Synthesis and anticancer evaluation of certain 4-anilinofuro[2,3-b] quinoline and 4-anilinofuro[3,2-c]quinoline derivatives

Article abstract of DOI:10.1016/j.ejmech.2005.04.003

Certain linear 4-anilinofuro[2,3-b]quinoline and angular 4-anilinofuro[3,2-c]quinoline derivatives were synthesized and evaluated in vitro against the full panel of NCI's 60 cancer cell lines. For the linear 4-anilinofuro[2,3-b]quinoline derivatives, 1-[4-(furo[2,3-b]quinolin-4-ylamino) phenyl]ethanone (5a) is the most cytotoxic with a mean GI₅₀ value of 0.025 μM. Substitution at either furo[2,3-b]quinoline ring (2a, 2b, and 5b) or 4-anilino moiety (3-7) led to a decrease of cytotoxicity. For the angular 4-anilinofuro[3,2-c]quinoline derivatives, (E)-1-[3-(furo[3,2-c]quinolin-4- ylamino)phenyl]ethanone oxime (14a) exhibited potent inhibitory activities on UO-31, UACC-257, and UACC-62, with GI₅₀ values of 0.03, < 0.01, and < 0.01 μM respectively. The same cytotoxicity profile was observed for its methyl counterpart, 14b, in which the GI₅₀ values against UO-31, UACC-257, and UACC-62 was < 0.01, 0.04 and < 0.01 μM respectively. These results deserve full attention especially because 14a and 14b are relatively non-cytotoxic with the mean GI₅₀ value of 7.73 and 8.91 μM respectively.

Full text of DOI:10.1016/j.ejmech.2005.04.003

European Journal of Medicinal Chemistry 40 (2005) 928–934
www.elsevier.com/locate/ejmech
Short communication
Synthesis and anticancer evaluation of certain
4-anilinofuro[2,3-b]quinoline
and 4-anilinofuro[3,2-c]quinoline derivatives
Yeh-Long Chen a, I.-Li Chen b, Tai-Chi Wang b, Chein-Hwa Han c, Cherng-Chyi Tzeng a,*
a Faculty of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung City 807, Taiwan, ROC
b Department of Pharmacy, Tajen Institute of Technology, Pingtung 9072, Taiwan, ROC
c Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan 710, Taiwan, ROC
Received 6 September 2004; received in revised form 25 March 2005; accepted 7 April 2005
Available online 23 May 2005
Abstract
Certain linear 4-anilinofuro[2,3-b]quinoline and angular 4-anilinofuro[3,2-c]quinoline derivatives were synthesized and evaluated in vitro
against the full panel of NCI’s 60 cancer cell lines. For the linear 4-anilinofuro[2,3-b]quinoline derivatives, 1-[4-(furo[2,3-b]quinolin-4-
ylamino)phenyl]ethanone (5a) is the most cytotoxic with a mean GI50 value of 0.025 µM. Substitution at either furo[2,3-b]quinoline ring (2a,
2b, and 5b) or 4-anilino moiety (3–7) led to a decrease of cytotoxicity. For the angular 4-anilinofuro[3,2-c]quinoline derivatives, (E)-1-[3-
(furo[3,2-c]quinolin-4-ylamino)phenyl]ethanone oxime (14a) exhibited potent inhibitory activities on UO-31, UACC-257, and UACC-62,
with GI50 values of 0.03, < 0.01, and < 0.01 µM respectively. The same cytotoxicity profile was observed for its methyl counterpart, 14b, in
which the GI50 values against UO-31, UACC-257, and UACC-62 was < 0.01, 0.04 and < 0.01 µM respectively. These results deserve full
attention especially because 14a and 14b are relatively non-cytotoxic with the mean GI50 value of 7.73 and 8.91 µM respectively.
© 2005 Elsevier SAS. All rights reserved.
Keywords: 4-Anilinofuro[2,3-b]quinoline; 4-Anilinofuro[3,2-c]quinoline; Cytotoxicity
1. Introduction
ety for a furan ring [4,5]. Among them, 1-[4-(furo[2,3-
b]quinolin-4-ylamino)phenyl]ethanone (5a) exhibited an
excellent cytotoxicity against the growth of 60 cancer cells
with a mean GI50 value of 0.025 µM [4]. Similar approaches
to this kind of compounds were also reported where benzene
moiety was isosterically replaced with thiazole ring [6,7]. The
present report describes the influence of substituents with
respect to the anticancer activity of 4-anilinofuro[2,3-
b]quinoline derivatives. To further explore the structure–
activity relationships, the linear furo[2,3-b]quinoline was
replaced with the angular furo[3,2-c]quinoline, which consti-
tutes an important group of natural products [8]. Recently,
we have synthesized certain a-methylidene-c-butyrolactone
bearing quinolones and evaluated their cytotoxicities on the
ground that through the intercalation of quinolone, the
a-methylidene-c-butyrolactone can specifically alkylate DNA
molecule [9]. This versatile a-methylidene-c-butyrolactone
moiety has also been appended on the 9-anilino group in an
attempt to prepare a bifunctional agents in which the furo[3,2-
c]quinoline ring functions as an intercalator while the lac-
tone ring plays the role of an alkylating unit.
