Synthesis, cytotoxicity and protein kinase C inhibition of arylpyrrolylmaleimides

Article abstract of DOI:10.1002/ardp.200700190

A series of novel arylpyrrolylmaleimides was synthesized and evaluated for their in-vitro cytotoxicity against various human cancer cell lines and their protein-kinase C inhibitory activity. Some of the compounds showed high or moderate cytotoxic activity

Full text of DOI:10.1002/ardp.200700190

Arch. Pharm. Chem. Life Sci. 2008, 341, 273–280
G.-Q. Xu et al.
273
Full Paper
Synthesis, Cytotoxicity and Protein Kinase C Inhibition of
Arylpyrrolylmaleimides
Gui-Qing Xu1, 2, Chong Zhang3, Lei Zhang3, Xing-Lu Zhou3, Bo Yang3, Qiao-Jun He3,
and Yong-Zhou Hu1
1
ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang
University, Hangzhou, China
2 College of Chemistry and Environmental Science, Henan Normal University, Xinxiang, China
3 Department of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
A series of novel arylpyrrolylmaleimides was synthesized and evaluated for their in-vitro cytotox-
icity against various human cancer cell lines and their protein-kinase C inhibitory activity.
Some of the compounds showed high or moderate cytotoxic activity against the tested cell lines.
Compound 6b is the most promising compound against the tested cancer cell lines; 6d and 6e
showed moderate protein-kinase C inhibition. Structure–activity relationships are discussed
based on the experimental data obtained.
Keywords: Arylpyrrolylmaleimides / Cytotoxic activity / Indolocarbazole analogues / PKC inhibitory activity /
Received: September 19, 2007; accepted: January 18, 2008
DOI 10.1002/ardp.200700190
Introduction
Cancer is the second leading cause of death in the world.
Currently, protein kinase C (PKC) has been shown to be
an important target in cancer chemotherapy. The devel-
opment of PKC inhibitors as cancer chemotherapy agents
is an active area of research. Indolocarbazole analogues,
such as NB-506 and enzastaurin, are in clinical trials for
their potential role in cancer therapy [1–5]. Bisarylmalei-
Figure 1. Structures of arylpyrrolylmaleimides 6a–i and 11a–k.
mide compounds, a kind of indolocarbazole analogues,
were reported to exhibit remarkable antitumor activities
[6–9]. These facts encouraged us to design a new series of
bisarylmaleimide analogues in order to find more potent
antitumor compounds, and to carry out a structure-activ-
ity relationship study. In this paper, we describe the syn-
thesis of the arylpyrrolylmaleimide compounds (Fig. 1),
the evaluation of these compounds as PKC inhibitor, and
their cytotoxic activity in vitro against various human
cancer cell lines.
Results and discussion
Our synthetic route to target indolopyrrolylmaleimides
6a–i is diagrammed in Scheme 1. Indole adducts 3a–c
were synthesized following the method described in the
literature with minor modifications [10, 11]. The indole-
N atoms of 3a–c were protected by di-tert-butyl dicarbon-
ate ((Boc)2O) to give intermediates 4a–c and then, con-
densation of 4a–c with pyrrole in the presence of lithium
hexamethyldisilazide (LiHMDS) in THF gave the desired
Correspondence: Yong-Zhou Hu, ZJU-ENS Joint Laboratory of Medici-
nal Chemistry, College of Pharmaceutical Sciences, Zhejiang University;
Hangzhou 310058, China.
E-mail: huyz@zju.edu.cn
Fax: +86 571 8820-8460
Abbreviations: protein kinase C (PKC); lithium hexamethyldisilazide
(LiHMDS); 4-dimethylaminopyridine (DMAP)
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274
G.-Q. Xu et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 273–280
Reaction conditions: (a) i, ethyl magnesium bromide, Et2O, benzene; ii, 2 (N-phenyl-3, 4-dichloromaleimide), THF, rt, overnight; (b) (Boc)2O, DMAP, THF, rt, 2 h; (c) pyrrole,
LiHMDS, THF, – 208C l rt, overnight; (d) 32% CH3NH2 in CH3OH, rt, 1 h; (e) NH4OAc, 1508C, 1.5 h.
Scheme 1. Synthetic route to compounds 6a–i.
Table 1. Cytotoxicity of compounds 6a–i against human cancer
cell lines in vitro.
key intermediates 5a–c, which were deprotected in the
presence of methylamine-methanol affording 6a–c [12].
Treatment of 5a with NH4OAc yielded a mixture of 6d
and 6g in 1 : 1 ratio, which could be easily separated by
column chromatography. Similarly, treatment of 5b or
5c with NH4OAc gave 6e and 6h or 6f and 6i, respectively
[12, 13].
HL60
PC-3
ECA-109 SMMC-
7721
A549
IC50 (lM)
bisindolyl-
6.78
10.3
15.9
13.2
4.14
maleimide
Arylpyrrolylmaleimides 11a–k were performed
according to the procedure of Scheme 2. 3-Hydroxymalei-
mides 8a–d, which were prepared via base-promoted
condensation of 7a–d with diethyl oxalate in the pres-
ence of t-BuOK [14, 15] and were converted into 9a–d by
reacting with oxalyl chloride [16]. Methylation of 9a–d
with iodomethane gave 10a–d. Condensation of 10a–d
with pyrrol in the presence of LiHMDS in THF afforded
the target compounds 11a–d. Similarly, compounds
11e–k were prepared through three steps from 7e–k.
All of the prepared compounds were evaluated for
their cytotoxicity in vitro against human cancer cell lines
using the MTT cytotoxicity assay according to the
reported methods [17].
6a
6b
6c
6d
6e
6f
6g
6h
6i
15.8
2.32
1.24
7.22
6.74
17.6
3.68
3.08
1.23
10.9
2.16
14.1
31.3
6.23
14.6
12.7
19.7
31.9
A50
6.21
39.2
A50
25.0
38.1
A50
12.5
A50
A50
4.12
5.40
29.7
15.6
21.8
41.5
9.55
A50
A50
35.4
A50
A50
36.0
A50
A50
A50
A50
compounds exhibited cytotoxic activity against tested
cancer cells. Among them, compound 6b showed signifi-
cant cytotoxic activity. Obviously, the cytotoxic potency
of this series of compounds was dependent on the sub-
stituents of indole and maleimide ring. The compounds
6b, 6e, and 6h containing bromo at the C-5 position of
indole ring, showed more potent cytotoxicity. The cyto-
toxicity of the compounds 6a, 6b, and 6c was improved
when the hydrogen of the nitrogen in maleimide ring
was replaced by methyl group.
