Synthesis and cytotoxic activity evaluation of indolo-, pyrrolo-, and benzofuro-quinolin-2(1H)-ones and 6-anilinoindoloquinoline derivatives.

Article abstract of DOI:10.1016/S0968-0896(02)00111-6

Certain indolo-, pyrrolo-, and benzofuro-quinolin-2(1H)-ones 4a,b, 6, 8, 16a-c and 6-anilinoindoloquinoline derivatives 10a,b, 11a,b, 12a,b have been synthesized and evaluated in vitro against a 3-cell lines panel consisting of MCF7 (Breast), NCI-H460 (Lu

Full text of DOI:10.1016/S0968-0896(02)00111-6

Bioorganic & Medicinal Chemistry 10 (2002) 2705–2712
Synthesis and Cytotoxic Activity Evaluation of Indolo-,
Pyrrolo-, and Benzofuro-Quinolin-2(1H)-Ones and
6-Anilinoindoloquinoline Derivatives
Yeh-Long Chen,* Chao-Ho Chung, I.-Li Chen, Po-Hsu Chen and Haw-Yaun Jeng
School of Chemistry, Kaohsiung Medical University, Kaohsiung City 807, Taiwan
Received 22 November 2001; accepted 4 March 2002
Abstract—Certain indolo-, pyrrolo-, and benzofuro-quinolin-2(1H)-ones 4a,b, 6, 8, 16a–c and 6-anilinoindoloquinoline derivatives
10a,b, 11a,b, 12a,b have been synthesized and evaluated in vitro against a 3-cell lines panel consisting of MCF7 (Breast), NCI-H460
(Lung), and SF-268 (CNS). Those active compounds 4a,b, 6, 8, 10a,b, 11a,b, 12a,b were then evaluated in the full panel of 60
human tumor cell lines derived from nine cancer cell types. The results have shown that cytotoxicity decreases in the order of
6-anilinoindoloquinolines>indoloquinolin-2(1H)-ones>pyrroloquinolin-2(1H)-ones>benzofuroquinolin-2(1H)-ones. Among them,
1-[3-(11H-indolo[3,2-c]quinolin-6ylamino)phenyl]ethanone oxime hydrochloride (11a) and its 2-chloro derivative (11b) were most
active, with mean GI50 values of 1.70 and 1.35 mM, respectively. Both compounds 11a,b were also found to inhibit the growth of
SNB-75 (CNS cancer cell) with a GI50 value of less than 0.01 mM, and, therefore, were selected for further evaluation for in vivo
antitumor activity. # 2002 Published by Elsevier Science Ltd.
Introduction
thalene-type skeleton with a restricted conformation.15
The isomeric pyrroloquinolin-2(1H)-ones 6 and 8 in
which the phenyl group is appended instead of fused
on the pyrrole moiety and the isosteric benzofuro-
quinolin-2(1H)-ones 16a–c were also synthesized and
evaluated. Besides, a number of 9-anilinoacridines have
been extensively studied as potential anticancer
agents,16ꢀ20 we have also prepared certain anilino
bearing indoloquinolines 10a,b, 11a,b and 12a,b for
cytotoxic evaluation.
Quinolin-2(1H)-one (carbostyril) skeleton is present in a
large number of biologically active compounds.1ꢀ12
Among them, carteolol had been used clinically as a
b-adrenergic blocking agent.8 Over the past few years,
we were particularly interested in synthesizing a-methyl-
idene-g-butyrolactones bearing heterocycles (quinoline,
coumarin, flavone, xanthone, and quinolin-2(1H)-one)
and evaluating their cardiovascular and cytotoxic
activities.9ꢀ12 Our results indicated that quinolin-2(1H)-
one derivatives were the most potent cytotoxic agents
among them.12 On the other hand, the indole skeleton is
a basic structure of certain natural alkaloids such as
vinblastine13 and vincristine14 which have been used
clinically as anticancer drugs. The present report
describes the preparation and cytotoxic evaluation of
indolo[3,2-c]quinolin-2(1H)-ones 4a,b whose structures
belong to potential DNA intercalators in which
2-phenyl group and bicyclic quinolin-2(1H)-one are
locked through a nitrogen bridge to form a coplanar
tetracyclic structure. This type of structure can also be
considered as potential antitumor 2-phenylnaph-
Chemistry
A general synthesis of indolo- and pyrrolo-quinolin-
2(1H)-ones 4a,b, 6 and 8 are shown in Scheme 1.
4-Hydrazinoquinolin-2(1H)-ones 2a,b were prepared by
the reaction of hydrazine with the corresponding
4-hydroxyquinolin-2(1H)-ones 1a,b.21,22 Treatment of
2a,b respectively with cyclohexanone gave the corre-
sponding hydrazones 3a,b. Their thermal Fischer indo-
lization followed by the dehydrogenation afforded the
desired indoloquinolin-2(1H)-ones 4a,b. The pyrrolo-
quinolin-2(1H)-ones 6 and 8 were obtained via the
thermal cyclization of their respective hydrazones 5 and
7 which in turn were prepared from 2a and phenyl-
acetaldehyde and deoxybenzoin, respectively.
*Corresponding author. Tel.: +886-7-3121101x2249; fax: +886-7-
3125339; e-mail: yeloch@cc.kmu.edu.tw
0968-0896/02/$ - see front matter # 2002 Published by Elsevier Science Ltd.
PII: S0968-0896(02)00111-6

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Y.-L. Chen et al. / Bioorg. Med. Chem. 10 (2002) 2705–2712
Scheme 1. Reagents: (i) NH2NH2, in ethoxyethanol; (ii) cyclohexanone in AcOH; (iii) Pd/C inPh2O; (iv) phenylacetaldehyde in AcOH; (v) deoxy-
benzoin in AcOH; (vi) Ph2O.
Scheme 2. Reagents: (i) POCl3; (ii) 3-aminoacetophenone in 2-BuOH; (iii) NH2OH or NH2OCH3 in MeOH.
