10
1.70
>10
>10
1.67
2.89
2.97
4.78
1.97
1.04
2.53
>10
0.30
2.20
1.50
0.56
0.72
0.50
1.84
1.72
0.77
1.69
0.34
0.58
3.59
0.46
3.10
3.27
0.92
2.04
0.99
3.16
0.61
0.37
0.33
2.83
0.38
0.99
0.59
0.16
0.32
0.40
0.81
0.49
0.20
0.42
0.12
0.16
0.49
0.24
1.31
0.61
0.30
2.93
0.31
0.72
0.31
0.18
0.25
2.57
0.05
0.21
5.94
1.68
3.51
1.21
0.63
3.53
1.95
5.13
1.73
1.72
>10
1.91
>10
>10
5.20
5.47
3.73
5.08
5.14
1.59
2.48
>10
0.41
3.52
8.72
9.67
5.03
>10
9.41
>10
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
9.45
5.49
>10
7.68
>10
>10
8.56
>10
9.76
>10
>10
5.00
6.91
>10
0.72
9.68
a
The IC50 values represent the inhibitory concentration of 50% of cell growth.
mixture was basified with saturated aqueous NaHCO3 and extrac-
ted with EtOAc (3 ꢂ 10 mL). The combined organic phase was
washed with brine, dried over anhydrous Na2SO4, and concentrated
under reduced pressure to give the crude product 5 (39 mg) as
a yellow oil (85% yield).
To a solution of compound 5 (1.0 equiv) in CH2Cl2 was added the
corresponding 3-aromatic acrylic acid (1.5 equiv), DMAP (1.0 equiv)
and EDC (1.5 equiv), and then the mixture was stirred at room
temperature for 7 h. The mixture was diluted with CH2Cl2, washed
with saturated aqueous NaHCO3 and brine, dried over anhydrous
Na2SO4, concentrated under reduced pressure to give the crude
product. Purification by column chromatography (CH2Cl2/
CH3OH ¼ 20:1) afforded compounds 6e29.
6.54e6.52 (d, J ¼ 6 Hz, 2H), 5.57e5.52 (d, J ¼ 15 Hz, 1H), 4.21 (t, 2H),
4.07 (s, 1H), 4.02 (s, 1H), 3.86 (m, 1H), 3.91 (s, 3H), 3.72 (m, 1H), 3.82
(s, 6H), 3.62 (s, 3H), 3.45 (m, 2H), 3.15 (dd, J ¼ 6, 12 Hz, 1H), 2.61 (m,
1H), 2.55 (m, 1H), 2.41 (s, 3H). 13C NMR (100 MHz, CDCl3):
d 167.74,
164.76, 148.14 (2C), 139.43, 137.84, 132.45, 130.86 (3C), 128.79 (3C),
128.01 (3C),125.73,124.94,122.18,113.00,110.42 (2C),109.73, 68.15,
63.01, 60.06, 56.26, 55.96, 55.87, 55.62, 55.56, 41.65, 38.72, 30.35,
28.91, 23.73.
6.3.3. 3-(4-Methoxyphenyl)-2-propenamide derivative (8)
White solid, mp: 107e109 ꢁC. [
a]
20: ꢀ10.7 (c 0.0028, CHCl3).
D
HRMS calcd. for C33H41N4O6 [M þ H]þ 625.3021, found 625.3022. 1H
NMR (400 MHz, CDCl3): d 7.42 (s, 1H), 7.40 (s, 1H), 7.36 (s, 1H), 6.94
(s, 1H), 6.96 (s, 1H), 6.65 (s, 1H), 6.63 (s, 1H), 6.59 (s, 1H), 6.57 (s, 1H),
5.49 (d, J ¼ 12 Hz, 1H), 5.12 (s, 1H), 4.12 (s, 1H), 4.01 (s, 1H), 3.92 (s,
3H), 3.90 (d, J ¼ 4 Hz, 1H), 3.86 (d, J ¼ 4 Hz, 1H), 3.83 (s, 6H), 3.82 (s,
3H), 3.66 (s, 3H), 3.44 (s, 1H), 3.42 (s, 1H), 3.14e3.18 (dd, J ¼ 6.12 Hz,
1H), 2.59 (m, 1H), 2.57 (d, J ¼ 12 Hz, 2H), 2.42 (s, 3H), 2.39 (d,
6.3.1. (2E)-N-{[(6S,7R,9R,14aS,15R)-7-Cyano-6,7,9,14,14a,15-
hexahydro-2,3,11,12-tetramethoxy-16-methyl-6,15-imino-5H-
isoquino[3,2-b][3]benzazocin-9-yl]methyl}-3-(4-fluorophenyl)-2-
propenamide (6)
Yellow solid, mp: 113e115 ꢁC. [
a
]
D
20: ꢀ11.3(c 0.0042, CHCl3).
J ¼ 8 Hz, 1H). 13C NMR (100 MHz, CDCl3):
d 165.84, 160.96, 148.53,
HRMS calcd. for C35H38F1N4O5 [M þ H]þ 613.2821, found 613.2820.
148.00, 146.66, 140.81, 129.44 (3C), 127.17, 126.53, 125.99, 125.15,
117.20, 114.18, 112.93, 110.49, 110.32, 109.70, 62.982, 60.04, 59.52,
56.23, 56.21, 55.92, 55.86, 55.66, 55.51, 55.37, 44.03, 41.80, 32.42,
26.00, 22.68.