First, indolopyrrolylmaleimides 6a–i and reference
compound (bisindolylmaleimide) were evaluated for
their cytotoxic activity in vitro against HL60, PC-3, ECA–
109, SMMC-7721, and A549. The results are reported in
Table 1. The data in Table 1 indicated that most of the
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Arch. Pharm. Chem. Life Sci. 2008, 341, 273–280
Synthesis and Cytotoxicity of Arylpyrrolylmaleimides
275
Reaction conditions: (a) (COOC2H5)2, t-BuOK, THF, 08C; (b) (COCl)2, CH2Cl2/DMF, rt; (c) CH3I, K2CO3, CuO, DMF, N2, rt; (d)
pyrrole, LiHMDS, THF, – 208C l rt, overnight.
Scheme 2. Synthetic route to compounds 11a–k.
Table 2. Cytotoxicity of compounds 11a–k against human can-
cer cell lines in vitro.
Table 3. PKC inhibitory activity of compounds 6a–e, h.
Compound
IC50 (lM)
HL60
PC-3
SGC7901 SMMC-
7721
A549
bisindolylmaleimide
6a
6b
0.35a)
0.68
1.06
IC50 (lM)
6c
0.76
bisindolyl-
maleimide
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
6.78
10.3
not eval- 13.2
uated
4.14
6d
6e
6h
11a
11d
11g
11h
11j
11k
0.50
0.25
10.8
19.8
16.5
A30.0
29.2
A50
A50
5.51
23.6
18.7
32.3
11.4
33.1
A50
A50
A50
A50
A50
A50
A50
A50
A50
A50
A50
A50
A50
A50
A50
A50
A50
56.1
19.5
A50
13.2
21.8
A50
A50
A50
A50
A50
A50
A50
A50
A50
A50
A50
A50
A50
A50
A50
A50
A50
A50
A50
A50
A30.0
A30.0
A50
25.8
A50
a)
Lit. [18]; IC50 = 0.55 lM.
16.2
40.2
ity as the reference drug. The substituents of indole ring
had a slight effect on the inhibition compared 6a with 6b
and 6c. The compound 6h, with the hydrogen of the
nitrogen in maleimide being replaced by phenyl, had
less inhibitory activity toward PKC. When a methyl group
is attached to the nitrogen in maleimide, compounds
6a–c exhibited 1.5 to l 3-fold less potency than bisindo-
lylmaleimide. On the other hand, compounds 6d and 6e
showed higher inhibitory activity. When the indole ring
of 6a was replaced by other aryl rings, the PKC inhibitory
activity was lower than for the reference drug and com-
pounds 6a–e, 6h. This fact showed that the indole ring of
bisarylmaleimides is critical to their PKC inhibitory
effect. The data of Table 1, Table 2, and Table 3 showed
that cytotoxicity and PKC inhibitory activity has some
relationship. Compared with compounds 11a–k, 6a–i
exhibited higher cytotoxicity and also had strong PKC
inhibition.
In order to find the effects of other aryl rings on the
cytotoxicity, a series of arylpyrrolylmaleimides 11a–k, in
which the indole ring was replaced by various aryl rings,
were evaluated for their cytotoxic activity in vitro against
HL60, PC-3, SGC7901, SMMC-7721, and A549 cell lines
(Table 2). Unfortunately, this kind of replacement did not
improve the cytotoxic potency. As shown in Table 2,
11a–k showed less cytotoxicity against tested cancer cell
lines compared to compounds 6a–i. It showed that the
indole ring is the best choice for maintaining the cytotox-
icity in these types of compounds.
Further study on the PKC inhibitory activity was per-
formed with selected compounds 6a–e, 6h, 11a, 11d,
11g, 11h, 11j, and 11k. Bisindolylmaleimide, a PKC inhib-
itor [18], was considered as the reference compound. The
results are presented in Table 3. From the data in Table 3,
compounds 6a–e exhibited similar PKC inhibitory activ-
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276
G.-Q. Xu et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 273–280
In conclusion, a novel series of arylpyrrolylmaleimide 4-Chloro-3-(5-methoxy-1H-indol-3-yl)-1-phenyl-1H-
compounds were prepared and some of them showed pyrrole-2,5-dione 3c
Yield 76%. Mp. 185–1878C. 1H-NMR (DMSO-d6) d: 3.78 (s, 3H); 6.90
(dd, J = 2.0, 8.4 Hz); 7.43–7.47 (m, 5H); 7.51–7.55 (m, 2H); 8.08 (d,
J = 3.2 Hz, 1H); 12.10 (s, 1H). Anal. calc. for C19H13ClN2O3: C 64.69,
H 3.71, N 7.94; Found: C 64.78, H 3.63, N 8.02.
high or moderate cytotoxicity against human cancer cell
lines. Among them, the most promising compound was
6b. Compounds 6d and 6e had the similar PKC inhibition
as the reference drug. 6a–c also showed moderate PKC
inhibition. The indole ring of bisarylmaleimides is
General procedure for the synthesis of 4a-c
important to both cytotoxicity and PKC inhibitory effect.
Di-tert-butyl dicarbonate (25 mmol) and catalytic amount of
DMAP (0.5%) were added to a solution of 3 (20 mmol) in THF
The authors have declared no conflict of interest.
(250 mL) and the mixture was stirred for 2 h at room tempera-
ture. After removal of the solvent in vacuo, the yellow residue
was recrystallized from petroleum ether/ethyl acetate to obtain
4a–c as a yellow crystalsline powder.
Experimental
4-Chloro-3-[1-(tert-butyloxycarbonyl)-1H-indol-3-yl]-1-
Chemistry
phenyl-1H-pyrrole-2,5-dione 4a
Melting points were determined with a Bꢀchi Melting Point B-
450 apparatus (Bꢀchi Labortechnik, Flawil, Switzerland). Infra-
red spectra (KBr pellets) were recorded on a FT/IR-4100 spectrom-
eter (Jasco, Japan). The 1H-NMR spectra were recorded in DMSO-
d6 or CDCl3 on Bruker Avance DMX 400 using TMS as an internal
standard (Bruker, Billerica, MA, USA). Chemical shifts are
expressed in parts per million d. ESI-MS were obtained on an
Esquire-LC-00075 mass spectrometer (Bruker, USA). Elemental
analysis was performed by ERBA-1110 analyzer (Carlo Erba,
Milan, Italy). All reactions were monitored by thin-layer chroma-
tography (TLC). All reagents were obtained from commercial
sources and used without further purification unless stated. The
solvents Et2O, THF, and benzene were distilled from sodium-ben-
zophenone, DMF was distilled from calcium hydride, and
(Boc)2O was distilled under pressure.
1
Yield 90%. Mp. 149–1528C. H-NMR (DMSO-d6) d: 1.70 (s, 9H);
7.33–7.36 (m, 1H); 7.39–7.43 (m, 4H); 7.45–7.52 (m, 2H); 7.90 (d,
J = 6.4 Hz, 1H); 8.25–8.27 (m, 2H). Anal. calc. for C23H19ClN2O4: C
65.33, H 4.53, N 6.62; Found: C 65.21, H 4.62, N 6.75.
