Synthesis and cytotoxicity of 2-methyl-1-substituted-imidazo[4,5-g]quinoline-4,9-dione and 7,8-dihydro-10H-[1,4]oxazino[3',4':2,3]imidazo[4,5-g]quinoline-5,12-dione derivatives

Article abstract of DOI:10.1016/S0968-0896(00)00132-2

2-Methyl-1-substituted-imidazo[4,5-g]quinoline-4,9-diones and 7,8-dihydro-10H-[1,4]oxazino -[3',4':2,3]imidazo[4,5-g]quinoline-5,12-dione (19) derivatives have been synthesized from 6,7-dichloro-5,8-quinolinedione for developing the new anticancer drugs. Our study on the cytotoxicity of imidazoquinolinedione derivatives has revealed that 7,8-dihydro-10H-[1,4]oxazino-[3',4':2,3]imidazo[4,5-g]quinoline-5,12-dione (19), a tetracyclic heteroquinone analogue, exhibited high cytotoxicity on human colon tumor cell (HCT 15) in vitro SRB assay. The IC₅₀ value of this compound was 0.026μg/mL whereas those of doxorubicin and cisplatin were 0.023μg/mL and 1.482μg/mL, respectively. Meanwhile compounds 5-7 and 12 in the series of 1-substituted-imidazoquinolinediones showed relatively good activity on human brain tumor cell lines (XF 498). Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(00)00132-2

Bioorganic & Medicinal Chemistry 8 (2000) 2079±2083
Synthesis and Cytotoxicity of 2-Methyl-1-substituted-imidazo
[4,5-g]quinoline-4,9-dione and 7,8-dihydro-10H-
[1,4]oxazino[30,40:2,3]imidazo[4,5-g]quinoline-
5,12-dione Derivatives
Myung-Eun Suh,a,* Min-Jung Kang,a Hee-Won Yoo,a,y
So-Young Parka and Chong-Ock Leeb
aDivision of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, South Korea
bPharmaceutical Screening Division, Korea Research Institute of Chemical Technology, TaeJon 305-606, South Korea
Received 24 March 2000; accepted 15 May 2000
AbstractÐ2-Methyl-1-substituted-imidazo[4,5-g]quinoline-4,9-diones and 7,8-dihydro-10H-[1,4]oxazino -[30,40:2,3]imidazo[4,5-g]quin-
oline-5,12-dione (19) derivatives have been synthesized from 6,7-dichloro-5,8-quinolinedione for developing the new anticancer drugs.
Our study on the cytotoxicity of imidazoquinolinedione derivatives has revealed that 7,8-dihydro-10H-[1,4]oxazino-[30,40:2,3]imidazo
[4,5-g]quinoline-5,12-dione (19), a tetracyclic heteroquinone analogue, exhibited high cytotoxicity on human colon tumor cell (HCT 15)
in vitro SRB assay. The IC50 value of this compound was 0.026 mg/mL whereas those of doxorubicin and cisplatin were 0.023 mg/mL and
1.482 mg/mL, respectively. Meanwhile compounds 5±7 and 12 in the series of 1-substituted-imidazoquinolinediones showed relatively
good activity on human brain tumor cell lines (XF 498). # 2000 Elsevier Science Ltd. All rights reserved.
Introduction
ring), the pyridyl and its substituted phenyl rings were
not essential for the activity in murine tumors, although
they enhanced activities against the human tumor cells.11
The synthetic analogues without the 7-aminoquinoline-
quinone moiety (B) were inactive as antitumor agents
(Fig. 1). The electron withdrawing groups at 6 and 7
positions of quinolinediones also contributed to the
activity12 and more condensed heterocyclic quinones
were reported to increase the antitumor activity.13 In
another article, Kuo et al.14 concluded 1-ethyl-2-methyl-
naphth[2,3-d]imidazole-4,9-dione showed excellent cyto-
toxicity on human ovarian cancer cell lines.
