Design, synthesis, and antitumor evaluation of novel acenaphtho[1,2-b]pyrrole-carboxylic acid esters with amino chain substitution

Article abstract of DOI:10.1016/j.bmc.2006.02.016

8-Oxo-8H-acenaphtho[1,2-b]pyrrole-9-carboxylic acid esters and derivatives were prepared and evaluated for cytotoxicity against A549 and P388 cell lines. Based on a novel chromophore precursor 8-oxo-8H-acenaphtho[1,2-b]pyrrol-9-carbonitrile 1, the very in

Full text of DOI:10.1016/j.bmc.2006.02.016

Bioorganic & Medicinal Chemistry 14 (2006) 4639–4644
Design, synthesis, and antitumor evaluation of
novel acenaphtho[1,2-b]pyrrole-carboxylic acid esters with
amino chain substitution
a
a,b,
a
a
a
a
*
Fengyu Liu, Xuhong Qian,
Jingnan Cui, Yi Xiao, Rong Zhang and Gangyue Li
a
State Key Laboratory of Fine Chemicals, Dalian University of Technology, PO Box 89, Zhongshan Road 158, Dalian 116012, China
b
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology,
Shanghai 200237, China
Received 15 January 2006; revised 5 February 2006; accepted 7 February 2006
Available online 3 March 2006
Abstract—8-Oxo-8H-acenaphtho[1,2-b]pyrrole-9-carboxylic acid esters and derivatives were prepared and evaluated for cytotoxicity
against A549 and P388 cell lines. Based on a novel chromophore precursor 8-oxo-8H-acenaphtho[1,2-b]pyrrol-9-carbonitrile 1, the
H
N
very insoluble 1 was converted to more soluble esters 5 and a series of 3-amino derivatives from 5 were obtained by mild S Ar
reaction between 5 and various amines. The biological evaluation indicated that methyl esters 5a are the most cytotoxic with
IC50 values of 0.45 and 0.80 lM (against A549 and P388, respectively) among the parent esters 5a–5f, but 3-amino derivatives
4
b and 4c of 5f with bromine showed the highest activity (with IC50 values of 0.019–0.60 lM) among the 3-amino derivatives.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Major progress in cancer chemotherapy requires new
drugs to eradicate the entire neoplastic diseases in
human being.Finding of novel structure leads that may
be of use in designing new, potent, selective, and less
toxic anticancer agents remains a major challenge for
1
–4
medicinal chemistry researchers.
Random screening
of natural products and synthetics has been the source
5
–7
of new leads in approaches to drug discovery.
In
our ongoing search for the new potential antitumor
agents, we therefore aimed to develop series of new
synthetic leads which are more accessible and more
amenable to optimization through analog synthesis.
In our previous work, we designed and synthesized an
excellent acenaphtho-heterocycle chromophoric precur-
sor, 8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile
Figure 1. Structure of amonafide and new acenaphtho-heterocyclic
derivatives.
1 (see Fig. 1), which was characteristic of a flat highly
electron-deficient heteroaromatic system. S Ar reac-
tion could easily occur between the precursor 1 and ali-
H
phatic amines in very mild conditions, and obtained
amino derivatives 3-amino-8-oxo-8H-acenaphtho[1,2-b]-
N
pyrrol-9-carbonitrile A (see Fig. 1) were typical ICT
8
(intramolecular charge transfer) fluorophores. It is well
known that many electron-deficient chromophoric sys-
tems containing planar polycycles represent a large
number of valuable antitumor agents, such as the
anthraquinone ring system in daunomycin, mitoxan-
Keywords: Acenaphtho[1,2-b]pyrrol-carboxylic acid esters; Antitumor;
Esterification; Nucleophilic substitution.
*
Corresponding author. Tel.: +86 411 83673466; fax: +86 411
3673488; e-mail: xhqian@ecust.edu.cn
8
0
968-0896/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.02.016

4640
F. Liu et al. / Bioorg. Med. Chem. 14 (2006) 4639–4644
tron, and doxorubicin, naphthalimide in amonafide, and
2
undesirable by-products. Thus, acidic condition was
selected to operate the hydrolysis of 1. Hydrolysis of 1
in 98% H SO at room temperature for 10 h afforded
8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carboxylic acid 2
in high yield (95%).
,9,10
acridine in DACA.
It was noted that A resemble
some valuable antitumor agents in structure, such as
amonafide (Fig. 1), namely they both possessed elec-
tron-deficient planar polycycles and basic side chains.
The similarity inspired us to assume that the derivatives
of A could show certain biological activity. Therefore, it
was desirable to investigate antitumor activity of amino
derivatives of A in order to find new structure leads.
2
4
Acid 2 was reacted with corresponding iodide or bro-
mide in CH CN in the presence of K CO to give ester
3
2
3
analogs 3a–f in acceptable yield, but with an exception,
yield of 3f was very low (18%).
However, in view of the fact that poor solubility of
precursor 8-oxo-8H-acenaphtho[1,2-b]pyrrol-9-carbo-
nitrile and derivatives A not only was unfavorable for
synthesis and purification of products, but also influ-
enced the performance of biological evaluation and
further application, it was necessary for us to attempt
structural modification to improve the solubility of pre-
cursor and derivatives. Considering highly electron-
deficient conjugated planar of precursor 1 to be re-
mained, cyano group was taken into account as a var-
iable site. Esters are usually more soluble in all organic
solvents, which is a significant advantage for both the
chemical preparation and purification. On the basis
of these considerations, we synthesized a series of
Before preparing amino derivatives of 8-oxo-8H-ace-
naphtho[1,2-b]pyrrole-9-carboxylic acid esters, prelimin-
ary biological activity of 3a–f against two cell lines was
evaluated. The results are showed in Table 1. Methyl ester
3a possessed strongest cytotoxicity with IC50 values of
0.45 and 0.80 lM (against A549 and P388, respectively).