Chlorination of 4a with phosphorus oxychloride gave
6-chloro-11H-indolo[3,2-c]quinoline (9a) as shown in
Scheme 2. Reaction of 9a with 3-aminoacetophenone
Preparation of benzofuroquinolin-2(1H)-ones 16a–c is
outlined in Scheme 3. 4-Hydroxy-3-phenylquinolin-
2(1H)-ones 13a–c were obtained from diethyl 2-phenyl-
malonate and appropriate anilines in an 1:1 fusion
reaction at 250–350 ꢁC.25,26 The Pd-catalyzed cyclode-
hydrogenation27 of 13a–c afforded their respective benzo-
furoquinolin-2(1H)-ones 16a–c. Compound 16b can
also be obtained by the acid-catalyzed cyclodehydration
of 3-hydroxy-7-methoxy-3-phenyl-1H-quinolin-2,4-dione
(14) which was prepared by the oxidation of 13b.28
afforded
1-[3-(11H-indolo[3,2-c]quinolin-6-ylamino)-
phenyl]ethanone hydrochloride (10a) which was treated
with hydroxylamine and methoxyamine, respectively, in
ethanol to give exclusively E-form isomer of oxime 11a
and O-methyl-oxime 12a.23,24 Accordingly, 11b and 12b
were prepared from 9b which in turn was obtained by
chlorination of 4b with POCl3.

Y.-L. Chen et al. / Bioorg. Med. Chem. 10 (2002) 2705–2712
2707
Scheme 3. Reagents: (i) neat, reflux; (ii) alkaline H2O2; (iii) P2O5, CH3SO3H; (iv) Pd/C in Ph2O; (v) pyridine HCl.
Compound 16c was also synthesized by the demethyl-
cyclization of 6-fluoro-4-hydroxy-3-(2-methoxyphenyl)-
quinolin-2(1H)-one (15) with pyridine hydrochloride.29
(negative numbers indicate cell kill) are passed on for
evaluation in the full panel of 60 cell lines over a 5-log
dose range. Results from Table 1indicated all of them,
with the exception of compounds 16a–c, pass the 3-cell
lines primary screening.
Results and Discussion
Those active compounds 4a,b, 6, 8, 10a,b, 11a,b, and
12a,b were tested in US National Cancer Institute’s
human tumor cell line screen.30 This assay involves
determination of a test agent’s effect on growth para-
meters against a panel of approximately 60 human
tumor cell lines, mostly derived from solid tumors. For
each compound, dose-response curves for each cell line
were measured with five different drug concentration,
the concentration causing 50% cell growth inhibition
(GI50) compared with the control were calculated and
summarized in Table 2. The tetracyclic indolo-
[3,2-c]quinolin-2(1H)-ones 4a and 4b demonstrated a
moderate inhibitory activity with a mean GI50 value of
19.0 and 18.2 mM respectively while the isomeric tricyclic
1H-pyrrolo[3,2-c]quinolin-2(1H)-one (6), in which a
phenyl ring was appended on the pyrrole moiety, was
less active with a mean GI50 of 27.5 mM. Additional
phenyl ring appended on the pyrrole moiety slightly
decreased cytotoxicity (6 versus 8). The anilino-sub-
stituent enhanced cytotoxicity of indolo[3,2-c]quinolin-
2(1H)-ones (10a, 4.26 mM versus 4a, 19.0 mM). The
cytotoxicity was further enhanced by converting the
ketone group of 10a and 10b to their respective oximes
11a (GI50 values of 1.70 mM) and 11b (1.35 mM). Fur-
thermore, 11a and 11b exhibited excellent selective inhi-
bition against CNS cancer cell lines with a GI50 value of
0.93 and 0.78 mM, respectively. However, the methoxy-
amino-counterparts 12a (6.92 mM) and 12b (7.76 mM),
were less active. The inhibitory activity of selective
compounds 4b, 6, 10a,b, and 11a,b against certain can-
cer cells is illustrated in Table 3. Compound 4b was not
only active against the growth of CCRF-CEM and SR
(leukemia), but also active against certain solid tumors
All compounds 4a,b, 6, 8, 10a,b, 11a,b, 12a,b, and 16a–c
were evaluated in vitro against a 3-cell lines panel con-
sisting of MCF7 (breast), NCI-H460 (lung), and SF-268
(CNS). In this protocol, each cell line is inoculated and
preincubated on a microtiter plate. Test agents are then
added at a single concentration (100 mM) and the cul-
ture incubated for 48 h. End-point determinations are
made with sulforhodamine B, a protein-binding dye.
Results for each test agent are reported as the percent of
growth of the treated cells when compared to the
untreated control cells. Compounds which reduced the
growth of any one of the cell lines to 32% or less
Table 1. Primary anticancer assay of indolo-, pyrrolo-, and benzo-
furo-quinolin-2(1H)-ones and 6-anilinoindoloquinoline derivatives
Compd
Percentage of growth inhibition
NCI-H460
(lung)
MCF7
(breast)
SF-268
(CNS)
4a
4b
6
29
3
25
8
36
22
18
34
34
29
40
19
8
10a
10b
11a
11b
12a
12b
16a
16b
16c
ꢀ32
ꢀ46
ꢀ53
ꢀ55
ꢀ64
ꢀ70
105
98
ꢀ7
ꢀ6
ꢀ74
ꢀ69
ꢀ94
ꢀ96
122
108
150
ꢀ4
ꢀ10
ꢀ85
ꢀ77
ꢀ79
ꢀ82
129
111
130
102

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Y.-L. Chen et al. / Bioorg. Med. Chem. 10 (2002) 2705–2712
Table 2. Inhibition of in vitro cancer cell lines by indolo- and pyrrolo-quinolin-2(1H)-ones and 6-anilinoindoloquinoline derivatives [average GI50
(mM)]a
Compd
Leuk
Lung
Colon
CNS
Mela
Ovari
Renal
Prosta
Breast
Meanb
4a
4b
6
21.4
11.5
10.7
11.0
4.37
6.46
1.66
1.29
6.46
6.46
16.6
20.4
33.9
28.8
3.72
3.63
1.82
1.23
6.02
6.92
4.79
16.2
17.0
53.7
3.89
4.36
1.17
0.89
4.90
5.62
4.64
20.4
47.9
19.9
22.4
15.8
49.0
22.9
21.9
46.8
50.1
16.2
12.9
31.6
25.7
18.6
25.7
50.1
26.3
20.4
21.4
34.7
21.9
19.0
18.2
27.5
30.2
8
28.2
10a
10b
11a
11b
12a
12b
5.014.57
4.07
0.93
0.78
5.62
3.98
3.98
4.79
5.01 4.26
4.47
2.04
1.82
8.51
8.32
1.86
2.19
1.95
8.91
9.12
4.57
1.90
1.58
8.13
5.62
5.01
2.57
1.99
11.5
13.2
6.92
1.86
1.70
7.08
9.77
4.26
1.70
1.35
6.92
7.76
11.0
aData obtained from NCI’s in vitro disease-oriented tumor cells screen. GI50: Drug molar concentration causing 50% cell growth inhibition.
