Design of antineoplastic agents based on the '2-phenylnaphthalene-type' structural pattern - Synthesis and biological activity studies of 11H-indolo[3.2-c]quinoline derivatives

Article abstract of DOI:10.1016/S0223-5234(02)01420-4

Designed as a new group of planar molecule containing the proposed 2-phenylnaphthalene-type structure, a number of 11H-indolo[3.2-c]quinoline derivatives were synthesized and evaluated biologically. Several compounds were found to possess cytotoxic activity against the growth of human promyelocytic leukemia cells (HL-60), against the small cell lung cancer (SCLC), and showed good response in the National Cancer Institute preclinical antitumor drug discovery 60-cell line panel.

Full text of DOI:10.1016/S0223-5234(02)01420-4

European Journal of Medicinal Chemistry 38 (2003) 101ꢀ107
/
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Short communication
Design of antineoplastic agents based on the ‘2-phenylnaphthalene-
type’ structural pattern*synthesis and biological activity studies of
11H-indolo[3.2-c]quinoline derivatives
/
Ling He a,*, He-Xi Chang b, Ting-Chao Chou c, Niramol Savaraj d, C.C. Cheng b,*
a West China School of Pharmacy, Sichuan University, Chengdu 610041, China
b Drug Development Laboratory, Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City,
KS 66160-7419, USA
c Laboratory of Preclinical Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA
d Department of Medicine, The University of Miami School of Medicine, Miami, FL 33136, USA
Received 12 April 2002; received in revised form 10 September 2002; accepted 18 September 2002
Abstract
Designed as a new group of planar molecule containing the proposed 2-phenylnaphthalene-type structure, a number of 11H-
indolo[3.2-c]quinoline derivatives were synthesized and evaluated biologically. Several compounds were found to possess cytotoxic
activity against the growth of human promyelocytic leukemia cells (HL-60), against the small cell lung cancer (SCLC), and showed
good response in the National Cancer Institute preclinical antitumor drug discovery 60-cell line panel.
´
# 2002 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: 2-Phenylnaphthalene-type; 11H-Indolo[3.2-c]quinoline derivatives; Antitumor activity
1. Introduction
have been scheduled to undergo further in vivo evalua-
tion.
A number of 3-phenylquinazolones (1) [1], benzox-
azolo[2.3-b]quinazolones (2a) [1], benzothiazolo[2.3-
b]quinazolones (2b) [1], benzo[b]naphtho[2.3-d]furan-
6,11-diones (3a) [2] and 5H-benzo[b]naphtho[2.3-d]pyr-
role-6,11-diones (3b) [3] were designed, synthesized and
evaluated biologically to examine the validity of the ‘2-
phenylnaphthalene-type’ hypothesis developed in our
laboratory. The hypothesis was originated from an
observation that many biologically active compounds
of natural and synthetic origin possess a tricycle
chemical structural pattern consisted of a phenyl ring
unit attached to the 2-position of a naphthalene nucleus,
or composed of various heterocyclic units with similar
structural arrangements [4]. Several compounds de-
signed in such manner were found to exhibit excellent
cytotoxic activity in a number of systems [1,2]. Some
An examination of the biological activity of com-
pounds 3-phenylquinazolones (1) with that of the
benzoxazolo- and benzothiazolo[2.3-b]quinazolones (2)
signified the importance of the coplanarity of the ring
units for desired biological action [1]. Since the planarity
of compounds in-group 2 are achieved through the
linkage between the benzene moiety and the 2-position
of the naphthalene-type unit, it was decided to alter-
natively link the benzene ring with the 1-position of the
naphthalene-type ring unit. Consequently, a study of
compounds containing the 11H-indolo[3.2-c]quinoline
(4) ring system was undertaken (Fig. 1).
A search in literature of compounds of this type
indicated that some possessed interesting biological
activities. There was an elegant study between the
antimalarial agent amodiaquine and its ring closed
3-chloro-8-methoxy-9-diethylaminomethyl-11H -in-
dolo[3.2-c]quinoline analogue on DNA binding and
RNA polymerase inhibition [5]. Also, a quinolinedione
* Corresponding authors.
E-mail address: lhe2001@sina.com.cn (L. He).