Heterocyclic quinones containing nitrogen atoms showed
excellent antitumor1,2 and other biological activity.3
Among the active heterocyclic aminoquinones, streptoni-
grin4,5 is a member of a group of antitumor agents which
possess an aminoquinone moiety, that includes mytomycin
C,6 actinomycin,7 rifamycin8 and geldanamycin.9 In
human clinical trials, streptonigrin was active against
malignant lymphomas, mycosis fungoids, and Hodgkin's
disease, orally or parenterally.
Studies on the activity of heterocyclic quinones containing
nitrogen atoms such as quinolinedione revealed that the
number and position of nitrogens are considerably
important for the cytotoxicity.10 Some important struc-
ture activity relationships (SAR) were reported.11 Anti-
tumor activity of streptonigrin (A) was completely lost
when the aminoquinone moiety (B) is blocked as in
azastreptonigrin (C).10 The methoxy group (quinone
However, most of the imidazonaphthoquinones did not
show any good cytotoxicity on human cancer cell lines.
This led us to examine the cytotoxicity of imidazoqui-
nolinediones as well as imidazoquinoxalinediones so as
to examine the e€ect of the number of nitrogen in the
nucleus of imidazoheterocyclic quinones. We reported
previously that some of the imidazoquinoxalinediones
showed marked cytotoxicity on human gastric adeno-
carcinoma cell lines in comparison with cisplatin and
adriamycin (doxorubicin).15
*Corresponding author: Tel.: +82-2-3277-3040; fax: +82-2-3277-
3051; e-mail: suh@mm.ewha.ac.kr
yPresent address: BUKWANG Pharmaceutical Ind. Co., Ltd, 398-1,
Daebang-Dong, Dongjak-Gu, Yeoeuido PO Box 572, Seoul, South
Korea.
Many derivatives of quinolinediones have been synthe-
sized and tested antitumor activity,14 but the synthesis and
0968-0896/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(00)00132-2

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M.-E. Suh et al. / Bioorg. Med. Chem. 8 (2000) 2079±2083
Figure 1. Streptonigrin structure (A), 7-aminoquinolinequinone moiety (B) that is responsible for the antitumor activity of streptonigrin and azas-
treptonigrin (C).
cytoxicity of imidazoquinolinediones has not been investi-
gated. The mechanism of the cytotoxicity exhibited by
most quinone derivatives was already studied as topoi-
somerase inhibitor via DNA-intercalation and reduction
of quinone moiety by oxidoreductase (DT-diaphor-
comparison with clinically used anticancer agents, cis-
platin and adriamycin.
Results
20
ase).16 19 According to Moore's thesis, the condition
of DNA- intercalator are the followings.
Chemistry
1. It is a plane tri or tetracyclic aromatic ring structure.
2. Its surface area is over 28A2
3. It has to be p-conjugated quinone containing a
nitrogen atom, because it makes possible to form
hydrogen bonding with DNA.
6,7-Dichloro-5,8-quinolinedione (1) was prepared accord-
ing to the literature.3 6-Amino-7-chloro-5,8-quinoline-
dione (3) was obtained by treating 1 with sodium azide in
acetic acid, followed by reduction of the resulting azide (2)
with sodium borohydride. Acetylation of 3 with acetic
anhydride in the presence of 10% sulfuric acid at 0 ꢀC
gave 6-acetamido-7-chloro-5,8-quinolinedione (4).3,21
Based on those considerations, we report here the synth-
esis of imidazoquinolinediones and examined their cyto-
toxicity to develop new antitumor imidazoquinones. We
could obtain 2-methyl-1-substituted-imidazo[4,5-g]quino-
line-4,9-diones (5--17) and oxazino-[30,40:2,3]imidazo-[4,5-
g]quinoline-5,12-dione analogues (18±20) from 6,7-di-
chloro-5,8-quinolinedione (1) as a starting material.
Human cancer cell lines of lung (A 549), ovarian (SK-
OV-3), melanoma (SK-MEL-2), brain (XF-498), colon
(HCT 15) cell lines were used for cytotoxicity test, in
4 was reacted with alkylamines or arylamines in the pre-
sence of base such as potassium carbonate to yield 1-alkyl-
2-methyl-imidazo[4,5-g]quinoline-4,9-diones (5±12) and
1-aryl-2-methyl-imidazo[4,5-g]quinoline-4,9-dione (13±
17) (Fig. 2).