bMean values over all cell lines tested. These cell lines are: Leuk (leukemia: CCRF-CEM, HL-60 (TB), K-562, MOLT-4, PRMI-8226, and SR); Lung
(non-small cell lung cancer: A549/ATCC, EKVX, HOP-62, HOP-92, NCI-H226, NCI-H23, NCI-H322M, and NCI-H522); Colon (colon cancer:
COLC 205, HCC-2998, HCT-116, HCT-15, HT29, KM12, and SW-620); CNS (CNS cancer: SF-268, SF-295, SF-539, SNB-19, SNB-75, and U251);
Mela (melanoma: LOX IMVI, MALME-3M, M14, SK-MEL-2, SK-MEL-28, SK-MEL-5, and UACC-257); Ovari (ovarian cancer: IGROV1,
OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, and SK-OV-3); Renal (renal cancer: 786–0, A498, ACHN, CAKI-1, RXF 393, SN12C, TK-10, and
UO-31); Prosta (prostate cancer: PC-3 and DU-145); and Breast (breast cancer: MCF7, MCF7/ADR-RES, MDA-MB-231/ ATCC, HS 578T,
MDA-MB-435, MDA-N and T-47D).
Table 3. Inhibitory activity of indolo- and pyrrolo- quinolin-2(1H)-
ones and 6-anilinoindoloquinoline derivatives Indolo[3,2-c]quinolin-
cytotoxicity. Among them, 6-anilinoindolo[3,2-c]quino-
lines 11a,b were the most cytotoxic and found to inhibit
the growth of SNB-75 with a GI50 value of less than
0.01 mM.
2(1H)-one derivatives on the selected cancer cell lines (GI50 (mM))a
Compd
4b
6
10a
10b
11a
11b
CCRF-CEM
SR
KM12
SW-620
SNB-75
SK-MEL-28
OVCAR-3
UO-310.55
MCF7
5.13
5.75
4.47
31.6
5.0130.2
40.7
17.8
0.40
5.75
ndb
27.5
nd
2.14
1.15
1.51
1.15
<0.01
ndb
2.45
ndb
0.54
1.15
1.07
<0.01
ndb
39.8
20.4
0.69
4.68
4.79
4.90
4.37
ndb
ndb
0.04
Experimental
b
General
nd
0.30
40.7
ndb
2.45
1.90
TLC: precoated (0.2 mm) silica gel 60 F254 plates from
EM Laboratories, Inc.; detection by UV light (254 nm).
Mp: Electrothermal IA9100 digital melting-point appa-
ratus; uncorrected. UV Specta (lmax (log e) in nm):
Shimadzu UV-160A UV–vis spectrophotometer. IR
spectra (cmꢀ1): Hitachi-260–30 infrared spectro-
3.24 6.032.31 22.5.511
15.8 32.4 0.41
0.44
1.26
0.70
aData obtained from NCI’s in vitro disease-oriented tumor cells
screen. GI50: drug molar concentration causing 50% cell growth inhi-
bition.
bNot detected.
photometer. H and 13C NMR spectra: Varian-Unity-
1
400 spectrometer at 400 and 100 MHz or Varian-
Gemini-200 spectrometer at 200 and 50 MHz, chemical
shifts d in ppm with SiMe4 as an internal standard
(=0 ppm), coupling constants J in Hz. Elemental ana-
lyses were carried out on a Heraeus CHN-O-Rapid ele-
mental analyzer, and results were within ꢂ0.4% of
calculated values.
such as KM12, SNB-75, and UO-31 with GI50 values of
4.47, 5.01, and 0.55 mM respectively. Compound 6 was
especially active against CCRF-CEM, SW-620, SK-
MEL-28, and UO-31with GI
values of 0.40, 0.69,
50
0.30, and 3.24 mM respectively. Selective cytotoxicity
was also observed for 10a (MCF7, 0.41 mM) and 10b
(OVCAR-3, 0.04 mM and MCF7, 0.44 mM). Among
these compounds, 11a and 11b were found to inhibit the
growth of SNB-75 with a GI50 value of less than
0.01 mM, respectively and therefore, were selected for
further evaluation for in vivo antitumor activity.
6-Chloro-4-hydrazino-quinolin-2(1H)-one (2b). To a sus-
pension of 6-chloro-4-hydroxyquinolin-2(1H)-one (1b,
0.97 g, 5 mmol) in ethoxyethanol (10 mL) was added
40% hydrazine hydrate (0.5 g, 10 mmol). The reaction
mixture was refluxed under N2 for 48 h. It was then
cooled with ice-bath, and the resulting precipitate was
collected by filtration and recrystallized from EtOH to
Conclusion
ꢁ
give 2b (0.51g, 49%) as a pink solid; mp: 308–309 C;
Three benzofuroquinolin-2(1H)-ones 16a–c were found
to be void of cytotoxicity. The tetracyclic indolo-
[3,2-c]quinolin-2(1H)-ones 4a,b were more cytotoxic
than the isomeric tricyclic 1H-pyrrolo[3,2-c]quinolin-
2(1H)-one 6, in which a phenyl ring was appended on
the pyrrole moiety. Additional phenyl ring appended on
the pyrrole moiety as in compound 8 further decreased
UV lmax nm (log e): 225 (4.40), 306 (3.86) in 0.1N
MeOH; IR nmax cmꢀ1: 1267, 1397, 1469, 1518, 1608,
1
1674, 3331, 3439 in KBr. H NMR (DMSO-d6) d 3.60
(br s, 2H, combined with H2O), 5.74 (s, 1H), 7.22 (d, 1H,
J=8.8 Hz), 7.46 (dd, 1H, J=8.8, 2.2 Hz), 7.98 (d, 1H,
J=2.2 Hz), 8.22 (br s, 1H), 10.85 (br s, 2H); 13C NMR
(DMSO-d6) d 90.99, 113.68, 117.31, 121.42, 124.71,

Y.-L. Chen et al. / Bioorg. Med. Chem. 10 (2002) 2705–2712
2709
1
129.90, 137.77, 153.20, 163.21. Anal. calcd for
.
C9H8ClN3O 0.5H2O: C, 49.44; H, 4.15; N, 19.22.