´
0223-5234/02/$ - see front matter # 2002 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
PII: S 0 2 2 3 - 5 2 3 4 ( 0 2 ) 0 1 4 2 0 - 4

102
L. He et al. / European Journal of Medicinal Chemistry 38 (2003) 101ꢀ107
/
oxyl compounds 6d, j, l, m, with hydrobromic acid and
acetic acid yielded the corresponding hydroxyl com-
pounds 6nꢀ
were obtained from the corresponding hydroxy sub-
stituted 11H-indolo[3.2-c]quinolines 6nꢀp etherification
with 2-(dimethylamino) ethyl chloride.
/
q. Subsequent the ether derivatives 6rꢀt
/
/
The other synthetic route was carried out as follows:
chlorination of 4-hydroxyquinoline (7a) with phospho-
rus oxychloride gave 4-chloroquinoline (7b), which
condensed with appropriate aniline to form 4-(substi-
tuted anilino) quinoline (8). This compound was
cyclized in refluxing acetic acid in the presence of
palladium(II) acetate to the corresponding 11H-in-
dolo[3.2-c]quinolone 6d and 6u [11,12] (Fig. 2).
Theoretically, 4-(substituted anilino) quinolines (8)
could also be cyclized to compounds of a different ring
system, 7H-pyrido[4.3.2-gh]phenanthridine (9). The
possibility of forming the general ring system 9 by this
route was ruled out by comparison of the NMR data
and physical constants of 8-methoxy-11H-indolo[3.2-
c]quinoline (6d) prepared by both routes. The NMR
interpretation is presented as follows: 1H-NMR (DMSO
plus CDCl3) ppm: 9.75 (s, 1H, Hh), 8.84 (dd, 1H, Ha_),
8.38 (dd, 1H, Hd), 7.94 (td, 1H, Hc), 7.88 (td, 1H, Hb),
7.80 (d, 1H, He), 7.75 (d, 1H, Hg), 7.26 (dd, 1H, Hf), 3.96
Fig. 1.
derivative, 3-methoxy-11H-indolo[3.2-c]quinoline-l,4-
dione, was found to inhibit DNA topoisomerases [6].
2. Chemistry
Two synthetic approaches for the preparation of
11H-indolo[3.2-c]quinolines were used. Refluxing 5
(s, 3H, Ã/OCH3).
The COSY spectrum of compound 10d prepared by
method A indicates that four aromatic proton peaks
(Ha, Hb, Hc and Hd) are derived from one ring and the
[7ꢀ
stituted 11H-indolo[3.2-c]quinoline 6aꢀ
Fischer indole synthesis. Demethylation of these meth-
/
10] with an aryl hydrazine gave the cyclized sub-
/m
by the
Fig. 2.

L. He et al. / European Journal of Medicinal Chemistry 38 (2003) 101ꢀ
/107
103
Table 1
Inhibitory action of 11H-indolo[3.2-c]quinoline derivatives
c
Compound
IC50 (mM)
NCI screen
a
b
HL-60
SCLC
10a
10b
10c
10d
10e
10f
10g
10h
10i
4.16
10.9
17.5
2.03
1.3
5.0
0.3
0.3
0.5
0.25
0.075
8
ꢁ
/
ꢂ
/
ꢁ
/
ꢁ
/
ꢁ
/
ꢁ
/
Fig. 3.
0.76
1.66
77
ꢁ
/
ꢁ
/
other three protons (He, Hf and Hg) are correlated as
postulated. Thus the possibility of forming the corre-
sponding ring isomer 9d has been ruled out (Fig. 3). A
number of substituted 11H-indolo[3.2-c]quinolines were
prepared and described in Section 4.
No effect
No effect
No effect
0.3
ꢁ
/
30.5
5.5
ꢂ
/
10j
ꢂ
/
10k
101
10m
10n
10o
10p
10q
10r
10s
10t
10u
2.66
4.48
1.3
ꢁ
/
2.0
1.0
ꢁ
/
ꢁ
/
ꢁ
/
0.99
1.06
4.37
3.14
5.79
0.23
0.47
5.0
5.0
5.0
ꢁ
/
ꢁ
/
0.75
0.75
ꢁ
/
ꢁ
/
3. Results and discussion
7.0
0.05
ꢂ
/
ꢁ
/
ꢁ
/
The 11H-indolo[3.2-c]quinolines designed and
synthesized were evaluated against the growth of human
promyelocytic leukemia cells (HL-60), cytotoxic against
the small-cell lung cancer (SCLC), and the National
Cancer Institute’s disease-oriented primary antitumor
screen 60 cell line panel [13] (see Table 1).
