Synthesis and anticancer evaluation of certain indolo[2,3-b]quinoline derivatives

Article abstract of DOI:10.1016/j.bmc.2004.09.025

The present report describes the synthesis and anticancer evaluation of certain 11-substituted 6H-indolo[2,3-b]quinolines and their methylated derivatives. These 6H-indolo[2,3-b]quinoline derivatives 11-13 were prepared from the commercially available 1,4

Full text of DOI:10.1016/j.bmc.2004.09.025

Bioorganic & Medicinal Chemistry 12 (2004) 6539–6546
Synthesis and anticancer evaluation of certain
indolo[2,3-b]quinoline derivatives
Yeh-Long Chen,* Hsien-Ming Hung, Chih-Ming Lu, Kuang-Chieh Li
and Cherng-Chyi Tzeng
Faculty of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung City 807, Taiwan
Received 20 August 2004; revised 10 September 2004; accepted 13 September 2004
Abstract—The present report describes the synthesis and anticancer evaluation of certain 11-substituted 6H-indolo[2,3-b]quinolines
and their methylated derivatives. These 6H-indolo[2,3-b]quinoline derivatives 11–13 were prepared from the commercially available
1,4-dihydroxyquinoline through alkylation, chlorination, nucleophilic reaction, and ring cyclization. Depending on the ratio of 11,
(MeO)2SO2, and K2CO3, alkylation occurred primarily on N-5 (1:0.8:0.8) or N-6 (1:1.5:1.5) leading to the isolation of 14a or 14b as
a major product. Accordingly, major product 15a (2/(MeO)2SO2/K2CO3 = 1:2:2) or 15b (1:1:1), respectively, was obtained by alkyl-
ation of 12 while 16a (13/(MeO)2SO2/K2CO3 = 1:2:2) or 16b (1:1:1), respectively, was obtained by alkylation of 13. The in vitro anti-
cancer assay indicated 5-methylated derivatives 14a, 15a, 16a are more cytotoxic than their respective 6-methylated counterparts
14b, 15b, 16b and 6H-indolo[2,3-b]quinoline precursors 11, 12, 13. Among them, 11-(4-methoxyanilino)-6-methyl-6H-indolo[2,3-
b]quinoline (16a) was the most cytotoxic with a mean GI50 value of 0.78lM and also exhibited selective cytotoxicities for HL-60
(TB), K-562, MOLT-4, RPMI-8226, and SR with GI50 values of 0.11, 0.42, 0.09, 0.14, and 0.19lM, respectively.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
(neocryptolepine), a tetracyclic indolo[2,3-b]quinoline
alkaloid, which proved to be an effective DNA interca-
lator.13–15 We expect these 4-anilino substituents to form
hydrogen bonding with DNA molecule during the inter-
calation process of tetracyclic indolo[2,3-b]quinoline
ring. Since m-AMSA has been clinically used for the
treatment of leukemia, the antileukemia activity of cer-
tain indolo[2,3-b]quinoline derivatives is also described
(Fig. 1).
Acridine derivatives, especially 9-anilinoacridines have
been extensively studied as potential chemotherapeutic
agents due to their capability of intercalating DNA lead-
ing to the inhibition of mammalian topoisomerase II.1–10
Among such derivatives, 40-(9-acridinylamino)methane-
sulfonyl-m-anisidine (amsacrine, m-AMSA) has been
clinically used for the treatment of leukemia and lym-
phoma.1 Further structural modification lead to the dis-
covery of an improved broad spectrum antitumor agent,
3-(9-acridinylamino)-5-(hydroxymethyl)aniline (AHMA),
which is capable of inhibiting the growth of certain solid
tumors such as mammary adenocarcinoma, melanoma,
and Lewis lung carcinoma in mice.10 These results
prompted us to synthesize and evaluate the anticancer
activity of bioisosteric 4-anilinofuro[2,3-b]quinoline
derivatives.11,12 Some of them were found to possess
potent and broad anticancer activities. To further
explore the structure–activity relationships, the tricyclic
furo[2,3-b]quinoline was replaced with cryptotackieine
2. Chemistry
Preparation of the indolo[2,3-b]quinoline derivatives
11–13 is outlined in Scheme 1.15,16 The commercially
available 2,4-dihydroxyquinoline (1) was methylated
with (MeO)2SO2 and K2CO3 in acetone to afford 4-
methoxy-1H-quinolin-2-one (2) in 76% yield. Reflux of
1 with aniline (neat) or p-anisidine (in Ph2O) afforded
4-anilino-2-quinolinones (3) or its 4-methoxy derivative
4, respectively. Chlorination of 2 was with POCl3 fol-
lowed by the treatment with benzotriazole in refluxed
ethoxyethanol afforded 2-benzotriazol-1-yl-4-methoxy-
quinoline (8) in a 49% overall yield. Accordingly, 9
and 10 were prepared from the respective quinolinyl
chlorides 6 and 7, which in turn were obtained from 3
Keywords: 6H-Indolo[2,3-b]quinoline; Cytotoxicity; Anticancer agents.
*
Corresponding author. Tel.: +886 7 3121101x2684; fax: +886 7
3125339; e-mail: yeloch@kmu.edu.tw
0968-0896/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.09.025

6540
Y.-L. Chen et al. / Bioorg. Med. Chem. 12 (2004) 6539–6546
NH2
H3CO
NHSO2CH3
R
OH
HN
HN
HN
N
N
N
N
H
Indolo[2,3-b]quinolines
m-AMSA
AHMA
Figure 1. Chemical structures of m-AMSA, AHMA, and indolo[2,3-b]quinoline derivatives.
R
OH
R
(CH3O)2SO2,
K2CO3, (CH3)2CO
POCl3, TEA
or NH2C6H5, neat reflux
or NH2C6H4-p-OCH3 in
Ph2O
N
H
O
N
H
O
N
Cl
2 R = OCH3
5 R = OCH3
1
3 R = NHC6H5
6 R = NHC6H5
4 R = NHC6H4-p-OCH3
7 R = NHC6H4-p-OCH3
N
R
R
N
1
11
N
H
PPA
140-150oC
N
6
EtOEtOH, reflux
N
N
N
N
5
H
N
11 R = OCH3
8 R = OCH3
12 R = NHC6H5
13 R = NHC6H4-p-OCH3
9 R = NHC6H5
10 R = NHC6H4-p-OCH3
Scheme 1.
and 4, respectively, in moderate overall yields (41–54%).
Decomposition of triazole 8 in polyphosphoric acid
(PPA) gave the tetracyclic 11-methoxy-6H-indolo[2,3-
b]quinoline (11) in 33% yield. The structure of 11 was
confirmed by 1H NMR, which showed a methoxy singlet
at d 4.24 and an indolyl-NH broad singlet at d 11.78
(Table 1). From the NOESY spectrum, the NOE inter-
actions were observed among methoxy protons (d
4.24), H–C(1) (d 8.29), and H–C(10) (d 8.21). Accord-
ingly, 11-anilinoindolo[2,3-b]quinolines 12 and 13 were
prepared by the thermal decomposition of triazoles 9
and 10, respectively.