4-Chloro-3-[5-bromo-1-(tert-butyloxycarbonyl)-1H-indol-
3-yl]-1-phenyl-1H-pyrrole-2,5-dione 4b
Yield 41%. Mp. 161-1638C. 1H-NMR (DMSO-d6) d: 7.45–5.47 (m,
3H); 7.54–7.55 (m, 2H); 7.61–7.64 (m, 2H); 8.09 (d, J = 8.8, 1H);
8.17 (s, 1H). Anal. calc. for C23H18BrClN2O4: C 55.06, H 3.62, N
5.58; Found: C 55.13, H 3.50, N 5.65.
4-Chloro-3-[5-methoxy-1-(tert-butyloxycarbonyl)-1H-
indol-3-yl]-1-phenyl-1H-pyrrole-2,5-dione 4c
Yield 45%. Mp. 176–1798C. 1H-NMR (DMSO-d6) d: 1.65 (s, 9H); 3.81
(s, 3H); 7.08 (dd, J = 2.0, 8.8 Hz, 1H); 7.34 (s, 1H); 7.46–7.48 (m,
3H); 7.53–7.57 (m, 2H); 8.05 (d, J = 8.8 Hz, 1H); 8.10 (s, 1H). Anal.
calc. for C24H21ClN2O5: C 63.65, H 4.67, N 6.19; Found: C 63.72, H
4.59, N 6.07.
General procedure for the synthesis of 3a–c
Ethyl magnesium bromide (105 mmol) in Et2O (40 mL) was
added dropwise to a solution of the appropriate indole 1
(100 mmol) in benzene (60 mL) at room temperature over 1 h
with stirring. After stirring for 30 min, the mixture was added
dropwise to a solution of 2 (70 mmol) in THF (50 mL) over 2 h.
The mixture was stirred overnight at room temperature. The
dark red mixture was poured into 1 M aqueous hydrochloric
acid (50 mL) and extracted with ethyl acetate (30 mL; 63). The
organic phase was successively washed with water and brine,
dried over Na2SO4, and concentrated in vacuo. The residue was
recrystallized from ethyl acetate to get 3a–c.
General procedure for the synthesis of 5a-c
LiHMDS (1 M in THF, 1.0–1.2 mmol) at –208C was added to a sol-
ution of 0.6 mmol of the pyrrole in THF (3 mL) under N2 and
stirred for 1 h. A solution of 4 (0.5 mmol) in THF (10 mL) was
then added dropwise over 40–60 min, followed by stirring at
08C overnight. The reaction mixture was poured into 0.5 M aque-
ous hydrochloric acid (30 mL), and the mixture was extracted
with ethyl acetate (15 mL; 63). The organic phase was succes-
sively washed with water and brine, dried over Na2SO4, and con-
centrated in vacuo. The residue was purified by flash column
chromatography on silica gel using petroleum ether/ethyl ace-
tate as eluent to afford 5a–c.
4-Chloro-3-(1H-indol-3-yl)-1-phenyl-1H-pyrrole-2,5–
dione 3a
1
Yield 82%. Mp. 203–2048C. H-NMR (DMSO-d6) d: 7.19–7.26 (m,
2H); 7.45–7.54 (m, 6H); 7.97 (d, J = 8.0 Hz, 1H); 8.13 (s, 1H); 12.18
(s, 1H). Anal. calc. for C18H11ClN2O2: C 66.99, H 3.44, N 8.68;
Found: C 66.87, H 3.39, N 8.73.
4-Chloro-3-(5-bromo-1H-indol-3-yl)-1-phenyl-1H-pyrrole-
3-[1-(tert-Butyloxycarbonyl)-1H-indol-3-yl]-4-(1H-pyrrol-
2,5-dione 3b
2-yl)-1-phenyl-1H-pyrrole-2,5-dione 5a
Yield 80%. Mp. 212–2148C. 1H-NMR (DMSO-d6) d: 7.37 (dd, J = 2.4,
7.6 Hz, 1H); 7.44–7.47 (m, 3H); 7.51–7.53 (m, 3H); 8.15 (s, 1H);
Yield 22%. Mp. 170–1728C. 1H-NMR (DMSO-d6) d: 1.69 (s, 9H);
6.18–6.20 (m, 1H); 6.29 (s, 1H); 6.45 (s, 1H); 7.02 (s, 1H); 7.18–7.20
(m, 2H); 7.35–7.40 (m, 2H); 7.45–7.50 (m, 4H); 8.00 (s, 1H); 8.28
(d, J = 8.8 Hz, 1H); 10.45 (s, 1H). Anal. calc. for C27H23N3O4: C 71.51,
H 5.11, N 9.27; Found: C 71.39, H 5.23, N 9.13.
8.20 (d,
J = 2.8 Hz, 1H); 12.36 (s, 1H). Anal. calc. for
C18H10BrClN2O2: C 53.83, H 2.51, N 6.97; Found: C 53.94, H 2.43, N
6.90.
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Arch. Pharm. Chem. Life Sci. 2008, 341, 273–280
Synthesis and Cytotoxicity of Arylpyrrolylmaleimides
277
chromatography on silica gel using petroleum ether/ethyl ace-
tate as eluent to yield 6d and 6g, respectively.
3-[5-Bromo-[1-(tert-butyloxycarbonyl)-1H-indol-3-yl]-4-
(1H-pyrrol-2-yl)-1-phenyl-1H-pyrrole-2,5-dione 5b
Yield 15%. Mp. 146-1498C. Anal. calc. for C27H22BrN3O4: C 60.91, H
4.17, N 7.89; Found: C 60.83, H 4.28, N 7.76.
6d: Yield 39%. Mp. A2508C. IR (KBr) cm– 1: 3410, 3360, 1694,
1418, 1346, 751. 1H-NMR (DMSO-d6) d: 6.07–6.09 (m, 1H); 6.23–
6.25 (m, 1H); 6.86–6.95 (m, 3H); 7.13 (t, J = 8.0 Hz, 1H); 7.47 (d, J =
8.0 Hz, 1H); 7.51 (d, J = 3.2 Hz, 1H); 10.92 (s, 1H); 11.00 (s, 1H);
11.75 (s, 1H). ESI-MS: 278 [M + 1]. Anal. calc. for C16H11N3O2: C
69.31, H 4.00, N 15.15; Found: C 69.40, H 4.09, N 15.06.