Reaction 1 with piperidine, morpholine or thiomorpho-
line in the presence of triethylamine or celium(III) chloride
Figure 2. Scheme of the synthetic method of 1-alkyl-imidazoquinoline-4,9-diones (5±12) and 1-aryl-imidazoquinoline-4,9-dione(13±17). R=5;
methyl, 6; ethyl, 7; propyl, 8; butyl, 9; cloroethyl, 10; ꢀ-hydroxyethyl, 11; isopropyl, 12; benzyl, 13; phenyyl, 14; 4-bromophenyl, 15; 4-ethoxyphentl,
16; 4-chlorophenyl, 17; 4-methylphenyl.

M.-E. Suh et al. / Bioorg. Med. Chem. 8 (2000) 2079±2083
2081
followed by cyclization with sodium azide22 gave the
tetracyclic imidazoquinolinedione analogues, 18, 19 and
20 respectively. (Fig. 3).
Table 1. Cytotoxicity Data on Human Lung Tumor Cell Lines (A 549),
Human Ovarian Tumor Cell Lines (SK-OV-3), Human Melanoma
Tumor Cell Lines (SK-MEL-2), Human Brain Tumor Cell Lines (XF
498) and Human Colon Tumor Cell Lines (HCT 15)
IC50 (mg/mL)
Cytotoxicity assay by SRB assay
Compounds
Cisplatin
Doxorubicin 0.005
A549 SK-OV-3 SK-MEL-2 XF 498 HCT 15
0.276
Human cancer cell lines of lung (A 549), ovarian (SK-OV-
3), melanoma (SK-MEL-2), brain (XF 498) and colon
(HCT 15) were used for cytotoxicity test in vitro using SRB
(Sulforhodamine B) assay.23,24 They were maintained as
stocks in RPMI 1640 (Gibco) supplemented with 10%
fetal bovine serum (Gibco). Cell cultures were passaged
once or twice weekly using trypsin-EDTA to detach the
cells from their culture ¯asks.
0.303
0.019
0.295
0.140
0.206
0.197
1.990
1.953
0.600
0.177
0.158
0.241
0.357
0.097
0.129
0.144
0.097
0.347
0.154
0.010
0.072
0.074
0.147
0.219
1.828
1.075
0.310
0.064
0.097
0.093
0.331
0.076
0.103
0.064
0.052
0.069
0.106
0.013
0.048
0.031
0.046
0.076
2.366
2.278
0.389
0.037
0.071
0.103
0.244
0.087
0.146
0.032
0.022
0.039
1.482
0.023
0.251
0.323
0.280
0.278
2.548
2.498
0.433
0.181
0.298
0.153
0.386
0.188
0.277
0.052
0.026
0.061
5
6
7
8
0.075
0.085
0.087
0.085
2.800
3.094
0.356
0.049
0.078
0.096
0.217
0.087
0.102
0.032
0.019
0.018
9
10
11
12
13
14
15
16
17
18
19
20
The rapidly growing cells were harvested, counted, and
inoculate at the appropriate concentrations (1±2Â104
cells/well) into 96-well microtiter plates. After incubation
for 24 h, the compounds dissolved in culture medium
were applied to the culture wells in triplicate followed
by incubating for 48 h at 37 ꢀC under 5% CO2 atmo-
sphere. The cultures ®xed with cold TCA were stained by
0.4% SRB dissolved in 1% acetic acid. After solubilizing
the bound dye with 10 mM unbu€ered tris base by gyro-
tory shaker, the absorbance at 520 nm was measured
with a microplate reader (Dynatech Model MR 700).
The cytotoxic activity was evaluated by measuring the
concentration of compounds required to inhibit the pro-
tein synthesis by 50% (IC50) in comparison with those of
doxorubicin and cisplatin (Table 1). Each value is the
mean of triplicate experiments.