0.075
5.0
ꢁ
/
ꢁ
/
ꢂ/
Descriptions of all the assay tests were given in our previous
publications [2].
a
Inhibitory concentration for m-AMSA is 0.055 mM.
Cytotoxicity against SCLC for established anticancer agents (IC50
b
mM) are as follows: cisplatin, 0.67; VP-16, 0.5; vinblastine, 0.004;
adriamycin, 0.04; mitoxantrone, 0.02; 5-FU, 5.4.
Generally, the 11H-indolo[3.2-c]quinolines showed
inhibitory activity in the NCI 60 cell, and the oxygen-
containing compounds (hydroxyl or methoxyl) exhibit
inhibitory activity against SCLC (see compounds 6d, 6e,
6k, 6p and 6q). However, substitution with multiple
hydroxyl groups on one molecule produced detrimental
effect against all three-test systems (6o). The three
compounds containing one or two of the 2-(dimethyla-
mino) ethoxyl side chain (6f, 6s and 6t) uniformly
demonstrated excellent activity in HL-60, SCLC and
the NCI tests. Activity of these long chain derivatives is
comparable to that against cisplatin, VP-16, vinblastine,
adriamycin and mitoxantrone [2] in SCLC tests. How-
ever, compound 6u, the structure of which somewhat
resembles the acridine m-AMSA [14], exhibited no
inhibitory activity in our tests.
c
National Cancer Institute preclinical 60 human tumor cell lines
drug-discovery screen: complete inhibition of cell growth detected
[log IC50 (M)] for at least one cell line at ꢂ
/
6: ꢁ
/
ꢁ
/
, ꢂ
/
5: ꢁ
/
, inactive: ꢂ.
/
4. Experimental
All melting points were taken on a Thomas-Hoover
1
melting point apparatus. H-NMR spectra in CDCl3 or
DMSO on Bruker AC-E200 (200MHz) using TMS as an
1
internal standard. The H-NMR spectra for compound
6d were acquired on Bruker AM-500 (500 MHz). Mass
spectra and ultraviolet absorption spectra were deter-
mined, respectively, by the University of Kansas Mass
Spectrometry Laboratory and Division of Biological
Sciences, Lawrence, KS. The M-H-W Laboratories,
Phoenix, AZ, performed elemental analyses.
The preceding information [1ꢀ3] and the presently
/
designed derivatives of the 11H-indolo[3.2-c]quinoline
(4) ring system indicated some interesting biological
activities for the compounds containing the proposed ‘2-
phenylnaphthalene-type’ chemical structure. Conse-
quently, we consider that these types of ring system
will be of biological importance. The ring system should
fulfil two requirements: (1) the basic conformation
should be coplanar; (2) the ‘2-phenyl’ ring should be
linked to the ‘naphthalene’ unit at position 1 or position
3. We believe that the potential of investigation along
this conception is unlimited and perhaps the usefulness
of this postulation could be appreciated in the future.
4.1. 4-(4-Methoxyanilino) quinoline (8a)
A stirring mixture of 0.45 g (2.76 mmol) of 4-
chloroquinoline (7), 0.35 g (2.85 mmol) of p-anisidine,
20 mL of EtOH and three drops of methanesulfonic acid
was refluxed for 6 h. The reaction mixture was
evaporated under reduced pressure. The residual paste
was triturated with ether. A yellow solid was formed,
which was dissolved in a small amount of MeOH. Cold
20% of NaOH was added to adjust the pH to 10. After

104
L. He et al. / European Journal of Medicinal Chemistry 38 (2003) 101ꢀ107
/
stirring for 10 min, the resulting off-white solid was
collected by filtration and washed with water. Yield of
4.5. 8-Chloro-11H-indolo[3.2-c]quinoline (6b, R1, R2,
R3, R5ꢃH; R4ꢃCl)
/
/
the pure product was 95% (0.65 g), m.p. 187ꢀ
/
189 8C (lit.