9-Anilinoacridine derivatives have been extensively stud-
ied as potential chemotherapeutic agents due to their capabil-
ity of intercalating DNA leading to the inhibition of mamma-
lian topoisomerase II [1–3]. Among such derivatives, 4′-(9-
acridinylamino)methanesulfonyl-m-anisidine (amsacrine,
m-AMSA) has been clinically used for the treatment of
leukemia and lymphoma [1]. Further structural modification
lead to the discovery of an improved broad spectrum antitu-
mor agent, 3-(9-acridinylamino)-5-(hydroxymethyl)aniline
(AHMA), which is capable of inhibiting the growth of cer-
tain solid tumors such as mammary adenocarcinoma, mela-
noma, and Lewis lung carcinoma in mice [3]. These results
prompted us to synthesize and evaluate 4-anilinofuro[2,3-
b]quinoline derivatives, which can be structurally related to
9-anilinoacridines by isosteric substitution of a benzene moi-
*
Corresponding author. Tel.: +886 7 312 1101x6985; fax: +886 7 312 5339.
E-mail address: tzengch@kmu.edu.tw (C.-C. Tzeng).
0223-5234/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2005.04.003

Y.-L. Chen et al. / European Journal of Medicinal Chemistry 40 (2005) 928–934
929
2. Chemistry
have synthesized furan derivatives from substituted 1,3-
diketones and chloroacetaldehyde in a single step. Thus, the
commercially available 2,4-dihydroxyquinoline was treated
with chloroacetaldehyde to give 10 in 82% yield. Chlorina-
tion of 10 with POCl3 gave 4-chlorofuro[3,2-c]quinoline (11)
[13] which was then treated with 3-aminoacetophenone in a
solution of EtOH/H2O (2:1) to afford the desired 1-[3-
(furo[3,2-c]quinolin-4-ylamino)phenyl]ethanone (12) in an
85% overall yield. Treatment of 12 with NH2OH gave exclu-
sively (E)-1-[3-(furo[3,2-c]quinolin-4-ylamino)phenyl]-
ethanone oxime (14a). The configuration of the oxime moi-
ety was determined by through-space nuclear Overhauser
effect spectroscopy (NOESY) which revealed coupling con-
nectivity to CH3 protons. Accordingly, (E)-1-[3-(furo[3,2-
c]quinolin-4-ylamino)phenyl]ethanone O-methyloxime (14b)
was obtained from the reaction of 12 and NH2OMe. Reac-
tion of 11 with 4-aminoacetophenone gave 1-[4-(furo[3,2-
c]quinolin-4-ylamino)phenyl]ethanone (13) which was then
treated with either NH2OH or NH2OMe to afford (E)-1-[4-
(furo[3,2-c]quinolin-4-ylamino)phenyl]ethanone oxime (15a)
and its methyl congener 15b respectively. Reformatsky-type
condensation of 12 and 13 with 2-(bromomethyl)acrylate and
Zinc powder in THF afforded 5-[3-(furo[3,2-c]quinolin-4-
ylamino)phenyl]-5-methyl-3-methylidenedihydrofuran-2-
one (16) and the positional isomer 17 respectively.
Preparation of the desired the linear 4-anilinofuro[2,3-
b]quinoline derivatives is outlined in Scheme 1. Reaction
of 3,4-dichloro-7-methoxyfuro[2,3-b]quinoline (1b) with
4-aminoacetophenone gave 1-[4-(3-chloro-7-methoxy-
furo[2,3-b]quinolin-4-ylamino)phenyl]ethanone (2b) which
was hydrogenated to give 1-[4-(7-methoxyfuro[2,3-b]qui-
nolin-4-ylamino)phenyl]ethanone (5b) in 46% overall yield.
Preparation of 5a from the known 3,4-dichlorofuro[2,3-
b]quinoline (1a) [10] has been previously described [4,5].
Treatment of 1a with substituted anilines afforded 3-chloro-
4-(substituted-phenylamino)furo[2,3-b]quinolines 3a,b which
was hydrogenated to afford 4-(substituted-phenylamino)-
furo[2,3-b]quinolines 6a,b in a good overall yield. Accord-
ingly, compound 7 was prepared from its 3-chloro precursor
4 which was obtained by the treatment of 1a with 2-amino-
4,5-dimethoxyacetophenone.
The angular 4-anilinofuro[3,2-c]quinoline derivatives were
synthesized from a sequence of reactions as depicted in
Scheme 2. The known 4-hydroxyfuro[3,2-c]-quinoline (10)
[11] was selected as the starting material, however, its prepa-
ration required five synthetic steps from 2-furan-3-yl-
[1,3]dioxolane (8) and therefore is too tedious to be fol-
lowed. According to the literature, Kraus and Ridgeway [12]
Scheme 1
.

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Y.-L. Chen et al. / European Journal of Medicinal Chemistry 40 (2005) 928–934
Scheme 2
.