3-[5-Methoxy-[1-(tert-butyloxycarbonyl)-1H-indol-3-yl]4-
(1H-pyrrol-2-yl)-1-phenyl-1H-pyrrole-2,5-dione 5c
Yield 17%. Mp. 160–1628C. 1H-NMR (DMSO-d6) d: 1.66 (s, 9H); 3.50
(s, 3H); 6.20–6.22 (m, 1H); 6.27–6.28 (m, 1H); 6.52 (d, J = 2.8 Hz,
1H); 6.56 (s, 1H); 6.96 (dd, J = 2.0, 7.2 Hz, 1H); 7.04 (s, 1H); 7.46–
7.48 (m, 2H); 7.52–7.56 (m, 2H); 7.96 (s, 1H); 8.01 (d, J = 7.2 Hz,
1H); 11.15 (s, 1H). Anal. calc. for C28H25N3O5: C 69.55, H 5.21, N
8.69; Found: C 69.69, H 5.23, N 8.76.
6g: Yield 42%. Mp. 2038C. IR (KBr) cm– 1: 3421, 3372, 1694,
1396, 1186, 739. 1H-NMR (DMSO-d6) d: 6.12–6.14 (m, 1H); 6.37 (br,
1H); 6.94 (d, J = 7.2 Hz, 2H); 6.99 (s, 1H); 7.13–7.17 (m, 1H); 7.34–
7.54 (m, 6H); 7.85 (d, J = 2.8 Hz, 1H); 11.10 (s, 1H); 11.82 (s, 1H).
ESI-MS: 354 [M + 1]. Anal. calc. for C22H15N3O2: C 74.78, H 4.28, N
11.89; Found: C 74.70, H 4.19, N 11.76.
3-[5-Bromo-(1H-indol-3-yl)]-4-(1H-pyrrol-2-yl)-1H-
pyrrole-2,5-dione 6e and 3-[5-Methoxy-(1H-indol-3-yl)]-4-
General procedure for the synthesis of 6a–c
Methylamine (32%) in methanol (3 mL) was added to compounds
5a–c (0.1 mmol), respectively and the mixture was stirred for 1–
2 h at room temperature. The solvent was removed in vacuo and
the residue was purified after chromatography on silica gel
using petroleum ether/ethyl acetate as eluent to afford com-
pounds 6a–c, respectively.
(1H-pyrrol-2-yl)-1-phenyl-1H-pyrrole-2,5-dione 6h
The same procedure as described above afforded compounds 6e
and 6h, respectively from 5b after purification by chromatogra-
phy on silica gel using petroleum ether/ethyl acetate as eluent.
6e: Yield 48%. Mp. A2508C. 1H-NMR (DMSO-d6) d: 6.12–6.14 (m,
1H); 6.27–6.29 (m, 1H); 6.96–6.98 (m, 2H); 7.24 (dd, J = 2.4,
8.4 Hz, 1H); 7.44 (d, J = 8.4 Hz, 1H); 7.82 (d, J = 2.4 Hz, 1H); 10.96 (s,
1H); 11.05 (s, 1H); 11.92 (s, 1H). ESI-MS: 357 [M + 1]. Anal. calc. for
C16H10BrN3O2: C 53.95, H 2.83, N 11.80; Found: C 53.89, H 2.90, N
11.69.
3-(1H-Indol-3-yl)-4-(1H-pyrrol-2-yl)-1-methyl-1H-pyrrole-
2,5-dione 6a
Yield 88%. Mp. 222–2248C. IR (KBr) cm– 1: 3370, 3304, 1680,
1
6h: Yield 40%. Mp. A2508C. 1H-NMR (DMSO-d6) d: 6.17–6.19 (m,
1H); 6.41 (br, 1H); 7.03 (s, 1H); 7.08 (s, 1H); 7.27 (dd, J = 1.2, 8.4 Hz,
1H); 7.15-7.54 (m, 6H); 7.89 (d, J = 2.8 Hz, 1H); 11.14 (s, 1H); 11.98
(s, 1H). ESI-MS: 433 [M + 1]. Anal. calc. for C22H14BrN3O2: C 61.13, H
3.26, N 9.72; Found: C 61.05, H 3.37, N 9.86.
1434, 732. H-NMR (DMSO-d6) d: 3.01 (s, 3H); 6.09–6.11 (m, 1H);
6.29 (br, 1H); 6.86–6.96 (m, 3H); 7.14 (t, J = 8.0 Hz, 1H); 7.48 (d, J =
8.0 Hz, 1H); 7.78 (d, J = 2.8 Hz, 1H); 11.02 (s, 1H); 11.77 (s, 1H). ESI-
MS: 292 [M + 1]. Anal. calc. for C17H13N3O2: C 70.09, H 4.50, N
14.42; Found: C 70.16, H 4.37, N 14.54.
3-[5-Bromo-(1H-indol-3-yl)]-4-(1H-pyrrol-2-yl)-1-methyl-
3-[5-Methoxy-(1H-indol-3-yl)]-4-(1H-pyrrol-2-yl)-1H-
1H-pyrrole-2,5-dione 6b
pyrrole-2,5-dione 6f and 3-[5-Methoxy-(1H-indol-3-yl)]-4-
(1H-pyrrol-2-yl)-1-phenyl-1H-pyrrole-2,5-dione 6i
Yield 81%. Mp. 219–2208C (dec.). IR (KBr) cm– 1: 3392, 3320, 1688,
1442, 1117, 739. 1H-NMR (DMSO-d6) d: 3.01 (s, 3H); 6.13–6.16 (m,
1H); 6.33–6.35 (m, 1H); 6.98–7.00 (m, 2H); 7.25 (dd, J = 2.0,
8.0 Hz, 1H); 7.44 (d, J = 8.0 Hz, 1H); 7.83 (d, J = 2.4 Hz, 1H); 11.06 (s,
1H); 11.94 (s, 1H). ESI-MS: 371 [M + 1]. Anal. calc. for C17H12BrN3O2:
C 55.15, H 3.27, N 11.35; Found: C 55.26, H 3.17, N 11.47.
The same procedure as described above afforded compounds 6f
and 6i, respectively from 5c after purification by chromatogra-
phy on silica gel using petroleum ether/ethyl acetate as eluent.
1
6f: Yield 45%. Mp. A2508C. H-NMR (DMSO-d6) d: 3.41 (s, 3H);
6.10–6.12 (m, 1H); 6.21–6.23 (m, 1H); 6.72 (dd, J = 2.4 , 8.4 Hz,
1H); 6.94–6.96 (m, 2H); 7.36 (d, J = 8.4 Hz, 1H); 7.54 (d, J = 2.0 Hz,
1H); 10.90 (s, 1H); 11.03 (s, 1H); 11.67 (s, 1H). ESI-MS: 308 [M + 1].
Anal. calc. for C17H13N3O3: C 66.44, H 4.26, N 13.67; Found: C
66.51, H 4.20, N 13.54.