Refluxed of 11, (MeO)2SO2, and K2CO3 in a ratio of
1:0.8:0.8 in acetone afforded a sole product of 11-meth-
oxy-5-methyl-5H-indolo[2,3-b]quinoline 14a in 50% yield
along with the recovery of 24% starting material (Table
2, entry 1). With a ratio of 1:1.5:1.5, the mixture of
14a,b, and 14c, was obtained in 7%, 52%, and 15%
yield, respectively, (entry 2). The position of methyl
Table 1. NMR spectral data of compounds 11–13 in DMSO-d6
H
11
12
13
dH
NOEb
NOEb
dH
NOEb
a
a
dH
a
1-H
2-H
8.29 (dd, 8.0, 1.8)
7.51 (m)
7.75 (m)
2-H, OCH3
1, 3-H
2, 4-H
8.38 (dd, 8.4, 1.2)
7.43 (m)
7.72 (m)
2-H NH–C(11)
1, 3-H
2, 4-H
8.42 (d, 8.0)
7.40 (m)
7.69 (m)
2-H NH–C(11)
1, 3-H
2, 4-H
3-H
4-H
7.99 (d, 8.4)
11.78
7.51 (m)
3-H
7-H
7.96 (dd, 8.8, 1.2)
11.66
7.43 (m)
3-H
7-H
7.92 (d, 8.0)
11.58
7.40 (m)
3-H
7-H
6-NH
7-H
8-H
6-NH, 8-H
7, 9-H
6-NH, 8-H
7, 9-H
8, 10-H
6-NH, 8-H
7, 9-H
8, 10-H
7.51 (m)
7.31 (m)
7.37 (m)
6.92 (m)
7.32 (m)
6.89 (m)
9-H
10-H
C(11)
8, 10-H
9-H, OCH3
1, 10-H
8.21 (d, 8.0)
4.33 (OCH3)
7.14 (d, 8.0)
9.21 (NH–C(11))
6.83 (m, 3 Ar–H)
7.18 (m, 2 Ar–H)
9-H, NH–C(11)
1, 10-H
6.99 (d, 7.6)
9.00 (NH–C(11))
3.68 (OCH3)
6.82 (m, 4 Ar–H)
9-H, NH–C(11)
1, 10-H
c
c
c
c
a Multiplicity and J values in Hz are given in parentheses.
b Protons observed NOE interactions in NOESY spectrum.
c The NOE interactions with other aromatic protons.

Y.-L. Chen et al. / Bioorg. Med. Chem. 12 (2004) 6539–6546
6541
OCH3
OCH3
11
OCH3
O
(CH3O)2SO2
K2CO3
1
(CH3)2CO
reflux
N
N
H
N
N
6
N
N
5
N
N
CH3
CH3
CH3
CH3
11
14a
14b
14c
R
R
R
H3C
HN
HN
N
(CH3O)2SO2
K2CO3
HN
(CH3)2CO
reflux
N
N
CH3
N
N
N
N
N
H
H
N
CH3
15a R = H
16a R = OCH3
15b R = H
16b R = OCH3
15c
12 R = H
13 R = OCH3
Scheme 2.
Table 2. Methylation reaction of 11-substituted-6H-indolo[2,3-b]quinoline (11–13) by various conditions
Entry
Reaction condition
Recovery (%)
Product yield (%)
1
2
3
4
5
6
7
11/(CH3O)2SO2/K2CO3 (1:0.8:0.8)
11/(CH3O)2SO2/K2CO3 (1:1.5:1.5)
12 (R = H)/CH3I/K2CO3 (1:2:1)
11 (24)
—
14a (50)
14a (7)
14b (0)
14c (0)
14c (15)
15c (0)
14b (52)
15b (11)
15b (49)
15b (18)
16b (40)
16b (15)
12 (48)
—
—
15a (21)
15a (20)
15a (44)
16a (12)
16a (45)
12 (R = H)/(CH3O)2SO2/K2CO3 (1:1:1)
12 (R = H)/(CH3O)2SO2/K2CO3 (1:2:2)
13 (R = OCH3)/(CH3O)2SO2/K2CO3 (1:1:1)
13 (R = OCH3)/(CH3O)2SO2/K2CO3 (1:2:2)
15c (trace)
15c (14)
—
13 (27)
13 (14)
—
group in 14a–c was confirmed by NOESY experiments
in which the NOE interactions was observed between
Me–N(5) protons (d 4.29) and H–C(4) (d 8.01) in
14a; Me–N(6) protons (d 3.94) and H–C(7) (d 7.63)
in 14b; Me–N(5) protons (d 4.18) and H–C(4) (d
7.82), and Me–N(6) protons (d 4.11) and H–C(7) (d
7.58) in 14c. Accordingly, refluxed of 4-anilino-6H-
indolo[2,3-b]quinoline (1 2), (MeO)2SO2, and K2CO3
in a ratio of 1:2:1 gave a mixture of 15a and 15b in
21% and 11% yield, respectively, along with the recov-
ery of 48% starting material (entry 3). With a ratio of
1:1:1, a mixture of 15a and 15b was obtained in 20%
and 49% yield, respectively, (entry 4) while a ratio of
1:2:2 gave 15a, 15b, and 15c in 44%, 18%, and 14%
yield, respectively, (entry 5). With a ratio of 13:(MeO)2-
SO2:K2CO3 = 1:1:1, compounds 13, 16a, and 16b were
obtained in 27%, 12%, and 40% yield, respectively,
while a ration of 1/2/2 gave 13, 16a, and 16b in 14%,
45%, and 15% yield, respectively, (entry 6) and (entry
7) (Scheme 2).
in the full panel of 60 human tumor cell lines derived
from nine cancer cell types (leukemia, nonsmall cell lung
cancer, colon cancer, CNS cancer, melanoma, ovarian
cancer, renal cancer, prostate cancer, and breast cancer).