3. Biological results and discussion
donating methoxy group improved cytotoxicity. In contrary,
methoxy group for relatively electron-rich reduced furo[2,3-
b]quinoline ring is unfavorable (5a vs. 5b) indicated an opti-
mum electronic environment is crucial. Each of the GI50 val-
ues for three representative cell lines, NCI-H460, MCF7, and
SF-268 is comparable to the mean GI50 value for all 60 can-
cer cells. For example, 2b possesses a mean GI50 value of
0.27 µM and the GI50 values of 0.22, 0.25, and 0.44 µM for
NCI-H460, MCF7, and SF-268 respectively. However,
UACC-62 was especially susceptible to 2b (GI50 = 0.01 µM),
5a (<0.01 µM), and 5b (0.09 µM) while UACC-257 was resis-
tant to 2b (11.8 µM) and 5a (15.8 µM). Compound 3a (mean
GI50 = 1.57 µM) and 6a (14.7 µM) are less cytotoxic than
their respective acetylated derivative 3b (0.18 µM) and 6b
(0.22 µM) implied the importance of acetyl group to form
H-bonding with DNA molecule. Replacement of the 1,3-
methylenedioxyl substituent with an ortho-dimethoxy group
led to the devoid of cytotoxicity (3b vs. 4; 6b vs. 7). Again,
UACC-62 was especially susceptible to 3a (GI50 = 0.14 µM)
and 6b (0.07 µM) while UACC-257 was resistant to 3a
(9.15 µM) and 3b (> 100 µM).
All compounds were evaluated in vitro against a three-cell
line panel consisting of MCF7 (Breast), NCI-H460 (Lung),
and SF-268 (CNS). In this protocol, each cell line is inocu-
lated and preincubated on a microtiter plate. Test agents are
then added at a single concentration (100 µM) and the culture
incubated for 48 h. End-point determinations are made with
alamar blue [14]. 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 are passed
on for evaluation in the full panel of 60 cell lines over a 5-log
dose range. The results indicated all of them, with exception
of 2a, 4 and 7, are active and were evaluated in vitro against
the full panel of NCI’s 60 cancer cell lines derived from nine
cancer cell types including leukemia, non-small cell lung can-
cer, colon cancer, CNS cancer, melanoma, ovarian cancer,
renal cancer, prostate cancer, and breast cancer [15]. For the
linear 4-anilinofuro[2,3-b]quinoline derivatives, 5a is the most
cytotoxic with a mean GI50 value of 0.025 µM (Table 1). Sub-
stitution at either furo[2,3-b]quinoline ring (2a, 2b, and 5b)
or 4-anilino moiety (3–7) led to a decrease of cytotoxicity.
7-Methoxy derivative 5b (a mean GI50 value of 0.49 µM) was
20-fold less cytotoxic than 5a while 3-chloro derivative 2a
became non-cytotoxic. Comparison of 2a and 2b, which bear
an electron-withdrawing 3-Cl substituent, an electron-
For the angular 4-anilinofuro[3,2-c]quinoline derivatives,
1-[3-(furo[3,2-c]quinolin-4-ylamino)phenyl]ethanone (12)
(mean GI50 = 25.5 µM) was less cytotoxic than its
4-acetylanilino counterpart 13 (8.99 µM) and both hydroxy-
imino and methoxyimino derivatives (14a: 7.73 µM; 14b:
8.91 µM). Cytotoxicity was increased by converting the car-

Y.-L. Chen et al. / European Journal of Medicinal Chemistry 40 (2005) 928–934
931
Table 1
In vitro cytotoxicity of 4-anilinofuro[2,3-b]quinoline and 4-anilinofuro[3,2-c]quinoline derivatives [GI50 (µM)]a
Compound
NCI-H460
(Lung)
0.22
MCF7
(Breast)
0.25
4.38
0.05
< 0.01
0.20
12.6
0.28
25.1
8.22
15.0
18.1
3.42
13.8
3.71
3.31
0.03
SF-268
(CNS)
0.44
6.28
0.51
0.01
0.18
15.6
0.85
22.2
14.0
11.9
15.4
6.31
16.4
10.5
2.95
0.40
UO-31
(Renal)
0.30
7.09
3.10
0.03
0.25
23.6
0.22
ndc
UACC-257
(Melanoma)
11.8
UACC-62
(Melanoma)
0.01
Meanb
2b
3a
3b
5a
5b
6a
6b
12
0.27
1.57
0.18
0.025
0.49
14.7
0.22
25.5
8.99
7.73
8.91
6.31
15.1
4.38
3.16
0.42
3.22
9.15
0.14
0.22
100
0.20
0.01
15.8
< 0.01
0.09
0.20
0.16
16.5
nd
13.9
0.32
0.22
0.07
20.5
100
nd
13
4.71
20.4
0.03
< 0.01
15.9
18.9
1.89
nd
13.2
10.7
14a
14b
15a
15b
16
4.34
< 0.01
0.04
< 0.01
< 0.01
14.7
11.8
1.82
5.11
15.6
17.2
12.2
15.6
0.02
0.65
17
m-AMSA
14.8
0.02
nd
0.03
0.63
3.16
0.32
a Data obtained from NCI’s in vitro disease-oriented tumor cell screen. GI50: drug molar concentration causing 50% cell growth inhibition.
b Mean values over all cell lines tested. Theses cell lines are: leukemia (CCRF-CEM, HL-60 (TB), K-562, MOLT-4, PRMI-8226, and SR); non-small 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).
c Not determined.
bonyl group to the respective hydroxyimino (12 vs. 14a; 13
vs. 15a). A substituent of hydroxyiminoethyl was more cyto-
toxic than the methoxyiminoethyl counterparts (14a vs. 14b;
15a vs. 15b). Both a-methylidene-c-butyrolactone deriva-
tives 16 (4.38 µM) and 17 (3.16 µM) exhibited strong inhibi-
tory activity against the growth of all cancer cell lines tested
indicating the important role played by the alkylating unit.