3-[5-Methoxy-(1H-indol-3-yl)]-4-(1H-pyrrol-2-yl)-1-
methyl-1H-pyrrole-2,5-dione 6c
Yield 79%. Mp. 227–2288C. IR (KBr) cm– 1: 3395, 3319, 1689,
6i: Yield 40%. Mp. 2028C. 1H-NMR (DMSO-d6) d: 3.44 (s, 3H);
6.17–6.19 (m, 1H); 6.25 (t, J = 2.4 Hz, 1H); 6.32 (d, J = 2.8 Hz, 1H);
6.34–6.36 (m, 1H); 6.76 (dd, J = 2.4, 8.8Hz, 1H); 6.99–7.01 (m, 1H);
7.06 (t, J = 2.4 Hz, 1H); 7.32–7.55 (m, 4H); 7.85 (d, J = 2.8 Hz, 1H);
11.29 (s, 1H); 11.74 (s, 1H). ESI-MS: 384 [M + 1]. Anal. calc. for
C23H17N3O3: C 72.05, H 4.47, N 10.96; Found: C 72.17, H 4.59, N
10.87.
1
1108, 735. H-NMR (DMSO-d6) d: 3.02 (s, 3H); 3.42 (s, 3H); 6.13–
6.15 (m, 1H); 6.25–6.27 (m, 2H); 6.74 (dd, J = 2.0, 8.4 Hz, 1H); 6.95-
6.97 (m, 3H); 7.35 (d, J = 8.4 Hz, 1H); 7.79 (d, J = 2.4 Hz,1H); 11.06
(s, 1H); 11.69 (s, 1H). ESI-MS: 322 [M + 1]. Anal. calc. for C18H15N3O3:
C 67.28, H 4.71, N 13.08; Found: C 67.20, H 4.62, N 13.21.
3-(1H-Indol-3-yl)-4-(1H-pyrrol-2-yl-1H-pyrrole-2,5-dione
6d and 3-(1H-Indol-3-yl)-4-(1H-pyrrol-2-yl)-1-phenyl-1H-
pyrrole-2,5-dione 6g
Compound 5a (0.2 mmol) was heated with ammonium acetate
(40 mmol) for 1 h at 1508C (bath temperature). The mixture was
cooled and extracted with ethyl acetate after the addition of
water. The organic layer was washed with brine, dried over
Na2SO4, and concentrated in vacuo. The residue was purified by
General procedure for the synthesis of 8a–k
At a temperature of 08C, t-BuOK (25 mmol, 1 M in THF) was
added dropwise to a THF (30 mL) solution of diethyl oxalate
(20 mmol) and 7a–k (10 mmol) in THF. After the reaction mix-
ture was stirred at 08C for 2 h, it was poured into 0.5 M aqueous
hydrochloric acid (50 mL). The mixture was extracted with ethyl
acetate (50 mL; 63). The organic phase was successively washed
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Arch. Pharm. Chem. Life Sci. 2008, 341, 273–280
with water and brine, dried over Na2SO4, and concentrated in
vacuo to afford crystals 8a–k.
3-Hydroxy-4-(thiophen-3-yl)-1-methyl-1H-pyrrole-2,5-
dione 8k
Yellow crystals. Yield 91%. Mp. 223–2258C. IR (KBr) cm– 1: 3238,
1698, 1673, 1350, 1172, 1040, 820.
3-Hydroxy-4-phenyl-1H-pyrrole-2,5-dione 8a
Light yellow crystals. Yield 66%. Mp. 214–2168C. IR (KBr) cm– 1
:
1
3270, 1776, 1701, 1383, 1268, 1119, 890. H-NMR (DMSO-d6) d:
General procedure for the synthesis of 9a–d and 10e–k
A solution of oxalyl chloride (15 mmol) in CH2Cl2 (5 mL) was
added dropwise to a solution of 8a–k (5 mmol) in 1 : 1 CH2Cl2/
DMF (15 mL) at rt. After 0.5 h the reaction mixture was poured
into cold water (50 mL) and extracted with CH2Cl2 (20 mL; 63).
The organic phase was successively washed with water and
brine, dried over Na2SO4, and concentrated in vacuo to afford
9a–d and 10e–k.
7.40–7.45 (m, 3H); 5.55–7.58 (m, 2H).
3-Hydroxy-4-(4-chlorophenyl)-1H-pyrrole-2,5-dione 8b
Yellow crystals. Yield 52%. Mp. 178–1808C. IR (KBr) cm– 1: 3295,
1709, 1393, 1299, 1092, 891.
3-Hydroxy-4-(1H-indol-1-yl)-1H-pyrrole-2,5-dione 8c
Light yellow crystals. Yield 70%. Mp. 1908C (dec.). IR (KBr) cm– 1
:
3-Chloro-4-phenyl-1H-pyrrole-2,5-dione 9a
Yellow crystals. Yield 83%. Mp. 159–1618C. IR (KBr) cm– 1: 3209,
2704, 1800, 1718, 1491, 1057, 845.
1
3265, 1766, 1701, 1380, 1298, 1089, 894. H-NMR (DMSO-d6) d:
6.73 (d, J = 4.0 Hz, 1H); 7.19 (t, J = 7.2 Hz, 1H); 7.25 (t, J = 7.6 Hz,
1H); 7.40 (d, J = 7.6 Hz, 1H); 7.51 (d, J = 4.0 Hz, 1H); 7.63 (d, J =
8.0 Hz, 1H); 10.66 (s, 1H).
3-Chloro-4-(4-chlorophenyl)-1H-pyrrole-2,5-dione 9b
Light yellow crystals. Yield 78%. Mp. 160–1638C. IR (KBr) cm– 1
:
3-Hydroxy-4-(naphthalen-1-yl)-1H-pyrrole-2,5-dione 8d
Orange crystals. Yield 48%. Mp. 237–2408C. IR (KBr) cm– 1: 3323,
1772, 1706, 1677, 1384, 1296, 1078, 896. H-NMR (DMSO-d6) d:
3251, 2696, 1798, 1733, 1487, 1049, 847.
1
3-Chloro-4-(1H-indol-1-yl)-1H-pyrrole-2,5-dione 9c
7.39–7.41 (m, 4H); 7.53 (m, 1H); 7.67–7.69 (m, 2H).
Light yellow crystals. Yield 68%. Mp. 227–2298C. 1H-NMR (DMSO-
d6) d: 6.83 (d, J = 4.0 Hz, 1H); 7.21 (t, J = 7.2 Hz, 1H); 7.27 (t, J =
7.6 Hz, 1H); 7.43 (d, J = 7.6 Hz, 1H); 7.54 (d, J = 4.0 Hz, 1H); 7.65 (d,
J = 8.0 Hz, 1H); 11.66 (s, 1H).
3-Hydroxy-4-(4-methoxyphenyl)-1-methyl-1H-pyrrole-
2,5-dione 8e
Yellow crystals. Yield 75%. Mp. 191–1948C. IR (KBr) cm– 1: 3260,
1698, 1668, 1604, 1514, 1087, 1027, 844.
3-Chloro-4-(naphthalen-1-yl)-1H-pyrrole-2,5-dione 9d
Light yellow crystals. Yield 73%. Mp. 166–1688C. 1H-NMR (CDCl3)
d: 7.56 (m, 4H); 7.63 (m, 1H); 7.94 (m, 1H); 8.00 (d, J = 8.0 Hz, 1H).