1H NMR (400 MHz, CDCl3):
d
7.34 (d, J ¼ 6 Hz, 2H), 7.32 (d, J ¼ 6 Hz,
2H), 7.26 (d, J ¼ 12 Hz,1H), 6.59 (s, 1H), 6.58 (s, 1H), 6.53 (s, 1H), 6.51
(s, 1H), 5.42 (d, J ¼ 15 Hz, 1H), 5.13 (s, 1H), 4.07 (s, 1H), 4.01 (s, 1H),
3.91 (s, 3H), 3.82 (s, 6H), 3.79 (m, 1H), 3.73e3.68 (dd, J ¼ 8.12 Hz,
1H), 3.62 (s, 3H), 3.43 (m, 2H), 3.18e3.13 (dd, J ¼ 10, 15 Hz, 1H),
2.59e2.51 (dd, J ¼ 8.12 Hz, 3H), 2.42 (s, 3H), 2.36 (d, J ¼ 12 Hz, 1H).
6.3.4. 3-(4-Chlorophenyl)-2-propenamide derivative (9)
Yellow solid, mp: 109e111 ꢁC. [
a
]
D
20: ꢀ14 (c 0.0045, CHCl3).
13C NMR (100 MHz, CDCl3):
d
165.73, 148.68, 148.03, 146.75, 146.40,
HRMS calcd. for C35H38ClN4O5 [M þ H]þ 629.2525, found 629.2524.
141.14, 131.94, 128.44 (2C), 128.31 (2C), 127.91, 126.35, 125.96,
125.12, 118.70, 117.48, 112.83, 110.52, 110.32, 109.72, 62.99, 60.07,
59.38, 56.21, 55.94, 55.86, 55.66, 55.58, 44.09, 41.70, 32.38, 28.74,
26.09.
1H NMR (400 MHz, CDCl3):
d
7.65 (d, J ¼ 6 Hz, 2H), 7.52 (d, J ¼ 6 Hz,
2H), 7.36 (d, J ¼ 12 Hz,1H), 6.61 (d, J ¼ 6 Hz, 2H), 6.54 (s, 1H), 6.52 (s,
1H), 5.55 (d, J ¼ 12 Hz,1H), 5.16 (s, 1H), 4.08 (s, 1H), 4.03 (s, 1H), 3.94
(m, 1H), 3.91 (s, 3H), 3.82 (s, 6H), 3.73e3.77 (dd. J ¼ 6, 12 Hz, 1H),
3.62 (s, 3H), 3.45 (m, 2H), 3.43 (m, 1H), 3.19e3.15 (dd, J ¼ 6, 12 Hz,
1H), 2.58e2.60 (dd, J ¼ 6.12 Hz, 2H), 2.42 (s, 3H), 2.38 (d, J ¼ 12 Hz,
6.3.2. 3-(4-Trifluorophenyl)-2-propenamide derivative (7)
Yellow solid, mp: 135e137 ꢁC. [
a]
20: ꢀ18.8 (c 0.0038, CHCl3).
1H). 13C NMR (100 MHz, CDCl3):
d 164.70, 148.51, 148.10 (2C),
D
HRMS calcd. for C36H38F3N4O5 [M þ H]þ 663.2789, found 663.2790.
146.70, 139.47, 137.80, 128.01 (4C), 126.65, 125.89, 125.73, 124.93,
122.06, 117.59, 113.14, 110.42, 110.37, 109.69, 62.93, 59.99, 59.48,
56.25, 55.92, 55.85, 55.58, 55.51, 44.02, 41.82, 32.40, 31.92, 25.98.
1H NMR (400 MHz, CDCl3):
d 7.69 (m, 2H), 7.65 (s, 1H), 7.62 (s, 1H),
7.52 (s, 1H), 7.49 (s, 1H), 7.38e7.33 (d, J ¼ 15 Hz, 1H), 6.60 (s, 2H),

674
J. Guo et al. / European Journal of Medicinal Chemistry 62 (2013) 670e676
6.3.5. 3-(3,4,5-Trimethoxyphenyl)-2-propenamide derivative (10)
1H), 7.02 (d, J ¼ 8 Hz, 1H), 6.92 (s, 1H), 6.89 (d, J ¼ 8 Hz, 1H), 6.54 (d,
J ¼ 8 Hz, 2H), 6.53 (d, J ¼ 8 Hz, 2H), 5.56 (d, J ¼ 12 Hz, 1H), 5.11 (s,
1H), 4.10 (s, 1H), 4.01 (s, 1H), 3.92 (s, 3H), 3.86 (s, 3H), 3.85 (s, 1H),
3.82 (s, 3H), 3.80 (s, 3H), 3.79 (t, 1H), 3.66 (s, 3H), 3.61 (s, 1H), 3.43
(d, J ¼ 3 Hz, 1H), 3.39 (m, 1H), 3.14 (dd, J ¼ 3, 9 Hz, 1H), 2.59e2.55
(dd, J ¼ 3, 6 Hz, 1H), 2.58e2.52 (dd, J ¼ 3, 6 Hz, 1H), 2.40 (s, 3H),
2.37e2.34 (dd, J ¼ 6, 12 Hz, 1H). 13C NMR (100 MHz, CDCl3):
White solid, mp: 128e130 ꢁC. [
a]
20: ꢀ27.8 (c 0.0027, CHCl3).
D
HRMS calcd. for C38H45N4O8 [M þ H]þ 685.3232, found 685.3237.
1H NMR (400 MHz, CDCl3):
d
7.32 (d, J ¼ 12 Hz,1H), 6.65 (s, 2H), 6.55
(s, 2H), 6.53 (s, 2H), 5.50 (d, J ¼ 12 Hz, 1H), 4.96 (s, 1H), 4.11 (s, 1H),
4.01 (s, 1H), 3.93 (s, 6H), 3.90 (d, J ¼ 6 Hz, 1H), 3.87 (s, 3H), 3.85 (s,
3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.59 (s, 3H), 3.46 (t, 1H), 3.44 (d,
J ¼ 6 Hz, 2H), 3.40 (s, 1H), 3.15 (dd, J ¼ 6, 12 Hz, 1H), 2.60e2.57 (dd,
J ¼ 6, 12 Hz, 1H), 2.56 (d, J ¼ 12 Hz, 1H), 2.43 (s, 3H), 2.37 (dd, J ¼ 6,
d
165.55, 159.87, 148.55, 148.06, 148.01, 146.63, 141.24, 135.86,
129.76, 126.57, 126.12, 125.08, 120.14, 119.97, 117.64, 115.59, 115.27,
113.22, 112.96, 110.54, 110.27, 109.71, 62.94, 60.02, 59.55, 56.17,
55.94, 55.87, 55.76, 55.57, 55.30, 44.10, 41.77, 32.45, 25.95, 22.67.