The present results also demonstrated compound 14a to
possess potent inhibitory activities on UO-31, UACC-257,
and UACC-62, with GI50 values of 0.03, < 0.01, and
< 0.01 µM respectively. The same cytotoxicity profile was
observed for its methyl counterpart, 14b, in which the GI50
values against UO-31, UACC-257, and UACC-62 was < 0.01,
0.04 and < 0.01 µM respectively. However, compounds 15a
and 15b, the positional isomers of 14a and 14b, respectively,
did not exhibit selective cytotoxicity.
pounds 15a and 15b, the positional isomers of 14a and 14b,
respectively, did not exhibit selective cytotoxicity suggested
the spatial arrangement of anilinofuro[3,2-c]quinoline deriva-
tives is crucial for cytotoxicity profile. These results deserve
full attention especially because 14a and 14b are relatively
non-cytotoxic with the mean GI50 value of 7.73 and 8.91 µM
respectively.
5. Experimental protocols
5.1. Chemistry
TLC: precoated (0.2 mm) silica gel 60 F254 plates from
EM Laboratories, Inc.; detection by UV light (254 nm).
Melting-point (m.p.): Electrothermal IA9100 digital m.p.
1
apparatus; uncorrected. H and 13C-NMR spectra: Varian-
Unity-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), cou-
pling constants J in Hz. Elemental analyses were carried out
on a Heraeus CHN-O-Rapid elemental analyzer, and results
were within 0.4% of calculated values.
4. Conclusion
A number of linear 4-anilinofuro[2,3-b]quinoline and
angular anilinofuro[3,2-c]-quinoline derivatives were synthe-
sized and evaluated for anticancer activities. For the linear
4-anilinofuro[2,3-b]quinolines, compounds 2b, 3b, 5a, 5b,
and 6b exhibited potent cytotoxicities with mean GI50 values
of 0.27, 0.18, 0.025, 0.49, and 0.22 µM respectively.Although
compounds 14a and 14b demonstrated only marginal cyto-
toxicity against all 60 cancer cells, they are capable of selec-
tively inhibiting one of the renal cancer cells, UO-31, and
two of the melanoma cancer cells, UACC-257 and UACC-
62, with GI50 value of less than 0.04 µM in each case. Com-
5.1.1. 1-[4-(3-Chloro-7-methoxyfuro[2,3-b]quinolin-4-
ylamino)phenyl]ethanone (2b)
To a solution of 3,4-dichloro-7-methoxyfuro[2,3-b]qui-
noline (1b, 268 mg, 1 mmol) and 4-aminoacetophenone
(270 mg, 2 mmol) in EtOH/H2O 2:1 (15 ml) was added con-
centrated HCl until pH 6 resulted. The mixture was refluxed
for 24 h. (TLC monitoring) and then the solvent evaporated

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Y.-L. Chen et al. / European Journal of Medicinal Chemistry 40 (2005) 928–934
in vacuo to give a residual solid, to which was added ice-
water (40 ml), and was neutralized with 1 N NaOH solution.
The resulting precipitate was collected and purified by flash
column chromatography (FC, silica gel CH2Cl2) to give 2b
128.92; 130.10; 139.53; 141.50; 141.60; 144.32; 146.26;
154.90; 160.80; 199.47. Anal. Calcd. for C21H17ClN2O4: C
63.56, H 4.32, N 7.06; found: C 63.44, H 4.35, N 7.03.
1
5.1.5. 1-[4-(7-Methoxyfuro[2,3-b]quinolin-4-ylamino)phe-
nyl]ethanone (5b)
(220 mg, 60%). M.p.: 235–236 °C; H-NMR (200 MHz,
CDCl3): d 2.54 (s, 3H, Me); 3.97 (s, 3H, OMe); 6.84 (m, 2H,
ArH); 7.05 (dd, 1H, J = 9.4, 2.4, H-C(6)); 7.12 (br s, 1H,
NH); 7.41 (d, 1H, J = 2.4, H-C(8)); 7.65 (s, 1H, H-C(2)); 7.74
(d, 1H, J = 9.4, H-C(5)); 7.86 (m, 2H, ArH). 13C-NMR
(50 MHz, CDCl3): d 26.23; 55.59; 106.98; 107.88; 110.18;
115.97; 116.19 (2C); 118.11; 125.10; 130.32 (2C); 130.82;
139.99; 140.23; 148.45; 148.82; 161.30; 196.46.Anal. Calcd.
for C18H11ClN2O3: C 63.82, H 3.27, N 8.27; found: C 63.76,
H 3.28, N 7.90. Anal. Calcd. for C20H15ClN2O3: C 65.49, H
4.12, N 7.64; found: C 65.64, H 4.19, N 7.68.