3-Hydroxy-4-(4-nitrophenyl)-1-methyl-1H-pyrrole-2,5-
dione 8f
Yellow crystals. Yield 68%. Mp. 247–2498C. IR (KBr) cm– 1: 3417,
3112, 1707, 1661, 1595, 1038, 865.
3-Chloro-4-(4-methoxyphenyl)-1-methyl-1H-pyrrole-2,5-
dione 10e
Light yellow crystals. Yield 78%. Mp. 109–1118C (Lit. [19]: 116–
1
1178C). H-NMR (CDCl3) d: 3.12 (s, 3H); 3.87 (s, 3H); 7.00 (m, 2H);
3-Hydroxy-4-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrole-
8.01 (m, 2H). ESI-MS: 252 [M + 1].
2,5-dione 8g
Orange crystals. Yield 79%. Mp. 213–2158C. IR (KBr) cm– 1: 3273,
2939, 1701, 1663, 1598, 1458, 1378, 1024.
3-Chloro-4-(4-nitrophenyl)-1-methyl-1H-pyrrole-2,5-dione
10f
Light yellow crystals. Yield 71%. Mp. 162–1638C. 1H-NMR (CDCl3)
d: 3.18 (s, 3H); 8.14 (m, 2H); 8.35 (m, 2H). ESI-MS: 267 [M + 1].
3-Hydroxy-4-(3,4,5-trimethoxyphenyl)-1-methyl-1H-
pyrrole-2,5-dione 8h
Yellow crystals. Yield 82%. Mp. 223–2268C. IR (KBr) cm– 1: 3220,
2944, 1772, 1687, 1684, 1382, 1126, 1010.
3-Chloro-4-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrrole-
2,5-dione 10g
Yellow crystals. Yield 65%. Mp. 176–1788C. IR (KBr) cm– 1: 2939,
1703, 1012, 855, 741. 1H-NMR (CDCl3) d: 3.13 (s, 3H); 3.94 (s, 3H);
3.95 (s, 3H); 6.97 (d, J = 8.4 Hz, 1H); 7.63 (d, J = 2.0 Hz, 1H); 7.72
(dd, J = 2.0, 8.4 Hz, 1H). ESI-MS: 282 [M + 1].
3-Hydroxy-4-(3,4-dioxomethenexyphenyl)-1-methyl-1H-
pyrrole-2,5-dione 8i
Yellow crystals. Yield 55%. Mp. 193–1968C. IR (KBr) cm– 1: 3240,
2931, 1776, 1671, 1383, 1119, 1021.
3-Chloro-4-(3,4,5-trimethoxyphenyl)-1-methyl-1H-
3-Hydroxy-4-(naphthalen-2-yl)-1-methyl-1H-pyrrole-2,5-
pyrrole-2,5-dione 10h
Light yellow crystals. Yield 72%. Mp. 122–1238C. 1H-NMR (CDCl3)
d: 3.14 (s, 3H); 3.91 (s, 6H); 3.93 (s, 3H); 7.31 (s, 2H). ESI-MS: 312 [M
+ 1].
dione 8j
Yellow crystals. Yield 71%. Mp. 230–2328C. IR (KBr) cm– 1: 3232,
1700, 1661, 1386, 1312, 1037.
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Arch. Pharm. Chem. Life Sci. 2008, 341, 273–280
Synthesis and Cytotoxicity of Arylpyrrolylmaleimides
279
3-Chloro-4-(3,4-dioxomethenexyphenyl)-1-methyl-1H-
General procedure for the synthesis of 11a–k
LiHMDS (1 M in THF, 1.0 mmol) at –208C was added to a solution
of 1.0 mmol of the pyrrole in THF (3 mL) under N2 and stirred for
1 h. A solution of 10a–k (0.5 mmol) in THF (10 mL) was then
added by drip over 40–60 min, followed by stirring at 08C over-
night. The reaction mixture was poured into 0.5 M aqueous
hydrochloric acid (30 mL), and the mixture was extracted with
ethyl acetate (20 mL; 63). The organic phase was successively
washed with water and brine, dried over Na2SO4, and concen-
trated in vacuo. The residue was purified by flash column chro-
matography on silica gel using petroleum ether / ethyl acetate as
eluent to afford 11a–k.
pyrrole-2,5-dione 10i
Yellow crystals. Yield 76%. Mp. 140–1428C. IR (KBr) cm– 1: 2911,
1713, 1494, 1438, 731. 1H-NMR (CDCl3) d: 3.13 (s, 3H); 6.05 (s, 2H);
6.93 (d, J = 8.0 Hz, 1H); 7.52 (d, J = 1.6 Hz, 1H); 7.72 (dd, J = 1.6,
8.0 Hz, 1H). ESI-MS: 266 [M + 1].
3-Chloro-4-(naphthalen-2-yl)-1-methyl-1H-pyrrole-2,5-
dione 10j
Yellow crystals. Yield 75%. Mp. 134–1358C. IR (KBr) cm– 1: 3467,
2944, 1705, 1442, 1382, 728.1H-NMR (CDCl3) d: 3.18 (s, 3H); 7.55–
7.60 (m, 2H); 7.87 (d, J = 8.4 Hz, 1H); 7.92-7.96 (m, 2H); 8.02 (dd, J =
2.4, 8.4 Hz, 1H); 8.51 (br, 1H). ESI-MS: 272 [M + 1].
3-Phenyl-4-(1H-pyrrol-2-yl)-1-methyl-1H-pyrrole-2,5-
dione 11a
3-Chloro-4-(thiophen-3-yl)-1-methyl-1H-pyrrole-2,5-dione
Light yellow crystals. Yield 36%. Mp. 145–1488C. IR (KBr) cm– 1
:
10k
3352, 1686, 1443, 1382, 1115, 737. 1H-NMR (CDCl3) d: 3.12 (s, 3H);
6.19–6.21 (m, 1H); 6.74 (br, 1H); 7.01 (br, 1H); 7.43–7.50 (m, 3H);
7.55 (d, J = 7.2 Hz, 2H); 10.46 (s, 1H). ESI-MS: 253 [M + 1]. Anal. calc.
for C15H12N2O2: C 71.42, H 4.79, N 11.10; Found: C 71.20, H 4.67, N
11.21.
Yellow crystals. Yield 72%. Mp. 97–988C. IR (KBr) cm– 1: 3129,
2946, 1682. 1H-NMR (CDCl3) d: 3.12 (s, 3H); 7.44 (m, 1H); 7.99 (dd, J
= 1.2, 5.2 Hz, 1H); 8.49 (dd, J = 1.2, 2.8 Hz, 1H). ESI-MS: 227 [M + 1].