Found: C, 49.52; H, 4.20; N, 19.29.
cmꢀ1: 1552, 1613, 1637, 3256, 3417 in KBr; H NMR
(DMSO-d6) d 7.22–7.64 (m, 5H), 8.20 (m, 2H), 11.42 (br
s, 1H), 12.55 (br s, 1H); 13C NMR (DMSO-d6) d 106.41,
111.63, 111.91, 115.99, 120.70, 120.98, 121.45, 122.05,
123.94, 124.34, 129.12, 137.67, 137.92, 140.65, 159.80.
Anal. calcd for C15H9ClN2O: C, 67.05; H, 3.38; N,
10.43. Found: C, 66.97; H, 3.46; N, 10.39.
4-(N0-Cyclohexylidenehydrazino)quinolin-2(1H)-one (3a).
A mixture of 2a22 (1.75 g, 10 mmol) and cyclohexanone
(1.47 g, 15 mmol) in glacial acetic acid (50 mL) was stir-
red at room temperature for 36 h. The solvent was
removed at reduced pressure, and EtOAc was added to
the residue. The precipitate that separated was collected
by filtration, washed with H2O, and dried to give 3a
(2.24 g, 88%) as a pink solid; mp: 259–260 ꢁC ; UV lmax
nm (log e): 224 (4.35), 315 (4.15) in MeOH; IR nmax
4-(N 0 -Phenethylidenehydrazino)quinolin-2(1H)-one (5).
This compound was prepared from 2a and phenylace-
taldehyde according to the method mentioned under the
synthesis of 3a in 91% yield: mp: 248–249 ꢁC; UV lmax
nm (log e): 225 (4.48), 312 (4.35) in MeOH; IR nmax
cmꢀ1: 1216, 1259, 1384, 1518, 1632, 3427 in KBr. H
cmꢀ1: 1393, 1417, 1493, 1541, 1601, 3447 in KBr; H
1
1
NMR (DMSO-d6) d 1.58–1.63 (m, 6H), 2.29–2.32
(m, 4H), 6.05 (s, 1H), 7.13 (m, 1H), 7.27 (m, 1H), 7.47
(m, 1H), 7.94 (m, 1H), 9.26 (br s, 1H), 10.98 (br s, 1H);
13C NMR (DMSO-d6) d 25.55, 26.17, 27.36, 27.68,
35.60, 93.79, 112.72, 116.21, 121.45, 122.75, 130.93,
139.28, 150.42, 161.67, 163.99. Anal. calcd for
C15H17N3O: C, 70.56; H, 6.71; N, 16.46. Found: C,
70.42; H, 6.88; N, 16.51.
NMR (DMSO-d6) d 3.66 (d, 2H, J=5.8 Hz), 6.05 (s, 1H),
7.13–7.47 (m, 8H), 7.78 (m, 1H), 7.90 (m, 1H), 10.35 (br s,
1H), 10.99 (br s, 1H); 13C NMR (DMSO-d6): d 38.37,
93.47, 111.69, 115.65, 120.57, 121.82, 126.54, 128.63 (2C),
128.85 (2C), 130.30, 137.18, 139.33, 146.80, 148.64,
162.85. Anal. calcd for C17H15N3O: C, 73.63; H, 5.45; N,
15.15. Found: C, 73.49; H, 5.43; N, 15.02.
3-Phenyl-1,5-dihydropyrrolo[3,2-c]quinolin-4-one (6). A
suspension of 5 (1.39 g, 5 mmol) in diphenyl ether
(10 mL) was heated to 250 ꢁC for 2 h. The mixture was
cooled to room temperature and diluted with a large
volume of n-hexane to precipitate a solid that was col-
lected, washed with n-hexane and dried under vacuum
to give 6 (1.05 g, 81%): mp: 329–330 ꢁC; UV lmax nm
(log e): 239 (4.36), 278 (4.05), 320 (4.20), 333 (4.21) in
MeOH; IR nmax cmꢀ1: 1247, 1379, 1419, 1490, 1575,
6-Chloro-4-(N0-cyclohexylidenehydrazino)quinolin-2(1H)-
one (3b). This compound was prepared from 2b accord-
ing to the method mentioned under the synthesis of 3a
in 90% yield: mp: 357–358 ꢁC; UV lmax nm (log e): 229
(4.16), 322 (4.18) in MeOH; IR nmax cmꢀ1: 1215, 1375,
1
1412, 1450, 1534, 1595, 1632, 2928, 3433 in KBr; H
NMR (DMSO-d6) d 1.64 (m, 6H), 2.33 (m, 2H), 2.50
(m, 2H), 6.07 (s, 1H), 7.26 (d, 1H, J=8.8 Hz), 7.50 (dd,
1H, J=8.8, 2.2 Hz), 8.13 (d, 1H, J=2.2 Hz), 9.25 (br s,
1H), 11.10 (br s 1H); 13C NMR (DMSO-d6) d 25.18,
25.77, 26.97, 27.30, 35.25, 94.82, 113.53, 117.27, 121.93,
124.71, 130.09, 138.01, 148.82, 160.27, 162.93. Anal.
calcd for C15H16ClN3O: C, 62.18; H, 5.57; N, 14.50.
Found: C, 62.30; H, 5.61; N, 14.42.
1
1601, 1643, 3423 in KBr; H NMR (DMSO-d6) d 7.16–
7.24 (m, 2H), 7.32–7.39 (m, 4H), 7.49 (d, 1H,
J=1.6 Hz), 7.87 (m, 2H), 8.06 (d, 1H, J=7.6 Hz), 11.11
(br s, 1H), 12.46 (br s, 1H); 13C NMR (DMSO-d6) d
107.12, 110.71, 112.71, 115.41, 120.66, 121.28, 123.16,
125.74, 127.36, 127.63 (2C), 128.85 (2C), 134.47, 135.87,
136.15, 159.72. Anal. calcd for C17H12N2O: C, 78.44; H,
4.65; N, 10.76. Found: C, 78.41; H, 4.83; N, 10.59.