A solution of 2b (366 mg, 1 mmol) in MeOH/CH2Cl2 (1:1,
100 ml) was hydrogenated for 3 h (TLC monitoring) under
H2 with Pd/C (20 mg). The reaction mixture was filtered and
the filtrate concentrated in vacuo to give a residual solid, which
was purified by FC (silica gel; CH2Cl2) to give 5b (252 mg,
1
76%). M.p.: 137–139 °C; H-NMR (200 MHz, CDCl3): d
2.58 (s, 3H, Me); 3.92 (s, 3H, OMe); 6.33 (d, 1H, J = 2.6,
H-C(3)); 7.05–7.14 (m, 3H, H-C(6) and Ar-H); 7.25 (br s,
1H, NH); 7.39 (d, 1H, J = 2.6, H-C(2)); 7.51 (d, 1H, J = 2.8,
H-C(8)); 7.91–7.98 (m, 3H, H-C(5) and Ar-H). 13C-NMR
(50 MHz, CDCl3): d 26.29; 55.48; 105.50; 107.09; 107.33;
114.60; 117.41; 117.80 (2C); 122.52; 130.18 (2C); 131.18;
138.76; 142.87; 146.34; 148.01; 160.76; 163.50; 196.61.Anal.
Calcd. for C20H16N2O3·H2O: C 68.56, H 5.18, N 7.99; found:
C 68.81, H 5.57, N 7.69.
5.1.2. Benzo [1,3]dioxol-5-yl-(3-chlorofuro[2,3-b]quinolin-
4-yl)amine (3a)
From 1a and 3,4-(methylenedioxy)aniline as described for
1
2b: 83% yield, m.p.: 154–156 °C; H-NMR (400 MHz,
CDCl3): d 5.97 (s, 2H, CH2); 6.51 (dd, 1H, J = 8.0, 1.6,ArH);
6.56 (d, 1H, J = 1.6, ArH); 6.72 (d, 1H, J = 8.0, ArH); 7.26
(m, 2H); 7.63 (s, 1H); 7.64 (ddd, 1H, J = 8.4, 6.8, 1.2, H-C(7));
7.78 (d, 1H, J = 8.4, H-C(8)); 8.04 (d, 1H, J = 8.4, H-C(5)).
13C-NMR (100 MHz, CDCl3): d 101.43; 103.23; 105.63;
108.48; 110.11; 114.07; 118.60; 123.47; 124.63; 128.59;
129.86; 137.83; 139.75; 143.88; 144.37; 146.54; 148.37;
160.45. Anal. Calcd. for C18H11ClN2O3: C 63.82, H 3.27, N
8.27; found: C 63.76, H 3.28, N 7.90.
Compounds 6a, 6b, and 7 were prepared from 3a, 3b, and
4, respectively, by the same procedures as described for 5b.
5.1.6. Benzo [1,3]dioxol-5-yl-furo[2,3-b]quinolin-4-
ylamine (6a)
1
Yield 77%; m.p.: 196–197 °C; H-NMR (200 MHz,
DMSO): d 5.87 (d, 1H, J = 2.8, H-C(3)); 6.05 (s, 2H, CH2);
6.81 (m, 3H, Ar-H); 7.01 (s, 1H, NH); 7.36 (d, 1H, J = 2.8,
H-C(2)); 7.44 (ddd, 1H, J = 8.4, 6.8, 1.2, H-C(6)); 7.67 (ddd,
1H, J = 8.4, 6.8, 1.2, H-C(7)); 8.02 (dd, 1H, J = 8.4, 1.2,
H-C(8)); 8.04 (dd, 1H, J = 8.4, 1.2, H-C(5)). 13C-NMR
(50 MHz, DMSO): d 101.64; 103.36; 105.48; 106.65; 108.50;
116.63; 118.26; 120.23; 123.36; 128.89; 129.11; 134.43;
141.91; 143.02; 145.63; 145.80; 148.33; 163.35.Anal. Calcd.
for C18H12N2O3: C 71.05, H 3.97, N 9.21; found: C 70.82, H
4.04, N 9.12.
5.1.3. 1-[6-(3-Chlorofuro[2,3-b]quinolin-4-yl)amino)benzo
[1,3]dioxol-5-yl]ethanone (3b)
From 1a and 6′-amino-3′,4′-(methylenedioxy)aceto-
phenone as described for 2b: 60% yield, m.p.: 226–228 °C;
1H-NMR (400 MHz, CDCl3): d 2.67 (s, 3H, Me); 5.91 (s, 2H,
CH2); 6.00 (s, 1H, ArH); 7.28 (s, 1H, ArH); 7.48 (ddd, 1H,
J = 8.4, 6.8, 1.2, H-C(6)); 7.74 (s, 1H, H-C(2)); 7.75 (ddd,
1H, J = 8.4, 6.8, 1.2, H-C(7)); 8.03 (d, 1H, J = 8.4, H-C(8));
8.12 (d, 1H, J = 8.4, H-C(5)); 11.62 (s, 1H, NH). 13C-NMR
(100 MHz, CDCl3): d 28.16; 95.66; 101.67; 109.44; 110.88;
112.14; 122.90; 123.66; 125.14; 128.98; 130.09; 139.13;
140.04; 141.88; 146.35; 147.11; 153.14; 160.75; 199.14.Anal.
Calcd. for C20H13ClN2O4: C 63.08, H 3.44, N 7.36; found: C
63.14, H 3.56, N 7.28.
