3-Aryl β-carbolin-1-ones as a new class of potent inhibitors of tumor cell proliferation: Synthesis and biological evaluation

Article abstract of DOI:10.1039/b412921k

A novel three-step synthesis of 3-aryl β-carbolin-1-ones from non-indole starting materials has been developed. The two nitrogen atoms in β-carbolin-1-one were introduced efficiently by Michael addition of ethyl acetamidocyanoacetate to chalcone. The desi

Full text of DOI:10.1039/b412921k

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A R T I C L E
3-Aryl b-carbolin-1-ones as a new class of potent inhibitors of tumor
cell proliferation: synthesis and biological evaluation
Shaozhong Wang,a Yanmei Dong,a Xinyan Wang,a Xiaoyi Hu,b Jun O Liub and Yuefei Hu*a
a Department of Chemistry, Tsinghua University, Beijing, 100084, P. R. China.
E-mail: yfh@mail.tsinghua.edu.cn; Fax: +86 10 6277 1149; Tel: +86 10 6279 5380
b Department of Pharmacology and Molecular Sciences, John Hopkins University School of
Medicine, 725 N. Wolfe Street, Baltimore, MD 21205, USA. E-mail: joliu@jhu.edu;
Fax: +01 410 955 4520; Tel: +01 410 955 4619
Received 23rd August 2004, Accepted 11th January 2005
First published as an Advance Article on the web 7th February 2005
A novel three-step synthesis of 3-aryl b-carbolin-1-ones from non-indole starting materials has been developed. The
two nitrogen atoms in b-carbolin-1-one were introduced efficiently by Michael addition of ethyl
acetamidocyanoacetate to chalcone. The desired pyridone and indole rings were assembled by an intramolecular
ketone–nitrile annulation mediated by aqueous HCl–HOAc and a Cu(I)-catalyzed intramolecular N-arylation of the
amide, respectively. The target compounds were found to possess significant activity against tumor cell proliferaton.
The two nitrogen atoms in target compound 4 were introduced
Introduction
efficiently by Michael addition of ethyl acetamidocyanoacetate
b-Carboline (1, Scheme 1) is a key pharmacophore present in a
(5) to chalcone (6), followed by the assembly of the pyridone
number of biologically important natural tricyclic alkaloids.1,2
and indole rings by an intramolecular ketone–nitrile annulation
Its structural variant b-carbolin-1-one (2) has served as an im-
and a Cu(I)-catalyzed intramolecular N-arylation of amide,
portant intermediate for the preparation of complex alkaloids3
respectively.
and has been found to possess potent bioactivities on the central
nervous system.4 In 2001, some A-ring alkoxy-substituted b-
carbolin-1-ones (3) were first reported in a patent literature to
inhibit colon and lung tumor.5 Subsequently, we have found that
3-aryl b-carbolin-1-ones (4) display strong anti-tumor activities.6
Herein we report a novel synthetic route for the preparation of
derivatives of 47 and their activities on HeLa cell proliferation.
Scheme 2 Retro-Synthesis of 3-aryl b-carbolin-1-one 4.
Results and discussion
Scheme 1 b-Carboline and b-carbolin-1-ones.
Assembly of adduct 7 by Michael addition
Significant efforts have been made to construct the skeleton
of b-carbolin-1-one (2) over recent years. Two major synthetic
strategies have been adopted for this purpose, initiated directly
or indirectly with a few indole derivatives. The first is to build
pyridone rings by using acid- or Pd-catalyzed intramolecular
cyclization of indole-2-carboxylic acid amides,5,8–9 or intramolec-
ular Heck reaction of 3-iodoindole-2-carboxylic acid amides.10
The other is to modify the corresponding tricyclic precursors,11–13
by for example dehydrogenation of polyhydro-b-carbolin-1-
Although ethyl acetamidocyanoacetate (5) has a suitable struc-
ture to be a nucleophilic donor for Michael addition, it has
rarely been employed for this purpose in the literature.17 One
of its nitrogen-containing groups was often “wasted” in other
applications.18 When we treated the mixture of 5 and chalcone
6a with an equimolar amount of EtONa in EtOH at room
temperature for 2 h, the desired adduct 7a was obtained in 32%
yield, with a tedious separation by chromatography. To optimize
the yield of this reaction, the bases and solvents used were altered
(Table 1) and 7a was obtained in 86% yield when the reaction
was carried out in THF with catalytic amount of t-BuONa (10%
mol) at 5–10 ◦C for 2 h. As shown in Scheme 3 and Table 2, the
additions of 5 to other chalcones 6b–i yielded the corresponding
adducts 7b–i in 76–88% yields under similar conditions.
3a–b
one or oxidation of b-carboline (1) to yield the corresponding
3e,g–i
N-oxides, followed by a thermal rearrangement.
For our
purpose to synthesize 3-aryl b-carbolin-1-one (4), these methods
suffered from either inaccessible starting materials or elaborate
multi-step syntheses.
As a number of lactams are readily prepared by ketone–
nitrile annulation14 and the N-arylation of amide can be
achieved via catalysis by Pd15 and/or Cu(I),16 a novel three-
step synthetic route for 3-aryl b-carbolin-1-one (4) from non-
indole starting materials was designed, as shown in Scheme 2.
For the atom-saving, attempts were made to use N-
(cyanomethyl)acetamide (9) as an alternative to 5 during
Michael addition (Scheme 4). Unfortunately, Michael addition
between 9 and 6j gave 1:2-adduct 10 as a unique or a major
product under a variety of conditions (such as NaOH, NaHCO3,
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 1 1 – 9 1 6
9 1 1
©

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Table 1 Effect of bases and solvents on the yield of 7a
as white crystals, but associated with low yields (24–46%) largely
due to the poor solubility of both substrate and product in the
solvent used. In our improved procedure, the best yield of 8a
(80%) was obtained by standing the mixture of 7a in aqueous
HCl–HOAc at room temperature for 5–7 h. Using the same
procedure, compounds 7b–i were converted to the corresponding
products 8b–i in 67–88% yields (Scheme 5, Table 2). We observed
that 8a–i are pure regioisomers in two groups 8a–g and 8h–i,
resulting from the stereochemistry of bromophenyl substituent.