Thus, 3a was selected as a precursor to be derivatized to
give amino derivatives. In addition, due to the presence
of a bromine atom in side chain, some derivatives of 3f
were also synthesized in order to investigate the influence
of halogen Br on the biological activity.
1
0
In our previous report, nucleophilic aromatic substitu-
tion of hydrogen (NASH) reaction of 1 could easily
occur with amines at room temperature due to a strong-
ly electron-deficient feature. The electron-withdrawing
ability of ester group was weaker than that of cyano
group, which resulted in the decreasing of electron-defi-
cient ability of ester analogs. Thus, the NASH reaction
of esters 3a and 3f with nucleophilic amines was operat-
8
-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carboxylic
acid
esters 3 and their amino derivatives 4 as modified ana-
logs of A in an attempt to evaluate their cytotoxic
activity against cell lines of A549 and P388, and looked
forward to the discovery of some potential antitumor
leads.
ed at 50–60 °C in CH CN and reaction time was
3
2. Chemistry
prolonged.
Preparation of title compounds is shown in Scheme 1.
Precursor 1 was prepared according to our previous
publication. Owing to highly electron-deficient features
of 1, it was easily attacked by the nucleophiles occurring
in basic medium, which resulted in the appearance of
3. Cytotoxic evaluation
8
The antitumor activities in vitro of these compounds
1
were evaluated by sulforhodamine B (SRB) assay
1
2 4 1 2 3 3
Scheme 1. Reagents and conditions: (i) 98% H SO , rt, 10 h; (ii) R X (X = Br, I), K CO , CH CN, 35–50 °C (X = I), reflux (X = Br), 12–24 h; (iii)
corresponding amines, 50–60 °C, reflux, 10–36 h.

F. Liu et al. / Bioorg. Med. Chem. 14 (2006) 4639–4644
Table 1. Cytotoxicity evaluation against A549 and P388 cell lines
4641
compounds described without an N-dialkyl group
basic side chain unexpectedly showed moderate activ-
ity, which suggested that the series of compounds
could possess different structure–activity relationship
from naphthalimide.
Compound
Cytotoxicity (IC50, lM)
a
b
A549
P388
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
0.45
0.80
1.35
1.51
2.20
2.77
1.34
5.65
0.27
0.80
2.05
2.98
9.75
2.14
5.51
Since most compounds especially 4l and 4m showed con-
siderable activity and could be further improved in
structure, they are potential leading compounds for
finding of valuable antitumor agents. Our research on
the novel acenaphtho-heterocycle structural manipula-
tion that is focused on the modification of cyano group
and ester group at 9-position and the variance of amino
substituents at 3-position and other biological evalua-
tion is still in progress.
a
b
c
d
e
f
10.1
0.80
3.41
31.1
19.7
11.3
3.08
6.69
1.24
4.12
g
h
i
0.95
1.40
7.08
c
ND
>50
8.03
c
ND
4
. Conclusion
j
1.03
1.41
k
1
m
n
In summary, a variety of 8-oxo-8H-acenaphtho[1,2-
b]pyrrole-9-carboxylic acid esters and their amino
derivatives were readily synthesized and were evaluat-
ed for their antitumor activity against cell lines of
A549 and P388. The results displayed that most of
the compounds showed considerable cytotoxicity.
The novel acenaphtho-heterocycle possesses simple
structure and can be easily improved structurally.
We believe that the discovery has provided a basis
for the screening of new antitumor leads with simple
structure.
0.60
0.14
1.67
0.032
0.019
3.90
a
b
c
Cytotoxicity against human lung cancer cells (A549) was measured by
11
sulforhodamine B dye-staining method.
Cytotoxicity against murine leukemia cells (P388) was measured by
12
micro-culture tetrazolium-formazan method.
ND = not determined.
against A549 (human lung cancer cell) and MTT tetra-
1
2
zolium dye assay against P388 (murine leukemia cell),
respectively (Table 1). The IC50 represents the drug con-
centration (micromolar) required to inhibit cell growth
by 50%.
5. Experimental
5.1. General
The results revealed that both 8-oxo-8H-acenaph-
tho[1,2-b]pyrrole-9-carboxylic acid esters and amino
derivatives of esters possessed desirable antitumor activ-
ity. Surprisingly, 3-amino derivatives 4a–j of 3a dis-
played weaker activity than that of parent 3a, and
only 4b showed similar activity to 3a. Also surprising
is considerably high activity of amino derivatives 4l
and 4m of 3f bearing Br in ester group chain (0.60 and
1
All the solvents were of analytic grade. H and
1
3
C NMR were obtained with a Bruker AV-400 spec-
trometer with chemical shifts reported as ppm (in
6
CDCl /DMSO-d TMS as internal standard). IR
3
was obtained using a Perkin-Elmer 2000 FTIR instru-
ment. High-resolution mass spectra (HRMS) were
obtained on a HPLC-Q-Tof MS (Micro) spectrome-
ter. Melting points were determined by an X-6
micro-melting point apparatus and are uncorrected.
Column chromatography was performed using silica
gel 200–300 mesh.
0
.032 lM for 4l, 0.14 and 0.019 lM for 4m against
A549 and P388, respectively), which was greatly higher
than that of the amino derivatives of methyl esters.
Thus, it was speculated that the well-known reactivity
of alkyl halide suggested that 2-bromoethyl ester moiety
might confer alkylating activity in this series of com-
pounds. The speculation was consistent with previous
5.2. 8-Oxo-8H-acenaphtho[1,2-b]pyrrole-9-carboxylic
acid (2)
1
3,14
report,
excellent leaving groups such as chloride
and bromide are required for cytotoxicity in an alkyl-
ation mechanism.