5,11-Dihydroindolo[3,2-c]quinolin-6-one (4a). A suspen-
sion of 3a (2.55 g, 10 mmol) in diphenyl ether (20 mL)
was heated to 250 ꢁC for 30 min. The mixture was
cooled to room temperature, and 10% Pd/C (250 mg)
was added, and heated at 250 ꢁC for another 3 h. The
reaction mixture was filtered, and the filtrate cooled to
room temperature. A large volume of n-hexane was
added to precipitate a solid that was collected, washed
with n-hexane and dried under vacuum to give 4a
(1.92 g, 82%): mp: 340 ꢁC; UV lmax nm (log e): 244
(4.63), 295 (4.06), 322 (4.07), 337 (4.35) in MeOH; IR
nmax cmꢀ1: 1215, 1341, 1396, 1454, 1552, 1637, 3160,
3210 in KBr; 1H NMR (DMSO-d6) d 7.23–7.65 (m, 6H),
8.20 (m, 2H), 11.43 (br s, 1H), 12.58 (br s, 1H); 13C
NMR (DMSO-d6) d 106.48, 111.74, 111.99, 116.10,
120.80, 121.10, 121.59, 122.16, 124.07, 124.40, 129.25,
137.75, 137.98, 140.76, 159.93. Anal. calcd for
C15H10N2O: C, 76.91; H, 4.30; N, 11.96. Found: C,
76.89; H, 4.45; N, 11.90.
4 - [N 0 - (1,2 - Diphenylethylidene)- hydrazino]quinolin - 2
(1H)-one (7). This compound was prepared from 2a
and deoxybenzoin according to the method mentioned
under the synthesis of 3a in 84% yield: mp: 250–251 ꢁC;
UV lmax nm (log e): 227 (4.47), 335 (4.33) in MeOH; 1H
NMR (DMSO-d6) d 4.52 (s, 2H), 6.37 (s, 1H), 7.14–7.50
(m, 12H), 7.90 (m, 2H), 9.55 (br s, 1H), 11.15 (br s, 1H);
13C NMR (DMSO-d6): d 31.98, 96.58, 112.41, 115.90,
120.92, 129.33, 130.69 (2C), 128.45 (2C), 128.81 (2C),
129.05 (2C), 129.21, 129.33, 130.76, 136.84, 138.02,
139.55, 149.22, 150.56, 163.06. Anal. calcd for
C23H19N3O: C, 78.16; H, 5.42; N, 11.89. Found: C,
78.02; H, 5.56; N, 11.75.
2,3-Diphenyl-1,5-dihydropyrrolo[3,2-c]quinolin-4-one (8).
This compound was prepared from 7 according to the
method mentioned under the synthesis of 6 in 82%
yield: mp: 327–328 ꢁC; UV lmax nm (log e): 241(4.48),
326 (4.24), 340 (4.20) in MeOH; IR nmax cmꢀ1: 1207,
2-Chloro-5,11-dihydroindolo[3,2-c]quinolin-6-one (4b).
This compound was prepared from 3b according to the
method mentioned under the synthesis of 4a in 82%
yield: mp: 381–384 ꢁC; UV lmax nm (log e): 251(4.52),
295 (4.08), 322 (4.28), 336 (4.35) in MeOH; IR nmax
1
1336, 1443, 1488, 1506, 1585, 1639, 3319 in KBr; H
NMR (DMSO-d6) d 7.20–7.38 (m, 13H), 8.27 (d, 1H,
J=8.0 Hz), 11.07 (br s, 1H), 12.40 (br s, 1H); 13C NMR
(DMSO-d6) d 112.51, 112.93, 115.46, 115.90, 119.68,

2710
Y.-L. Chen et al. / Bioorg. Med. Chem. 10 (2002) 2705–2712
121.23, 122.18, 126.16 (2C), 127.37, 128.33 (2C), 128.53
(2C), 131.14 (2C), 131.86, 132.29, 132.68, 134.41, 134.81,
136.31, 159.31. Anal. calcd for C23H16N2O: C, 82.12; H,
4.79; N, 8.33. Found: C, 82.04; H, 4.83; N, 8.10.
under the synthesis of 10a in 69% yield: mp: 307–
309 ꢁC; UV lmax nm (log e): 226 (4.45), 262 (4.55), 338
(4.04) in MeOH; IR nmax cmꢀ1: 1213, 1281, 1360, 1478,
1580, 1606, 1638, 1671, 3416 in KBr; 1H NMR (DMSO-
d6) d 2.63 (s, 3H), 7.42 (m, 1H), 7.55–8.08 (m, 7H), 8.22
(m, 1H), 8.43 (d, 1H, J=8.0 Hz), 8.74 (dd, 1H, J=8.0,
1.4 Hz), 10.31 (br s, 1H), 13.00 (br s, 1H), 14.24 (br s,
1H); 13C NMR (DMSO-d6) d 26.88, 102.17, 112.68,
113.43, 119.34, 121.14, 121.86, 122.00, 123.11, 124.00,
125.46, 126.12 (2C), 128.90, 130.29, 131.02, 135.22,
137.60, 138.28, 138.98, 143.26, 148.00, 197.50. Anal.
6-Chloro-11H-indolo[3,2-c]quinoline (9a). A mixture of
4a (2.34 g, 10 mmol) and POCl3 (20 mL) was refluxed
for 18 h. After cooling, the mixture was poured into ice-
water (150 mL) and extrated with EtOAc. The EtOAc
extract was washed with aqueous K2CO3, brine, and
dried over Na2SO4. The organic layer was concentrated
in vacuo to give a brown solid, which was recrystallized
with acetone to give 9a (1.72 g, 68%): mp: 280–282 ꢁC;
UV lmax nm (log e): 235 (4.56), 256 (4.47), 272 (4.67),
289 (4.28), 323 (3.80) in MeOH; IR nmax cmꢀ1: 1248,
1360, 1450, 1502, 1566, 1593 in KBr; 1H NMR (DMSO-
d6) d 7.39–7.86 (m, 5H), 8.07 (dd, 1H, J=2.0, 7.8 Hz),
8.45 (d, 1H, J=7.6 Hz), 8.57 (dd, 1H, J=2.0, 7.6 Hz),
13.17 (br s, 1H); 13C NMR (DMSO-d6) d 106.79,
111.36, 112.18, 116.49, 120.78, 121.22, 122.23, 126.08,
126.30, 128.28, 128.35, 129.21, 138.80, 141.93, 144.35.
Anal. calcd for C15H9ClN2: C, 71.29; H, 3.59; N, 11.09.
Found: C, 71.05; H, 3.62; N, 11.12.
.
calcd for C23H16ClN3O HCl 0.4H2O: C, 64.32; H, 4.18;
N, 9.78. Found: C, 64.26; H, 4.29; N, 9.76.