5.1.7. 1-[6-(Furo[2,3-b]quinolin-4-yl)amino)benzo
[1,3]dioxol-5-yl]ethanone (6b)
1
Yield 74%; m.p.: 254–256 °C; H-NMR (400 MHz,
CDCl3): d 2.66 (s, 3H, Me); 5.99 (s, 2H, CH2); 6.49 (s, 1H,
ArH); 6.57 (d, 1H, J = 2.6, H-C3); 7.31 (s, 1H, ArH); 7.53
(ddd, 1H, J = 8.4, 6.8, 1.4, H-C(6)); 7.66 (d, 1H, J = 2.6,
H-C(2)); 7.74 (ddd, 1H, J = 8.4, 6.8, 1.4, H-C(7)); 8.12 (dd,
1H, J = 8.6, 0.8, H-C(8)); 8.21 (dd, 1H, J = 8.6, 0.8, H-C(5));
11.87 (s, 1H, NH). 13C-NMR (100 MHz, CDCl3): d 28.25;
96.86; 101.88; 105.72; 109.62; 110.53; 113.58; 121.14;
122.32; 124.69; 128.83; 129.44; 138.36; 140.62; 144.22;
144.36; 146.01; 153.02; 162.79; 199.65. Anal. Calcd. for
C20H14N2O4: C 69.36, H 4.07, N 8.09; found: C 69.11, H
4.15, N 8.02.
5.1.4. 1-[2-(3-Chlorofuro[2,3-b]quinolin-4-yl)-4,5-
dimethoxyphenyl]ethanone (4)
From 1a and 2-amino-4,5-dimethoxyacetophenone as
1
described for 2b: 70% yield, m.p.: 234–235 °C; H-NMR
(400 MHz, CDCl3): d 2.71 (s, 3H, Me); 3.45 (s, 3H, OMe);
3.91 (s, 3H, OMe); 6.10 (s, 1H, ArH); 7.30 (s, 1H, ArH); 7.46
(ddd, 1H, J = 8.4, 6.8, 1.2, H-C(6)); 7.74 (ddd, 1H, J = 8.4,
6.8, 1.2, H-C(7)); 7.74 (s, 1H, H-C(2)); 8.01 (dd, 1H, J = 8.4,
0.8, H-C(8)); 8.12 (d, 1H, J = 8.4, H-C(5)); 11.53 (s, 1H, NH).
13C-NMR (100 MHz, CDCl3): d 28.02; 55.67; 56.59; 98.36;
110.96; 111.14; 112.02; 113.92; 122.02; 124.07; 124.63;
5.1.8. 1-[2-(Furo[2,3-b]quinolin-4-yl)-4,5-dimethoxyphe-
nyl]ethanone (7)
1
Yield 74%; m.p.: 195–197 °C; H-NMR (400 MHz,
CDCl3): d 2.70 (s, 3H, Me); 3.69 (s, 3H, OMe); 3.95 (s, 3H,

Y.-L. Chen et al. / European Journal of Medicinal Chemistry 40 (2005) 928–934
933
OMe); 6.55 (d, 1H, J = 2.4, H-C(3)); 6.59 (s, 1H, ArH); 7.32
5.1.11. 1-[4-(Furo[3,2-c]quinolin-4-ylamino)phenyl]etha-
none (13)
Compound 13 was obtained from 11 and 4-amino-
(s, 1H, ArH); 7.55 (ddd, 1H, J = 8.4, 6.8, 1.2, H-C(6)); 7.65
(d, 1H, J = 2.4, H-C(2)); 7.75 (ddd, 1H, J = 8.4, 6.8, 1.2,
H-C(7)); 8.13 (dd, 1H, J = 8.4, 1.2, H-C(8)); 8.25 (dd, 1H,
J = 8.4, 1.2, H-C(5)); 11.38 (s, 1H, NH). 13C-NMR (100 MHz,
CDCl3): d 28.07; 55.88; 56.61; 99.71; 106.06; 109.41; 113.48;
113.88; 120.73; 122.26; 124.64; 128.66; 129.59; 138.83;
141.71; 142.15; 143.65; 145.87; 154.74; 162.79; 199.93.Anal.
Calcd. for C21H18N2O4·0.4H2O: C 68.25, H 5.13, N 7.58;
found: C 68.10, H 5.11, N 7.54.
acetophenone as described for 12, which was purified by FC
(n-hexane/AcOEt 2:1) and recrystallized from EtOH in 93%
1
yield. M.p.: 238–239 °C; H-NMR (400 MHz, DMSO): d
2.61 (s, 3H, Me); 7.52 (ddd, 1H, J = 8.0, 6.8, 0.8, H-C(7));
7.62 (d, 1H, J = 2.0, H-C(3)); 7.70 (ddd, 1H, J = 8.4, 6.8, 1.6,
H-C(8)); 7.94 (dd, 1H, J = 8.4, 0.8, H-C(9)); 8.05 (m, 2H,
Ar-H); 8.16 (dd, 1H, J = 8.0, 1.6, H-C(6)); 8.24 (d, 1H,
J = 2.0, H-C(2)); 8.34 (m, 2H, Ar-H); 9.80 (br s, 1H, NH),
11.98 (br s, 1H, HCl). 13C-NMR (100 MHz, DMSO): d 26.51;
105.82; 111.65; 114.60; 118.52; 119.58; 124.21; 127.12;
128.96; 129.67; 130.34; 144.51; 145.42; 145.66; 148.42;
155.68; 196.76. Anal. Calcd. for C19H14N2O2cHCl: C 67.36,
H 4.46, N 8.27; found: C 67.76, H 4.55, N 8.28.