8-Oxo-8H-acenaphtho[1,2-b]pyrrol-9-carbonitrile 1 (10 mmol)
was added to 10 mL of 98% H SO at room tempera-
2
4
ture. The reaction mixture was stirred for 10 h and then
poured onto crushed ice. The solid precipitate was fil-
tered, washed by water, and dried to give a brown yel-
Moreover, the derivatives bearing aminoalkyl amine
substituent, whether chain aliphatic amines 4f, 4g, 4l,
and 4m or alicyclic amines 4b, possessed higher activ-
ity than that of other amino-substituted derivatives. In
fact, the requirement for a basic side chain, such as an
N-dialkyl group, in enhancing antitumor activity was
demonstrated in naphthalimide, pyridocarbazoles,
anthracyclines, acridines, and phenazines, among oth-
1
low powder. Yield 95%. Mp 245 °C dec. H NMR
6
*
(400 MHz, DMSO-d ) d = 11.41(s, 1H, OH ), 8.95 (d,
1H, J = 7.2 Hz), 8.55 (d, 1H, J = 8.0 Hz), 8.53 (d, 1H,
J = 7.2 Hz), 8.48 (d, 1H, J = 8.0 Hz), 7.96 (dd, 1H,
J = 8.0 Hz, J = 7.2 Hz), 7.88 (dd, 1H, J = 8.0 Hz,
1
2
1
À1
À
J2 = 7.2 Hz). IR (KBr) cm : 3208, 1774, 1700, 1636,
1583, 1570. MS m/z (MÀH) 248.1(API-ES).
2
,15,16
ers.
But unlike naphthalimide compounds, those

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F. Liu et al. / Bioorg. Med. Chem. 14 (2006) 4639–4644
5.3. General procedure for the preparation of 8-oxo-8H-
acenaphtho[1,2-b]pyrrole-9-carboxylic acid esters (3a–c)
5.4.1. 8-Oxo-8H-acenaphtho[1,2-b]pyrrole-9-carboxylic
acid ethoxycarbonylmethyl ester (3d). Yield 93%. Mp
1
1
67–168 °C H NMR (400 MHz, CDCl ): d = 9.10 (d,
3
8
-Oxo-8H-acenaphtho[1,2-b]pyrrol-9-carboxylic acid 2
6 mmol) and corresponding iodide (30 mmol) were add-
ed to 50 mL CH CN in the presence of K CO
1H, J = 7.6 Hz), 8.75 (d, 1H, J = 7.6 Hz), 8.32 (d, 1H,
J = 8.0 Hz), 8.27 (d, 1H, J = 8.0 Hz), 7.87 (dd, 1H,
J = 8.0 Hz, J = 7.6 Hz), 7.77 (dd, 1H, J = 8.0 Hz,
(
3
2
3
1
2
1
*
(
6.5 mmol). The mixture was stirred for 12–16 h at
J = 7.6 Hz), 4.45 (s, 2H, COOCH COOC H ), 4.25
2 2 2 5
*
3
5–50 °C, then was filtered and the filtrate was obtained.
(q, 2H, J = 7.0 Hz, COOCH CH ), 1.30 ppm (t, 3H,
2 3
À1
J = 7.0 Hz, COOCH CH ). IR (KBr) cm : 3057,
2 3
*
The solvent was removed under reduced pressure and
the residue was subjected to column chromatography
on silica gel. 3a–c were separated with CH Cl /CH OH
2985, 2924, 1770, 1746, 1712, 1643, 1584, 1571. HRMS
(ESI) m/z (M+Na) calcd for C H NNaO 358.0691,
found 358.0682.
+
2
2
3
19 13
5
1
20:1(v/v) as yellow powders.
5
.3.1. 8-Oxo-8H-acenaphtho[1,2-b]pyrrole-9-carboxylic
5.4.2. 8-Oxo-8H-acenaphtho[1,2-b]pyrrole-9-carboxylic
1
1
acid methyl ester (3a). Yield 98%. Mp 202 °C dec. H
NMR (400 MHz, CDCl ): d = 9.12 (d, 1H,
acid benzyl ester (3e). Yield 51%. Mp 215 °C dec. H
NMR (400 MHz, CDCl ): d = 9.08 (d, 1H, J = 7.6 Hz),
3
3
J = 7.2 Hz), 8.75 (d, 1H, J = 7.6 Hz), 8.31 (d, 1H,
J = 8.0 Hz), 8.25 (d, 1H, J = 8.0 Hz), 7.87 (dd, 1H,
J = 8.0 Hz, J = 7.2 Hz), 7.77 (dd, 1H, J = 8.0 Hz,
8.72 (d, 1H, J = 7.6 Hz), 8.27 (d, 1H, J = 8.0 Hz), 8.21
(d, 1H, J = 8.0 Hz), 7.84 (dd, 1H, J1 = 8.0 Hz,
J = 7.6 Hz), 7.72 (dd, 1H, J = 8.0 Hz, J = 7.6 Hz),
1
2
1
2
1
2
*
À1
J = 7.6 Hz), 3.20 ppm (s, 3H, CH ). IR (KBr) cm
3
:
068, 2933, 1765, 1712, 1645, 1586, 1571. HRMS
7.48 (d, 2H, J = 7.2 Hz), 7.34 (t, 1H, J = 7.2 Hz), 7.29
*
2
3
(d, 2H, J = 7.2 Hz), 4.85 ppm (s, 2H, COOCH Ph).
2
+
ESI) m/z (M+H) calcd for C H NO 264.0661,
13
(
found 264.0672.