(E)-1-[3-(11H-Indolo[3,2-c]quinolin-6-ylamino)phenyl]-
ethanone oxime hydrochloride (11a). To a suspension of
10a (1.76 g, 5 mmol) in MeOH (10 mL) was added
NH2OH HCl (0.52 g, 7.5 mmol). The reaction mixture
was refluxed for 1h and allowed to cool to room tem-
perature. The solvent was removed in vacuo, and the
residue was triturated with H2O (20 mL), filtered, and
washed with H2O. The crude product was recrystallized
from EtOH to give 1.39 g (76%) of 11a as a yellow solid:
mp: 286–290 ꢁC; UV lmax nm (log e): 225 (4.45), 260
(4.57), 337 (4.04) in MeOH; IR nmax cmꢀ1: 1218, 1309,
1456, 1579, 1607, 1635, 3420 in KBr; 1H NMR (DMSO-
d6) d 2.20 (s, 3H), 7.37–7.92 (m, 9H), 8.04 (d, 1H,
J=8.0 Hz), 8.47 (d, 1H, J=8.0 Hz), 8.65 (d, 1H,
J=8.0 Hz), 10.28 (br s, 1H), 11.35 (br s, 1H), 12.80 (br
s, 1H), 14.00 (br s, 1H); 13C NMR (DMSO-d6) d 11.57,
102.07, 106.79, 112.64, 113.40, 121.21, 121.79, 121.99,
122.88, 123.77, 123.83, 124.52, 125.08, 125.31, 126.06,
129.89, 130.92, 137.12, 138.59, 138.89, 143.03, 148.24,
2,6-Dichloro-11H-indolo[3,2-c]quinoline (9b). This com-
pound was prepared from 4b according to the method
mentioned under the synthesis of 9a in 63% yield: mp:
285–287 ꢁC; UV lmax nm (log e): 235 (4.27), 257 (4.02),
270 (4.42), 287 (3.86), 322 (3.58) in MeOH; IR nmax
cmꢀ1: 1265, 1366, 1526, 1589 in KBr; 1H NMR
(DMSO-d6)
d 7.42–7.85 (m, 4H), 8.06 (d, 1H,
J=8.4 Hz), 8.44 (d, 1H, J=8.0 Hz), 8.67 (d, 1H,
J=8.0 Hz), 13.55 (br s, 1H). 13C NMR (DMSO-d6) d
111.37, 112.36, 116.45, 121.25, 121.42, 122.61, 126.24,
126.44, 127.79, 129.15, 129.47, 138.97, 142.20, 143.86,
144.20. Anal. calcd for C15H8Cl2N2: C, 62.74; H, 2.81;
N, 9.76. Found: C, 62.65; H, 2.93; N, 9.69.
.
152.45. Anal. calcd for C23H18N4O HCl: C, 68.57; H,
4.75; N, 13.91. Found: C, 68.31; H, 4.77; N, 13.80.
(E)-1-[3-(2-Chloro-11H-indolo[3,2-c]quinolin-6-ylamino)-
phenyl]ethanone oxime hydrochloride (11b). This com-
pound was prepared from 10b according to the method
mentioned under the synthesis of 11a in 88% yield: mp:
282–284 ꢁC (recrystallization from EtOH); UV lmax nm
(log e): 224 (4.52), 260 (4.65), 337 (4.11) in MeOH; IR
nmax cmꢀ1: 1234, 1321, 1385, 1427, 1544, 1580, 1605,
1642, 3418 in KBr; 1H NMR (DMSO-d6) d 2.20 (s, 3H),
7.38–7.91(m, 8H), 8.06 (d, 1H, J=7.8 Hz), 8.44 (d, 1H,
J=8.0 Hz), 8.72 (dd, 1H, J=7.8, 1.0 Hz), 10.38 (br s,
1H), 11.36 (br s, 1H), 12.92 (br s, 1H), 14.00 (br s, 1H);
13C NMR (DMSO-d6) d 11.49, 101.92, 107.01, 112.60,
113.30, 119.27, 121.13, 121.77, 121.93, 122.99, 123.80,
124.55, 125.30, 125.99, 129.84, 130.92, 135.11, 136.96,
138.56, 138.87, 143.06, 148.08, 152.32. Anal. calcd for
1-[3-(11H-Indolo[3,2-c]quinolin-6-ylamino)phenyl]ethanone
hydrochloride (10a). A mixture of 9a (1.27 g, 5 mmol) and
3-aminoacetophenone (1.01 g, 7.5 mmol) in 2-butanol
(10 mL) was refluxed for 4 h (by TLC monitoring). The
mixture was then cooled and evaporated in vacuo to give a
residue which was treated with H2O (50 mL). The result-
ing precipitate was filtered and washed with H2O. The
crude product was chromatographed on a column of
silica gel using CH2Cl2:MeOH=10:1 to give 1.38 g
(78%) of 10a as a yellow solid: mp: 310–312 ꢁC ; UV
lmax nm (log e): 225 (4.43), 264 (4.53), 336 (4.02) in
MeOH; IR nmax cmꢀ1: 1213, 1281, 1399, 1456, 1580,
1606, 1638, 1672, 3428 in KBr; 1H NMR (DMSO-
d6)d2.63 (s, 3H), 7.32–8.10 (m, 9H), 8.26 (s, 1H), 8.43
(d, 1H, J=7.6 Hz), 8.71 (m, 1H), 10.39 (br s, 1H), 13.00
(br s, 1H), 14.08 (br s, 1H); 13C NMR (DMSO-d6)d26.82,
102.23, 112.56, 113.50, 119.77, 121.06, 121.83 (2C), 123.07,
123.70, 125.21, 125.76, 125.93, 128.52, 130.11, 130.80,
135.74, 137.90, 138.14, 138.91, 143.13, 148.03, 197.51.
.
C23H17ClN4O HCl 0.3H2O: C, 62.40; H, 4.23; N, 12.66.
Found: C, 62.38; H, 4.33; N, 12.71.
(E)-1-[3-(11H-Indolo[3,2-c]quinolin-6-ylamino)phenyl]-
ethanone O-methyloxime hydrochloride (12a). This com-
pound was prepared from 10a and 40% O-methylhy-
droxylamine hydrochloride according to the method
mentioned under the synthesis of 11a in 78% yield: mp:
265–268 ꢁC (recrystallization from EtOH); UV lmax nm
(log e): 224 (4.53), 260 (4.67), 337 (4.15) in MeOH; IR
nmax cmꢀ1: 1407, 1453, 1542, 1600, 1642, 3412 in KBr;
1H NMR (DMSO-d6) d 2.23 (s, 3H), 3.94 (s, 3H), 7.39–
.