Conclusion
The 20 derivatives of 2-methyl-1-substituted-imidazo
[4,5-g]quinoline-4,9-diones and 7,8-dihydro-10H-[1,4] oxa-
zino[30,40:2,3]imidazo[4,5-g]quinoline-5,12-dione deriva-
tives were synthesized. They were tested for cytotoxicity
in vitro in comparison with cisplatin and doxorubicin.
Most of them showed cytotoxic e€ect against various
human tumor cell lines. They are valuable to be tested for
in vivo antitumor activity in human cancer xenograft
models.
Discussion
The position of the nucleophilic substitution of the
compound 1 with amines can be deduced to be at C-6
position based on Pratt's theory25 and our previous
result on the reaction 1 with ethyl acetoacetate, in which
the structure of the condensation product was con®rmed
by X-ray crystallography.26
Experimental
Materials and methods
All of the compounds synthesized except for the com-
pounds 8 and 9 exhibited potent cytotoxicity against all the
human cancer cell lines tested. Their activities were higher
than cisplatin but somewhat lower than doxorubicine
(Table 1). The imidazoquinolinedione 8 and 9 having
chloroethyl and b-hydroxyethyl respectively had sig-
ni®cantly lower activity as compared with cisplatin.
1H NMR spectra were recorded on a 300 MHz Varian
Gemini NMR spectrometer. Samples were dissolved in
DMSO-d6 and CDCl3. Elemental analyses were per-
formed using ThermoQuest (CE Instruments) EA 1110.
IR spectra were recorded on a Perkin Elmer 1420 Infrared
spectrometer. Melting points were measured by electro-
thermal digital melting point (Buchi). Most reagents were
purchased from Aldrich Chemical Company. 6,7-Di-
chloro-5,8-quinolinedione (1), 6-azido-7-chloro-5,8-qui-
nolinedione (2), 6-amino-7-chloro-5,8-quinolinedione (3),
6-acetamido-7-chloro-5,8-quinolinedione (4) were pre-
pared according to the literature.21
General procedure for the preparation of 2-methyl-1-sub-
stituted-imidazo[4,5-g]quinoline-4,9-diones (5±12 and 14±17)
1-Methyl-2-methyl-imidazo[4,5-g]quinoline-4,9-diones (5).
Methylamine (40% in water, 0.7 mL) and anhydrous
potassium carbonate (1.32 g, 9.55 mmol) were added to a
solution of 6-acetamido-7-chloro-5,8-quinolinedione (4)
Figure 3. Scheme of the synthetic method of the tetracyclic imidazo-
quinolinedione derivatives, 18, 19 and 20.

2082
M.-E. Suh et al. / Bioorg. Med. Chem. 8 (2000) 2079±2083
Microanalysis.
Calculated
Found
5 (C12H9N3O2)
6 (C13H11N3O2)
C, 63.43; H, 3.99; N, 18.49
C, 64.72; H, 4.60; N, 17.42
C, 61.54; H, 4.76; N, 15.38
C, 66.90; H, 5.61; N, 15.60
C, 55.99; H, 3.73 ;N, 15.08
C, 65.49; H, 5.20; N, 16.24
C, 71.28; H, 4.32; N, 13.85
C, 55.46; H, 2.74; N, 11.41
C, 68.10; H, 4.70; N, 12.33
C, 63.07; H, 3.11; N, 12.98
C, 71.28; H, 4.32; N, 13.85
C, 66.40; H, 4.38; N, 16.59