For each compound, dose–response curves for each cell
line were measured with five different drug concentra-
tion, the concentration causing 50% cell growth inhibi-
tion (GI50) compared with the control were
calculated.1811-Methoxy-6H-indolo[2,3-b]quinoline (11)
and its 6-methyl derivative 14b were inactive, the 5,6-di-
methyl derivative 14c (40.74lM) exhibited a moderate
activity, while the 5-methyl derivative 14a (mean
GI50 = 10.72lM) demonstrated a fairly good cytotoxic-
ity. Similar structure–activity relationships were ob-
served in which 11-anilino-6H-indolo[2,3-b]quinoline
(12) was inactive, its 6-methyl derivative 15b
(16.98lM) exhibited a marginal cytotoxicity, while the
5-methyl derivative 15a (1.95lM) proved to be the most
cytotoxic; 11-(4-methoxyanilino)-6H-indolo[2,3-b]quin-
oline (13) and its 6-methyl derivative 16b (22.91lM)
were weakly active while the 5-methyl derivative 16a
(0.78lM) was the most cytotoxic. These indolo[2,3-
b]quinoline derivatives demonstrated selective activity
against the growth of leukemia cells in which the GI50
value for the individual cell line was less than the mean
GI50 as shown in Table 4. Compounds 15a,c, and 16a
are especially cytotoxic for MOLT-4 with GI50 values
of 0.32, 0.66, and 0.09lM, respectively. Compound
16a also demonstrated selective cytotoxicities for HL-
60 (TB), K-562, MOLT-4, RPMI-8226, and SR with
GI50 values of 0.11, 0.42, 0.09, 0.14, and 0.19lM,
respectively.
3. Pharmacological results and discussion
All compounds were evaluated in vitro against a 3-cell
line panel consisting of MCF7 (Breast), NCI-H460
(Lung), and SF-268 (CNS).17 Results from Table 3 indi-
cated all the methylated 6H-indolo[2,3-b]quinoline
derivatives 14–16 are active with exception of 14b while
their precursors 11–13 are inactive with exception of 13,
which exhibited a weak inhibitory activity on the growth
of NCI-H460. Those active compounds were evaluated

6542
Y.-L. Chen et al. / Bioorg. Med. Chem. 12 (2004) 6539–6546
Table 3. In vitro primary anticancer assay of indolo[2,3-b]quinoline
derivatives
anticancer assay indicated 5-methylated derivatives
14a, 15a, 16a are more cytotoxic than their respective
6-methylated counterparts 14b, 15b, 16b and 6H-indo-
lo[2,3-b]quinoline precursors 11, 12, 13. Among them,
11-(4-methoxyanilino)-6-methyl-6H-indolo[2,3-b]quino-
line (16a) is the most cytotoxic with a mean GI50 of
0.78lM. Compounds 15a,c, and 16a are especially cyto-
toxic for MOLT-4 with GI50 values of 0.32, 0.66, and
0.09lM respectively.
Compound
Growth percentages (at 100lM)a
Mean GI50
(lM)b,c
NCI-H460
(Lung)
MCF7
(Breast)
SF-268
(CNS)
8
11
83
70
55
16
16
82
24
ꢀ1
11
ꢀ1
0
75
47
51
63
21
73
34
ꢀ1
16
ꢀ1
7
91
58
59
108
67
98
50
0
Ndd
Nd
12
13
Nd
12.88
10.72
Nd
14a
14b
14c
15a
15b
15c
16a
16b
m-AMSA
40.74
1.95
16.98
1.51
0.78
22.91
0.46
5. Experimental
5.1. General
76
ꢀ1
55
68
Nd
TLC: precoated (0.2mm) silica gel 60 F254 plates from
EM Laboratories, Inc.; detection by UV light
(254nm). All chromatographic separations were per-
formed using silica gel (Merck 60 230–400 mesh). Mp:
Yamato MP-21 melting-point apparatus; uncorrected.
UV spectra (kmax (loge) in nm): Hitachi U-3210 spectro-
photometer. IR spectra (cmꢀ1): Nicolet Magana-IR 550
20
Nd
44
Nd
a In this protocol, each cell line is inoculated and preincubated on a
microtiter plate. Test agents are then added at a single concentration
(100lM) and the culture incubated for 48h. End-point determina-
tions are made with alamar blue.17 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 (negative numbers indicate
cell kill) are passed on for evaluation in the full panel of 60 cell lines
over a 5-log dose range.
1
infrared spectrophotometer. H and 13C NMR spectra:
Varian-Unity-400 spectrometer at 400 and 100MHz or
Varian-Gemini-200 spectrometer at 200 and 50MHz,
chemical shifts d in ppm with SiMe4 as an internal
standard (= 0ppm), coupling constants J in Hz. Elemen-
tal analyses were carried out on a Heraeus CHN-O-Ra-
pid elemental analyzer, and results were within 0.4% of
calculated values.
b Data obtained from NCIÕs in vitro disease-oriented tumor cell
screen.18 GI50: Drug molar concentration causing 50% cell growth
inhibition.
c Mean values over all cell lines tested. These cell lines are: leukemia
(CCRF-CEM, HL-60 (TB), K-562, MOLT-4, PRMI-8226, and SR);
nonsmall cell lung cancer (A549/ATCC, EKVX, HOP-62, HOP-92,
NCI-H226, NCI-H23, NCI-H322M, and NCI-H522); colon cancer
(COLC 205, HCC-2998, HCT-116, HCT-15, HT29, KM12, and SW-
620); CNS cancer (SF-268, SF-295, SF-539, SNB-19, SNB-75, and
U251); melanoma (LOX IMVI, MALME-3M, M14, SK-MEL-2,
SK-MEL-28, SK-MEL-5, and UACC-257); ovarian cancer
(IGROV1, OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, and SK-
OV-3); renal cancer (786-0, A498, ACHN, CAKI-1, RXF 393,
SN12C, TK-10, and UO-31); prostate cancer (PC-3 and DU-145);
and breast cancer (MCF7, MCF7/ADR-RES, MDA-MB-231/
ATCC, HS 578T, MDA-MB-435, MDA-N, and T-47D).
d Not determined.
5.1.1. 4-Methoxy-1H-quinolin-2-one (2). A mixture of
4-hydroxy-1H-quinolin-2-one (1, 3.20g, 20mmol) and
K2CO3 (5.5g, 40mmol) in acetone (50mL) was refluxed
for 3h. The mixture was cooled to room temperature,
dimethylsulfate (5.1g, 40mmol) was added, and the mix-
ture was refluxed for another 2h (TLC monitoring).
Most of the solvent was removed in vacuo, and the
resulting precipitate that separated was collected by fil-
tration, washed with H2O, and dried to give 2 (2.66g,
76%) as a pale-yellow solid. Mp: 253–255ꢁC (lit:19
254–255ꢁC); UVmax nm (loge): 226.4 (4.61), 265.0
(3.77), 274.0 (3.76), 313.8 (3.70) in MeOH; IR mmax
1
cmꢀ1: 1236, 1391, 1609, 1674, 3324 in KBr; H NMR
4. Conclusion
(200MHz, DMSO): 3.93 (s, OCH3), 5.89 (s, H–C(3)),
7.16 (m, H–C(6)), 7.29 (m, H–C(5)), 7.51 (m, H–C(7)),
7.77 (m, H–C(8)), 11.35 (br s, NH). 13C NMR
(50MHz, DMSO): 56.05, 96.61, 114.49, 115.15, 121.30,
122.15, 130.90, 138.58, 163.13 (C(2)), 163.19 (C(4)).