12 Hz, 1H). 13C NMR (100 MHz, CDCl3):
d 165.11, 148.57, 148.07,
146.71, 139.78, 135.58, 132.90, 129.05 (3C), 129.00 (3C), 126.55,
125.88, 124.99, 120.20, 117.54, 113.06, 110.45, 110.37, 109.68, 62.95,
60.00, 59.41, 56.24, 55.92, 55.86, 55.59, 55.52 (2C), 55.39, 44.03,
41.76, 32.37, 31.91, 26.04, 22.67.
6.3.10. 3-(4-Ethylphenyl)-2-propenamide derivative (15)
White solid, mp: 120e122 ꢁC. [
a
]
D
20: ꢀ32.8 (c 0.0022, CHCl3).
HRMS calcd. for C37H43N4O5 [M þ H]þ 623.3228, found 623.3224.
6.3.6. 3-(2,3,4-Trimethoxyphenyl)-2-propenamide derivative (11)
1H NMR (400 MHz, CDCl3):
d
7.40 (d, J ¼ 16 Hz, 1H), 7.33 (d, J ¼ 8 Hz,
White solid, mp: 123e125 ꢁC. ꢁC. [
a]
20: ꢀ28.1 (c 0.0028, CHCl3).
2H), 7.21 (d, J ¼ 8 Hz, 2H), 6.59 (d, J ¼ 8 Hz, 2H), 6.53 (d, J ¼ 8 Hz,
2H), 5.54 (d, J ¼ 16 Hz,1H), 5.12 (s, 1H), 4.09 (s, 1H), 4.01 (s, 1H), 3.92
(s, 3H), 3.83 (s, 6H), 3.79 (s, 1H), 3.69 (d, J ¼ 8 Hz, 1H), 3.62 (s, 3H),
3.60 (d, J ¼ 8 Hz, 1H), 3.43 (d, J ¼ 8 Hz, 1H), 3.11e3.17 (dd, J ¼ 8,
16 Hz, 1H), 2.66 (dd, J ¼ 8, 16 Hz, 2H), 2.58 (d, J ¼ 8 Hz, 1H), 2.53 (d,
J ¼ 16 Hz, 1H), 2.49 (s, 1H), 2.39 (s, 3H), 2.34 (s, 1H), 1.25 (s, 3H). 13C
D
HRMS calcd. for C38H45N4O8 [M þ H]þ 685.3232, found 685.3233.
1H NMR (400 MHz, CDCl3):
d
7.63 (d, J ¼ 16 Hz, 1H), 7.16 (d, J ¼ 8 Hz,
1H), 6.71 (d, J ¼ 8 Hz, 1H), 6.60 (s, 2H), 6.56 (s, 1H), 6.55 (s, 1H), 5.65
(d, J ¼ 16 Hz, 1H), 5.10 (s, 1H), 4.12 (s, 1H), 4.00 (s, 1H), 3.93 (s, 3H),
3.91 (d, J ¼ 6 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.83 (s, 3H), 3.82 (s,
3H), 3.67 (s, 3H), 3.56 (s, 3H), 3.48 (d, J ¼ 6 Hz, 2H), 3.42 (s, 1H), 3.40
(t, 1H), 3.17e3.11 (dd, J ¼ 6.12 Hz, 1H), 2.60 (m, 1H), 2.56 (m, 1H),
2.40 (s, 3H), 2.33 (d, J ¼ 12 Hz, 1H). 13C NMR (100 MHz, CDCl3):
NMR (100 MHz, CDCl3):
d 168.00, 148.74, 148.30, 146.90, 140.16,
132.69, 131.12, 130.91, 130.00, 129.93, 129.04 (2C), 126.91, 126.22,
125.30, 119.61, 116.16, 115.99, 113.34, 110.69, 110.61, 109.94, 68.40,
63.20, 60.25, 59.76, 56.48, 56.16, 55.83, 55.77, 44.24, 42.07, 38.97,
32.68, 30.60, 29.16, 23.98.
d
165.72, 153.39 (2C), 148.46, 148.04, 147.99, 146.50, 141.66, 139.64,
130.08 (2C), 126.70, 126.04, 125.02, 118.69, 117.62, 113.05, 110.49,
110.18, 109.72, 105.17 (2C), 62.93, 60.92, 59.90, 59.49, 56.19, 56.07,
55.95, 55.86, 55.57, 55.44, 55.30, 44.12, 41.79, 32.41, 25.95, 22.67.
6.3.11. 3-(2,4-Dimethoxyphenyl)-2-propenamide derivative (16)
Yellow film. [
a
]
20: ꢀ8.95 (c 0.0016, CHCl3). HRMS calcd. for
6.3.7. 3-(4-tert-Butylphenyl)-2-propenamide derivative (12)
C37H43N4O7 [M þD H]þ 655.3126, found 655.3125. 1H NMR
Yellow solid, mp: 119e121 ꢁC. [
a
]
20: ꢀ33.7 (c 0.0029, CHCl3).