[15] m.p. 259ꢀ262 8C). The molecular formula given in
the reference was C16H15N2O rather than C16H14N2O).
/
This compound [18] was obtained by Method A in
51% yield, m.p. ꢀ300 8C (from EtOAc, silica gel). UV
/
lmax (MeOH): 242 nm (log o 4.01), 275 (4.10), 295
(3.73), 328 (3.20). MS (m/z): 252 [Mꢁ]. Anal.
(C15H9CIN2) Calc.: C, 71.29; H, 3.59; N, 11.08; Found:
C, 70.88; H, 3.80; N, 10.84%.
4.2. 4-[(2-Methoxy-4-methanesulfonamido)
anilino]quinoline (8b)
This compound was obtained in a similar manner as
for the preparation of 8a. Yield of the light yellow
4.6. 8-Bromo-11H-indolo[3.2-c]quinoline (6c, R1, R2,
hydrochloride salt was 39%, m.p. 274ꢀ
m.p. 267ꢀ270 8C). Its light gray free base was obtained
by treating the salt with aqueous NaOH, m.p. 244ꢀ
/
276 8C. (lit. [16]
/
R3, R5ꢃ
/
H; R4ꢃBr)
/
/
245 8C.
This compound was obtained by Method A in 52%
yield, m.p. 336ꢀ338 8C (from EtOAc, silica gel). MS (m/
/
1
1]. H-NMR (DMSO-d6) ppm: d 9.80 (s,
z): 296 [Mꢁꢂ
/
4.3. General procedure for the preparation of 11H-
indolo[3,2-c]quinolines (6)
1H), 8.30 (s, 1H), 7.21ꢀ
/
7.29 (m, 4H), 6.86ꢀ6.93 (m, 3H).
/
Anal. (C15H9BrN2) Calc.: C, 60.63; H, 3.05; N.9.43;
Found: C, 60.81; H, 3.16; N, 9.50%.
4.3.1. Method A
To a stirring mixture of the appropriate phenyl
hydrazine (9, 0.058 mol) in 100 mL of 1-butanol and
the appropriate 2,3-dihydroquinoline-4-one (8, 0.052
mol) was added dropwise, with heating, 26 mL of
concentrated HCl. The mixture was refluxed for 20 h,
then was cooled and refrigerated overnight. The result-
ing yellow solid was collected by filtration. Dissolving
the product in a mixture of water and methanol, and
4.7. 8-Methoxy-11H-indolo[3.2-c]quinoline (6d, R1, R2,
R3, R5ꢃ
/
H; R4ꢃOCH3)
/
This compound was obtained by Method A in 45%
yield, m.p. 320ꢀ322 8C (from EtOH). The compound
/
was also obtained by Method B by refluxing a mixture
of 0.6 g of 12a and 0.66 of palladium(II) acetate in 100
ml of acetic acid under nitrogen overnight, and the
product was obtained in 57% yield as a light yellow solid
adjusting the pH to 8ꢀ9 with 10% NaOH obtained the
/
free base. The product was purified either by recrystal-
lization from EtOH or through a silica gel column using
EtOAc as eluent. Most compounds were prepared by
this method.
(from EtOH and EtOAc), m.p. 319ꢀ320 8C. Both
/
products were identical by comparison of their NMR
spectra (see discussion in the Chemistry Section). MS
(m/z): 248 [Mꢁ]. Anal. (C16H12N2O) Calc.: C, 77.26; H,
4.86; N, 11.26; Found: C, 77.10; H, 4.59; N, 10.98%.
4.3.2. Method B
A stirred mixture of 1 mmol of the appropriate 4-
(substituted anilino) quinoline and 1.8 mmol of palla-
dium(II) acetate in 60 mL of acetic acid was heated
under reflux in the presence of nitrogen for 7 h. The
resulting solid was collected by filtration and purified
through column chromatography. Compounds 6d and
6u were prepared by this method.