A number of 11-substituted 6H-indolo[2,3-b]quinoline
and their methylated derivatives were synthesized and
evaluated for their cytotoxic activities. The preliminary
Table 4. Antileukemia activity of indolo[2,3-b]quinoline derivatives [GI50 (lM)]
Compound
Cell lines
MOLT-4
Mean GI50 (lM)
HL-60(TB)
K-562
RPMI-8226
SR
13
14a
4.98
9.88
Nd
7.17
11.5
1.84
5.11
2.23
0.42
5.57
0.79
2.35
4.70
0.32
7.89
0.66
0.09
1.88
0.016
2.33
6.04
1.08
3.34
1.58
0.14
3.77
0.20
3.83
7.10
Nd
12.88
10.72
1.95
15a
15b
Nd
Nd
16.98
1.51
0.78
15c
16a
0.99
0.11
3.99
0.025
0.34
0.19
2.75
0.016
16b
m-AMSA
22.91
0.46

Y.-L. Chen et al. / Bioorg. Med. Chem. 12 (2004) 6539–6546
6543
Anal. Calcd for C10H9NO2: C 68.56, H 5.18, N 8.00.
Found: C 68.42, H 5.30, N 7.91.
5.1.5. 4-Anilino-2-chloroquinoline (6). Compound 6 was
obtained from 3 as described for 5 in 72% yield. Mp:
166–168ꢁC; UVmax nm (loge): 223.0 (4.59), 244.0
(4.40), 328.4 (4.17) in MeOH; IR mmax cmꢀ1: 1265,
1359, 1445, 1573, 3199 in KBr; 1H NMR (400MHz,
DMSO): 6.66 (s, H–C(3)), 7.26 (m, H–C(6)), 7.41 (m,
2 arom. H), 7.49 (m, 2 arom. H), 7.59 (m, 1 arom. H),
7.76 (m, H–C(7)), 7.80 (dd, J = 8.4, 1.6Hz, H–C(5)),
8.42 (d, J = 8.0Hz, H–C(8)), 9.32 (br s, NH–C(4)). 13C
NMR (100MHz, DMSO): 99.72, 118.50, 122.26,
123.78 (2C), 125.09, 125.28, 128.20, 129.64 (2C),
130.66, 139.40, 148.06, 150.80 (C(4)), 150.84 (C(2)).
Anal. Calcd for C15H11ClN2: C 70.73, H 4.35, N
11.00. Found: C 70.64, H 4.50, N 11.04.
5.1.2. 4-Anilino-1H-quinolin-2-one (3). A mixture of 1
(8.05g, 50mmol) and aniline (150g, 1.61mol) was ref-
luxed for 18h. After the mixture was cooled to room
temperature, the precipitate that separated was collected
by filtration. The filter cake was poured into 5% NaH-
CO3 aqueous (200mL) with vigorous stirring for 1h,
the solid was separated was filtered and washed with
H2O, and dried. Crystallization of the crude product
from MeOH to give 3 (8.86g, 75%). Mp: 316–318ꢁC;
UV kmax nm (loge): 226.6 (4.67), 314.9 (4.16) in MeOH;
1
IRmax cmꢀ1: 1263, 1395, 1589, 1643, 3277 in KBr; H
NMR (200MHz, DMSO): 5.68 (s, H–C(3)), 7.16–7.55
(m, 8 arom. H), 8.11 (d, J = 7.6Hz, H–C(8)), 8,63 (br
s, NH–C(4)), 11.05 (br s, NH). 13C NMR (50MHz,
DMSO): 94.38, 113.91, 115.62, 120.74, 122.41, 123.68
(2C), 124.21, 129.25 (2C), 130.51, 139.37, 140.07,
150.02 (C(4)), 162.83 (C(2)). Anal. Calcd for
C15H12N2O: C 76.25, H 5.12, N 6.77. Found: C 76.08,
H 5.24, N 6.87.
5.1.6. 2-Chloro-4-(4-methoxyanilino)quinoline (7). Com-
pound 7 was obtained from 4 as described for 5 in
75% yield. Mp: 211–213ꢁC; UV
nm (loge): 222.6
max
(4.65), 244.0 (4.36), 328.4 (4.14) in MeOH; IR mmax
cmꢀ1: 1261, 1432, 1573, 3196 in KBr; 1H NMR
(200MHz, DMSO): 3.81 (s, OCH3), 6.39 (s, H–C(3)),
7.06 (m, 2 arom. H), 7.32 (m, 2 arom. H), 7.56 (m, H–
C(6)), 7.74 (m, 2 H–C(5, 7)), 8.40 (d, J = 8.2Hz, H–
C(8)), 9.22 (br s, NH–C(4)). 13C NMR (50MHz,
DMSO): 55.31, 98.83, 114.93 (2C), 118.14, 122.13,
125.12, 126.55 (2C), 128.14, 130.56, 131.69, 147.97,
150.86, 151.95 (C(2)), 157.15 (C(4)). Anal. Calcd for
C16H111ClN2O: C 67.49, H 4.60, N 9.84. Found: C
67.36, H 4.56, N 9.88.
5.1.3. 4-(4-Methoxyanilino)-1H-quinolin-2-one (4). A
mixture of 1 (1.93g, 12mmol) and p-anisidine (1.48g,
12mol) in diphenyl ether (10mL) was refluxed for 8h
(by TLC monitoring). After the mixture was cooled
to room temperature and added n-hexane (80mL), the
precipitate that separated was collected by filtration.
The filter cake was with n-hexane, 5% NaHCO3, and
dried. Crystallization of the crude product from MeOH
to give 4 (2.18g, 68%). Mp: 306ꢁC (dec); UV kmax nm
5.1.7. 2-(Benzotriazol-1-yl)-4-methoxyquinoline (8). A
mixture of 5 (1.00g, 5.16mmol) and benzotriazole
(0.63g, 5.29mmol) was heated at 110ꢁC for 1h (TLC
monitoring). After the mixture was cooled to room tem-
perature, the residue was precipitated from ammonia
water and stirred for 30min. The resulting precipitate
that separated was collected by filtration, washed with
H2O, and dried to give a crude solid, which was recrys-
tallized with MeOH to give 8 (0.8g, 56%): mp: 176–
178ꢁC; UV kmax nm (loge): 205.4 (4.60), 244.8 (4.63),
(loge): 224.6 (4.68), 314.0 (4.15) in MeOH; IRmax cmꢀ1
:
1239, 1509, 1642, 3439 in KBr; 1H NMR (400MHz,
DMSO): 3.79 (s, OCH3), 5.41 (s, H–C(3)), 7.00 (m, 2
arom. H), 7.17 (m, H–C(6)), 7.23 (m, 2 arom. H),
7.28 (d, J = 8.0Hz, H–C(5)), 7.50 (m, H–C(7)), 8.11
(d, J = 8.0Hz, H–C(8)), 8.52 (br s, NH–C(4)), 10.97
(br s, NH). 13C NMR (100MHz, DMSO): 55.31,
92.95, 113.72, 114.59 (2C), 115.66, 120.73, 122.30,
126.53 (2C), 130.47, 132.38, 139.36, 151.21, 156.66
(C(4)), 162.99 (C(2)). Anal. Calcd for C16H14N2O2: C
72.16, H 5.30, N 10.52. Found: C 72.07, H 5.36, N
10.52.