Anal. calcd for C23H17N3O HCl 0.3H2O: C, 70.42; H,
4.78; N, 10.71. Found: C, 70.46; H, 4.83; N, 10.66.
1-[3-(2-Chloro-11H-indolo[3,2-c]quinolin-6-ylamino)phe-
nyl]ethanone hydrochloride (10b). This compound was
prepared from 9b according to the method mentioned

Y.-L. Chen et al. / Bioorg. Med. Chem. 10 (2002) 2705–2712
2711
8.05 (m, 10H), 8.47 (d, 1H, J=7.8 Hz), 8.66 (d, 1H,
J=7.4 Hz), 10.20 (br s, 1H), 12.90 (br s, 1H), 14.00 (br
s, 1H); 13C NMR (DMSO-d6) d 12.29, 61.61, 102.08,
106.63, 112.49, 113.43, 121.10, 121.70, 121.78, 122.79,
123.45, 123.89, 124.86, 125.07, 125.87, 125.99, 129.80,
130.68, 137.32, 138.80, 139.07, 142.88, 148.24, 153.57.
2-Fluoro-5H-11-oxa-5-aza-benzo[a]fluoren-6-one (16c).
This compound was prepared from 13c according to
the method mentioned under the synthesis of 16a in
27% yield: mp: 287–290 ꢁC recrystallization from
EtOH; lit.29 mp: 298–300 ꢁC); UV lmax nm (log e): 231
(4.47), 287 94.08), 299 (4.15), 335 (4.12), 350 (4.04) in
MeOH; IR nmax 1220, 1341, 1449, 1572, 1662,
.
Anal. calcd for C24H20N4O HCl 0.8H2O: C, 66.83; H,
5.28; N, 12.99. Found: C, 66.52; H, 5.39; N, 13.04.
1
3332 cmꢀ1: in KBr; H NMR (DMSO-d6) d 7.47–7.61
(m, 4H), 7.86 (m, 2H), 8.15 (m, 1H). 12.08 (br s, 1H).
(E)-1-[3-(2-Chloro-11H-indolo[3,2-c]quinolin-6-ylamino)-
phenyl]ethanone O-methyloxime hydrochloride (12b).
This compound was prepared from 10b and 40% O-
methylhydroxylamine hydrochloride according to the
method mentioned under the synthesis of 11a in 76%
yield: mp: 345–346 ꢁC (recrystallization from EtOH);
UV lmax nm (log e): 225 (4.56), 260 (4.71), 337 (4.14) in
MeOH; IR nmax cmꢀ1: 1426, 1538, 1578, 1603, 1644,
Acknowledgements
Financial support of this work by the National Science
Council of the Republic of China (NSC 89–2320-B-037–
058) is gratefully acknowledged. We also thank
National Cancer Institute (NCI) of the United States
for the anticancer screenings and the National Center
for High-Performance Computing for providing com-
puter resources and chemical database services.
1
3414 in KBr; H NMR (DMSO-d6) d 2.22 (s, 3H), 3.94
(s, 3H), 7.39–8.06 (m, 9H), 8.46 (d, 1H, J=8.0 Hz), 8.68
(d, 1H, J=8.0 Hz), 10.25 (br s, 1H), 12.98 (br s, 1H),
14.10 (br s, 1H); 13C NMR (DMSO-d6) d 12.36, 61.69,
102.08, 112.61, 113.47, 119.66, 121.16, 121.69, 121.87,
123.08, 123.90, 124.84, 124.97, 125.22, 125.96, 129.92,
130.85, 135.68, 137.38, 137.44, 138.94, 143.07, 148.22,
References and Notes
.
.
1. Tominaga, M.; Tone, H.; Nakagawa, K.; Takada, K.;
Hoshino, Y.; Watanabe, K. Chem. Pharm. Bull. 1981, 29,
2166.
2. Nishi, T.; Yamamoto, K.; Shimizu, T.; Kanbe, T.; Kimura,
Y.; Nakagawa, K. Chem. Pharm. Bull. 1983, 31, 798.
3. Nishi, T.; Tabusa, F.; Tanaka, T.; Shimizu, T.; Kanbe, T.;
Kimura, Y.; Nakagawa, K. Chem. Pharm. Bull. 1983, 31, 1151.
4. Nishi, T.; Tabusa, F.; Tanaka, T.; Ueda, H.; Shimizu, T.;
Kanbe, T.; Kimura, Y.; Nakagawa, K. Chem. Pharm. Bull.
1983, 31, 852.
5. Alabaster, C. T.; Bell, A. S.; Campbell, S. F.; Ellis, P.;
Henderson, C. G.; Roberts, D. A.; Ruddock, K. S.; Samuels,
G. M. R.; Stefaniak, M. H. J. Med. Chem. 1988, 31, 2048.
6. Alabaster, C. T.; Bell, A. S.; Campbell, S. F.; Ellis, P.;
Henderson, C. G.; Morris, D. S.; Roberts, D. A.; Ruddock,
K. S.; Samuels, G. M. R.; Stefaniak, M. H. J. Med. Chem.
1989, 32, 575.
7. Fujioka, T.; Teramoto, S.; Mori, T.; Hosokawa, T.;
Sumida, T.; Tominaga, M.; Yabuuchi, Y. J. Med. Chem. 1992,
35, 3607.
8. Lipworth, B. J.; Grove, A. Br. J. Clin. Pharm. 1997, 43, 9.
9. Tzeng, C. C.; Wang, T. C.; Chen, Y. L.; Wang, C. J.;
Chang, Y. L.; Teng, C. M. Helv. Chim. Acta 1997, 80, 1161.
10. Wang, T. C.; Chen, Y. L.; Tzeng, C. C.; Liou, S. S.;
Tzeng, W. F.; Chang, Y. L.; Teng, C. M. Helv. Chim. Acta
1998, 81, 1038.
11. Chen, Y. L.; Wang, T. C.; Fang, K. C.; Chang, N. C.;
Tzeng, C. C. Heterocycles 1999, 50, 453.
12. Tzeng, C. C.; Lee, K. H.; Wang, T. C.; Han, C. H.; Chen,
Y. L. Pharmaceut. Res. 2000, 17, 715.
153.63. Anal. calcd for C24H19ClN4O HCl 0.5H2O: C,
62.62; H, 4.60; N, 12.17. Found: C, 62.46; H, 4.82;
N, 12.06.