5.1.9. 4-Chlorofuro[3,2-c]quinoline (11)
A mixture of 2,4-dihydroxyquinoline (9, 2.42 g, 15 mmol),
KI (0.50 g) and 40% chloroacetaldehyde (5.20 ml, 6.28 g,
32 mmol) in 1.0 N KOH (20 ml) was heated at reflux for 4 h
(TLC monitoring).After cooling, the resulting precipitate was
collected, washed with H2O, purified by FC (CH2Cl2/EtOAc
3:1) and recrystallized from EtOH to give 10 (3.05 g, 82%).
M.p.: 245–246 °C; 1H-NMR (400 MHz, DMSO): d 7.07 (d,
1H, J = 2.4, H-C(3)); 7.29 (ddd, 1H, J = 8.0, 6.8, 1.2, H-C(8));
7.47 (dd, 1H, J = 8.4, 1.2, H-C(7)); 7.53 (ddd, 1H, J = 8.4,
6.8, 1.2, H-C(9)); 7.92 (dd, 1H, J = 8.0, 1.2, H-C(6)); 8.09
(d, 1H, J = 2.4, H-C(2)); 11.74 (br s, 1H, NH). 13C-NMR
(100 MHz, DMSO): d 107.60; 111.15; 115.45; 115.90;
120.04; 122.18; 129.38; 136.90; 145.37; 155.27; 158.75.
A mixture of 10 (0.22 g, 1.19 mmol), POCl3 (4 ml) and
Et3N (1 ml) was heated at 110 °C for 8 h. To the cold reaction
mixture was added ice-water (20 ml), and neutralized with
10 N NaOH. The brown precipitate was collected, washed
with cold H2O and purified by FC (CH2Cl2) to give 11 (0.21 g,
5.1.12. (E)-1-[3-(Furo[3,2-c]quinolin-4-ylamino)phenyl]e-
thanone oxime (14a)
To a suspension of 12 (151 mg, 0.50 mmol) in ethanol
(5 ml) was added NH2OH·HCl (70 mg, 1 mmol). The reac-
tion mixture was refluxed for 30 min (TLC monitoring), then
concentrated in vacuo to give a solid which was collected,
washed by H2O (20 ml), and crystallized from EtOH to give
14a (144 mg, 90%). M.p.: 224–226 °C; 1H-NMR (200 MHz,
DMSO): d 2.21 (s, 3H, Me); 7.50 (m, 3H, H-C(7) and Ar-H);
7.64 (d, 1H, J = 2.0, H-C(3)); 7.70 (ddd, 1H, J = 8.4, 7.2, 1.4,
H-C(8)); 7.91 (m, 2H, H-C(9) andAr-H); 8.14 (m, 2H, H-C(6)
and Ar-H); 8.28 (d, 1H, J = 2.0, H-C(2)); 10.65 (br s, 1H,
NH); 11.29 (br s, 1H, NOH). 13C-NMR (50 MHz, DMSO): d
11.54; 107.40; 110.85; 112.94; 120.28; 121.42; 121.69;
123.62; 123.88; 124.29; 125.44; 129.77; 130.65; 136.32;
138.51; 146.84; 148.61; 152.38; 156.18. Anal. Calcd. for
C19H15N3O2c0.2H2O: C 71.11, H 4.84, N 13.09; found: C
71.08, H 4.93, N 13.11.
1
86%). M.p.: 111–112 °C; H-NMR (200 MHz, CDCl3): d
7.03 (d, 1H, J = 2.2, H-C(3)); 7.64 (m, 1H, H-C(8)); 7.73 (m,
1H, H-C(7)); 7.82 (d, 1H, J = 2.2, H-C(2)); 8.14 (dd, 1H,
J = 8.0, 2.0, H-C(9)); 8.25 (dd, 1H, J = 7.4, 2.0, H-C(6)). 13C-
NMR (50 MHz, CDCl3): d 106.33, 116.65, 119.80, 120.11,
127.19, 128.81, 129.21, 144.29, 145.03, 145.22, 156.38.