C, 61.18; H, 3.55; N, 16.46
C, 57.39 ;H, 3.64; N, 14.99; S, 11.42
C, 63.80; H, 4.09; N, 18.13
C, 64.49; H, 4.62; N, 17.38
C, 61.36; H, 4.73; N, 15.79
C, 66.54; H, 6.00; N, 15.36
C, 55.96; H, 3.76; N, 14.72
C, 65.89; H, 5.48; N, 15.94
C, 70.93; H, 4.45; N, 14.17
C, 55.17; H, 2.69; N, 11.38
C, 68.47; H, 4.99; N, 11.93
C, 63.25; H, 3.16; N, 13.18
C, 70.89; H, 4.68; N, 13.79
C, 66.24; H, 4.42; N, 16.94
C, 61.56; H, 3.60; N, 16.07
C, 57.74; H, 3.35; N, 14.99; S, 11.65
7 (C14H13N3O.2H2O)
8 (C15H15N3O2)
9 (C13H10ClN3O.21/5H2O)
11 (C14H13N3O.21/9CH4O)
12 (C18H13N3O2)
14 (C17H10BrN3O2)
15 (C19H15N3O3.1/6C2H6O)
16 (C17H10ClN3O2)
17 (C18H13N3O2)
18 (C14H11N3O2)
19 (C13H9N3O3)
20 (C13H9N3O2S.1/5C2H6O)
(500 mg, 1.99mmol) in absolute ethanol (15 mL) and the
reaction mixture was re¯uxed for 5 h. The solvent was
evaporated under reduced pressure. Water was added to
this residue, the residue was extracted with methylene
chloride, and the organic layer was dried over anhydrous
magnesium sulfate. The solvent was evaporated under
reduced pressure, and the residue was loaded on a silica gel
column (Kieselgel 9385, 230±400 mesh) and eluted with n-
hexane:ethylacetate (1:3): Yield, 150 mg (33.3%); mp
>268ꢀC; 1H NMR d 2.52 (s, 3H, CH3, C2), 3.97 (s, 3H, N-
CH3), 7.6 (dd, 1H, CH, C6), 8.5 (d, 1H, CH, C5), 9.0 (d,
1H, CH, C7); IR 1680cm 1. Anal. (C12H9N3O2) C, H, N.
1-(ꢀ-Hydroxyethyl)-2-methyl-imidazo[4,5-g]quinoline-4,9-
diones (10). The general procedure was followed for 12h
at rt using ethanolamine (0.24 mL, 3.98mmol) and
recrystallized from ethyl acetate/n-hexane: Yield, 280 mg
(30.4%); mp 250 ꢀC; 1H NMR d 2.5 (s, 3H, CH3, C2), 3.9
(t, 2H, N-CH2CH2OH), 4.5 (t, 2H, N-CH2CH2OH), 7.6
(dd, 1H, C6), 8.4 (d, 1H, C5), 8.9 (d, 1H, C7); IR 3380,
1680cm 1, Anal. (C13H11N3O3) C, H, N
1-Isopropyl-2-methyl-imidazo[4,5-g]quinoline-4,9-diones
(11). The general procedure was followed for 24 h using
isopropylamine (0.24 g, 3.98 mmol) and recrystallized
from methanol: Yield, 150 mg (30%); mp >268 ꢀC; H
1
1-Ethyl-2-methyl-imidazo[4,5-g]quinoline-4,9-diones (6).
Yield, 220 mg (46%); mp 259 ꢀC; 1H NMR d 1.5 (t, 3H, N-
CH2CH3), 2.6 (s, 3H, CH3 C2), 4.5 (q, 2H, N-CH2CH3),
7.5 (dd, 1H, CH, C6), 8.5 (d, 1H, CH, C5), 9.0 (d, 1H, CH,
C7); IR 1680cm 1. Anal. (C13H11N3O2) C, H, N.
NMR d 1.7 (d, 6H, CH(CH3)2), 2.7 (s, 3H, CH3, C2), 5.2
(m, 1H, CH(CH3)2), 7.8 (dd, 1H, CH, C6), 8.6 (d, 1H,
CH, C5), 9.0 (d, 1H, CH, C7); IR 1680 cm 1. Anal. (C14
H13N3O2) C, H, N.
1-Benzyl-2-methyl-imidazo[4,5-g]quinoline-4,9-diones (12).
The general procedure was followed for 24 h at rt using
benzylamine (0.44 mL, 3.98 mmol) and puri®ed by chro-
matography (ethyl acetate:n-hexane=2:1): Yield, 140 mg
2-Methyl-1-propyl-imidazo[4,5-g]quinoline-4,9-diones (7).