4.8. 8-Hydroxy-11H-indolo[3.2-c]quinoline (6e, R1, R2,
R3, R5ꢃ
/
H; R4ꢃOH)
/
A mixture of 5.3 g of 6d, 130 mL of 48% hydrobromic
acid and 500 mL of acetic acid was refluxed under
nitrogen for 10 h. The pH of the reaction mixture was
adjusted to 6 with 20% NaOH and extracted with
EtOAc. The organic layer was concentrated under
reduced pressure and the yellow solid was recrystallized
4.4. 11H-Indole[3.2-c]quinoline hydrochloride (6a, R1,
R2, R3, R4, R5ꢃH)
/
from EtOHꢀ
/
EtOAc to give 3.73 g (89% yield) of 6e,
This compound was obtained in 40% yield by the
general procedure described in Method A, m.p. 328ꢀ
m.p. ꢀ
/
330 8C. UV lmax (MeOH): 232 nm (log o 4.27),
/
260 (4.01), 285 (4.20), 304 (3.94). MS (m/z): 234 [Mꢁ].
1H-NMR (DMSO-d6 plus D2O) ppm: d 9.89 (s, 1H),
8.88 (dd, 1H), 8.32 (d, 1H), 7.93 (m, 4H), 7.32 (dd, 1H).
330 8C (recrystallized from EtOH) [17,18]. UV lmax
(MeOH): 235 nm (log o 4.50), 274 (4.52), 290 (4.08), 323
(3.50). MS (m/z): 218 [Mꢁ]. Anal. (C15H10N2×
/HC1)
Anal. (C15H10N2O×
N, 8.41; Found: C, 53.85; H, 3.75; N, 8.25%.
/
HBr×/H2O) Calc.: C, 54.07; H, 3.93;
Calc.: C, 70.73; H, 4.35; N, 10.99; Found: C, 70.61; H,
4.41; N, 11.10%.

L. He et al. / European Journal of Medicinal Chemistry 38 (2003) 101ꢀ
/107
105
4.9. 8-[2-(Dimethylamino) ethoxy]-11H-indolo[3.2-
c]quinoline (6f, R1, R2, R3, R5ꢃH; R4ꢃ
O(CH2)2N(CH3)2)
4.13. 3-Chloro-8-methoxy-11H-indolo[3.2-c]quinoline
(6j, R1ꢃCl; R4ꢃOCH3; R2, R3, R5ꢃH)
/
/
/
/
/
3-Chloro-8-methoxy-11H-indolo[3.2-c]quinoline (6j,
R1ꢃCl; R4ꢃOCH3; R2, R3, R5ꢃH) was obtained by
Method A in 41% yield, m.p. ꢀ340 8C (EtOH). MS (m/
z): 282 [Mꢁ]. Anal. (C16H11ClN2O×
HCl×0.5H2O) Calc.:
/
/
/
A mixture of 0.7 g (3 mmol) of 6e, 0.65 g (4.5 mmol)
of 2-(dimethylamino) ethyl chloride hydrochloride, 2.1 g
(15 mmol) of potassium carbonate and 150 ml of CHCl3
was refluxed with stirring for 4 h. To the mixture was
added 20 ml of water and refluxing was continued for
another 24 h. The reaction mixture was cooled and
/
/
/
C, 58.56; H, 3.99; N, 8.54; Found: C, 58.84; H, 4.23; N,
8.55%.
extracted with chloroform (3ꢄ
extract was washed successively with 20 ml of 20%
NaOH and brine (2ꢄ50 ml). The organic layer was
dried (magnesium sulfate) and the solvent concentrated
in vacuo. The resulting yellowꢀbrown solid was acid-
/
50 ml). The combined
4.14. 3-Chloro-7,8,9-trimethoxy-11H-indolo[3.2-
c]quinoline (6k, R1ꢃ
/
Cl; R2ꢃ
/
H; R3, R4, R5ꢃOCH3)
/
/
3-Chloro-7,8,9-trimethoxy-11H-indolo[3.2-c]quino-
line (6k, R1ꢃCl; R2ꢃH; R3, R4, R5ꢃOCH3) was
obtained by Method A in 34% yield, m.p. 290ꢀ292 8C
(EtOAcꢀ
dimethyl acetamide). MS (m/z): 342 [Mꢁ].