Since the stereochemistry will disappear automatically in next
step, they were therefore not defined.
Entry
Base/mol
Solvent
Temp./◦C
Yield of 7a (%)
1
2
3
4
5
6
7
EtONa (1.0)
EtONa (1.0)
EtOH
THF
t-BuOH
THF
THF
THF
THF
25–30
25–30
25–30
25–30
25–30
25–30
5–10
32
45
47
70
74
75
86
t-BuONa (1.0)
t-BuONa (1.0)
t-BuONa (0.5)
t-BuONa (0.1)
t-BuONa (0.1)
Scheme 3 Introduction of two nitrogen atoms by Michael addition.
Table 2 The preparation of compounds 7, 8 and 4
Yields (%)
Scheme 5 Efficient ketone–nitrile annulation.
Preparation of 2-aryl b-carbolin-1-one 4 by Cu(I)-promoted
intramolecular N-arylation of amide
6,7,8,4
R
R1
Ar
7
8
4
When compound 8a was treated with Pd(OAc)2–P(o-tolyl)3–
Cs2CO3, a crystalline product was obtained in good yield. How-
ever, instead of an N-arylation product, the product was assigned
as 4-(2-bromophemyl)-2-oxo-6-phenyl-1,2-dihydro-pyridine-3-
carboxylic acid ethyl ester (11, Scheme 6). Since 11 was also
obtained without Pd(OAc)2 and P(o-tolyl)3, its formation must
result from a Cs2CO3 promoted elimination of acetoamino
group.19
a
b
c
d
e
f
g
h
i
H
H
H
H
H
H
C6H5
86
88
76
77
83
81
76
84
77
80
77
67
84
81
76
88
80
80
68
67
70
60
64
62
65
72
60
4-ClC6H4
4-MeC6H4
C6H5
4-ClC6H4
4-MeC6H4
C6H5
OCH2O
OCH2O
OCH2O
MeO
MeO
MeO
MeO
MeO
MeO
4-ClC6H4
4-MeC6H4
Scheme 4 1:2-adduct 10 as a unique or major product.
pyridine or piperidine as base, THF or EtOH as solvent),
because two acidic protons on the methylene in 9 were involved
in the reaction.
Scheme 6 Cu(I)-catalyzed intramolecular N-arylation of amide.
The construction of dihydropyridone 8 by intramolecular
ketone–nitrile annulation
Fortunately, when compound 8a was treated under improved
Goldberg reaction conditions (CuI–NaH–DMF at 90 ◦C for
2 h), the target compound 3-phenyl b-carbolin-1-one (4a) was
obtained in 20% yield. By varying the reaction conditions, we
found that the yield of 4a was affected significantly by the
solvents and the amount of NaH used. As shown in Table 3,
the best yield (68%) was obtained by refluxing the mixture of
8a–CuI–NaH (1 : 2 : 4 by mole) in DME followed by work-up
with 10% aqueous NH4OH. Under similar conditions, 8b–i were
converted into the corresponding 4b–i smoothly and in moderate
yields (60–72%, Table 2). The structure of 4g was confirmed by
its single crystal X-ray diffraction analysis (Fig. 1).20†
The intermediate 7 can be further elaborated by two possible
pathways: the indole ring is built first by an intramolecular
N-arylation of amide, or the pyridone ring is constructed
preferentially by an intramolecular ketone–nitrile annulation.
Unfortunately, 7a did not result in any indole product in the in-
tramolecular N-arylation of amide catalyzed by Pd(OAc)2–P(o-
◦
15b
15d
tolyl)3–Cs2CO3 or Pd(OAc)2–DPEphos–Cs2CO3 at 100 C
in toluene for 10 h, while chalcone 6a was recovered in almost
quantitative yield. A control experiment revealed that this result
arose from retro-Michael addition of 7a catalyzed by Cs2CO3.
Moreover, we found that compound 7a was extremely sensitive
to base and that the retro-Michael addition can take place even
in the presence of Na2CO3.
Since N-[4-(2-bromophenyl)-2-oxo-6-phenyl-1,2-dihydropyri-
dine-3-yl]acetamide (12) was captured during the reaction and
it can be converted into 4a with CuI–NaH, a tandem reaction
Next, a neutral ketone–nitrile annulation of 7a catalyzed by
14d–e
RuH2(PPh3)4
in aqueous DME gave an unseparated mixture.
Finally, we found that acid-catalyzed ketone–nitrile annulation
† CCDC reference number 254765. See http://www.rsc.org/suppdata/
ob/b4/b412921k/ for crystallographic data in .cif or other electronic
format.
14b–c
14a,f
of 7a mediated by H3PO4–P2O5
or EtOH–H2SO4
pro-
ceeded smoothly to give the desired product dihydopyridone 8a
9 1 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 1 1 – 9 1 6

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Table 3 Effect of solvent and NaH on the yield of 4aa
8 conveniently. Finally, the target compound 4 was obtained
by a Cu(I)-catalyzed intramolecular N-arylation of the amide.
The resulting compounds 4a–i were tested in a tumor cell
proliferation assay using the HeLa cell line and the results proved
that the aromatic groups substituted on C3 in 4 are essential for
their bioactivities.
Solvent
NaH : 4a/mol : mol) Temp./◦C Time/hb Yield (%)
DMF
DMF
Pyridine
DMA
DME
2
4
4
4
4
90
90
110
90
2
2
4
4
7
20
45
< 10
< 10
68
84
Experimental
a Two equivalents of CuI was used. b The time at which 8a was exhausted.