310.4 (4.25), 323.0 (4.15) in MeOH; IR mmax cmꢀ1
:
1292, 1404, 1452, 1591 in KBr; 1H NMR (200MHz,
DMSO): 4.23 (s, OCH3), 7.59 (m, 2 arom. H), 7.82
(m, 3 arom. H), 8.16 (m, 3 arom. H), 8.93 (d,
J = 8.4Hz, H–C(8)). 13C NMR (50MHz, DMSO):
56.75, 92.29, 115.35, 119.65, 119.98, 121.76, 125.55,
126.19, 128.22, 129.48, 131.07, 131.21, 146.26, 146.56,
151.12, 164.01. Anal. Calcd for C16H12N4O: C 69.55,
H 4.38, N 20.28. Found: C 69.42, H 4.29, N 20.44.
5.1.4. 2-Chloro-4-methoxyquinoline (5). A solution of 2
(5.1g, 29.2mmol) in POCl3 (50mL) and trimethylamine
(3.0g, 29.6mmol) was heated at 90ꢁC for 2h (TLC mon-
itoring). After cooling, the mixture was poured into ice
water (150mL) and neutralized with saturated Na2CO3
until pH7 resulted. The resulting precipitate that sepa-
rated was collected by filtration, washed with H2O,
and dried to give a brown solid, which was recrystallized
with MeOH to give 5 (4.93g, 87%). Mp: 78–80ꢁC; UV
kmax nm (loge): 227.6 (4.85), 276.0 (3.89), 311.2 (3.28)
in MeOH; IR mmax cmꢀ1: 1318, 1417, 1568, 1581 in
5.1.8. 4-Anilino-2-(benzotriazol-1-yl)quinoline (9). Com-
pound 9 was obtained from 6 as described for 8 in
74% yield. Mp: 244–245ꢁC; UV
nm (loge): 202.4
max
(4.74), 243.2 (4.57), 306.4 (4.33) in MeOH; IR mmax
cmꢀ1: 1283, 1411, 1541, 1588, 3335 in KBr; H NMR
1
(400MHz, DMSO): 7.28 (m, 1 arom. H), 7.53 (m, H–
C(6) and 4 arom. H), 7.61 (m, 1 arom. H), 7.74 (m,
2H–C(3, 7)), 7.82 (m, 1 arom. H), 8.05 (d, J = 7.6Hz,
1 arom. H), 8.17 (d, J = 8.0Hz, H–C(5)), 8.50 (d,
J = 7.6Hz, 1 arom. H), 8.91 (d, J = 8.4Hz, H–C(8)),
9.39 (br s, NH–C(4)). 13C NMR (50MHz, DMSO):
90.84, 115.41, 118.82, 119.46, 122.26, 123.74 (2C),
124.94, 125.10, 125.24, 128.79, 129.12, 129.64 (2C),
1
KBr; H NMR (CDCl3): 4.05 (s, OCH3), 6.73 (s, H–
C(3)), 7.50 (m, H–C(6)), 7.70 (m, H–C(7)), 7.95 (d,
J = 8.6Hz, H–C(5)), 8.12 (dd, J = 8.2, 1.4Hz, H–C(8)).
13C NMR (CDCl3): 56.25, 101.21, 120.37, 122.01,
126.09, 127.99, 130.95, 147.99, 151.52 (C(2)), 163.87
(C(4)). Anal. Calcd for C10H8ClNO: C 62.03, H 4.16,
N 7.23. Found: C 61.97, H 4.19, N 7.22.

6544
Y.-L. Chen et al. / Bioorg. Med. Chem. 12 (2004) 6539–6546
130.67, 131.11, 139.79, 146.12, 147.19, 151.00, 151.13.
Anal. Calcd for C21H15N5: C 74.76, H 4.48, N 20.76.
Found: C 74.78, H 4.63, N 20.80.
5.1.12. 11-(4-Methoxyanilino)-6H-indolo[2,3-b]quinoline
(13). Compound 13 was obtained from 10 as described
for 11, which was purified by flash column chromatogra-
phy (FC, CH2Cl2/MeOH = 100:7) and recrystallized
from MeOH in 32% yield. Mp: 280–282ꢁC; UV kmax
nm (loge): 202.4 (4.19), 220.2 (4.18), 235.0 (4.17),
275.6 (4.44), 348.6 (3.58), 400.0 (3.73) in MeOH; IR mmax
5.1.9. 2-(Benzotriazol-1-yl)-4-(4-methoxyanilino)quino-
line (10). Compound 10 was obtained from 7 as de-
scribed for 8 in 55% yield. Mp: 236–238ꢁC; UVmax nm
(loge): 202.8 (4.58), 242.4 (4.43), 305.2 (4.16) in MeOH;
1
cmꢀ1: 1033, 1236, 1510, 1575, 1612, 1419 in KBr; H
1
IR mmax cmꢀ1: 1242, 1411, 1534, 1585, 3275 in KBr; H
NMR (400MHz, DMSO): 3.68 (s, OCH3), 6.82 (m, 4
arom. H), 6.89 (m, H–C(9)), 6.99 (d, J = 7.6Hz, H–
C(10)), 7.32 (m, H–C(8)), 7.40 (m, 2H–C(2, 7)), 7.69
(m, H–C(3)), 7.92 (d, J = 8.0Hz, H–C(4)), 8.42 (d,
J = 8.0Hz, H–C(1)), 9.00 (br s, NH–C(11)), 11.58 (br
s, H–N(6)). 13C NMR (100MHz, DMSO): 55.14
(OCH3), 106.73, 109.73, 114.36 (2C), 118.39 (2C),
118.65, 119.02, 119.81, 121.31, 123.36, 124.43, 126.06,
127.15, 128.62, 137.05, 140.20, 140.82, 147.49, 153.49,
154.38. Anal. Calcd for C22H17N3O: C 77.86, H 5.05,
N 12.38. Found: C 77.91, H 5.00, N 12.42.