/
/
/
/
ified with ethanolic hydrogen chloride to give the
/
product as a hydrochloride salt. Recrystallization from
/
ethanol gave yellow crystals, m.p. 292ꢀ
was 850 mg (75%). MS (m/z): 305 [Mꢁ]. Anal.
2HCl) Calc.: C, 60.32; H, 5.59; N, 11.10;
/
293 8C. The yield
Anal. (C18H15ClN2O3) Calc.: C, 63.07; H, 4.41; N,
8.17; Found: C, 62.93; H, 4.65; N, 7.96%.
(C19H19N3O×
/
Found: C, 60.42; H, 5.69; N, 11.03%.
4.15. 3-Methoxy-11H-indolo[3.2-c]quinoline (6l, R1ꢃ
/
OCH3; R2, R3, R4, R5ꢃH)
/
3-Methoxy-11H-indolo[3.2-c]quinoline (6l, R1ꢃ
OCH3; R2, R3, R4, R5ꢃH) was obtained by Method
A in 53% yield, m.p. 312ꢀ314 8C (EtOH) [18].
/
4.10. 7,8,9-Trimethoxy-11H-indolo[3.2-c]quinoline (6g,
/
R1, R2ꢃ
/
H; R3, R4, R5ꢃOCH3)
/
/
7,8,9-Trimethoxy-11H-indolo[3.2-c]quinoline (6g, R1,
R2ꢃH; R3, R4, R5ꢃOCH3) was obtained by Method
A in 42% yield, m.p. 285ꢀ287 8C (EtOAc). MS (m/z):
308 [Mꢁ]. H-NMR (DMSO-d6) ppm: d 9.88 (s, 1H),
8.68ꢀ8.51 (m, 3H), 7.93ꢀ7.72 (m, 4H). Anal.
4.16. 3-Methoxy-8-methyl-11H-indolo[3.2-c]quinoline
(6m, R1ꢃOCH3, R2, R3, R5ꢃH; R4ꢃCH3)
/
/
/
/
/
/
1
3-Methoxy-8-methyl-11H-indolo[3.2-c]quinoline (6m,
R1ꢃOCH3, R2, R3, R5ꢃH; R4ꢃCH3) was obtained
by Method A in 60% yield, m.p. 320ꢀ321 8C (MeOH)
[19]. MS (m/z): 262 [Mꢁ], 263 [Mꢁꢁ
1]. Anal.
1/2H2O) Calc.: C, 59.31; H, 4.98;
/
/
/
/
/
(C18H16N2O3) Calc.: C, 70.12; H, 5.23; N, 9.08; Found:
C, 69.97; H, 5.39; N, 9.00%.
/
/
(C17H14N2O×
/
2HC1×
/
N, 8.13; Found: C, 59.73; H, 5.11; N, 7.90%.
4.11. 3,8-Dichloro-11H-indolo[3,2-c]quinoline (6h, R1,
R4ꢃ
/
Cl; R2, R3, R5ꢃH)
/
4.17. 3,8-Dimethoxy-11H-indolo[3.2-c]quinoline (6n,
R1, R4ꢃ
/
OCH3; R2, R3, R5ꢃH)
/
3,8-Dichloro-11H-indolo[3.2-c]quinoline (6h, R1,
R4ꢃCl; R2, R3, R5ꢃH) was obtained by Method A
in 56% yield, m.p. ꢀ330 8C (MeOH). MS (m/z): 286
[Mꢁꢂ
1]. Anal. (C15H8Cl2N2) Calc.: C, 62.74; H, 2.81;
/
/
3,8-Dimethoxy-11H-indolo[3.2-c]quinoline (6n, R1,
R4ꢃOCH3; R2, R3, R5ꢃH) was obtained by Method
A in 47% yield, m.p. 307ꢀ310 8C (MeOH). MS (m/z):
HCl) Calc.: C, 64.87; H,
/
/
/
/
/
N, 9.76; Found: C, 62.49; H, 2.66; N, 9.97%.
273 [Mꢁ]. Anal. (C17H14N2O2×
/
4.80; N, 8.89; Found: C, 64.68; H, 5.06; N, 8.76%.