The IR spectra were recorded on a Nicolet FT-IR 5DX
spectrometer as KBr pellets. The 1H NMR spectra were recorded
on a Bruker ACF-300 spectrometer in CDCl3 with TMS as
internal reference. The J values are given in Hz. MS spectra
were obtained on a VG-ZAB-HS mass spectrometer with 70
eV. The elemental analyses were performed on a Perkin-Elmer
240C instrument.
General procedure for the preparation of 7a–i by Michael
addition
To a cold solution (ice–water bath) of ethyl acetamido-
cyanoacetate (5, 3.4 g, 20 mmol) and chalcone (6, 10 mmol)
in anhydrous THF (50 mL) was added solid t-BuONa (96 mg,
1.0 mmol) in one portion. After the resultant mixture was stirred
at 5–10 ◦C for 2 h (monitored by TLC), the solvent was removed
under a vacuum. The residue was dissolved in CH2Cl2 and
washed with saturated aqueous solution of Na2CO3. The organic
layer was dried over Na2SO4 and removal of the solvent gave the
crude product, which was purified by chromatography [silica
gel, 50% EtOAc in petroleum ether (60–90 ◦C)] to yield pure
compound 7.
Fig. 1 The X-ray crystal structure of compound 4g.
sequenced by the cleavage of the ester, a decarboxylation–
aromatization and an N-arylation of the amide was proposed
(Scheme 6). CuI played a critical role in both the initiation step to
cleave the ester and in the end step to promote the intramolecular
N-arylation of intermediate 12 to give target compound 4.
2-Acetylamino-2-cyano-3-(2-bromophenyl)-5-oxo-5-phenyl-
pentanoic acid ethyl ester (7a). Mp 166–170 ◦C (EtOH);
(found: C, 57.71; H, 4.85; N, 6.15%. C22H21BrN2O4 requires:
C, 57.78; H, 4.63; N, 6.13%); mmax/cm−1 3360, 2981, 2247,
1757, 1689, 1673, 1596; dH 8.35 (1H, s), 8.01–7.88 (3H, m),
7.65–7.44 (5H, m), 7.23–7.20 (1H, m), 4.83 (1H, dd, J = 8.0,
2.9), 4.14–3.90 (3H, m), 3.72 (1H, dd, J = 19.3, 2.8), 2.12
(3H, s), 0.95 (3H, t, J = 7.2); m/z 458 (M + 2, 0.1%), 105 (100).
2-Acetylamino-2-cyano-3-(2-bromophenyl)-5-oxo-5-(4-chloro-
phenyl)pentanoic acid ethyl ester (7b). Mp 152–156 ◦C (EtOH);
(found: C, 53.74; H, 4.14; N, 5.75%. C22H20BrClN2O4 requires:
C, 53.73; H, 4.10; N, 5.70%); mmax/cm−1 3252, 2972, 2246, 1762,
1685, 1665; dH 8.18 (1H, s), 7.97–7.94 (2H, m), 7.88 (1H, dd,
J = 7.9, 1.4), 7.59 (1H, dd, J = 8.0, 1.3), 7.50–7.48 (2H, m),
7.44–7.39 (1H, m), 7.23–7.19 (1H, m), 4.81 (1H, dd, J = 7.9,
3.1), 4.09–3.91 (3H, m), 3.68 (1H, dd, J = 19.1, 3.1), 2.12
(3H, s), 0.95 (3H, t, J = 7.1); m/z 492 (M+, 1.2%), 241 (100).
Biological evaluation
The compounds 4a–i were tested in a tumor cell proliferation
assay using the HeLa cell line. Although compound 2 is
inactive against HeLa cells, addition of an aromatic group at
C3 of compound 2 gave rise to potent inhibitors of HeLa
cell proliferation with IC50 values in the low micromolar range
(Table 4 and Experimental section). Substitution at the C6 and
C7 positions decreased (4d–f) or completely eliminated (4g–i)
activity. Together, these results indicate that the compounds
accessible through the method disclosed in this manuscript have
potential as inhibitors of tumor cell growth. The experiments
also prove that the aromatic groups substituted on C3 in 4 are
essential for their bioactivities.
2-Acetylamino-2-cyano-3-(2-bromophenyl)-5-oxo-5-(4-methyl-
phenyl)pentanoic acid ethyl ester (7c). Mp 146–148 ◦C (EtOH);
(found: C, 58.62; H, 4.73; N, 6.06%. C23H23BrN2O4 requires: C,
58.61; H, 4.92; N, 5.94%); mmax/cm−1 3371, 2987, 2247, 1760,
1692, 1669, 1604; dH 8.41 (1H, s), 7.92–7.89 (3H, m), 7.58
(1H, dd, J = 8.0, 1.3), 7.44–7.39 (1H, m), 7.31–7.28 (2H, m),
7.23–7.17 (1H, m), 4.81 (1H, dd, J = 8.2, 2.7), 4.10–3.91 (3H,
m), 3.68 (1H, dd, J = 19.2, 2.8), 2.45 (3H, s), 2.11 (3H, s), 0.92
(3H, t, J = 7.1); m/z 470 (M+, 0.9%), 119 (100).