(400 MHz, CDCl3):
d
7.68 (d, J ¼ 12 Hz, 1H), 7.35 (d, J ¼ 4 Hz, 1H),
HRMS calcd. for C39H47N4O5 [M þ H]þ D651.3541, found 651.3541. 1H
6.60 (d, J ¼ 4 Hz, 1H), 6.56 (s, 1H), 6.55 (s, 1H), 6.53 (dd, J ¼ 4, 8 Hz,
1H), 6.50 (d, J ¼ 4 Hz, 1H), 6.41 (d, J ¼ 4 Hz, 1H), 5.69 (d, J ¼ 12 Hz,
1H), 5.12 (s, 1H), 4.13 (s, 1H), 3.99 (s, 1H), 3.90 (s, 3H), 3.85 (d,
J ¼ 4 Hz, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H), 3.80 (s, 3H), 3.78
(d, J ¼ 4 Hz,1H), 3.65 (s, 3H), 3.75 (m, 1H), 3.48 (d, J ¼ 8 Hz,1H), 3.38
(d, J ¼ 4 Hz, 1H), 3.10e3.15 (dd, J ¼ 4, 12 Hz, 1H), 2.57 (d, J ¼ 8 Hz,
1H), 2.45 (d, J ¼ 12 Hz, 1H), 2.39 (s, 3H), 2.36 (d, J ¼ 4 Hz, 1H). 13C
NMR (400 MHz, CDCl3):
d 7.39 (m, 2H), 7.37 (m, 2H), 7.34 (m, 1H),
6.61 (s, 1H), 6.58 (s, 1H), 6.55 (s, 1H), 6.51 (s, 1H), 5.58e5.54 (d,
J ¼ 12 Hz, 1H), 5.12 (s, 1H), 4.13 (s, 1H), 4.01 (s, 1H), 3.91 (s, 3H), 3.82
(s, 6H), 3.65 (s, 3H), 3.87e3.85 (d, J ¼ 6 Hz, 1H), 3.61 (s, 1H), 3.48 (d,
J ¼ 6 Hz, 1H), 3.41 (m, 2H), 3.18e3.12 (dd, J ¼ 6, 12 Hz, 1H), 2.57 (m,
1H), 2.54 (d, J ¼ 12 Hz,1H), 2.40 (s, 3H), 2.34e2.32 (d, J ¼ 12 Hz, 1H),
1.32 (s, 12H). 13C NMR (100 MHz, CDCl3):
d
165.71, 153.26, 148.58,
NMR (100 MHz, CDCl3): d 166.55, 162.28, 159.40, 148.38, 147.97,
148.01, 146.69 (2C), 141.09, 131.69, 129.73 (2C), 127.68, 126.01 (2C),
125.75, 125.10, 118.72, 117.56, 112.85, 110.49 (2C), 110.29, 109.70,
62.97, 60.09, 59.45, 56.21, 55.93, 55.85, 55.71, 55.57, 44.05, 41.75,
34.83, 32.40, 31.91, 31.19, 27.10, 26.01, 22.68.
146.51, 136.03, 129.50, 126.66, 126.31, 125.46, 123.56, 117.80, 117.68,
116.59, 112.76, 112.22, 110.60, 110.32, 109.81, 105.04, 98.36, 62.97,
60.11, 59.77, 56.14, 56.01, 55.93, 55.88, 55.61, 55.46, 55.38, 44.30,
41.78, 32.52, 25.85, 22.67.
6.3.8. 3-(2-Methoxyphenyl)-2-propenamide derivative (13)
6.3.12. 3-(Naphthalen-2-yl)-2-propenamide derivative (17)
White solid, mp: 110e112 ꢁC. [
a
]
20: ꢀ10.9 (c 0.0028, CHCl3).
Yellow film. [
a
]
20: ꢀ17.1 (c 0.0043, CHCl3). HRMS calcd. for
D
HRMS calcd. for C36H41N4O6 [M þ H]þ 625.3021, found 625.3022. 1H
C39H41N4O5 [M þD H]þ 645.3071, found 645.3070. 1H NMR
NMR (400 MHz, CDCl3):
d
7.37e7.33 (d, J ¼ 16 Hz, 1H), 7.31e7.29 (d,
(400 MHz, CDCl3):
d
8.26e8.22 (d, J ¼ 12 Hz, 1H), 8.14e8.12 (d,
J ¼ 8 Hz, 1H), 7.27 (s, 1H), 7.03e7.01 (d, J ¼ 8 Hz, 1H), 6.92 (s, 1H),
6.90e6.88 (d, J ¼ 8 Hz, 1H), 6.57e6.50 (m, 3H), 5.63e5.59 (d,
J ¼ 16 Hz, 1H), 5.09 (s, 1H), 4.10 (s, 1H), 4.01 (s, 1H), 3.92 (s, 3H), 3.87
(d, J ¼ 8 Hz, 1H), 3.82 (m, 9H), 3.79 (t, 1H), 3.66 (s, 3H), 3.61 (d,
J ¼ 4 Hz, 1H), 3.43 (m, 1H), 3.38 (m, 1H), 3.16e3.10 (dd, J ¼ 8.16 Hz,
1H), 2.68e2.59 (dd, J ¼ 8, 16 Hz, 1H), 2.54 (d, J ¼ 16 Hz, 1H), 2.39 (s,
J ¼ 12 Hz, 1H), 7.88e7.85 (dd, J ¼ 8, 12 Hz, 2H), 7.60e7.58 (d,
J ¼ 8 Hz, 1H), 7.55 (s, 1H), 7.53 (s, 1H), 7.51 (s, 1H), 7.50 (s, 1H), 6.58
(s, 1H), 6.55 (s, 1H), 5.70e5.66 (d, J ¼ 12 Hz, 1H), 5.24 (s, 1H), 4.19 (s,
1H), 4.05 (s, 1H), 3.83e3.81 (m, 9H), 3.69e3.64 (dd, J ¼ 8,12 Hz,1H),
3.61 (s,1H), 3.54e3.51 (q,1H), 3.45 (s, 3H), 3.45e3.40 (m, 2H), 3.17e
3.11 (dd, J ¼ 8, 16 Hz, 1H), 2.61e2.54 (m, 2H), 2.49e2.45 (d,
3H), 2.34 (m, 1H). 13C NMR (100 MHz, CDCl3):
d
165.55, 159.87,
J ¼ 16 Hz, 1H), 2.38 (s, 3H). 13C NMR (100 MHz, CDCl3):
d 165.41,
148.55, 148.06, 148.01, 146.63, 145.24, 135.86, 127.76, 126.57, 126.12,
125.08, 120.14, 119.97, 117.64, 115.59, 115.27, 113.22, 112.96, 110.54,
110.27, 109.71, 62.94, 60.12, 59.55, 56.17, 55.94, 55.87, 55.76, 55.57,
55.31, 44.10, 41.77, 32.45, 25.95, 23.67.