C NMR (100 MHz, CDCl ): 178.8, 168.9, 166.5,
3
1
6
10
3
143.0, 137.1, 136.3, 136.2, 134.1, 132.7, 132.2, 131.6,
129.2, 129.0, 128.9, 128.2, 128.0, 127.4, 125.5, 121.4,
41.8. IR (KBr) cm : 1768, 1711, 1641, 1586, 1571.
À1
5
.3.2. 8-Oxo-8H-acenaphtho[1,2-b]pyrrole-9-carboxylic
1
+
HRMS (ESI) m/z (M+Na) calcd for C H NNaO
362.0793, found 362.0807.
acid ethyl ester (3b). Yield 83%. Mp 214–215 °C. H
NMR (400 MHz, CDCl ): d = 9.11 (d, 1H, J = 7.2 Hz),
2
2
13
3
3
8
(
.73 (d, 1H, J = 7.6 Hz), 8.29 (d, 1H, J = 8.0 Hz), 8.24
d, 1H, J = 8.0 Hz), 7.86 (dd, 1H, J1 = 8.0 Hz,
J = 7.6 Hz), 7.76 (dd, 1H, J = 8.0 Hz, J = 7.6 Hz),
5.4.3. 8-Oxo-8H-acenaphtho[1,2-b]pyrrole-9-carboxylic
acid 2-bromo-ethyl ester (3f). Yield 18%. Mp 205–
2
1
2
*
1
3.76 (q, 2H, J = 7.2 Hz, CH CH ), 1.31 (t, 3H,
*
J = 7.2 Hz, CH CH ). C NMR (100 MHz, CDCl3):
206 °C. H NMR (400 MHz, CDCl ): d = 9.10 (d, 1H,
2
3
3
1
3
J = 7.6 Hz), 8.74 (d, 1H, J = 7.6 Hz), 8.31 (d, 1H,
J = 7.6 Hz), 8.26 (d, 1H, J = 8.0 Hz), 7.86 (dd, 1H,
J = 7.6 Hz, J = 7.6 Hz), 7.77 (dd, 1H, J = 8.0 Hz,
J = 7.6 Hz), 4.13 (t, 2H, J = 6.4 Hz, CH CH Br), 3.66
2 2 2
(t, 2H, J = 6.4 Hz, CH CH Br). C NMR (100 MHz,
2 2
2
3
1
1
1
1
78.6, 168.9, 166.5, 142.9, 136.8, 136.0, 133.8, 132.5,
32.0, 131.51, 129.1, 127.8, 127.3, 125.4, 121.3, 39.0,
3.3. IR (KBr) cm : 3102, 2978, 1766, 1704, 1647,
1
2
1
À1
*
+
13
*
587, 1572. HRMS (ESI) m/z (M+Na) calcd for
C H NNaO 300.0637, found 300.0642.
1
CDCl ): d = 178.7, 168.7, 166.3, 142.9, 137.2, 136.5,
7
11
3
3
1
34.2, 132.7, 132.3, 131.6, 129.3, 128.1, 127.5, 125.3,
121.3, 39.5, 28.3. IR (KBr) cm : 3063, 2921, 1769,
À1
5
.3.3. 8-Oxo-8H-acenaphtho[1,2-b]pyrrole-9-carboxylic
1
+
1712, 1647, 1585, 1572. HRMS (ESI) m/z (M+Na) calcd
acid butyl ester (3c). Yield 40%. Mp 167–168 °C. H
NMR (400 MHz, CDCl ): d = 9.07 (d, 1H, J = 7.6 Hz),
for C H BrNNaO 377.9742, found 377.9730.
17 10
3
3
8
(
.70 (d, 1H, J = 7.6 Hz), 8.27 (d, 1H, J = 8.0 Hz), 8.21
d, 1H, J = 8.0 Hz), 7.83 (dd, 1H, J1 = 8.0 Hz,
J = 7.6 Hz), 7.73 (t, 1H, J = 8.0 Hz, J = 7.6 Hz),
5.5. General procedure for the preparation of 3-substi-
tuted-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carboxylic
acid esters (4a–n)
2
1
2
*
3.69 (t, 2H, J = 7.2 Hz, OCH ), 1.68 (m, 2H,
2
J = 7.2 Hz, OCH CH ), 1.38 (m, 2H, J = 7.2 Hz,
CH CH ), 0.96 ppm (t, 3H, J = 7.2 Hz, CH CH ).
2
*
2
2
*
*
8-Oxo-8H-acenaphtho[1,2-b]pyrrol-9-carboxylic acid esters
(0.5 mmol) and corresponding amines (2 mmol) in
3
2
3
À1
IR (KBr) cm : 3096, 2942, 1769, 1710, 1645, 1587,
1
for C H NNaO 328.0950, found 328.0940.
+
572, 1508, 1436. HRMS (ESI) m/z (M+Na) calcd
CH CN (20 mL) were stirred for 1–2 h at 50–60 °C.
3
The solvent was removed under reduced pressure and
the residue was subjected to column chromatography
on silica gel. 3-substituted products 4a–n were separated
with CH Cl /CH OH 20:1(v/v) as dark purple powders.
1
9
15
3
5.4. General procedure for the preparation of 8-oxo-8H-
acenaphtho[1,2-b]pyrrole-9-carboxylic acid esters (3d–f)
2
2
3
8
(
-Oxo-8H-acenaphtho[1,2-b]pyrrol-9-carboxylic acid 6
6 mmol) and corresponding bromide (12 mmol) were
added to 50 mL CH CN in the presence of K CO
5.5.1. 3-Thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyr-
role-9-carboxylic acid methyl ester (4a). Yield 40%. Mp
1
245 °C dec. H NMR (400 MHz, CDCl ): d = 9.00 (d,
3
2
3
3
(
6.5 mmol). The mixture was refluxed for 16–24 h, then
1H, J = 8.0 Hz), 8.75 (d, 1H, J = 7.2 Hz), 8.43 (d, 1H,
J = 8.0 Hz), 7.80 (dd, 1H, J = 8.0 Hz, J = 7.2 Hz),
7.19 (d, 1H, J = 8.0 Hz), 3.72 (br s, 4H,
was filtered and the filtrate was obtained. The solvent
was removed under reduced pressure and the residue
was subjected to column chromatography on silica gel.