Conclusion
A novel three-step synthetic route to a group of bioactive
3-aryl b-carbolin-1-ones (4) was developed by using non-
indole starting materials. Ethyl acetamidocyanoacetate (5) was
employed as a nucleophilic donor in a Michael addition for
the introduction of two nitrogen-containing functional groups
to the adduct 7. An intramolecular ketone–nitrile annulation
of 7 mediated by aqueous HCl–HOAc yielded dihydopyridone
Table 4 The inhibition of HeLa cell proliferation by compounds 4a–i and 2
Compound
IC50/lM
STDEV/lM
Compound
IC50/lM
STDEV/lM
4a
4b
4c
4d
4e
1.50
1.17
1.20
>30
17.11
0.48
0.087
0.087
—
4f
4g
4h
4i
2
2.11
NAa
NAa
>30
NAa
0.046
—
—
—
—
2.13
a No inhibition was observed at 30 lM.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 1 1 – 9 1 6
9 1 3

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2-Acetylamino-2-cyano-3-(2-bromo-4,5-methylenedioxy)-5-oxo-
5-phenylpentanoic acid ethyl ester (7d). Mp 196–200 ◦C
(EtOH); (found: C, 55.15, H, 4.28; N, 5.57%. C23H21BrN2O6
requires: C, 55.10; H, 4.22; N, 5.59%); mmax/cm−1 3251, 3030,
2246, 1758, 1682, 1654, 1598; dH 8.24 (1H, s), 8.02 (2H, d, J =
7.3), 7.69–7.62 (1H, m), 7.52 (2H, t, J = 7.5), 7.35 (1H, s), 7.07
(1H, s), 6.03 (2H, s), 4.75 (1H, dd, J = 8.1, 2.7), 4.09–4.0 (3H,
m), 3.67 (1H, dd, J = 19.2, 2.7), 2.12 (3H, s), 1.08 (3H, t, J =
7.1); m/z 502 (M + 2, 4.4%), 500 (M+, 4.7), 105 (100).
3-Acetylamino-4-(2-bromophenyl)-2-oxo-6-phenyl-1,2,3,4-tetro-
hydropyridine-3-carboxylic acid ethyl ester (8a). Mp 212–
◦
216 C (EtOAc); (found: C, 57.62; H, 4.59; N, 6.08%. C22H21-
BrN2O4 requires: C, 57.78; H, 4.63; N, 6.13%); mmax/cm−1 3416,
3373, 1734, 1704, 1674, 1599; dH 7.62 (1H, s), 7.59 (1H, s),
7.55–7.46 (2H, m), 7.45–7.40 (3H, m), 7.27–7.25 (2H, m),
7.19–7.15 (1H, m), 6.72 (1H, s), 5.57 (1H, d, J = 2.5), 5.26
(1H, s), 4.27–4.06 (2H, m), 2.13 (3H, s), 1.27 (3H, t, J = 7.2);
m/z 458 (M + 2, 0.2%), 456 (M+, 0.2), 290 (100).
3-Acetylamino-4-(2-bromophenyl)-2-oxo-6-(4-chlorophenyl)-
1,2,3,4-tetrohydropyridine-3-carboxylic acid ethyl ester (8b).
Mp 228–230 ◦C (EtOAc); (found: C, 53.81; H, 4.10; N,
5.72%. C22H20BrClN2O4 requires: C, 53.73; H, 4.10; N, 5.70%);
mmax/cm−1 3409, 3266, 1740, 1704, 1660; dH 7.62 (1H, d, J =
1.0), 7.59 (1H, s), 7.41 − 7.38 (4H, m), 7.27–7.16 (3H, m), 6.69
(1H, s), 5.56 (1H, d, J = 2.5), 5.25 (1H, s), 4.27–4.09 (2H, m),
2.12 (3H, s), 1.28 (3H, t, J = 7.2); m/z 492 (M + 2, 0.4%), 490
(M+, 0.4), 324 (100).
2-Acetylamino-2-cyano-3-(2-bromo-4,5-methylenedioxy)-5-oxo-
5-(4-chlorophenyl)pentanoic acid ethyl ester (7e). Mp 168–
172 ◦C (EtOH); (found: C, 51.53, H, 3.76; N, 5.43%. C23H20Br-
ClN2O6 requires: C, 51.56; H, 3.76; N, 5.23%); mmax/cm−1 3251,
3035, 2246, 1760, 1684, 1655, 1589; dH 8.07 (1H, s), 7.97–7.93
(2H, m), 7.51–7.47 (2H, m), 7.31 (1H, s), 7.00 (1H, s), 6.03
(2H, s), 4.73 (1H, dd, J = 7.9, 3.2), 4.09–3.95 (3H, m), 3.62 (1H,
dd, J = 19.1, 3.2), 2.06 (3H, s), 1.08 (3H, t, J = 7.1); m/z 536
(M + 2, 0.1%), 139 (100).
3-Acetylamino-4-(2-bromophenyl)-2-oxo-6-(4-methylphenyl)-
1,2,3,4-tetrohydropyridine-3-carboxylic acid ethyl ester (8c).
Mp 246–248 ◦C (EtOAc); (found: C, 58.53; H, 4.80; N, 5.79%.
C23H23BrN2O4 requires: C, 58.61; H, 4.92; N, 5.94%); mmax/cm−1
3414, 3368, 1733, 1704, 1675; dH 7.62–7.59 (1H, m), 7.39–7.33
(3H, m), 7.27–7.20 (4H, m), 7.18–7.12 (1H, m), 6.70 (1H, s),
5.56 (1H, d, J = 2.5), 5.23 (1H, s), 4.25–4.09 (2H, m), 2.40
(3H, s), 2.13 (3H, s), 1.27 (3H, t, J = 7.2); m/z 472 (M + 2,
0.2%), 470 (M+, 0.2), 304 (100).
2-Acetylamino-2-cyano-3-(2-bromo-4,5-methylenedioxy)-5-oxo-
5-(4-methylphenyl)pentanoic acid ethyl ester (7f). Mp 180–
184 ◦C (EtOH); (found: C, 55.90; H, 4.69; N, 5.25%. C24H23Br-
N2O6 requires: C, 55.94; H, 4.50; N, 5.44%); mmax/cm−1 3257,
3035, 2247, 1761, 1678, 1655, 1607; dH 8.33 (1H, s), 7.91 (2H, d,
J = 8.2), 7.36 (1H, s), 7.31 (2H, d, J = 8.0), 7.00 (1H, s), 6.03
(2H, s), 4.73 (1H, dd, J = 8.2, 2.7), 4.09–3.95 (3H, m), 3.63
(1H, dd, J = 19.1, 2.8), 2.43 (3H, s), 2.10 (3H, s), 1.07 (3H, t,
J = 7.1); m/z 516 (M + 2, 0.1%), 514 (M+, 0.2), 119 (100).