4.12. 3-Bromo-8-chloro-11H-indolo[3.2-c]quinoline (6i,
4.18. 3,7,8,9-Tetramethoxy-11H-indolo[3.2-c]quinoline
R1ꢃ
/
Cl; R4ꢃ
/
Br; R2, R3, R5ꢃH)
/
(6o, R1, R3, R4, R5ꢃ
/
OCH3, R4ꢃH)
/
3-Bromo-8-chloro-11H-indolo[3.2-c]quinoline
R1ꢃCl; R4ꢃBr; R2, R3, R5ꢃH) was obtained by
Method A in 41% yield, m.p. ꢀ340 8C (EtOAcꢀ
dimethyl acetamide). MS (m/z): 330 [Mꢁꢂ
1]. Anal.
(C15H8BrCIN2) Calc.: C, 54.33; H, 2.43; N, 8.45;
Found: C, 54.13; H, 2.66; N, 8.34%.
(6i,
3,7,8,9-Tetramethoxy-11H-indolo[3.2-c]quinoline
(6o, R1, R3, R4, R5ꢃOCH3, R4ꢃH) was obtained by
Method A in 50% yield, mp 278ꢀ280 8C (EtOH). MS
(m/z): 338 [Mꢁ]. Anal. (C19H18N2O4×
HC1) Calc.: C,
/
/
/
/
/
/
/
/
/
/
60.88; H, 5.11; N, 7.47; Found: C, 60.70; H, 5.22; N,
7.29%.

106
L. He et al. / European Journal of Medicinal Chemistry 38 (2003) 101ꢀ107
/
4.19. 3-Hydroxy-11H-indolo[3.2-c]quinoline (6p, R1ꢃ
/
separated and the aqueous phase was extracted with
CHCl3 (3ꢄ80 ml). The combined organic solution was
washed successively with 20 ml of 20% NaOH and brine
(2ꢄ30 ml), dried (magnesium sulfate) and evaporated.
OH; R2, R3, R4, R5ꢃH)
/
/
A mixture of 3 g of 6l, 60 ml of 48% hydrobromic acid
and 100 ml of acetic acid was refluxed with stirring
under nitrogen for 34 h. The reaction mixture was
concentrated under reduced pressure and the residue
was neutralized with saturated sodium bicarbonate to
/
The residue was dissolved in 50 ml of EtOH and
acidified with concentrated HCl. The resulting white
solid was recrystallized from EtOH to give 1.05 g (65%
yield) of 6s, m.p. 300ꢀ
/
302 8C. MS (m/z): 305 [Mꢁ].
pH 7ꢀ
filtration and recrystallized from EtOAc. The yellow
solid product melted at 320ꢀ323 8C. The yield was 2.4 g
/
8. The resulting light brown solid was collected by
Anal. (C19H19N3O×
/
2HCl) Calc.: C, 60.32; H, 5.59; N,
11.10; Found: C, 60.12; H, 5.86; N, 11.08%.
/
(97%). UV lmax (MeOH): 244 nm (log o 3.98), 275
(4.25), 290 (3.70). MS (m/z): 234 [Mꢁ]. Anal.
(C15H10N2O) Calc.: C, 76.91; H, 4.30; N, 11.96; Found:
C, 76.78; H, 4.50; N, 11.77%.
4.23. 3,8-Bis[2-(dimethylanuno) ethoxy]-11H-
indolo[3.2-c]quinoline (6t, R1, R4ꢃ
/
O(CH2)2N(CH3)2), R2, R3, R5ꢃH)
/
A mixture of 1 g (4 mmol) of 6q, 1.73 g (12 mmol) of
2-(dimethylamino) ethyl chloride hydrochloride, 5.52 g
(40 mmol) of potassium carbonate, 200 ml of CHCl3, 50
ml of water and 50 ml of MeOH was refluxed with
vigorous stirring for 48 h. The separation and purifica-
tion and acidification procedures were similar to that for
the preparation of 6s, the yield of 6t as a trihydrochlor-
4.20. 3,8-Dihydroxy-11H-indolo[3.2-c]quinoline (6q,
R1, R4ꢃ
/
OH; R2, R3, R5ꢃH)
/
3,8-Dihydroxy-11H-indolo[3.2-c]quinoline (6q, R1,
R4ꢃOH; R2, R3, R5ꢃH) was prepared in a manner
/
/
similar to that for the preparation of 6p from 2 g of 6n,
40% of 48% hydrobromic acid and 160 ml of acetic acid
to give, after neutralization and recrystallization from
water, 1.34 g of yellow solid, m.p. 235 8C (dec.). MS (m/
ide salt was 1.1 g (55%), m.p. 262ꢀ
/
264 8C. MS (m/z):
392 [Mꢁ]. Anal. (C23H28N4O2×
H, 6.23; N, 11.16; Found; C, 54.89; H, 6.23; N, 10.96%.