2-Methoxy-5H-11-oxa-5-aza-benzo[a]fluoren-6-one (16a).
A mixture of 4-hydroxy-6-methoxy-3-phenylquinolin-
2(1H)-one (13a, 1.34 g, 5 mmol)25 and 10% Pd/C
(0.015 g) in diphenyl ether (50 mL) was refluxed for 48 h.
The mixture was cooled to room temperature, triturated
with n-hexane, and the resulting precipitate collected,
which was then dissolved in hot DMF (100 mL) and fil-
tered to remove Pd/C. The filtrate was concentrated to
dryness, and the residual solid recrystallized from EtOH
to give 0.48 g (36%) of 16a as a pale-yellow solid: mp:
294–296 ꢁC (recrystallization from EtOH); UV lmax nm
(log e): 239 (4.52), 293 (4.18), 303 (4.23), 346 (4.13), 361
(4.05) in MeOH; IR nmax 1223, 1348, 1452, 1562, 1660,
3320 cmꢀ1: in KBr; 1H NMR (DMSO-d6) d 3.86 (s, 3H),
6.97 (dd, 1H, J=2.4, 8.8 Hz), 7.25 (d, 1H, J=2.0 Hz),
7.38–7.50 (m, 3H), 7.81(dd, 1H, J=1.2, 8.0 Hz), 7.96
(d, 1H, J=8.8 Hz), 8.06 (m, 1H), 11.87 (br s, 1H); 13C
NMR (DMSO-d6) d 54.46, 99.10, 104.59, 111.42,
111.60, 120.84, 122.68, 124.01, 124.50, 125.68, 130.02,
140.40, 154.51, 158.32, 159.30, 161.46. Anal. calcd for
C16H11NO3: C, 72.45; H, 4.18; N, 5.28. Found: C,
72.26; H, 4.29; N, 5.16.
3-Methoxy-5H-11-oxa-5-aza-benzo[a]fluoren-6-one (16b).28
This compound was prepared from 13b according to
the method mentioned under the synthesis of 16a in
32% yield: mp: 282–285 ꢁC (recrystallization from
EtOH); UV lmax nm (log e): 232 (4.49), 260 (4.16), 297
(4.24), 327 (4.33), 343 (4.36) in MeOH; IR nmax 1235,
13. Rowinsky E. K.; Donehower R. C. In The Chemotherapy
Source Book; Perry, M. C., Ed.; Williams and Wilkins Balti-
more, 1998; Vol. 2; p 387.
14. Donehower R. C.; Rowinsky E. K. In Cancer: Principles
and Practice of Oncology; De Vita, V. T.; Hellman, S.;
Rosenberg, S. A., Eds.; J. B. Lippincott Company Philadel-
phia, 1993; p 409.
15. Chen, C. C.; Liu, D. F.; Chou, T. C. Heterocycles 1993,
35, 775.
16. Atwell, G. J.; Cain, B. F.; Seelye, R. N. J. Med. Chem.
1972, 15, 611.
1
1346, 1448, 1558, 1663, 3328 cmꢀ1: in KBr; H NMR
(DMSO-d6) d 3.89 (s, 3H), 7.27 (dd, 1H, J=2.8, 9.0 Hz),
7.44–7.57 (m, 4H), 7.84 (m, 1H), 8.12 (m, 1H). 11.91 (br
s, 1H); 13C NMR (DMSO-d6) d 55.60, 102.11, 107.07,
110.24, 111.03, 111.76, 117.77, 120.48, 121.28, 123.90,
124.58, 126.32, 132.96, 154.60, 154.74, 161.55.
17. Denny, W. A.; Atwell, G. J.; Cain, B. F. J. Med. Chem.
1978, 21, 5.

2712
Y.-L. Chen et al. / Bioorg. Med. Chem. 10 (2002) 2705–2712
18. Denny, W. A.; Atwell, G. J.; Cain, B. F.; Leo, A.;
Panthananickal, A.; Hansch, C. J. Med. Chem. 1982, 25,
276.
19. Gamage, S. A.; Tepsiri, N.; Wilairat, P.; Wojcik, S. J.;
Figgitt, D. P.; Ralph, R. K.; Denny, W. A. J. Med. Chem.
1994, 37, 1486.
24. Chen, Y. L.; Fang, K. C.; Sheu, J. Y.; Hsu, S. L.; Tzeng,
C. C. J. Med. Chem. 2001, 44, 2374.
25. Stadlbauer, W.; Laschober, R.; Lutschounig, H.; Schind-
ler, G.; Kappe, Th. Monatsh. Chem. 1992, 123, 617.
26. Stadlbauer, W.; Kappe, Th. Monatsh. Chem. 1985, 116,
1005.
20. Gamage, S. A.; Figgitt, D. P.; Wojcik, S. J.; Ralph, R. K.;
Ransijn, A.; Mauel, J.; Yardley, V.; Snowdon, D.; Croft, S. L.;
Denny, W. A. J. Med. Chem. 1997, 40, 2634.
21. Fadda, A. A.; Khahil, A. M.; El-Habbal, M. M. J. Indian
Chem. Soc. 1991, 68, 393.
22. Nguyen, C. H.; Marchand, C.; Delage, S.; Sun, J.-S.;
Garestier, T.; Helene, C.; Bisagni, E. J. Am. Chem. Soc. 1998,
120, 2501.
27. Stadlbauer, W.; Laschober, R.; Kappe, Th. Liebigs Ann.
Chem. 1990, 531.
28. Kappe, Th.; Brandner, A.; Stadlbauer, W. Monatsh.
Chem. 1987, 118, 1177.
29. Yamaguchi, S.; Tsuzuki, K.; Kinoshita, M.; Oh-hira, Y.;
Kawase, Y. J. Heterocycles Chem. 1989, 26, 281.
30. Monks, A.; Scudiero, D.; Skehaan, P.; Shoemaker, R.;
Paull, K.; Vistica, D.; Hose, C.; Langley, J.; Cronise, P.; Vai-
gro-Wolff, A.; Gray-Goodrich, M.; Campbell, H.; Mayo, J.;
Boyd, M. J. Natl. Cancer Inst. 1991, 83, 757.
23. Fang, K. C.; Chen, Y. L.; Sheu, J. Y.; Wang, T. C.; Tzeng,
C. C. J. Med. Chem. 2000, 43, 3809.