3-Acetylamino-4-(2-bromo-4,5-methylenedioxyphenyl)-2-oxo-
6-phenyl-1,2,3,4-tetrohydropyridine-3-carboxylic acid ethyl ester
2-Acetylamino-2-cyano-3-(2-bromo-4,5-dimethoxyphenyl)-5-
oxo-5-phenylpentanoic acid ethyl ester (7g). Mp 214–216 ◦C
(EtOH); (found: C, 55.61; H, 5.00; N, 5.46%. C24H25BrN2O6
requires: C, 55.72; H, 4.87; N, 5.41%); mmax/cm−1 3377, 2987,
2248, 1757, 1683, 1665, 1602; dH 8.36 (1H, s), 8.03–8.0 (2H,
m), 7.66 (1H, t, J = 7.2), 7.52 (2H, J = 7.9), 7.43 (1H, s), 6.98
(1H, s), 4.70 (1H, dd, J = 8.1, 2.7), 4.14–3.95 (6H, m), 3.87
(3H, s), 3.70 (1H, dd, J = 19.1, 2.7), 2.11 (3H, s), 1.01 (3H, t,
J = 7.1); m/z 518 (M + 2, 1.3%), 516 (M+, 1.2), 105 (100).
◦
(8d). Mp 248–250 C (EtOAc); (found: C, 55.22; H, 4.28; N,
5.67%. C23H21BrN2O6 requires: C, 55.10; H, 4.22; N, 5.59%);
mmax/cm−1 3421, 3239, 1748, 1703, 1676, 1651; dH 7.50–7.41 (6H,
m), 7.03 (1H, s), 6.73 (1H, s), 6.72 (1H, s), 5.98 (2H, s), 5.46
(1H, d, J = 2.5), 5.21 (1H, s), 4.30–4.13 (2H, m), 2.13 (3H, s),
1.30 (3H, t, J = 7.2); m/z 502 (M + 2, 0.1%), 500 (M+, 0.1),
334 (100).
3-Acetylamino-4-(2-bromo-4,5-methylenedioxyphenyl)-2-oxo-
6-(4-chlorophenyl)-1,2,3,4-tetrohydropyridine-3-carboxylic acid
ethyl ester (8e). Mp 256–260 ◦C (EtOAc); (found: C, 51.65; H,
3.93; N, 5.25%. C23H20BrClN2O6 requires: C, 51.56; H, 3.76; N,
5.23%); mmax/cm−1 3404, 3297, 1739, 1704, 1658; dH 7.48–7.41
(5H, m), 7.03 (1H, s), 6.71 (1H, s), 6.69 (1H, s), 5.98 (2H, s),
5.45 (1H, d, J = 2.5), 5.20 (1H, s), 4.30–4.11 (2H, m), 2.13
(3H, s), 1.27 (3H, t, J = 7.1); m/z 538 (M + 4, 0.3%), 537 (M +
3, 0.3), 536 (M + 2, 0.3), 535 (M + 1, 0.2), 534 (M+, 0.3), 368
(100).
2-Acetylamino-2-cyano-3-(2-bromo-4,5-dimethoxyphenyl)-5-oxo-
5-(4-chlorophenyl)pentanoic acid ethyl ester (7h). Mp 196–
198 ◦C (EtOH); (found: C, 52.13; H, 4.32; N, 5.28%. C24H24Br-
ClN2O6 requires: C, 52.24; H, 4.38; N, 5.08%); mmax/cm−1 3265,
3068, 2247, 1758, 1688, 1660, 1590; dH 8.22 (1H, s), 7.97 (2H, d,
J = 8.5), 7.50 (2H, d, J = 8.4), 7.42 (1H, s), 6.99 (1H, s), 4.68
(1H, dd, J = 8.1, 2.5), 4.05–3.91 (6H, m), 3.87 (3H, s), 3.65 (1H,
dd, J = 19.1, 2.5), 2.11 (3H, s), 1.02 (3H, t, J = 7.1); m/z 552
(M + 2, 0.5%), 139 (100).
3-Acetylamino-4-(2-bromo-4,5-methylenedioxyphenyl)-2-oxo-
6-(4-methylphenyl)-1,2,3,4-tetrohydropyridine-3-carboxylic acid
ethyl ester (8f). Mp 214–216 ◦C (EtOAc); (found: C, 55.85; H,
4.46; N, 5.62%. C24H23BrN2O6 requires: C, 55.93; H, 4.50; N,
5.44%); mmax/cm−1 3384, 3223, 1730, 1703, 1662; dH 7.38–7.35
(3H, m), 7.24 (2H, d, J = 8.0), 7.03 (1H, s), 6.72 (1H, s),
6.71 (1H, s), 5.98 (2H, s), 5.45 (1H, d, J = 2.5), 5.17 (1H, s),
4.31–4.10 (2H, m), 2.40 (3H, s), 2.13 (3H, s), 1.27 (3H, t, J =
7.1); m/z 516 (M + 2, 0.2%), 514 (M+, 0.2), 348 (100).
2-Acetylamino-2-cyano-3-(2-bromo-4,5-dimethoxyphenyl)-5-
oxo-5-(4-methylphenyl)pentanoic acid ethyl ester (7i). Mp
184–188 ◦C (EtOH); (found: C, 56.57; H, 5.10; N, 5.40%.
C25H27BrN2O6 requires: C, 56.51; H, 5.12; N, 5.27%); mmax/cm−1
3268, 2995, 2247, 1760, 1682, 1661, 1606; dH 8.45 (1H, s), 7.92
(2H, d, J = 8.0), 7.44 (1H, s), 7.31 (2H, d, J = 8.0), 6.98 (1H, s),
4.68 (1H, dd, J = 6.8, 2.5), 4.04–3.95 (6H, m), 3.87 (3H, s), 3.67
(1H, dd, J = 19.1, 1.6), 2.45 (3H, s), 2.11 (3H, s), 1.01 (3H, t,
J = 7.1); m/z 532 (M + 2, 1.3%), 530 (M+, 1.2), 119 (100).