148.53, 148.05, 146.68, 137.99, 133.59, 131.64, 131.39, 129.99, 128.62,
126.57, 126.51, 126.15, 126.03, 125.66, 125.18, 124.58, 123.51, 123.36,
122.39, 117.71, 112.94, 110.52, 110.28, 109.73, 62.95, 60.03, 59.58,
56.13, 55.95, 55.87, 55.56, 55.42, 44.09, 41.80, 32.49, 25.92, 22.67.
6.3.9. 3-(3-Methoxyphenyl)-2-propenamide derivative (14)
6.3.13. 3-(Pyridin-2-yl)-2-propenamide derivative (18)
White solid, mp: 121e123 ꢁC. [
a
]
D
20: ꢀ16.2 (c 0.0028, CHCl3).
Yellow solid. Mp: 163e165 ꢁC. [
a]
20: ꢀ24.8 (c 0.0035, CHCl3).
D
HRMS calcd. for C36H41N4O6 [M þ H]þ 625.3021, found 625.3023. 1H
HRMS calcd. for C34H38N5O5 [M þ H]þ 596.2867, found 597.2826. 1H
NMR (400 MHz, CDCl3):
d
7.37 (d, J ¼ 12 Hz, 1H), 7.30 (d, J ¼ 8 Hz,
NMR (400 MHz, CDCl3):
d
8.59 (d, J ¼ 8 Hz,1H), 7.69 (d, J ¼ 8 Hz,1H),

J. Guo et al. / European Journal of Medicinal Chemistry 62 (2013) 670e676
675
7.38 (d, J ¼ 12 Hz, 1H), 7.32 (d, J ¼ 8 Hz, 1H), 7.22 (d, J ¼ 12 Hz, 1H),
6.63 (s, 1H), 6.56 (s, 2H), 6.52 (s, 1H), 6.36 (d, J ¼ 12 Hz, 1H), 5.29 (s,
1H), 4.14 (s, 1H), 4.09 (s, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H),
3.74 (m, 1H), 3.65 (s, 3H), 3.58 (s, 1H), 3.39 (d, J ¼ 8 Hz, 1H), 3.34 (d,
J ¼ 12 Hz, 1H), 3.28 (m, 1H), 3.14e3.08 (dd, J ¼ 8, 12 Hz, 1H), 2.60 (d,
J ¼ 8 Hz, 1H), 2.56 (m, 2H), 2.36 (s, 3H). 13C NMR (100 MHz, CDCl3):
3H), 3.78 (d, J ¼ 4 Hz, 1H), 3.65 (s, 3H), 3.60 (d, J ¼ 4 Hz, 2H), 3.12
(dd, J ¼ 4 Hz, 1H), 2.56 (d, J ¼ 8 Hz, 1H), 2.54 (d, J ¼ 8 Hz, 1H), 2.39 (s,
3H), 2.34 (d, J ¼ 4 Hz, 1H).
6.3.18. 3-(3,4-Dimethoxyphenyl)-2-propenamide derivative (23)
White solid. Mp: 114e116 ꢁC. ꢁC. [
a]
20: ꢀ7.72 (c 0.0025, CHCl3).
D
d
165.20, 152.89, 149.61, 148.48, 148.06, 147.99, 146.62, 139.37,
HRMS calcd. for C37H43N4O7 [M þ H]þ 655.3126, found 655.3125. 1H
136.97, 126.59, 126.51, 125.13, 124.51, 124.11, 123.91, 117.75, 112.74,
110.82, 110.47, 109.66, 62.94, 60.23, 59.87, 56.17, 55.99, 55.92, 55.62
(2C), 55.60, 44.35, 41.71, 32.57, 25.89.
NMR (400 MHz, CDCl3):
d
8.59- 8.58 (dd, J ¼ 8, 16 Hz, 1H), 7.37 (m,
1H), 7.36e7.35 (d, J ¼ 16 Hz, 1H), 7.34 (m, 1H), 6.62 (s, 1H), 6.60 (s,
1H), 6.57 (s, 1H), 6.56 (s, 1H), 5.60e5.57 (d, J ¼ 12 Hz, 1H), 5.13 (s,
1H), 4.09 (s, 1H), 4.03 (s, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H),
3.84 (s, 3H), 3.83 (s, 3H), 3.79 (m, 1H), 3.66e3.64 (d, J ¼ 4 Hz, 1H),
3.63 (s, 3H), 3.42 (m, 2H), 3.35 (d, J ¼ 4 Hz, 1H), 3.15e3.19 (dd, J ¼ 4,
12 Hz, 1H), 2.55 (d, J ¼ 8 Hz, 1H), 2.45 (d, J ¼ 12 Hz, 1H), 2.42 (s, 3H),
6.3.14. 3-(3-Chloro-4-fluorophenyl)-2-propenamide derivative (19)
White solid. Mp: 125e127 ꢁC. [
a]
20: ꢀ21.1 (c 0.0032, CHCl3).
D
HRMS calcd. for C35H37ClFN4O5 [M þ H]þ 647.2431, found 647.2427.