3d–f were separated with CH Cl /CH OH 80:1(v/v) as
2
yellow powders.
1
2
*
*
–N(CH CH ) S), 3.17 (s, 3H, COOCH 3), 3.00 ppm
2
2 2
1
3
*
(br s, 4H, –N(CH CH ) S). C NMR (100 MHz,
2 2 2
2
3
CDCl ): d = 178.1, 169.5, 167.3, 159.8, 142.7, 135.6,
3

F. Liu et al. / Bioorg. Med. Chem. 14 (2006) 4639–4644
4643
*
À1
1
1
1
32.9, 132.5, 132.4, 131.2, 127.6, 126.8, 121.8, 116.4,
15.5, 56.1, 28.1, 24.0. IR (KBr) cm : 2906, 1766,
705, 1633, 1571, 1511. HRMS (ESI) m/z (M+Na)
(s, 6H, CH N(CH ) ). IR (KBr) cm : 2923, 1765+,
2
3 2
À1
1703, 1685, 1654, 1626, 1563; HRMS(ESI) m/z (M+H)
calcd for C H N O 350.1505, found 350.1505.
+
2
0
20
3
3
calcd for C H N NaO S 387.0779, found 387.0768.
2
0
16
2
3
5.5.7. 3-(3-Dimethylamino-propylamino)-8-oxo-8H-ace-
naphtho[1,2-b]pyrrole-9-carboxylic acid methyl ester
5.5.2. 3-(4-Methyl-piperazin)-8-oxo-8H-acenaphtho[1,2-
b]pyrrole-9-carboxylic acid methyl ester (4b). Yield
1
(4g). Yield 35%. Mp 186–187 °C. H NMR (400 MHz,
1
6
3
8%. Mp 210 °C dec. H NMR (400 MHz, CDCl3):
d = 9.01 (d, 1H, J = 8.0 Hz), 8.77 (d, 1H, J = 7.6 Hz),
.46 (d, 1H, J = 8.4 Hz), 7.78 (dd, 1H, J = 8.0 Hz,
DMSO-d ): d = 8.79 (d, 2H, J = 8.8 Hz), 8.59 (d, 1H,
J = 7.6 Hz), 7.84 (dd, 1H, J = 7.6 Hz, J = 8.0 Hz),
*
1
2
8
6.99 (d, 1H, J = 8.8 Hz), 3.61 (br s, 2H, NHCH CH ),
2 2
1
*
J = 7.6 Hz), 7.17 (d, 1H, J = 8.4 Hz), 3.55 (br s, 4H,
2
3.17 (br s, 2H, (CH ) NCH CH ), 2.98 (s, 3H,
3 2 2 2
*
*
*
*
–
N(CH CH ) NCH ), 3.17 (s, 3H, COOCH ), 3.46
2
COOCH ), 2.38 ppm (s, 6H, N(CH ) ), 1.95 (m, 2H,
3 3 2
2 2
3
3
À1
NHCH CH ). IR (KBr) cm : 3047, 2912, 1749, 1702,
2 2
*
*
(br s, 4H, –N(CH CH ) NCH ), 2.48 ppm (br s, 3H,
NCH ). IR (KBr) cm : 2929, 1765, 1702, 1629, 1572,
509. HRMS (ESI) m/z (M +
C H N O 362.1505, found 362.1449.
2
2 2
À1
3
+
1624, 1567, 1545, 1511. HRMS (ESI) m/z (M+H) calcd
for C H N O 364.1661, found 364.1665.
3
+
H) calcd for
1
2
1
22
3
3
2
1
20
3
3
5.5.8. 3-(2-Ethylsulfonyl-ethylamino)-8-oxo-8H-acenaph-
tho[1,2-b]pyrrole-9-carboxylic acid methyl ester (4h).
5
9
>
.5.3. 3-Morpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-
-carboxylic acid methyl ester (4c). Yield 40%. Mp
1
Yield 40%. Mp 135–136 °C. H NMR (400 MHz,
1
6
*
300 °C. H NMR (400 MHz, CDCl ): d = 8.98 (d,
DMSO-d ): d = 9.21 (br s, 1H, NH ), 8.85–8.89 (m,
2H), 8.65 (d, 1H, J = 7.2 Hz), 7.87 (dd, 1H,
J = 7.2 Hz, J = 8.4 Hz), 7.04 (d, 1H, J = 8.8 Hz), 3.77
3
1
J = 8.4 Hz), 7.77 (dd, 1H, J = 8.0 Hz, J = 7.6 Hz),
7
–
3
H, J = 8.0 Hz), 8.72 (d, 1H, J = 7.6 Hz), 8.46 (d, 1H,
1
2
1
2
*
.16 (d, 1H, J = 8.4 Hz), 4.05 (br s, 4H,
*
(q, 2H, NHCH CH , J = 6.4 Hz), 2.99 (s, 3H,
2 2
*
*
*
N(CH CH ) O), 3.46 (br s, 4H, –N(CH CH ) O),
2 2
COOCH ), 2.92 (t, 2H, NHCH CH , J = 6.8 Hz),
3 2 2
2
2 2
2
*
13
.17 ppm (s, 3H, COOCH ). C NMR (100 MHz,
*
*
2.64 (q, 2H, SCH ),1.23 ppm (t, 3H, CH ). IR (KBr)
3
3
2
À1
+
CDCl ): d = 178.1, 169.5, 167.3, 158.8, 142.7, 135.7,
cm
:
HRMS (ESI) m/z (M+H)
calcd for
3
1
1
1
33.0, 132.6, 132.4, 131.3, 130.8, 127.2, 126.7, 121.8,
15.4, 66.9, 54.0, 24.0. IR (KBr) cm : 2923, 1767,
702, 1631, 1576, 1519. HRMS (ESI) m/z (M+H) calcd
C H N O S 367.1116, found 367.1124.