3-Acetylamino-4-(2-bromo-4,5-dimethoxyphenyl)-2-oxo-6-
phenyl-1,2,3,4-tetrohydropyridine-3-carboxylic acid ethyl ester
General procedure for the preparation of 2-pyridone 8a–i
◦
(8g). Mp 216–220 C (EtOAc); (found: C, 55.74; H, 4.84; N,
To a cold solution (ice–water bath) of aqueous HCl (37%, 5 mL)
and HOAc (50 mL) was added solid compound 7 (10 mmol) in
one portion. After the resultant mixture was stirred at room
temperature for 5–7 h (monitored by TLC), it was poured
into ice–water. The mixture was neutralized to pH 7 by solid
NaHCO3 and extracted with CH2Cl2. The combined organic
layers were washed with H2O and dried over Na2SO4. The
solvent was removed to yield a residue, which was purified by
recrystallization to give pure compound 8.
5.51%. C24H25BrN2O6 requires: C, 55.72; H, 4.87; N, 5.41%);
mmax/cm−1 3366, 3219, 1746, 1704, 1658; dH7.48–7.40 (6H, m),
7.04 (1H, s), 6.73 (1H, s), 6.71 (1H, s), 5.47 (1H, d, J = 2.5),
5.24 (1H, d, J = 6.3), 4.32–4.09 (2H, m), 3.89 (3H, s), 3.79
(3H, s), 2.13 (3H, s), 1.27 (3H, t, J = 7.2); m/z 518 (M + 2,
4.0%), 516 (M+, 4.5), 378 (100).
3-Acetylamino-4-(2-bromo-4,5-dimethoxyphenyl)-2-oxo-6-(4-
chlorophenyl)-1,2,3,4-tetrohydropyridine-3-carboxylic acid ethyl
9 1 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 1 1 – 9 1 6

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ester (8h). Mp 238–242 ◦C (EtOAc); (found: C, 52.19; H,
4.44; N, 5.07%. C24H24BrClN2O6 requires: C, 52.24; H, 4.38; N,
5.08%); mmax/cm−1 3369, 3219, 1756, 1704, 1664; dH 7.46 (1H, s),
7.38(4H, s), 7.03 (1H, s), 6.72 (1H, s), 6.42 (1H, s), 5.67 (1H, d,
J = 5.0), 5.23 (1H, d, J = 6.1), 4.32–4.26 (2H, m), 3.86 (3H, s),
3.75 (3H, s), 1.88 (3H, s), 1.27 (3H, t, J = 7.1); m/z 554 (M +
4, 3.4%), 552 (M + 2, 11.2), 550 (M+, 8.4), 412 (100).
3-Acetylamino-4-(2-bromo-4,5-dimethoxyphenyl)-2-oxo-6-(4-
methylphenyl)-1,2,3,4-tetrohydropyridine-3-carboxylic acid ethyl
ester (8i). Mp 228–230 ◦C (EtOAc); (found: C, 56.53; H, 5.28;
N, 5.47%. C25H27BrN2O6 requires: C, 56.51; H, 5.12; N, 5.27%);
mmax/cm−1 3364, 3242, 1749, 1705, 1662; dH 7.34–7.32 (3H, m),
7.22 (2H, d, J = 8.0), 7.04 (1H, s), 6.75 (1H, s), 6.39 (1H, s),
5.67 (1H, d, J = 5.7), 5.22 (1H, d, J = 6.2), 4.36–4.24 (2H, m),
3.88 (3H, s), 3.75 (3H, s), 2.38 (3H, s), 1.90 (3H, s), 1.27 (3H, t,
J = 7.1); m/z 532 (M + 2, 7.0%), 530 (M+, 6.1), 392 (100).
341 (M + 3, 7.0%), 340 (M + 2, 35.0), 339 (M + 1, 22.3), 338
(M+, 100).
3-(4-Methylphenyl)-6,7-methylenedioxy-2,9-dihydro-b-car-
bolin-1-one (4f). Mp 338–340 ◦C (MeOH); (found: C, 71.71;
H, 4.49; N, 8.57%. C19H14N2O3 requires: C, 71.69; H, 4.43;
N, 8.80%); mmax/cm−1 3092, 2972, 1638; dH (DMSO-d6) 11.84
(1H, s), 11.37 (1H, s), 7.66 (2H, dd, J = 7.9, 1.2), 7.57 (1H, d,
J = 1.3), 7.28 (2H, d, J = 7.4), 7.24 (1H, d, J = 1.5), 6.96 (1H,
d, J = 1.3), 6.06 (2H, s), 2.35 (3H, s); m/z 320 (M + 2, 3.2%),
319 (M + 1, 21.2), 318 (M+, 100).
3-Phenyl-6,7-dimethoxy-2,9-dihydro-b-carbolin-1-one (4g).
Mp 306–308 ◦C (MeOH); (found: C, 71.24; H, 5.08; N, 8.56%.
C19H16N2O3 requires: C, 71.24; H, 5.03; N, 8.74%); mmax/cm−1
3392, 3174, 1635, 1596; dH (DMSO-d6) 11.75 (1H, s), 11.40
(1H, s), 7.79 (2H, d, J = 7.3), 7.64 (1H, s), 7.51–7.46 (2H, m),
7.42–7.37 (1H, m), 7.35 (1H, s), 6.98 (1H, s), 3.85 (3H, s),
3.84 (3H, s); m/z 322 (M + 2, 2.2%), 321 (M + 1, 22.6), 320
(M+, 100).
General procedure for the preparation of
3-phenyl-2,9-dihydro-1H-pyrido [3,4-b]indol-1-one (4a–i)
3-(4-Chlorophenyl)-6,7-dimethoxy-2,9-dihydro-b-carbolin-1-
one (4h). Mp 316–318 ◦C; (found: C, 64.40; H, 4.25; N, 7.75%.