1H NMR (400 MHz, CDCl3):
d
7.62 (d, J ¼ 15 Hz, 1H), 7.46 (dd, J ¼ 8,
2.36 (m, 1H). 13C NMR (100 MHz, CDCl3):
d 164.67, 150.51, 149.93,
12 Hz, 1H), 7.12 (dd, J ¼ 8, 12 Hz, 1H), 7.05 (dd, J ¼ 8, 12 Hz, 1H), 6.57
(d, J ¼ 8 Hz, 2H), 6.53 (d, J ¼ 8 Hz, 2H), 5.46 (d, J ¼ 15 Hz, 1H), 5.12 (s,
1H), 4.08 (d, J ¼ 16 Hz, 1H), 4.01 (m, 1H), 3.92 (s, 1H), 3.87 (s, 3H),
3.83 (s, 3H), 3.82 (s, 3H), 3.77 (d, J ¼ 8 Hz, 1H), 3.62 (m, 1H), 3.60 (s,
3H), 3.43 (m, 2H), 3.15 (dd, J ¼ 6, 12 Hz, 1H), 2.57 (d, J ¼ 6 Hz, 1H),
2.50 (dd, J ¼ 6,12 Hz,1H), 2.43 (s, 3H), 2.35 (d, J ¼ 6 Hz,1H). 13C NMR
148.45, 148.09, 146.62, 137.48, 133.71, 130.23, 126.77, 125.99, 124.98,
123.67 (2C), 121.83 (2C), 117.65, 113.14, 110.46, 110.39, 109.71, 62.92,
60.04, 59.57, 56.23, 56.09, 55.93, 55.86, 55.51 (2C), 44.11, 41.80,
32.41, 31.90, 25.93, 22.67.
6.3.19. 3-(2,3-Dimethoxyphenyl)-2-propenamide derivative (24)
(100 MHz, CDCl3):
d
164.91, 163.97, 148.54, 148.14, 146.65, 135.51,
White solid. Mp: 117e119 ꢁC. [
a
]
20: ꢀ17.7 (c 0.0018, CHCl3).
D
135.38, 128.79 (3C), 125.90, 124.95, 122.29, 117.25, 117.06, 114.80,
114.63, 112.85, 110.52, 110.42, 109.67, 96.10, 62.95, 60.09, 59.31,
56.14, 55.96, 55.90, 55.56, 55.33, 43.99, 41.70, 32.40, 31.92, 22.68.
HRMS calcd. for C37H43N4O7 [M þ H]þ 655.3126, found 655.3125. 1H
NMR (400 MHz, CDCl3):
d
7.33 (d, J ¼ 12 Hz, 1H), 7.01 (dd, J ¼ 4 Hz,
1H), 6.97 (d, J ¼ 4 Hz, 1H), 6.87 (d, J ¼ 8 Hz, 1H), 6.58 (d, J ¼ 8 Hz,
2H), 6.54 (d, J ¼ 8 Hz, 2H), 5.45 (d, J ¼ 12 Hz,1H), 5.00 (s,1H), 4.09 (s,
1H), 4.01 (s, 1H), 3.96 (s, 3H), 3.90 (s, 3H), 3.89 (s, 3H), 3.83 (s, 3H),
3.81 (s, 3H), 3.79 (m, 1H), 3.68 (d, J ¼ 4 Hz, 1H), 3.62 (s, 3H), 3.42 (m,
2H), 3.36 (d, J ¼ 4 Hz, 1H), 3.11e3.17 (dd, J ¼ 8, 12 Hz, 1H), 2.56 (d,
J ¼ 4 Hz, 1H), 2.46 (d, J ¼ 12 Hz, 1H), 2.40 (s, 3H), 2.33 (d, J ¼ 8 Hz,
6.3.15. 3-(Quinolin-4-yl)-2-propenamide derivative (20)
Yellow film. [
a
]
20: ꢀ27.1 (c 0.0037, CHCl3). HRMS calcd. for
C38H40N5O5 [M þD H]þ 646.3024, found 646.3020. 1H NMR
(400 MHz, CDCl3):
d
8.98 (d, J ¼ 4 Hz, 1H), 8.15 (s, 1H), 8.12 (d,
J ¼ 4 Hz, 1H), 8.08 (s, 1H), 7.71e7.75 (dd, J ¼ 8, 16 Hz, 1H), 7.55e7.59
(dd, J ¼ 8, 16 Hz, 1H), 7.43 (d, J ¼ 4 Hz, 1H), 6.58 (t, 3H), 6.52 (d,
J ¼ 8 Hz, 1H), 5.70 (d, J ¼ 16 Hz, 1H), 5.26 (dd, J ¼ 8, 16 Hz, 1H), 4.09
(s, 1H), 4.04 (s, 1H), 3.85 (s, 6H), 3.82 (s, 3H), 3.80 (s, 1H), 3.74 (d,
J ¼ 8 Hz, 1H), 3.62 (s, 1H), 3.53 (s, 3H), 3.44 (d, J ¼ 8 Hz, 1H), 3.14e
3.20 (dd, J ¼ 8, 16 Hz, 1H), 2.58e2.61 (dd, J ¼ 8, 12 Hz, 1H), 2.53 (d,
J ¼ 12 Hz, 1H), 2.50 (d, J ¼ 4 Hz, 1H), 2.40 (s, 3H), 2.34 (d, J ¼ 4 Hz,
1H). 13C NMR (100 MHz, CDCl3):
d 165.94, 149.122, 148.05 (2C),
146.60, 141.32 (2C), 130.73, 127.48, 125.10, 121.79 (2C), 117.35,
112.92, 112.21, 110.99, 110.63, 110.51, 110.24, 109.97, 109.75, 62.96,
59.99, 59.43, 56.13, 55.97, 55.87 (3C), 55.80 (2C), 55.58, 55.48, 44.13,
41.74, 32.38, 25.89.