General procedure for the synthesis of 10a–d
K2CO3 (5 mmol) and CuO (0.15 mmol) were added to a solution of
9a–d (5 mmol) in dry DMF (10 mL) at 208C followed by the addi-
tion of CH3I (25 mmol) under N2. After the material disappeared,
the reaction mixture was poured into water (50 mL) and
extracted with CH2Cl2 (30 mL; 63). The organic phase was suc-
cessively washed with water and brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified after chromatog-
raphy on silica gel using petroleum ether / ethyl acetate as elu-
ent to afford crystals 10a–d.
3-(4-Chlorophenyl)-4-(1H-pyrrol-2-yl)-1-methyl-1H-
pyrrole-2,5-dione 11b
1
Yellow crystals. Yield 31%. Mp. 1908C (dec.). H-NMR (CDCl3) d:
3.11 (s, 3H); 6.20–6.23 (m, 1H); 6.73 (br, 1H); 7.03–7.05 (m, 1H);
7.45 (d, J = 8.4 Hz, 2H); 7.52 (d, J = 8.8 Hz, 2H); 10.55 (s, 1H). ESI-
MS: 287 [M + 1]. Anal. calc. for C15H11ClN2O2: C 62.84, H 3.87, N
9.77; Found: C 62.20, H 3.67, N 9.41.
3-(1H-Indol-1-yl)-4-(1H-pyrrol-2-yl)-1-methyl-1H-pyrrole-
3-Chloro-4-phenyl-1-methyl-1H-pyrrole-2,5-dione 10a
Light yellow crystals. Yield 98%. Mp. 72–748C. IR (KBr) cm– 1
:
2,5-dione 11c
1
3471, 1699, 1452, 1382, 995, 738, 690. 1H-NMR (CDCl3) d: 3.15 (s,
Yellow crystals. Yield 17%. Mp. 1908C (dec.). H-NMR (CDCl3) d:
3.17 (s, 3H); 6.03 (br, 1H); 6.17 (br, 1H); 6.79 (d, J = 3.2 Hz, 1H); 6.92
(d, J = 8.4 Hz, 1H); 7.05 (br, 1H); 7.19 (t, J = 7.2 Hz, 2H); 7.30 (d, J =
3.5 Hz, 1H); 7.70 (d, J = 7.2 Hz, 1H); 10.42 (s, 1H). ESI-MS: 292 [M +
1]. Anal. calc. for C17H13N3O2: C 70.09, H 4.50, N 14.42; Found: C
70.20, H 4.67, N 14.21.
3H); 7.47–7.50 (m, 3H); 7.93 (m, 2H). ESI-MS: 222 [M + 1].
3-Chloro-4-(4-chlorophenyl)-1-methyl-1H-pyrrole-2,5-
dione 10b
Light yellow crystals. Yield 83%. Mp. 120–1218C (Lit. [19]: 122–
1
1248C). H-NMR (CDCl3) d: 3.16 (s, 3H); 7.48–7.50 (m, 2H); 7.93–
7.95 (m, 2H). ESI-MS: 256 [M + 1].
3-(Naphthalen-1-yl)-4-(1H-pyrrol-2-yl)-1-methyl-1H-
pyrrole-2,5-dione 11d
1
Yellow crystals. Yield 20%. Mp. 1908C (dec.). H-NMR (CDCl3) d:
3-Chloro-4-(1H-indol-1-yl)-1-methyl-1H-pyrrole-2,5-dione
3.19 (s, 3H); 6.03 (br, 1H); 6.30 (t, J = 2.0 Hz, 1H); 6.96 (t, J = 2.8 Hz,
1H); 7.42 (t, J = 8.0 Hz, 1H); 7.50 (br, 1H); 7.52 (d, J = 6.8 Hz, 1H);
7.64 (d, J = 8.4 Hz, 1H); 7.93 (d, J = 8.0 Hz, 1H); 7.97 (d, J = 7.6 Hz,
1H); 10.47 (s, 1H). ESI-MS: 303 [M + 1]. Anal. calc. for C19H14N2O2: C
75.48, H 4.67, N 9.27; Found: C 75.20, H 4.77, N 9.41.
10c
Yellow crystals. Yield 65%. Mp. 131–1338C. IR (KBr) cm– 1: 3134,
2924, 1718, 1650, 1445, 763. 1H-NMR (CDCl3) d: 3.18 (s, 3H); 6.80
(d, J = 4.0 Hz, 1H); 7.26 (t, J = 7.6 Hz, 1H); 7.32 (t, J = 7.6 Hz, 1H);
7.38 (d, J = 7.6 Hz, 1H); 7.46 (d, J = 3.6 Hz, 1H); 7.64 (d, J = 7.2 Hz,
1H). ESI-MS: 261 [M + 1].
3-(4-Methoxyphenyl)-4-(1H-pyrrol-2-yl)-1-methyl-1H-
3-Chloro-4-(naphthalen-1-yl)-1-methyl-1H-pyrrole-2,5-
pyrrole-2,5-dione 11e
1
dione 10d
Yellow crystals. Yield 24%. Mp. 1908C (dec.). H-NMR (CDCl3) d:
Yellow crystals. Yield 95%. Mp. 120–1228C. IR (KBr) cm– 1: 3469,
2938, 1714, 1628, 1439, 1379, 732. 1H-NMR (CDCl3) d: 3.21 (s, 3H);
7.54 (m, 4H); 7.62 (m, 1H); 7.93 (m, 1H); 8.00 (d, J = 8.0 Hz, 1H).
ESI-MS: 272 [M + 1].
3.11 (s, 3H); 3.88 (s, 3H); 6.21 (br, 1H); 6.81 (br, 1H); 6.98–7.00 (m,
3H); 7.53–7.55 (m, 2H); 10.46 (s, 1H). ESI-MS: 283 [M + 1]. Anal.
calc. for C16H14N2O3: C 68.07, H 5.00, N 9.92; Found: C 68.20; H
5.19, N 9.41.
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Arch. Pharm. Chem. Life Sci. 2008, 341, 273–280
were seeded in 96-well plate at the concentration of 4000 cells
per well in RPMI 1640 medium. After culturing for 24 h at 378C
in 5% CO2 atmosphere, cells were incubated with various concen-
trations of tested compounds for 48 h. MTT was added at a final
concentration of 0.25 mg/mL and after 4 h incubation 100 lL of
DMSO was added to each well and the optical density was meas-
ured at 570 nm. The IC50 values were calculated according to the
Logit method after getting the inhibitory rate.
PKC was purchased from Promega, USA. Samples were assayed
for PKC inhibitory activity according to the PKC assay protocol.
Sample solutions were dissolved in DMSO. The gel was examined
under UV light and quantified by spectrophotometry. Data show
IC50 values expressed in mM.