NMR (400MHz, DMSO): 7.12 (m, 2 arom. H), 7.42 (m,
2 arom. H), 7.49 (s, H–C(3)), 7.55 (m, H–C(6)), 7.60 (m,
1 arom. H), 7.75 (m, H–C(7)), 7.82 (m, 1 arom. H), 8.04
(dd, J = 8.4, 2.4Hz, 1 arom. H), 8.18 (d, J = 8.4Hz, H–
C(5)), 8.50 (d, J = 8.4Hz, 1 arom. H), 8.92 (d,
J = 8.0Hz, H–C(8)), 9.29 (br s, NH–C(4)). 13C NMR
(100MHz, DMSO): 55.23, 89.81, 114.87 (2C), 115.40,
118.40, 119.40, 122.07, 124.90, 125.16, 126.47 (2C),
128.69, 129.05, 130.53, 131.08, 131.99, 146.04, 147.05,
151.01, 152.07, 157.03. Anal. Calcd for C22H17N5O: C
71.92, H 4.66, N 19.06. Found: C 71.90, H 4.72, N
19.10.
5.1.13. 11-Methoxy-5-methyl-5H-indolo[2,3-b]quino-
line (14a), 11-methoxy-6-methyl-6H-indolo[2,3-b]quino-
line (14b), and 5,6-dimethyl-5,6-dihydroindolo[2,3-
b]quinolin-11-one (14c). General procedure A for the
methylation reactions of 11–13 by dimethylsulfate and
K2CO3 in acetone (Table 2, entry 1). A mixture of 11
(150mg, 0.6mmol), K2CO3 (66mg, 0.48mmol), and
dimethylsulfate (61mg, 0.48mmol) in acetone (5mL)
was refluxed for 24h. The solvent was removed in vacuo,
and the residue was poured into water (50mL), neutral-
ized with 5% HCl until pH7 resulted, and extracted with
EtOAc (50mL · 3). The organic layer was washed with
a saturated NaHCO3 solution, dried over Na2SO4, and
evaporated in vacuo. Purification by FC (CH2Cl2/
MeOH = 100:7) to give the reactant 11 (36mg, 24%
recovered) first and then 14a (79mg, 50%). Compound
14a mp: 184–186ꢁC (recrystallized from MeOH); UVmax
nm (loge): 207.4 (4.35), 277.0 (4.73), 281.4 (4.73), 332.6
(4.21), 347.4 (4.20) in MeOH; IR mmax cmꢀ1: 1241, 1281,
1492, 1520, 1569, 1638 in KBr; 1H NMR (400MHz,
DMSO): 4.29 (two s, CH3–N(5), OCH3), 7.22 (m, H–
C(9)), 7.48 (m, H–C(2)), 7.54 (m, H–C(8)), 7.60 (dd,
J = 8.0, 0.8Hz, H–C(7)), 7.90 (m, H–C(3)), 8.01 (d,
J = 8.4Hz, H–C(4)), 8.12 (ddd, J = 7.6, 1.2, 0.8Hz, H–
C(10)), 8.32 (dd, J = 8.4, 1.2Hz, H–C(1)). 13C NMR
(100MHz, DMSO): 32.71 (CH3–N(5)), 62.11 (11-
OCH3), 114.81, 115.27, 116.66, 117.14, 119.43, 121.74,
122.03, 123.10, 123.73, 127.86, 131.34, 137.97, 153.80,
157.54, 157.65 (C(5a or 11)). Anal. Calcd for
C10H9NO2: C 68.56, H 5.18, N 8.00. Found: C 68.42,
H 5.30, N 7.91.
5.1.10. 11-Methoxy-6H-indolo[2,3-b]quinoline (11). A
mixture of 8 (1.78g, 6.44mmol) in PPA (18mL) was
heated at 140–150ꢁC for 2h (TLC monitoring). After
cooling, the mixture was poured into ice water
(100mL) and neutralized with saturated Na2CO3 until
pH8.5 resulted. The resulting precipitate that separated
was collected by filtration, washed with H2O, and dried
to give a crude solid, which was purified by flash column
chromatography (FC, silica gel CH2Cl2/MeOH 20:1)
and recrystallized from EtOH to give 11 (0.53g, 33%).
Mp: 231–232ꢁC; UV kmax nm (loge): 223.8 (4.50),
270.4 94.93), 314.0 (4.14), 327.8 (4.31), 365.2 (3.62) in
MeOH; IR mmax cmꢀ1: 1233, 1291, 1406, 1584, 1616,
1647 in KBr; 1H NMR (400MHz, DMSO): 4.24 (s,
OCH3), 7.31 (m, H–C(9)), 7.51 (m, 3H–C(2, 7, 8)),
7.75 (m, H–C(3)), 7.99 (d, J = 8.4Hz, H–C(4)), 8.21 (d,
J = 8.0Hz, H–C(10)), 8.29 (dd, J = 8.0, 1.6Hz, H–
C(1)), 11.78 (br s, H–N(6)). 13C NMR (100MHz,
DMSO): 61.83 (OCH3–C(11)), 108.22, 110.81, 118.65,
118.82, 120.06, 122.10, 122.54, 123.49, 127.21, 127.71,
129.18, 140.67, 148.09, 154.84, 157.88. Anal. Calcd for
C16H12N2O 0.1H2O: C 76.84, H 4.92, N 11.20. Found:
C 76.71, H 4.94, N 11.17.
5.1.11. 11-Anilino-6H-indolo[2,3-b]quinoline (12). Com-
pound 12 was obtained from 9 as described for 11 in
56% yield. Mp: 312–314ꢁC; UVmax nm (loge): 219.8
(4.55), 233.8 (4.52), 274.2 (4.90), 346.6 (4.07), 381.6
(4.05), 399.0 (4.11) in MeOH; IR mmax cmꢀ1: 1231,
1251, 1501, 1578, 1614, 3398 in KBr; 1H NMR
(400MHz, DMSO): 6.83 (m, 3 arom. H), 6.92 (m, H–
C(9)), 7.14 (d, J = 8.0Hz, H–C(10)), 7.18 (m, 2 arom.
H), 7.37 (m, H–C(8)), 7.43 (m, 2H-(2, 7)), 7.72 (m, H–
C(3)), 7.96 (dd, J = 8.8, 1.2Hz, H–C(4)), 8.38 (dd,
J = 8.4, 1.2Hz, H–C(1)), 9.21 (br s, NH–C(11)), 11.66
(br s, H–N(6)). 13C NMR (100MHz, DMSO): 108.85,
109.99, 115.97 (2C), 118.84, 119.69, 119.73, 119.81,
121.70, 123.58, 124.57, 126.60, 127.26, 128.77, 129.09
(2C), 139.77, 140.56, 143.93, 147.54, 154.29. Anal. Calcd
for C21H15N3: C 81.53, H 4.89, N 13.58. Found: C
81.44, H 4.96, N 13.61.