6.3.20. 3-[4-(Pyridin-2-yl)-phenyl]-2-propenamide derivative (25)
1H). 13C NMR (100 MHz, CDCl3):
d
164.15, 149.87, 148.53, 148.13
Yellow film. [
a
]
20: ꢀ56.6 (c 0.006, CHCl3). HRMS calcd. for
D
(2C), 146.73 (2C), 135.26, 129.84, 127.38, 127.22, 126.68, 126.14,
125.94, 124.93, 123.72 (2C), 123.27, 117.90 (2C), 117.80, 117.61, 113.27,
110.44, 109.71, 62.90, 60.02, 59.54, 56.23, 55.95, 55.86, 55.56, 55.50,
55.44, 44.19, 41.80, 32.39, 25.98.
C40H42N5O5 [M þ H]þ 672.3180, found 672.3168. 1H NMR (400 MHz,
CDCl3):
d
8.7 (d, J ¼ 4 Hz, 2H), 8.03 (d, J ¼ 8 Hz, 1H), 7.76 (d, J ¼ 4 Hz,
2H), 7.52 (d, J ¼ 8 Hz, 2H), 7.42 (d, J ¼ 16 Hz, 1H), 6.60 (d, J ¼ 8 Hz,
2H), 6.55 (d, J ¼ 8 Hz, 2H), 5.63 (d, J ¼ 16 Hz, 1H), 5.18 (s, 1H), 4.10 (s,
1H), 4.02 (s, 1H), 3.93 (s, 3H), 3.87 (d, J ¼ 8 Hz, 1H), 3.83 (s, 3H), 3.81
(s, 3H), 3.68 (d, J ¼ 8 Hz, 1H), 3.64 (s, 3H), 3.43 (d, J ¼ 8 Hz, 2H),
3.11e3.20 (dd, J ¼ 12, 16 Hz, 1H), 2.59 (d, J ¼ 12 Hz, 1H), 2.50 (d,
J ¼ 12 Hz, 2H), 2.40 (s, 3H), 2.35 (m, 1H). 13C NMR (100 MHz, CDCl3):
6.3.16. 3-(4-Aminophenyl)-2-propenamide derivative (21)
Yellow film. [
a
]
20: ꢀ50.8 (c 0.0025, CHCl3). HRMS calcd. for
D
C35H40N5O5 [M þ H]þ 610.3024, found 610.3012. 1H NMR (400 MHz,
CDCl3):
d
7.32 (d, J ¼ 8 Hz, 1H), 7.22 (d, J ¼ 12 Hz, 1H), 6.65 (d,
d 165.39, 156.50, 149.76, 148.54, 148.53, 148.01, 146.68, 140.63,
J ¼ 8 Hz, 2H), 6.59 (d, J ¼ 8 Hz, 2H), 6.53 (d, J ¼ 8 Hz, 2H), 6.49 (m,
1H), 5.37 (d, J ¼ 12 Hz,1H), 5.06 (s,1H), 4.09 (s,1H), 3.99 (s,1H), 3.92
(s, 3H), 3.87 (d, J ¼ 12 Hz, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.65 (s, 3H),
3.61 (d, J ¼ 4 Hz, 1H), 3.43 (m, 2H), 3.11e3.18 (dd, J ¼ 8, 12 Hz, 1H),
2.56 (d, J ¼ 4 Hz, 1H), 2.46 (d, J ¼ 12 Hz, 1H), 2.44 (d, J ¼ 4 Hz, 1H),
136.84, 136.77, 134.97, 128.28, 127.30, 127.22, 126.60, 126.07, 125.08,
123.54, 122.42, 120.57, 120.06, 117.69, 113.02, 110.60, 110.49, 110.30,
109.68, 62.94, 60.00, 59.56, 56.24, 55.91, 55.85, 55.63, 55.53, 55.55,
44.05, 41.80, 32.45, 25.91.
2.39 (s, 3H), 2.34 (m, 1H). 13C NMR (100 MHz, CDCl3):
d
166.43,
6.3.21. 3-[4-(Morpholin-4-yl)-phenyl]-2-propenamide derivative
148.73, 148.37, 148.21, 146.87, 141.49, 131.28, 129.78, 126.83, 126.32,
125.52, 125.09, 123.80, 117.99, 115.74, 115.05, 114.58, 113.13, 112.49,
110.73, 110.57, 109.96, 63.24, 60.28, 59.82, 57.06, 56.33, 56.10, 55.91,
55.85, 55.81, 44.25, 42.07, 33.27, 26.16.
(26)
Yellow solid. Mp: 152e154 ꢁC. [
a]
20: ꢀ113 (c 0.0042, CHCl3).
HRMS calcd. for C39H46N5O6 [M þ H]þD680.3443, found 680.3450.
1H NMR (400 MHz, CDCl3):
d
7.34 (d, J ¼ 8 Hz, 2H), 7.28 (d, J ¼ 12 Hz,
1H), 6.87 (d, J ¼ 8 Hz, 2H), 6.60 (d, J ¼ 8 Hz, 2H), 6.53 (d, J ¼ 8 Hz,
2H), 5.41 (d, J ¼ 12 Hz, 1H), 5.07 (m, 1H), 4.09 (s, 1H), 4.00 (s, 1H),
3.92(s, 3H), 3.90 (d, J ¼ 4 Hz, 1H), 3.86 (s, 3H), 3.84 (s, 1H), 3.82 (s,
3H), 3.80 (d, J ¼ 4 Hz,1H), 3.68 (s,1H), 3.66 (s, 3H), 3.57 (d, J ¼ 12 Hz,
1H), 3.42 (m, 4H), 3.23 (d, J ¼ 4 Hz, 4H), 3.11e3.18 (dd, J ¼ 8, 16 Hz,
1H), 2.57 (d, J ¼ 8 Hz, 1H), 2.53 (d, J ¼ 8 Hz, 1H), 2.40 (s, 3H), 2.35 (d,
6.3.17. 3-(4-tert-Butoxyphenyl)-2-propenamide derivative (22)
White solid. Mp: 113e115 ꢁC. [
a]
20: ꢀ21.7 (c 0.0018, CHCl3).