/3HC1) Calc.: C, 55.04;
z): 250 [Mꢁ]. Anal. (C15H10N2O2×
/1/2H2O) Calc.: C,
69.49; H, 4.28; N, 10.81; Found: C, 69.11; H, 4.62; N,
10.62%.
4.24. 6-Methoxy-8-methanesulfonamido-11H-
indolo[3.2-c]quinoline (6u, R1, R3, R5ꢃ
/
H; R2ꢃOCH3;
/
R4ꢃNHSO2CH3)
/
4.21. 3,7,8,9-Tetrahydroxy-11H-indolo[3.2-c]quinoline
H)
(6r, R1, R3, R4, R5ꢃ
/
OH; R2ꢃ
/
A mixture of 0.4 g (1 mmol) of 8b, 0.4 g (1.8 mmol) of
palladium(II) acetate and 60 ml of acetic acid was
refluxed under nitrogen for 7 h. The reaction mixture
was evaporated to syrup. To the residue was added 50
ml of water and, under cooling; its pH was adjusted to 8.
After overnight standing in a refrigerator, the mixture
was filtered and the brownish yellow solid was purified
by means of silica gel column chromatography using
3,7,8,9-Tetrahydroxy-11H-indolo[3.2-c]quinoline (6r,
R1, R3, R4, R5ꢃOH; R2ꢃH) was prepared in a
/
/
manner similar to that for the preparation of 6p and
6q from 6o, hydrobromic and acetic acid in 83% yield
without neutralization. After recrystallization from
acetic acid the yellow solid melted at 290 8C (dec). UV
lmax (MeOH): 253 nm (log o 4.26), 280 (3.86), 338
ethyl acetateꢀmethanol (9:1) as eluent. After addition of
/
(3.70). MS (m/z): 282 [Mꢁ]. Anal. (C15H10N2O4ꢀ
/
HBr)
10 mL of water to the eluent, the resulting solid was
collected by filtration and 0.1 g (28% yield) of 6u of
brownish yellow solid was obtained, m.p. 294 8C (dec.).
Calc.: C, 49.61; H, 3.05; N, 7.71; Found: C, 49.80; H,
3.21; N, 7.60%.
MS (m/z): 341 [Mꢁ]. Anal. (C17H15N3O3S×
/H2O) Calc.:
4.22. 3-[2-(Dimethylamino)ethoxy]-11H-indolo[3.2-
C, 56.81; H, 4.77; N, 11.69. Found: C, 56.99; H, 4.40; N,
11.66%.
c]quinoline (6s, R1ꢃ/O(CH2)2N(CH3)2; R2, R3, R4,
R5ꢃ H)
/
A mixture of 1 g (4.3 mmol) of 6p, 1 g (6.5 mmol) of 2-
(dimethylamino) ethyl chloride hydrochloride, 5.9 g (43
mmol) of potassium carbonate and 400 ml of CHCl3
was refluxed with stirring for 24 h. To the suspension
was added 60 ml of water and 100 ml of MeOH and the
mixture was refluxed again for 24 h with stirring. The
suspension gradually dissolved and a yellow solution
resulted. The reaction mixture was cooled and, on
standing, two layers separated. The organic phase was
Acknowledgements
This investigation supported by the Kansas Health
Foundation Fund #411606 and the Shawnee Mission La
Sertoma Club Cancer Research Fund (L.H., H.X.C. and
C.C.C.), NCI grant CA 18856 and Elsa U. Pardee
Foundation Fund (T.C.C.) and a V.A. research grant
(N.S.). The authors also thank the National Cancer
Institute for conducting the in vitro disease-oriented

L. He et al. / European Journal of Medicinal Chemistry 38 (2003) 101ꢀ
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