Yield, 160 mg (32.6%); mp 174 C; H NMR d 0.9 (t,
ꢀ
3H, N-CH2CH2CH3), 1.8 (m, 2H, N-CH2CH2CH3), 2.5
1
(23.3%); mp 171±172 ꢀC; H NMR d 2.6 (s, 3H, CH3,
1
(s, 3H, CH3, C2), 4.4 (t, 2H, N-CH2CH2CH3), 7.8 (dd,
1
1H, C6), 8.4 (d, 1H, C5), 9.0 (d, 1H, C7); IR 1680 cm
Anal. (C14H13N3O2) C, H, N.
.
C2), 5.7 (s, 2H, CH2-Ar), 7.2±7.4 (m, 5H, CH2-Ar), 7.6
(dd, 1H, CH, C6), 8.5 (d, 1H, CH, C5), 9.0 (d, 1H, CH,
C7); IR 1672 cm 1. Anal. (C18H13N3O2) C, H, N.
1-Butyl-2-methyl-imidazo[4,5-g]quinoline-4,9-diones (8).
The general procedure was followed for 12h using n-
butylamine (0.41 mL, 3.98mmol) and puri®ed by chro-
matography (ethyl acetate:n-hexane=2:1): Yield, 87mg
(20.2%); mp 119 C; H NMR d 0.9 (t, 3H, N-CH2CH2
CH2CH3), 1.4 (m, 2H, N-CH2CH2CH2CH3), 1.8 (m, 2H,
N-CH2CH2CH2CH3), 2.5 (s, 3H, CH3, C2), 4.4 (t, 2H, N-
CH2CH2CH2CH3), 7.8 (dd, 1H, C6), 8.4 (d, 1H, C5), 9.0
(d, 1H, C7); IR 1680cm 1. Anal. (C15H15N3O2) C, H, N.
2-Methyl-1-phenyl-imidazo[4,5-g]quinoline-4,9-diones (13).
The general procedure was followed for 7 h at rt using
aniline (0.36 mL, 3.98mmol): Yield, 160 mg (28%); mp
275 ꢀC.21 1H NMR d2.5 (s, 3H, CH3, C2), 7.6 (m, 5H, N-
phenyl), 7.8 (dd, 1H, C6), 8.5(d, 1H, C5), 9.0 (d, 1H, C7);
IR 1680cm 1. Anal.(C17H11N3O2) C, H, N.
ꢀ
1
1-(4-Bromophenyl)-2-methyl-imidazo[4,5-g]quinoline-4,9-
diones (14). The general procedure was followed for 6 h
using 4-bromoaniline 0.68g (3.98 mmol) and puri®ed by
chromatography (ethyl acetate:n-hexane=2:1): Yield,
1-(ꢀ-Chloroethyl)-2-methyl-imidazo[4,5-g]quinoline-4,9-
diones (9). The general procedure was followed for 12h
using b-chloroethylamine HCl (0.47 g, 3.98mmol) in
320 mg (22%); mp 249 ꢀC; H NMR d 2.4 (s, 3H, CH3,
1
.
water (1 mL) and puri®ed by chromatography (ethyl acet-
ate:n-hexane=2:1): Yield, 120 mg (12.5%); mp 247 ꢀC; 1H
NMR d 2.1 (s, 3H, CH3, C2), 4.2 (t, 2H, N-CH2CH2Cl),
4.6 (t, 2H, N-CH2CH2Cl), 7.6 (d, 1H, C6), 8.5 (d, 1H,
CH, C5), 9.0 (d, 1H, CH, C7); IR 1700 cm 1. Anal.
(C13H10ClN3O2) C, H, N.
C2), 7.2 (d, 2H, phenyl), 7.6±7.8 (dd, d, 1H, 2H, C6,
phenyl), 8.5 (d, 1H, CH, C5), 9.0 (d, 1H, CH, C7); IR
1680cm 1. Anal. (C17H10BrN3O2) C, H, N.