(Table 2, entry 2). The reaction was performed from 11
(199mg, 0.8mmol), K2CO3 (165mg, 1.2mmol), and
dimethylsulfate (151mg, 1.2mmol) in acetone (10mL)
according to general procedure A described above to
give 14a (15mg, 7%), 14b (109mg, 52%), and 14c
(31mg, 15%). Compound 14b mp: 130–132ꢁC (recrystal-
lized from MeOH); UV kmax nm (loge): 222.0 (4.31),
273.2 (4.77), 313.4 (3.92), 327.6 (4.10), 371.2 (3.41) in
MeOH; IR mmax cmꢀ1: 1290, 1394, 1569, 1606, 1636 in
KBr; 1H NMR (400MHz, DMSO): 3.94 (s, CH3–
N(6)), 4.25 (s, OCH3), 7.37 (m, H–C(9)), 7.53 (m, H–

Y.-L. Chen et al. / Bioorg. Med. Chem. 12 (2004) 6539–6546
6545
C(2)), 7.63 (m, 2H–C(7, 8)), 7.78 (m, H–C(3)), 8.06 (d,
J = 8.4Hz, H–C(4)), 8.25 (dd, J = 7.8, 0.8Hz, H–
C(10)), 8.31 (dd, J = 8.4, 1.2Hz, H–C(1)). 13C NMR
(100MHz, DMSO): 27.67 (CH3–N(6)), 61.86 (OCH3),
107.96, 109.20, 117.92, 118.86, 120.34, 122.13, 122.58,
123.32, 127.24, 127.71, 129.34, 141.58, 147.77, 153.88,
157.95. Anal. Calcd for C17H14N2O: C 77.84, H 5.38,
N 10.68. Found: C 77.92, H 5.45, N 10.76. Compound
14c mp: 271–273ꢁC (recrystallized from EtOH); UV
kmax nm (loge): 235.3 (4.44), 282.3 (4.48), 316.5 (3.88),
H–C(7)), 7.74 (m, H–C(3)), 8.04 (dd, J = 8.4, 1.2Hz,
H–C(4)), 8.42 (dd, J = 8.4, 0.8Hz, H–C(1)), 9.26
(br s, NH–C(11)). 13C NMR (100MHz, DMSO): 27.62
(CH3–N(6)), 108.23, 108.46, 116.20 (2C), 118.43,
119.06, 119.26, 119.91, 121.92, 123.68, 124.50, 126.70,
127.41, 129.08, 129.14 (2C), 140.05, 141.52, 143.81,
147.27, 153.43. Anal. Calcd for C22H17N3: C 81.71, H
5.30, N 12.99. Found: C 81.76, H 5.45, N 12.91.
(Table 2, entry 4). The reaction was performed from 12
(186mg, 0.6mmol), K2CO3 (83mg, 0.6mmol), and
dimethylsulfate (76mg, 0.6mmol) in acetone (10mL)
according to general procedure A described above to
give 15a (38mg, 20%), and 15b (96mg, 49%).
341.2 (3.96), 362.5 (3.71) in MeOH; IR mmax cmꢀ1
:
1242, 1387, 1466, 1511, 1537, 1579, 1589, 1616, 3424
in KBr; H NMR (400MHz, DMSO): 4.11 (s, CH3–
1
N(6)), 4.18 (s, CH3–N(5)), 7.28 (m, H–C(9)), 7.33 (m,
H–C(8)), 7.58 (d, J = 8.0Hz, H–C(7)), 7.77 (m, 1H–
C(3)), 7.82 (d, J = 8.0Hz, H–C(4)), 8.26 (dd, J = 8.4,
1.6Hz, H–C(10)), 8.34 (dd, J = 7.6, 1.2Hz, H–C(1)).
13C NMR (100MHz, DMSO): 34.02 (CH3–N(6)),
37.58 (CH3–N(5)), 103.60, 109.77, 116.39, 119.88,
121.71, 122.00, 122.92, 123.16, 124.88, 125.23, 131.28,
137.55, 141.37, 148.49, 171.83 (C@O). Anal. Calcd for
C17H14N2O: C 77.84, H 5.38, N 10.68. Found: C
77.88, H 5.52, N 10.70.
(Table 2, entry 5). The reaction was performed from 12
(186mg, 0.6mmol), K2CO3 (166mg, 1.2mmol), and
dimethylsulfate (151mg, 1.2mmol) in acetone (10mL)
according to general procedure A described above to
give 15a (85mg, 44%), 15b (35mg, 18%), and 15c
(27mg, 14%). Compound 15c mp: 164–165ꢁC (recrystal-
lized from MeOH); UV kmax nm (loge): 226.9 (4.36),
249.6 (4.26), 280.9 (4.63), 368.4 (3.96), 398.1 (3.98) in
MeOH; IR mmax cmꢀ1: 1242, 1440, 1486, 1570, 1590,
1
5.1.14. 11-Anilino-5-methyl-5H-indolo[2,3-b]quino-
line (15a), 11-anilino-6-methyl-6H-indolo[2,3-b]quin-
oline (15b), and 11-(N-methylanilino)indolo[2,3-b]quin-
olin-11-one (15c). The methylation reaction of 12 by CH3I
and K2CO3 in acetone (Table 2, entry 3). A mixture of 12
(108mg, 0.35mmol), K2CO3 (48mg, 0.35mmol), and
CH3I (99mg, 0.7mmol) in acetone (10mL) was refluxed
for 18h. The solvent was removed in vacuo, and the res-
idue was poured into water (50mL), neutralized with 5%
HCl until pH7 resulted, and extracted with CH2Cl2
(50mL·3). The organic layer was washed with a satu-
rated NaHCO3 solution, dried over Na2SO4 and evapo-
rated in vacuo. Purification by FC (CH2Cl2/
MeOH = 40:3–5:1) to give 15b (13mg, 11%) first, the
reactant 12 (52mg, 48% recovered) second, and then
15a (24mg, 21%). Compound 15a mp: 255–257ꢁC
(recrystallized from EtOH); UV kmax nm (loge): 213.2
(4.34), 244.1 (4.36), 272.1 (4.60), 338.2 (3.90), 375.0
(4.08) in MeOH; IR mmax cmꢀ1: 1241, 1262, 1496,
1620, 3292 in KBr; H NMR (400MHz, DMSO): 4.31
(s, NCH3–C(11)), 6.78 (m, 2H–C(9, 10)), 6.94 (m, 3
arom. H), 7.24 (m, 2 arom. H), 7.27 (m, H–C(8)), 7.49
(m, 2H–C(2, 7)), 7.88 (m, H–C(3)), 7.99 (d, J = 8.4Hz,
H–C(4)), 8.51 (dd, J = 8.0, 0.8Hz, H–C(1)), 9.45 (br s,
H–N(6)). 13C NMR (100MHz, DMSO): 33.08 (NCH3-
C(11)), 113.21, 116.84, 117.60, 118.24 (2C), 118.46,
121.47, 121.51, 123.61, 124.68, 125.33, 126.76, 129.56
(2C), 131.38, 138.03, 140.78, 143.35, 153.85, 157.01.