3-(4-Nitrophenyl)-4-(1H-pyrrol-2-yl)-1-methyl-1H-pyrrole-
2,5-dione 11f
Yellow crystals. Yield 40%. Mp. 2008C (dec.). IR (KBr) cm– 1: 3394,
2921, 1741, 1685, 1594, 759. 1H-NMR (CDCl3) d: 3.14 (s, 3H); 6.25
(br, 1H); 6.71 (br, 1H); 7.10 (br, 1H); 7.31–7.33 (m, 2H); 7.80–7.83
(m, 2H); 10.69 (s, 1H). ESI-MS: 298 [M + 1]. Anal. calc. for
C15H11N3O4: C 60.61, H 3.73, N 14.14; Found: C 60.20, H 3.49, N
14.41.
3-(3,4-Dimethoxyphenyl)-4-(1H-pyrrol-2-yl)-1-methyl-1H-
pyrrole-2,5-dione 11g
Yellow crystals. Yield 33%. Mp. 1908C (dec.). IR (KBr) cm– 1: 3390,
2924, 1690, 1451, 1413, 1260, 734. 1H-NMR (CDCl3) d: 3.11 (s, 3H);
3.86 (s, 3H); 3.94 (s, 3H); 6.21 (br, 1H); 6.85 (br, 1H); 6.96 (d, J =
8.0 Hz, 1H); 7.00 (br, 1H); 7.11 (d, J = 2.0 Hz, 1H); 7.20 (dd, J = 2.0,
8.0 Hz, 1H); 10.47 (s, 1H). ESI-MS: 313 [M + 1]. Anal. calc. for
C17H16N2O4: C 65.3, H 5.16, N 8.97; Found: C 65.20, H 5.39, N 8.71.
References
[1] M. Ohkubo, H. Kawamoto, T. Ohno, M. Nakano, H. Morish-
3-(3,4,5-Trimethoxyhenyl)-4-(1H-pyrrol-2-yl)-1-methyl-
ima, Tetrahedron 1997, 53, 585–592.
1H-pyrrole-2,5-dione 11h
[2] F. Kanzawa, K. Nishio, N. Kubota, N. Saijo, Cancer Res. 1995,
55, 2806–2813.
1
Yellow crystals. Yield 21%. Mp. 1908C (dec.). H-NMR (CDCl3) d:
3.12 (s, 3H); 3.84 (s, 6H); 3.94 (s, 3H); 6.24 (br, 1H); 6.80 (s, 2H); 7.03
(br, 1H); 7.12 (m, 1H); 10.46 (s, 1H). ESI-MS: 343 [M + 1]. Anal. calc.
for C18H18N2O54: C 63.15, H 5.30, N 8.18; Found: C 63.20, H 5.39, N
8.01.
[3] H. Komatani, H. Kotani, Y. Hara, R. Nakagawa, et al., Cancer
Res. 2001, 61, 2827–2832.
[4] C. Carrasco, H. Vezin, W. D. Wilson, Anticancer Drug Des.
2001, 16, 99–107.
[5] M. M. Faul, J. R. Gillig, M. R. Jirousek, L. M. Ballas, et al.,
Bioorg. Med. Chem. Lett. 2003, 13, 1857–1859.
3-(3,4-Dioxomethenephenyl)-4-(1H-pyrrol-2-yl)-1-methyl-
1H-pyrrole-2,5-dione 11i
[6] E. Caballero, M. Adeva, S. Calderꢁn, H. Sahagffln, et al., Bio-
org. Med. Chem. 2003, 11, 3413–3421.
Yellow crystals. Yield 18%. Mp. 1908C (dec.). IR (KBr) cm– 1: 3391,
2922, 1691, 1443, 1243, 741. 1H-NMR (CDCl3) d: 3.10 (s, 3H); 6.21
(br, 1H); 6.30 (s, 2H); 6.83 (br, 1H); 6.91 (d, J = 8.4 Hz, 1H); 7.01 (br,
1H); 7.04 (d, J = 1.2 Hz, 1H); 7.10 (dd, J = 1.2, 8.0 Hz, 1H), 10.48 (s,
1H). ESI-MS: 297 [M + 1]. Anal. calc. for C16H12N2O4: C 64.86, H
4.08, N 9.46; Found: C 65.00, H 4.39, N 9.61.
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2006, 47, 433–436.
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Med. Chem. Lett. 2004, 14, 5171–5174.
3-(Naphthalen-2-yl)-4-(1H-pyrrol-2-yl)-1-methyl-1H-
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pyrrole-2,5-dione 11j
Yellow crystals. Yield 22%. Mp. 1958C (dec.). IR (KBr) cm– 1: 3385,
[11] M. Gallant, J. T. Link, S. J. Danishefsky, J. Org. Chem. 1993,
58, 343–349.
1
2923, 1686, 1447, 738. H-NMR (CDCl3) d: 3.15 (s, 3H); 6.18 (br,
1H); 6.77 (br, 1H); 7.02 (br, 1H); 7.52–7.56 (m, 2H); 7.65 (dd, J =
2.0, 8.4 Hz, 1H); 7.87-7.93 (m, 3H); 8.08 (s, 1H); 10.51 (s, 1H). ESI-
MS: 303 [M + 1]. Anal. calc. for C19H14N2O2: C 75.48, H 4.67, N 9.27;
Found: C 75.23, H 4.78, N 9.31.
[12] M. Ohkubo, T. Nishimura, H. Jona, T. Honma, H. Morish-
ima, Tetrahedron 1996, 52, 8099–8112.
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dron 1988, 10, 2887–2892.
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Lett. 1999, 40, 1109–1112.
3-(Thiophen-3-yl)-4-(1H-pyrrol-2-yl)-1-methyl-1H-pyrrole-
2,5-dione 11k
[15] T. A. Engler, K. Furness, S. Malhotra, C. Sanchez-Martinez,
Yellow crystals. Yield 84%. Mp. 163–1658C. IR (KBr) cm– 1: 3397,
et al., Bioorg. Med. Chem. Lett. 2003, 13, 2261–2267.
1
1686, 1430, 751. H-NMR (CDCl3) d: 3.11 (s, 3H); 6.26–6.28 (m,
[16] H. C. Zhang, G. H. Kuo, B. E. Maryanoff, H. Ye, et al., U.S.
1H); 6.96(br, 1H); 7.04 (br, 1H); 7.41–7.43 (m, 1H); 7.46 (d, J =
8.0 Hz, 1H); 7.80 (m, J = 3.2 Hz, 1H); 10.51 (s, 1H). ESI-MS: 259 [M +
1]. Anal. calc. for C13H10N2O2S: C 60.45, H 3.90, N 10.85; Found: C
60.23, H 3.78, N 10.71.
Pat. 0006095.
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Pharmacology
The cytotoxicity of compounds 6a–i and 11a–k was evaluated
against human cell lines by the MTT method in vitro. The cells
[19] M. Augustin, J. Faust, M. Koehler, Prakt. Chem. 1983, 325,
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