20 19 2 3
À1
+
5.5.9. 3-(3-Methylsulfonyl-propylamino)-8-oxo-8H-ace-
naphtho[1,2-b]pyrrole-9-carboxylic acid methyl ester
for C H N O 349.1188, found 349.1189.
2
2
0
17
4
1
(
4i). Yield 41%. Mp 280 °C dec. H NMR (400 MHz,
6
*
5
.5.4. 3-Piperidin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-
carboxylic acid methyl ester (4d). Yield 36%. Mp 148–
DMSO-d ): d = 9.33 (br s, 1H, NH ), 8.93 (d, 1H,
J = 8.4 Hz), 8.84 (d, 1H, J = 8.8 Hz), 8.62 (d, 1H,
J = 7.6 Hz), 7.86 (dd, 1H, J = 7.6 Hz, J = 8.4 Hz),
1
6
1
1
49 °C. H NMR (400 MHz, DMSO-d ): d = 8.84 (d,
H, J = 8.0 Hz), 8.58 (d, 1H, J = 7.6 Hz), 8.51 (d, 1H,
J = 8.0 Hz), 7.88 (dd, 1H, J = 7.6 Hz, J = 8.0 Hz),
1
2
*
7.04 (d, 1H, J = 8.8 Hz), 3.65 (q, 2H, NHCH CH ,
2
2
*
J = 6.0 Hz), 2.97 (s, 3H, COOCH ), 2.63 (t, 2H,
3
1
2
*
*
7
.35 (d, 1H, J = 8.0 Hz), 4.17 (br s, 4H,
*
SCH , J = 6.8 Hz), 2.09 (s, 3H, SCH ), 2.00 ppm (t,
2 3
*
*
À1
2H, NHCH CH , J = 6.8 Hz). IR (KBr) cm : 2925,
2 2
–
s, 4H, –N(CH CH ) CH ), 1.74 ppm (br s, 2H,
N(CH CH ) CH ), 2.99 (s, 3H, COOCH ), 1.84 (br
*
2
2 2
2
3
2676, 1745, 1708, 1640, 1624, 1593, 1561. HRMS(ESI)
m/z (M+H) calcd for C H N O S 367.1116, found
367.1104.
2
2 2
2
*
2
À1
+
–
N(CH CH ) CH ). IR (KBr) cm : 2923, 1708,
2 2
2
20 19
2
3
+
630, 1573, 1540, 1519. HRMS (ESI) m/z (M+H) calcd
1
for C H N O 347.1396, found 347.1386.
2
1
19
2
3
5
.5.10.
3-(2-Phenylamino-ethylamino)-8-oxo-8H-ace-
naphtho[1,2-b]pyrrole-9-carboxylic acid methyl ester
5
.5.5.
3-[(Thiophen-2-ylmethyl)-amino]-8-oxo-8H-ace-
naphtho[1,2-b]pyrrole-9-carboxylic acid methyl ester
1
(4j). Yield 32%. Mp 180 °C dec. H NMR (400 MHz,
DMSO-d ): d = 9.24 (br s, 1H, NH CH CH NHPh),
2 2
1
6
*
(
4e). Yield 41%. Mp 240 °C dec. H NMR (400 MHz,
6
*
d -DMSO): d = 9.71(br s, 1H, NH ), 8.87 (d, 1H,
J = 8.0 Hz), 8.77 (d, 1H, J = 8.8 Hz), 8.60 (d, 1H,
J = 7.6 Hz), 7.86 (dd, 1H, J = 7.6 Hz, J = 8.0 Hz),
8.85 (d, 1H, J = 8.8 Hz), 8.79 (d, 1H, J = 7.6 Hz), 8.61
(d, 1H, J = 8.0 Hz), 7.86 (dd, 1H, J1 = 7.6 Hz,
J2 = 8.0 Hz), 7.10 (t, 2H, J = 8.0 Hz), 7.01 (d, 1H,
J = 8.8 Hz), 6.64 (d, 2H, J = 7.6 Hz), 6.56 (t, 1H,
1
2
7
.46 (d, 1H, J = 3.6 Hz), 7.23 (d, 1H, J = 3.6 Hz), 7.09
d, 1H, J = 8.8 Hz), 7.02 (dd, 1H, J1 = 3.6 Hz,
*
(
J = 3.6 Hz), 4.98 (s, 2H, CH ), 2.97 ppm (s, 3H,
COOCH ). IR (KBr) cm : 3298, 2923, 1748, 1710,
3
1693, 1624, 1563, 1525. HRMS (ESI) m/z (M+Na)
calcd for C H N NaO S 397.0623, found 397.0614.
J = 7.0 Hz), 5.85 (br s, 1H, NHCH CH NH Ph), 3.74
2
2
*
*
(br s, 2H, NHCH CH NHPh), 3.46 (br s, 2H,
2 2
2
2
*
À1
*
*
NHCH CH NHPh), 2.97 ppm (s, 3H, COOCH ). IR
2 2 3
+
À1
(KBr) cm : 3015, 2919, 1749, 1699, 1624, 1599, 1567,
calcd for
+
1505. HRMS (ESI) m/z (M+H)
C H N O 398.1505, found 398.1497.