C19H15ClN2O3 requires: C, 64.30; H, 4.26; N, 7.89%); mmax/cm−1
3114, 1633, 1607; dH (DMSO-d6) 11.79 (1H, s), 11.47 (1H, s),
7.81 (2H, dd, J = 8.6, 1.8), 7.63 (1H, s), 7.54 (2H, dd, J = 8.7,
1.8), 7.38 (1H, s), 6.97 (1H, s), 3.85 (3H, s), 3.84 (3H, s); m/z
357 (M + 3, 7.0%), 356 (M + 2, 33.2), 355 (M + 1, 26.1), 354
(M+, 100).
A mixture of 8 (5 mmol), CuI (1.9 g, 10 mmol) and NaH (480 mg,
20 mmol) in anhydrous DME (100 mL) was heated to reflux
under N2 for 7–10 h (minitored by TLC). After the most of
DME was removed under a vacuum, 10% aqueous solution of
NH4OH (100 mL) was added. The resultant mixture was stirred
for 2 h at room temperature and the solid was collected. The
crude product was purified by chromatography (silica gel, 10%
MeOH in EtOAc) to give pure compound 4.
3-(4-Methylphenyl)-6,7-dimethoxy-2,9-dihydro-b-carbolin-1-
one (4i). Mp 330–332 ◦C (MeOH); (found: C, 71.79; H, 5.45;
N, 8.32%. C20H18N2O3 requires: C, 71.84; H, 5.43; N, 8.38%);
mmax/cm−1 3166, 1630, 1603; dH (DMSO-d6) 11.72 (1H, s), 11.36
(1H, s), 7.69 (2H, d, J = 7.9), 7.63 (1H, s), 7.31–7.27 (3H, m),
6.97 (1H, s), 3.84 (6H, s), 2.39 (3H, s); m/z 336 (M + 2, 3.3%),
335 (M + 1, 23.0), 334 (M+, 100).
N -(3-Benzoyl-1-cyano-2,4,6-triphenylcyclohex-3-enyl)acet-
amide (10). Mp 188–190 ◦C (EtOAc–PE); (found: C, 82.20;
H, 5.70; N, 5.51%. C34H28N2O2 requires: C, 82.23; H, 5.68;
N, 5.64%); mmax/cm−1 3300, 1640, 1600, 1580; dH 9.58 (1H, s),
7.66–7.02 (18H, m), 6.59 (2H, d, J = 6.4), 5.81 (1H, d, J = 6.8),
5.61 (1H, d, J = 3.8), 5.26 (1H, d, J = 2.9), 4.93 (1H, d, J =
6.9), 1.56 (3H, s); m/z 496 (M+, 12.8%), 391 (100), 349 (22.1),
332 (5.4), 271 (16.0), 191 (20.1), 115 (12.1), 105 (88.3), 43 (40.4).
4a
3-Phenyl-2,9-dihydro-b-carbolin-1-one (4a) . Mp 300–
302 ◦C (MeOH); (found: C, 78.44; H, 4.65; N, 10.61%.
C17H12N2O requires: C, 78.44; H, 4.65; N, 10.76%); mmax/cm−1
3110, 3051, 1636, 1620, 1598; dH (500 MHz, DMSO-d6)11.96
(1H, s), 11.60 (1H, s), 8.10 (1H, d, J = 8.0), 7.77 (2H, d, J =
7.5), 7.54 (1H, d, J = 8.5), 7.47 (2H, t, J = 8.5), 7.47 (2H, t, J =
7.0), 7.43–7.39 (2H, m), 7.37 (1H, s), 7.19 (1H, t, J = 7.5); dC
(500 MHz, DMSO-d6) 157.0, 140.3, 137.2, 135.5, 129.6, 129.2,
128.0, 127.4, 125.7, 123.1, 122.4, 120.5, 113.4, 99.6; m/z 262
(M + 2, 6.2%), 261 (M + 1, 60.5), 260 (M+, 100).
3-(4-Chlorophenyl)-2,9-dihydro-b-carbolin-1-one (4b). Mp
344–346 ◦C (MeOH); (found: C, 69.26; H, 3.77; N, 9.40%.
C17H11ClN2O requires: C, 69.28; H, 3.76; N, 9.50%); mmax/cm−1
3115, 2971, 1635; dH (DMSO-d6) 12.05 (1H, s), 11.66 (1H, s),
8.11 (1H, d, J = 7.9), 7.83 (2H, dd, J = 6.8, 1.9), 7.56–7.53 (3H,
m), 7.46–7.42 (2H, m), 7.23 (1H, t, J = 7.2); m/z 297 (M + 3,
5.8%), 296 (M + 2, 33.1), 294 (M+, 100).
3-(4-Methylphenyl)-2,9-dihydro-b-carbolin-1-one (4c). Mp
326–328 ◦C (MeOH); (found: C, 78.80; H, 5.05; N, 10.00%.
C18H14N2O requires: C, 78.81; H, 5.14; N, 10.21%); mmax/cm−1
3141, 2972, 1635; dH (DMSO-d6) 11.98 (1H, s), 11.55 (1H, s),
8.11 (1H, d, J = 7.9), 7.70 (2H, d, J = 8.1), 7.53 (1H, d, J =
8.3), 7.43 (1H, t, J = 7.2), 7.37 (1H, s), 7.30 (2H, d, J = 8.1),
7.20 (1H, t, J = 7.2), 2.37 (3H, s); m/z 276 (M + 2, 1.6%), 275
(M + 1, 19.8), 274 (M+, 100).
3-Phenyl-6,7-methylenedioxy-2,9-dihydro-b-carbolin-1-one (4d).
Mp 342–344 ◦C (MeOH); (found: C, 71.03; H, 3.91; N, 9.08%.