1-(4-Ethoxyphenyl)-2-methyl-imidazo[4,5-g]quinoline-4,9-
diones (15). The general procedure was followed for 6 h

M.-E. Suh et al. / Bioorg. Med. Chem. 8 (2000) 2079±2083
2083
using p-phenetidine (0.55 g, 3.98mmol) and recrystallized
from ethanol: Yield, 550 mg (42%); mp 188±190 ꢀC; H
NMR d 1.5 (t, 3H, Ar-O-CH2CH3), 2.4 (s, 3H, CH3, C2),
4.1 (q, 2H, Ar-O-CH2CH3), 7.0 (d, 2H, phenyl), 7.2 (d, 2H,
phenyl), 7.6 (d, 1H, CH, C6), 8.5 (d, 1H, CH, C5), 9.0 (d,
1H, CH, C7 ); IR 1680cm 1. Anal. (C19H15N3O3) C, H, N.
(t, t, 4H, C8, C7), 7.8 (dd, 1H, C3), 8.4 (d, 1H, C4), 9.0 (d,
1H, C2); IR 1680cm 1. Anal.(C13H9N3O2S.1/5C2H6O)
C, H, N.
1
Acknowledgement
1-(4-Chlorophenyl)-2-methyl-imidazo[4,5-g]quinoline-4,9-
diones (16). The general procedure was followed for 6 h
using 4-chloroaniline (0.51 g, 3.98 mmol) and puri®ed by
chromatography (ethyl acetate:n-hexane=2:1): Yield,
250 mg (40%); mp 208 ꢀC; 1H NMR d 2.5 (s, 3H,
The author wish to thank the ®nancial support of the
Korea Research Foundation made in the program Year
1997.
CH3,C2), 7.3, 7.6 (d, d, 4H, phenyl), 7.6 (dd, 1H, CH, C6),
References
1
8.6 (d, 1H, CH,C5), 9.0 (d, 1H, CH, C7); IR 1680cm
Anal. (C17H10ClN3O2) C, H, N.
.
1. Renault, S. G.; Renault, J.; Baron, M.; Servolles, P.; Paoletti,
C.; Cros, S. Eur. J. Med. Chem.-Chim. Ther. 1985, 20, 144.
2. Hayashi, T.; Smith, F. T.; Lee, K. H. J. Med. Chem. 1987,
26, 2005.
3. Schellhammer, C. W.; Petersen, S. Ann 1959, 624, 108.
4. Cone, R.; Hasan, S. K.; Lown, J. W.; Morgen, A. R. J.
Biochemi. 1976, 54, 219.
5. Yomashita, Y.; Kawada, S.; Fujii, N.; Nakana, W. Cancer
Res. 1990, 50, 5841.
6. Webb, J. S.; Cousulin, D. B.; Pidacks, C.; Lancaster, J. E.
J. Am. Chem. Soc. 1962, 84, 3185.
2-Methyl-1-(4-methylphenyl)-imidazo[4,5-g]quinoline-4,9-
diones (17). The general procedure was followed for 24 h
at 45 ꢀC using ꢁ-toluidine (0.54 g, 3.98mmol): Yield,
210 mg (40%); mp 262 ꢀC; 1H NMR d 2.4 (s, 3H, phenyl-
CH3), 2.5 (s, 3H, CH3, C2), 7.8 (dd, 1H, C6), 7.2, 7.4 (d, d,
1
4H, phenyl), 8.4 (d, 1H, C5), 9.0 (d, 1H, C7); IR 1680 cm
Anal. (C18H13N3O2) C, H, N.
.
7,8,9,10 - tetrahydropyridino[10,20:2,3]imidazo[4,5 - g]quino-
line-5,12-dione(18). Piperidine (0.23 mL, 2.3 mmol) and
triethylamine (0.23 mL, 2.3 mmol) were added to a
solution of 6,7-dichloro-5,8-quinolinedione (1) (500 mg,
1.99 mmol) in acetone (15 mL) and the reaction mixture
was stirred for 1 h. The solvent was evaporated under
reduced pressure, and the residue was dissolved in DMF
(20 mL). Sodium azide (0.16 g, 2.5 mmol) was added to
this solution, and the reaction mixture was re¯uxed for
12 h. The mixture was ®ltered, the ®ltrate was extracted
methylene chloride, and the organic layer was dried over
anhydrous magnesium sulfate. The solvent was evapo-
rated under reduced pressure, and the residue was trea-
ted with aꢀctive carbon in ethanol: Yield, 260 mg (52%);
mp >268 C; 1H NMR d 2.0, 2.2 (m, m, 4H, C9, C8), 3.1
(t, 2H, C10), 4.5 (t, 2H, C7), 7.7 (dd, 1H, C3), 8.4 (d, 1H,
C4), 9.0 (d, 1H, C2); IR 1670 cm 1. Anal.(C14H11N3O2)
C, H, N.