Anal. Calcd for C22H17N3: C 81.71, H 5.30, N 12.99.
Found: C 81.61, H 5.33, N 12.84.
5.1.15. 11-(4-Methoxyanilino)-5-methyl-5H-indolo[2,3-
b]quinoline (16a) and 11-(4-methoxyanilino)-6-methyl-
6H-indolo[2,3-b]quinoline (16b) (Table 2, entry 6). The
reaction was performed from 13 (204mg, 0.6mmol),
K2CO3 (83mg, 0.6mmol), and dimethylsulfate (76mg,
0.6mmol) in acetone (10mL) according to general pro-
cedure
A
described above. Purification by FC
1
1588, 1620, 3395 in KBr; H NMR (400MHz, DMSO):
(CH2Cl2/MeOH = 10:1–1:1) to give 16a (26mg, 12%)
first, the reactant 13 (56mg, 27% recovered) second,
and then 16b (85mg, 40%). Compound 16a mp: 155–
157ꢁC (recrystallized from EtOH); UV kmax nm (loge):
235.3 (4.38), 248.5 (4.44), 282.4 (4.57), 332.4 (3.86),
386.8 (4.04) in MeOH; IR mmax cmꢀ1: 1243, 1384, 1512,
4.34 (s, CH3 -N(5)), 6.58 (d, J = 7.6Hz, H–C(10)), 6.83
(m, H–C(9)), 7.05 (m, 3 arom. H), 7.28 (m, 2 arom.
H), 7.33 (m, H–C(8)), 7.57 (d, J = 8.0Hz, H–C(7)),
7.63 (m, H–C(2)), 7.98 (m, H–C(3)), 8.13 (d,
J = 8.8Hz, H–C(4)), 8.71 (d, J = 8.0Hz, H–C(1)),
10.00 (br s, NH–C(11)). 13C NMR (100MHz, DMSO):
34.34 (CH3 –N(5)), 113.67, 116.07, 117.60, 119.51
(2C), 119.86, 121.11, 122.76, 122.87, 124.16, 124.94,
126.49, 127.32, 129.09, 129.13 (2C), 132.03, 137.01,
141.60, 143.62, 152.06. Anal. Calcd for C22H17N3: C
81.71, H 5.30, N 12.99. Found: C 81.86, H 5.43, N
13.06. Compound 15b mp: 198–200ꢁC (recrystallized
from EtOH); UV kmax nm (loge): 222.4 (4.50), 234.4
(4.47), 275.8 (4.83), 347.6 (4.00), 384.0 (3.94), 403.0
(4.02) in MeOH; IR mmax cmꢀ1: 1250, 1320, 1397,
1488, 1563, 1598, 3218 in KBr; 1H NMR (400MHz,
DMSO): 3.94 (s, CH3–N(6)), 6.84 (m, 3 arom. H), 6.98
(m, H–C(9)), 7.13 (d, J = 7.8Hz, H–C(10)), 7.18 (m, 2
arom. H), 7.45 (m, 2H–C(2, 8)), 7.56 (d, J = 8.0Hz,
1
1541, 1591, 3392 in KBr; H NMR (400MHz, DMSO):
3.74 (s, OCH3), 4.30 (s, CH3–N(5)), 6.47 (d, J = 8.0Hz,
H–C(10)), 6.83 (m, H–C(9)), 6.90 (m, 2 arom. H),
7.10 (m, 2 arom. H), 7.31 (m, H–C(8)), 7.55 (d,
J = 8.0Hz, H–C(7)), 7.63 (m, H–C(2)), 7.98 (m, H–
C(3)), 8.12 (d, J = 8.8Hz, H–C(4)), 8.76 (d, J = 8.0Hz,
H–C(1)), 10.00 (br s, HN–C(11)). 13C NMR
(100MHz, DMSO): 33.77 (CH3–N(5)), 55.36 (OCH3),
106.65, 114.32, 114.42 (2C), 114.53, 115.82, 116.99,
119.30, 121.88 (2C), 122.26, 124.08, 124.73, 125.95,
131.68, 134.98, 137.19, 143.77, 146.50, 153.28, 155.37.
Anal. Calcd for C23H19N3O: C 78.16, H 5.42, N 11.89.
Found: C 78.19, H 5.49, N 11.62. Compound 16b mp:
173–175ꢁC (recrystallized from EtOH); UV kmax nm

6546
Y.-L. Chen et al. / Bioorg. Med. Chem. 12 (2004) 6539–6546
3. Denny, W. A.; Cain, B. F.; Atwell, G. J.; Hansch, C.;
Panthananickal, A.; Leo, A. J. Med. Chem. 1982, 25, 276–
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Figgitt, D. P.; Ralph, R. K.; Denny, W. A. J. Med. Chem.
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(loge): 223.5 (4.42), 238.2 (4.43), 273.5 (4.56), 352.9
(3.49), 404.4 (3.99) in MeOH; IR mmax cmꢀ1: 1242,
1291, 1384, 1419, 1441, 1509, 1619, 3239 in KBr; H
1
NMR (400MHz, DMSO): 3.68 (s, OCH3), 3.91 (s,
CH3–N(6)), 6.82 (m, 4 arom. H), 6.95 (m, H–C(9)),
7.00 (d, J = 7.2Hz, H–C(10)), 7.42 (m, 2H–C(2, 8)),
7.52 (d, J = 8.0Hz, H–C(7)), 7.72 (m, H–C(3)), 7.99
(dd, J = 8.4, 1.2Hz, H–C(4)), 8.45 (dd, J = 8.4, 1.2Hz,
H–C(1)), 9.06 (br s, NH–C(11)). 13C NMR (100MHz,
DMSO): 27.46 (CH3–N(6)), 55.13 (OCH3), 106.06,
108.16, 114.34 (2C), 118.60 (2C), 119.03, 119.13,
119.17, 121.48, 123.42, 124.32, 126.11, 127.32, 128.87,
136.90, 141.04, 141.14, 147.21, 153.50, 153.60. Anal.
Calcd for C23H19N3O: C 78.16, H 5.42, N 11.89. Found:
C 78.04, H 5.46, N 11.76.
(Table 2, entry 7). The reaction was performed from 13
(204mg, 0.6mmol), K2CO3 (166mg, 1.2mmol), and
dimethylsulfate (151mg, 1.2mmol) in acetone (10mL)
according to general procedure A described above to
give 16a (96mg, 45%), the reactant 13 (28mg, 14%
recovered), and 16b (32mg, 15%).
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Acknowledgements
Financial support of this work by the National Science
Council of the Republic of China is gratefully acknowl-
edged. 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 computer resources and chemical database
services.
17. Gray, G. D.; Wickstrom, E. Biotechniques 1996, 21, 780–
782.
References and notes
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