D
HRMS calcd. for C39H47N4O6 [M þ H]þ 667.3490, found 667.3490. 1H
NMR (400 MHz, CDCl3):
d
7.34 (d, J ¼ 8 Hz, 1H), 7.32 (d, J ¼ 4Hz, 2H),
6.98 (d, J ¼ 8 Hz, 2H), 6.58 (d, J ¼ 12 Hz, 2H), 6.52 (d, J ¼ 12 Hz, 2H),
5.47 (d, J ¼ 8 Hz, 1H), 5.09 (s, 1H), 4.09 (s, 1H), 4.01 (s, 1H), 3.92 (d,
J ¼ 12 Hz,1H), 3.90 (s, 3H), 3.85 (d, J ¼ 4 Hz, 1H), 3.82 (s, 3H), 3.81 (s,
J ¼ 12 Hz, 1H). 13C NMR (100 MHz, CDCl3):
d 166.29, 152.38, 148.67,
148.22 (2C), 146.84, 141.20, 129.48 (2C), 126.84, 126.27, 125.88,

676
J. Guo et al. / European Journal of Medicinal Chemistry 62 (2013) 670e676
125.45, 123.83, 117.97, 116.47, 114.99 (2C), 113.09, 110.70, 110.52,
109.95, 66.94 (2C), 63.21, 60.25, 59.79, 56.44, 56.14, 56.09, 55.95,
55.79 (2C), 48.57 (2C), 44.25, 42.06, 32.70, 26.16.
humidified at 5% CO2. Briefly, cells were placed in the appropriate
media on 96-well plates in a 100 mL total volume at a density of 1e
2.5 ꢂ 104 cells/mL and were allowed to adhere for 24 h before
treatment with tested compounds in DMSO solution (10ꢀ6, 10ꢀ7
,
6.3.22. 3-(1-Methyl-1H-pyrrol-2-yl)-2-propenamide derivative
10ꢀ8 mol/L final concentration). The cells were incubated for 72 h
after treated with different concentrations of all tested compounds,
and cell viability was assayed by MTT assay. The 50% inhibitory
concentration (IC50) was defined as the concentration that reduced
the absorbance of the untreated wells by 50% of vehicle in the MTT
assay. Assays were performed in triplicate on three independent
experiments.
(27)
White solid. Mp: 101e103 ꢁC. [
a
]
D
20: ꢀ42.3 (c 0.0018, CHCl3).
HRMS calcd. for C34H40N5O5 [M þ H]þ 598.3024, found 598.3024.
1H NMR (400 MHz, CDCl3):
d
7.36 (d, J ¼ 16 Hz, 1H), 6.08 (t,1H), 6.62
(d, J ¼ 4 Hz, 1H), 6.56 (d, J ¼ 8 Hz, 2H), 6.53 (d, J ¼ 8 Hz, 2H), 6.17 (t,
1H), 5.32 (d, J ¼ 16 Hz, 1H), 5.01 (d, J ¼ 4 Hz, 1H), 4.07 (m, 1H), 3.98
(s, 1H), 3.87 (d, J ¼ 4 Hz, 1H), 3.92 (s, 3H), 3.82 (s, 3H), 3.81 (s, 3H),
3.73 (s, 3H), 3.62 (s, 3H), 3.74 (s, 1H), 3.40 (m, 1H), 3.37 (d, J ¼ 8 Hz,
1H), 3.10e3.19 (dd, J ¼ 8, 16 Hz, 1H), 2.54 (m, 1H), 2.48 (d, J ¼ 4 Hz,
1H), 2.44 (d, J ¼ 4 Hz, 1H), 2.40 (s, 3H), 2.35 (d, J ¼ 8 Hz, 1H). 13C
Acknowledgments
We thank Specialized Research Fund for the Doctoral Program of
Higher Education (No. 200800230030) for financial support.
NMR (100 MHz, CDCl3):
d 166.20, 148.46, 147.95, 147.91, 146.64,
129.23, 129.09, 126.46, 126.05, 125.74, 123.58, 117.73, 114.45, 112.81,
110.45, 110.39, 110.20, 109.93, 109.70, 109.24, 62.96, 60.05, 59.69,
56.14, 55.88, 55.85, 55.71, 55.68, 55.56, 44.34, 41.81, 34.13, 32.41,
25.98.
Appendix A. Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.ejmech.2013.01.
033.
6.3.23. 3-(5-Chlorothiophen-2-yl)-2-propenamide derivative (28)
Yellow solid. Mp: 110e112 ꢁC. [
a
]
20: ꢀ96.8 (c 0.0075, CHCl3).
D
HRMS calcd. for C33H36ClN4O5S [M
þ
H]þ 635.2089, found
635.2095. 1H NMR (400 MHz, CDCl3):
d
7.33 (d, J ¼ 15 Hz, 1H), 6.96
References
(d, J ¼ 4 Hz, 1H), 6.85 (d, J ¼ 4 Hz, 1H), 6.60 (s, 1H), 6.54 (d, J ¼ 3 Hz,
2H), 6.49 (d, J ¼ 3 Hz, 1H), 5.40 (d, J ¼ 15 Hz, 1H), 5.07 (m, 1H), 4.08
(s, 1H), 3.98 (s, 1H), 3.92 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H), 3.79 (d,
J ¼ 4 Hz, 1H), 3.73 (s, 3H), 3.71 (d, J ¼ 6 Hz, 1H), 3.48 (m, 1H), 3.40 (d,
J ¼ 6 Hz, 1H), 3.09e3.17 (dd, J ¼ 6, 18 Hz, 1H), 2.59 (d, J ¼ 6 Hz, 1H),
2.53 (d, J ¼ 9 Hz, 1H), 2.45 (d, J ¼ 9 Hz, 1H), 2.38 (s, 3H), 2.34 (d,
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