2
1
14
2
3
2
4
20
2
3
5.5.6. 3-(Dimethylamino-ethylamino)-8-oxo-8H-acenaph-
tho[1,2-b]pyrrole-9-carboxylic acid methyl ester (4f). Yield
5.5.11. 3-Thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyr-
role-9-carboxylic acid 2-bromo-ethyl ester (4k). Yield
35%. Mp 173 °C dec. H NMR (400 MHz, CDCl3):
d = 9.03 (d, 1H, J = 8.4 Hz), 8.78 (d, 1H, J = 7.2 Hz),
1
6
3
8%. Mp 220 °C dec. H NMR (400 MHz, DMSO-d ):
d = 8.84 (d, 2H, J = 8.8 Hz), 8.62 (d, 1H, J = 7.2 Hz),
.85 (dd, 1H, J = 7.2 Hz, J = 8.0 Hz), 7.02 (d, 1H,
1
7
1
2
*
J = 8.8 Hz), 3.71 (br s, 2H, NHCH CH ), 2.98 (s, 3H,
2
8.44 (d, 1H, J = 8.0 Hz), 7.82 (dd, 1H, J = 7.2 Hz,
J2 = 8.4 Hz), 7.20 (d, 1H, J = 8.0 Hz), 4.11((t, 2H,
2
1
*
*
COOCH ), 2.84 (br s, 2H, CH N(CH ) ), 2.41 ppm
2
3
3 2

4644
F. Liu et al. / Bioorg. Med. Chem. 14 (2006) 4639–4644
*
*
J = 6.4 Hz, OCH ), 3.64 (t, 2H, J = 6.4 Hz, CH Br),
2
plan for High-Tech (2003AA2Z3520) is greatly appreci-
ated. This work is also supported by Dalian Excellent
Young Scientist Research Fund.
2
*
3
–
1
.72 (br s, 4H, –N(CH CH ) S), 3.00 ppm (br s, 4H,
2 2 2
À1
*
N(CH CH ) S). IR (KBr) cm : 2916, 1753, 1703,
2 2 2
+
628, 1601, 1570. HRMS (ESI) m/z (M+H) calcd for
C H BrN O S 457.0222, found 457.0211.
3
2
1
18
2
References and notes
5
naphtho[1,2-b]pyrrole-9-carboxylic acid 2-bromo-ethyl
.5.12.
3-(Dimethylamino-ethylamino)-8-oxo-8H-ace-
1
2
. Mereyala, H. B.; Joe, M. Curr. Med. Chem. Anti-Cancer
Agents 2001, 1, 293.
. Bra n˜ a, M. F.; Ramos, A. Curr. Med. Chem. Anti-Cancer
Agents 2001, 1, 237.
1
ester (4l). Yield 38%. Mp >300 °C. H NMR (400 MHz,
6
DMSO-d ): d = 8.85 (d, 1H, J = 8.0 Hz), 8.78 (d, 1H,
J = 8.8 Hz), 8.60 (d, 1H, J = 7.2 Hz), 7.85 (dd, 1H,
J = 7.2 Hz, J = 8.0 Hz), 7.03 (d, 1H, J = 8.8 Hz), 3.92
1
3. Tsuchiya, T.; Takagi, Y.; Yamada, H. Bioorg. Med. Chem.
Lett. 2000, 10, 203.
2
*
(
CH Br), 3.69 (t, 2H, J = 6.4 Hz, NHCH ), 2.69 (t, 2H,
t, 2H, J = 6.4 Hz, OCH ), 3.71 (t, 2H, J = 6.4 Hz,
2
*
*
4. (a) Li, Y.; Xu, Y.; Qian, X., et al. Bioorg. Med. Chem.
Lett. 2003, 13, 3513; (b) Qian, X.; Li, Y.; Xu, Y., et al.
Bioorg. Med. Chem. Lett. 2004, 14, 2665; (c) Li, Y.; Xu,
Y.; Qian, X., et al. Tetrahedron Lett. 2004, 45, 1247; (d)
Xu, Y.; Qu, B.; Qian, X.; Li, Y., et al. Bioorg. Med. Chem.
Lett. 2005, 15, 1139; (e) Li, Zh.; Yang, Q.; Qian, X.
Bioorg. Med. Chem. Lett. 2005, 15, 1769.
2
2
*
J = 6.4 Hz,
*
CH N(CH ) ),
2.29 ppm
N(CH ) ). IR (KBr) cm : 2928, 1750, 1698, 1625,
(s,
6H,
2
3 2
À1
3
2
+
572, 1546. HRMS (ESI) m/z (M+H) calcd for
1
C H BrN O 442.0766, found 442.0753.
2
1
21
3
3
5.5.13. 3-(3-Dimethylamino-propylamino)-8-oxo-8H-ace-
naphtho[1,2-b]pyrrole-9-carboxylic acid 2-bromo-ethyl
5
. (a) Tsubuki, M.; Kanai, K.; Nagase, H.; Honda, T.
Tetrahedron 1999, 55, 2493; (b) Kigoshi, H.; Suenaga, K.;
Takagi, M.; Akao, A., et al. Tetrahedron 2002, 58, 1075;
(c) Langlois, N.; Rojas-Rousseau, A.; Gaspard, C.;
Werner, G. H.; Darro, F. J. Med. Chem. 2001, 44, 3754;
1
ester (4m). Yield 35%. Mp 220 °C dec. H NMR
6
(
400 MHz, DMSO-d ): d = 9.52 (br s, NH), 8.84 (d,
1
H, J = 8.0 Hz), 8.83 (d, 1H, J = 8.8 Hz), 8.63 (d, 1H,
J = 7.6 Hz), 7.88 (dd, 1H, J = 7.6 Hz, J = 8.0 Hz),
(
d) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.;
1
2
McPhail, A. T. J. Am. Chem. Soc. 1971, 93, 2325; (e)
Schiff, P. B.; Fant, J.; Horwitz, S. B. Nature 1979, 277,
7
OCH ), 3.71 (t, 2H, J = 6.4 Hz, CH Br), 3.63 (br s,
.05 (d, 1H, J = 8.8 Hz), 3.93 (t, 2H, J = 6.4 Hz,
*
*
2
2
6
65.