C18H12N2O3 requires: C, 71.05; H, 3.97; N, 9.21%); mmax/cm−1
3084, 2893, 1635, 1613; dH (DMSO-d6) 11.85 (1H, s), 11.41
(1H, s), 7.79–7.76 (2H, m), 7.57 (1H, d, J = 0.2), 7.51–7.41
(3H, m), 7.28 (1H, s), 6.97 (1H, s), 6.06 (2H, s); m/z 306 (M +
2, 2.7%), 305 (M + 1, 20.8), 304 (M+, 100).
4-(2-Bromophemyl)-2-oxo-6-phenyl-1,2-dihydropyridine-3-car-
boxylic acid ethyl ester (11). A mixture of 8a (457 mg, 1 mmol)
and ◦Cs2CO3 (652 mg, 2 mmol) in toluene (10 mL) was stirred at
100 C for 10 h and cooled to room temperature. Then it was
poured into 2% aqueous solution of HCl and extracted with
diethyl ether. The combined organic layers were washed with
H2O and dried over Na2SO4. The solvent was removed to give
crude product, which was purified by chromatography to give
350 mg (88%) of pure product 11; mp 200–202 ◦C (EtOAc–PE);
(found: C, 60.30; H, 4.00; N, 3.60%. C20H16BrNO3 requires:
C, 60.32; H, 4.05; N, 3.53%); mmax/cm−1 1738, 1627, 1608; dH
7.97–7.93 (2H, m), 7.67 (1H, d, J = 7.8), 7.51–7.49 (3H, m),
7.36 (1H, d, J = 1.1), 7.31–7.28 (2H, m), 6.78 (1H, s), 4.12–4.04
(2H, m), 0.92 (3H, t, J = 7.1); m/z 399 (M + 2, 1.6%), 397 (M+,
1.6), 290 (100).
N-[4-(2-Bromophenyl)-2-oxo-6-phenyl-1,2-dihydropyridine-
3-yl]acetamide (12). The compound was captured as an
intermediate by quenching the reaction of 8a to 4a after
it was carried out for 2 h and was separated by column
chromatography under the exact same conditions by which 4a
3-(4-Chlorophenyl)-6,7-meth◦ylenedioxy-2,9-dihydro-b-car-
bolin-1-one (4e). Mp 334–336 C (MeOH); (found: C, 64.05;
H, 3.51; N, 8.16%. C18H11ClN2O3 requires: C, 63.82; H, 3.27; N,
8.27%); mmax/cm−1 3181, 3101, 2975, 1635, 1619; dH (DMSO-d6)
11.90 (1H, s), 11.48 (1H, s), 7.79 (2H, dd, J = 8.5, 1.4), 7.56–7.52
(3H, m), 7.31 (1H, d, J = 1.4), 6.97 (1H, s), 6.06 (2H, s); m/z
◦
was separated; mp 228–230 C (EtOAc–PE); (found: C, 59.56;
H, 4.04; N, 7.33%. C19H15BrN2O2 requires: C, 59.55; H, 3.95;
N, 7.31%); mmax/cm−13261, 2924, 2853, 1640, 1529, 759; dH
(DMSO-d6) 1.75 (s, 3H), 6.45 (s, 1H), 7.31 (d, 2H, J = 4.9),
7.40 (d, 1H, J = 7.4), 7.45–7.47 (m, 3H), 7.69 (d, 1H, J = 7.9),
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 1 1 – 9 1 6
9 1 5

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7.77 (t, 2H, J = 3.6), 9.05 (s, 1H), 12.16 (s, 1H); dC (DMSO-d6)
169.3, 161.7, 148.4, 144.3, 139.2, 134.0, 133.4, 130.9, 130.7,
130.5, 129.7, 128.1, 127.6, 124.9, 122.0, 107.2, 23.3. m/z 384
(M + 2, 14.3%), 382 (M+, 13.6), 342 (100).
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6 S. Wang, PhD Thesis, Nanjing University, China, 2002.
7 A brief communication on the synthesis of 3-aryl b-carbolin-1-ones
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Materials and methods in a tumor cell proliferation assay using
the HeLa cell line
Cells were grown in a humidified incubator at 37 ◦C in an atmo-
sphere of 5% CO2. Bovine Aortic Endothelial Cells (BAECs)
were obtained from Clonetics (San Diego) and cultured in
DMEM with 10% fetal bovine serum (FBS) and 50 units ml−1
penicillin, plus 50 lg mL−1 streptomycin (P/S). HeLa cells were
obtained from American Type Culture Collection (ATCC) and
cultured in RPMI 1640 containing 10% fetal bovine serum (FBS)
and 50 units ml−1 penicillin plus 50 lg mL−1 streptomycin (P/S).
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Cell proliferation assay
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Proliferating cells were seeded into a 96-well plate and grown in
the presence of varying concentrations of testing compounds or
carrier solvent (0.1% DMSO) for 24 h. Cells were pulsed with
[3H]thymidine (6.7 Ci mmol−1, 1 lCi per well) for an additional
6 h and harvested with a semiautomated cell harvester onto glass
fiber papers for scintillation counting. All assays were performed
in triplicate and are presented as the mean SD.
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We are grateful to the National Natural Science Foundation of
China for financial support.
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20 Crystal data for compound 4g: C19H15N2O3·CH3OH, M = 351.37,
˚
˚
˚
monoclinic; a = 9.2371(6) A, b = 7.4210(5) A, c = 25.1558(17) A;
V = 1714.9(2) A3, T = 293 K; space group: P21/n; Z = 4; absorption
coefficient: 0.096 mm−1, 10 057 reflections measured, 3970 unique
[R(int) = 0.0438]; final R indices [I > 2r(I)]: R1 = 0.0646, wR2 =
0.1930; R indices (all data): R1 = 0.0783, wR2 = 0.2036.
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97; (c) O. Ritzeler, A. Castro, L. Grenier, F. Soucy, EP 1134221,
9 1 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 1 1 – 9 1 6