7. Brochamann, H. Fortschr. Chem. Org. Naturst. 1966, 18, 1.
8. Sensi, P. Res. Prg. Org. Biol. Med. Chem. 1964, 1, 337.
9. Hamilton, L. O.; Fuller, W.; Reich, E. Nature(London)
1963, 198, 538.
10. Kremer, W. B.; Laszlo, J. Cancer Chemotheraphy Rep.
1967, 51, 19.
11. Foye, W.O. Cancer chemotherapeutic Agents. 1995, 651.
12. Lown, J. W.; Joshus, A. V.; Lee, J. S. Biochemistry 1982,
21, 419.
13. Yamashita, Y.; Tsubata, Y.; Suzuki, T.; Miyashi, T.;
Mukai, T.; Tanaka, Chem. Lett. 1990, 1990, 445.
14. Kuo, S.C; Toshiro, I.; Huang, L. J.; Lednica, D. J. Med.
Chem. 1996, 39, 1447.
15. Yoo, H. W.; Suh, M. E.; Park, S. W. J. Med. Chem. 1998,
41, 4716.
16. Lin, A. J.; Lillis, B. J.; Sartorelli, A. C. J. Med. Chem.
1975, 18, 917.
17. Yamashita, Y.; Kawada, S.; Fujii, N.; Nakano, H. Cancer
Res. 1990, 50, 5841.
18. Morton, R. A., Ed.; Biochemistry of Quinones. Academic:
New York.
19. Beall, H. D.; Siegel, D.; Liu, Y.; Bolton, E. M. Biochem.
Pharmacolog. 1996, 51, 645.
20. Moore, M. H.; Hunter, W. H.; Kennard, O. J. Mol. Biol.
1987, 206, 693.
21. Schellhammer, G. W.; Petersen, S. USP 1963, 3, 084.165.
22. Yami, A. S. Indian J. Chem. Sect. B. 1991, 30B (8), 808.
23. Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.;
McMahon, J. B.; Vistica, D. T.; Warren, J. T.; Bokesch, H.;
Kenney, S.; Boyd, M. R. J. Natl. Cancer Inst. 1990, 82, 1107.
24. Rubinstein, L. V.; Shoemaker, R. H.; Paull, K. D.; Simon,
R. M.; Tosini, S.; Skehan, P.; Scudiero, D.; Monks, A.; Boyd,
M. R. J. Natl. Cancer Inst. 1990, 82, 1113.
7,8 - dihydro - 10H - [1,4]oxazino[30,40:2,3]imidazo[4,5 - g]
quinoline-5,12-dione (19). 19 was prepared from 1, cer-
ium chloride (0.2 g, 1.19mmol) and morpholine (0.21 mL,
2.38 mmol) as described for 18: Yield, 330 mg (32.7%);
mp>268ꢀC; 1H NMR d 4.2 (t, 2H, C7), 4.6 (t, 2H, C8), 5.2
(s, 2H, C10), 7.8 (dd, 1H, C3), 8.4 (d, 1H, C4), 9.0 (d, 1H,
C2); IR 1680 cm 1. Anal.(C13H9N3O3) C, H, N.
7,8 - dihydro - 10H - [1,4]thiazino[30,40:2,3]imidazo[4,5 - g]
quinoline-5,12-dione (20). 20 was prepared from 1, cer-
ium chloride (0.2g, 1.19mmol) and thiomorpholine
(0.23 mL, 2.38mmol) as described for 18: Yield, 450 mg
(42%); mp >268ꢀC; 1H NMR d 4.2 (s, 2H, C10), 4.5±4.9
25. Yolanda, T. P. J. Am. Chem. Soc. 1962, 27, 3905.
26. Suh, M. E.; Cli€ord, G. Yakhak Hoeiji 1996, 40, 382.