*
*
2
H, NHCH ), 2.67 (br s, 2H, CH
2
N(CH3)2),
2
6
. (a) Antonini, I.; Polucci, P.; Magnano, A.; Martelli, S. J.
Med. Chem. 2001, 44, 3329; (b) Tandon, V. K.; Yadav, D.
B.; Chaturvedib, A. K.; Shuka, P. K. Bioorg. Med. Chem.
Lett. 2005, 15, 3288; (c) Andreani, A.; Granaiola, M.;
Leoni, A.; Locatelli, A.; Morigi, R.; Rambaldi, M.;
Garaliene, V. J. Med. Chem. 2002, 45, 2666; (d) Magnano,
A.; Sparapani, S.; Lucciarini, R.; Michela, M.; Amantini,
C.; Santonib, G.; Antonini, I. Bioorg. Med. Chem. 2004,
*
2
CH CH CH ). IR (KBr) cm : 2938, 2776, 1748,
.40 ppm (s, 6H, N(CH ) ), 1.96 (m, 2H,
*
3
2
À1
2
2
2
1
698, 1626, 1571, 1546, 1507. HRMS (ESI) m/z
+
(
M+H) calcd for C H BrN O S 456.0923, found
22 24 3 3
4
56.0930.
5
naphtho[1,2-b]pyrrole-9-carboxylic acid 2-bromo-ethyl
.5.14.
3-(2-Phenylamino-ethylamino)-8-oxo-8H-ace-
1
2, 5941.
1
7. Adel, N.; John, M. O.; Richard, A. H. Chem. Rev 1997,
97, 449.
ester (4n). Yield 30%. Mp 240 °C dec. H NMR
6
(
NH CH CH NHPh), 8.84 (d, 1H, J = 8.8 Hz), 8.80 (d,
400 MHz, DMSO-d ): d = 9.15 (br s, 1H,
8
. Xiao, Y.; Liu, F.; Qian, X.; Cui, J. Chem. Commun. 2005,
39.
. Zhang, S.; Jia, Z.; Wang, Y. Bioorg. Med. Chem. 2002, 10,
*
2
2
2
1
H, J = 7.6 Hz), 8.60 (d, 1H, J = 8.0 Hz), 7.88 (dd, 1H,
J = 7.6 Hz, J = 8.0 Hz), 7.11 (t, 2H, J = 8.0 Hz), 7.03
9
1
2
3899.
10. Lorente, A.; V a´ zquez, Y. G.; Fern a´ ndez, M. J.; Ferr a´ ndez,
A. Bioorg. Med. Chem. 2004, 12, 43072.
11. Skehan, P.; Storeny, R.; Scudiero, D.; Monks, A.;
McMahon, J.; Vistica, D.; Warren, J. T.; Bokesc, H.;
Kenney, S.; Boyd, M. R. J. Natl. Cancer Inst. 1990, 82,
(
1
3
d, 1H, J = 8.8 Hz), 6.66 (d, 2H, J = 7.6 Hz), 6.54 (t,
*
H, J = 7.0 Hz), 5.82 (br s, 1H, NHCH CH NH Ph),
2 2
*
2
.92 (t, 2H, J = 6.4 Hz, OCH ), 3.75 (br s, 2H,
*
*
NHCH CH NHPh), 3.70 (t, 2H, J = 6.4 Hz, CH Br),
3
3
(
found 490.0760.
2
2
2
À1
.43 (br s, 2H, NHCH CH NHPh). IR (KBr) cm :
2 2
*
1
107.
12. Kuroda, M.; Mimaki, Y.; Sashida, Y.; Hirano, T.; Oka,
299, 3047, 1750, 1699, 1625, 1600, 1569. HRMS
+
ESI) m/z (M+H) calcd for C H BrN O 490.0766,
25 22 3 3
K.; Dobashi, A.; Li, H.; Harada, N. Tetrahedron 1997, 53,
1
1549.
1
3. Ballistreri, F. P.; Barresi, V.; Benedetti, P.; Caltabiano, G.;
Fortuna, C. G.; Longo, M. L.; Musumarra, G. Bioorg.
Med. Chem. 2004, 12, 1689.
5
.6. In vitro growth delay assays
The prepared compounds were submitted to Shanghai
Institute of Materia Medica and Department of Biosci-
ence and Biotechnology in Dalian University of Tech-
14. (a) Meade, E. A.; Wotring, L. L.; Drach, J. C.;
Townsend, L. B. J. Med. Chem. 1993, 36, 3834; J.
Med. Chem 1997, 40, 794; (b) Thompson, M. D.;
Cupps, T. L.; Wise, D. S.; Wotring, L. L.; Townsend, L.
B. J. Med. Chem. 1997, 40, 766; (c) Skibo, E. B.;
Huang, X.; Martinez, R.; Lemus, R. H.; Craigo, W. A.
J. Med. Chem. 2002, 45, 5543.
nology, respectively, with
cytotoxicities tested.
a
view to get their
1
5. Snyder, R. D.; Hendry, L. B. Environ. Mol. Mutagenesis
005, 45, 100.
Acknowledgments
2
1
6. (a) Ferguson, L. R.; Denny, W. A. J. Med. Chem. 1979,
22, 251; (b) Wilson, W. R.; Harris, N. M.; Ferguson, L. R.
Cancer Res. 1984, 44, 4420.
Financial support by National Basic Research Program
of China (2003CB114400) and under the auspices of 863