5.1.10. 1-[3-(Furo[3,2-c]quinolin-4-ylamino)phenyl]etha-
none (12)
5.1.13. (E)-1-[3-Furo[3,2-c]quinolin-4-ylamino]phenyl]e-
thanone O-methyloxime (14b)
To a solution of 11 (408 mg, 2 mmol) and 3-amino-
acetophenone (406 mg, 3 mmol) in EtOH/H2O (2:1, 20 ml)
was added concentrated HCl until pH 6 resulted. The mix-
ture was refluxed for 40 min and then the solvent evaporated
in vacuo to give a residual solid, which was suspended in
ice-water (40 ml) and neutralized with 2 N NaOH. The result-
ing precipitate was collected and purified by FC (n-
hexane/EtOAc 2:1) to give 12 (602 mg, 99%). M.p.: 233–
To a suspension of 12 (151 mg, 0.5 mmol) in EtOH (5 ml)
was added NH2OMe·HCl (84 mg, 1 mmol). The reaction mix-
ture was refluxed for 30 min (TLC monitoring), then concen-
trated in vacuo to give a solid which was collected, washed
by H2O (20 ml), and crystallized from MeOH to give 14b
1
(145 mg, 87%). M.p.: 222–223 °C; H-NMR (400 MHz,
1
DMSO): d 2.23 (s, 3H, Me); 3.94 (s, 3H, NOMe); 7.54–7.74
(m, 5H, 3H-C(3, 7, 8) and Ar-H); 7.84 (m, 1H, Ar-H); 7.97
(d, 1H, J = 8.4, H-C(9)); 8.06 (m, 1H, Ar-H), 8.16 (d, 1H,
J = 8.0, H-C(6)); 8.32 (d, 1H, J = 1.2, H-C(2)); 11.38 (br s,
1H, NH); 15.25 (br s, 1H, HCl). 13C-NMR (100 MHz,
DMSO): d 12.36; 61.71; 107.47; 110.87; 112.98; 120.28;
121.23; 121.70; 123.28; 124.10; 124.84; 125.44; 129.87;
130.62; 136.56; 137.38; 146.80; 148.65; 153.63; 156.13.Anal.
Calcd. for C20H17N3O2cHCl: C 65.31, H 4.93, N 11.42; found:
C 64.99, H 5.02, N 11.21.
234 °C; H-NMR (200 MHz, DMSO): d 2.65 (s, 3H, Me);
7.66 (m, 4H, H-C(8) andAr-H); 7.78 (d, 1H, J = 2.2, H-C(3));
8.00 (m, 3H, 2H-C(7, 9) and Ar-H); 8.19 (dd, 1H, J = 8.0,
1.2, H-C(6)), 8.35 (d, 1H, J = 2.2, H-C(2)); 8.38 (br s, 1H,
NH), 11.60 (br s, 1H, HCl); 13C-NMR (50 MHz, DMSO): d
26.87, 107.23, 110.97, 113.15, 120.19, 121.11, 123.35,
125.34, 125.78, 128.19, 130.06, 130.45, 137.29, 137.70,
138.05, 146.71, 148.61, 156.09, 197.52. Anal. Calcd. for
C19H14N2O2cHCl: C 67.36, H 4.46, N 8.27; found: C 67.02,
H 4.49, N 8.19.

934
Y.-L. Chen et al. / European Journal of Medicinal Chemistry 40 (2005) 928–934
5.1.14. (E)-1-[4-(Furo[3,2-c]quinolin-4-ylamino)phenyl]e-
thanone oxime (15a)
tallized from EtOAc in 88% yield. M.p.: 109–111 °C;
1H-NMR (200 MHz, DMSO): d 1.72 (s, 3H, Me); 3.23 (m,
2H, H-C(4′)); 5.77 (t, 1H, J = 2.4, C(3′)=CH); 6.10 (t, 1H,
J = 2.4, C(3′)=CH); 7.41 (m, 3H, H-C(7) and Ar-H); 7.56 (d,
1H, J = 2.2, H-C(3)); 7.60 (m, 1H, H-C(8)); 7.81 (dd, 1H,
J = 8.4, 1.2, H-C(9)); 8.07 (d, 1H, J = 8.0, 1.2, H-C(6)); 8.15
(m, 2H, Ar-H); 8.18 (d, 1H, J = 2.2, H-C(2)); 9.39 (br s, 1H,
NH). 13C-NMR (50 MHz, DMSO): d 29.15; 41.92; 84.00;
105.68; 111.20; 114.29; 119.28 (2C); 122.15; 123.26; 124.65
(2C); 126.81; 128.50; 135.78; 137.42; 140.39; 144.83; 145.01;
145.33; 148.76; 155.27; 169.31. Anal. Calcd. for
C23H18N2O3c0.4H2O: C 73.16, H 5.02, N 7.42; found: C
73.47, H 5.11, N 7.07.
From 13 and NH2OH·HCl as described for 14a: 88% yield.
M.p.: 267–268 °C; 1H-NMR (400 MHz, DMSO): d 2.21 (s,
3H, Me); 7.55 (m, 1H, H-C(7)); 7.69 (m, 2H, H-C(3, 8)); 7.78–
7.86 (m, 4H, Ar-H); 7.95 (d, 1H, J = 8.4, H-C(9)); 8.15 (d,
1H, J = 8.4, H-C(6)); 8.31 (d, 1H, J = 2.0, H-C(2)); 10.74 (br
s, 1H, NH); 11.22 (br s, 1H, NOH). 13C-NMR (100 MHz,
DMSO): d 11.36; 106.74; 110.94; 113.29; 119.94 (2C);
120.92; 122.59; 124.82; 126.22; 126.51 (2C); 129.42; 129.97;
133.56; 137.42; 146.31; 148.43; 152.35; 155.85.Anal. Calcd.
for C19H15N3O2c0.2H2O: C 71.11, H 4.84, N 13.09; found: C
71.45, H 4.84, N 12.73.
5.1.15. (E)-1-[4-Furo[3,2-c]quinolin-4-ylamino]phenyl]e-
thanone O-methyloxime (15b)
Acknowledgements
From 13 and NH2OMe·HCl as described for 14b: 84%
yield. M.p.: 231–232 °C; H-NMR (400 MHz, DMSO): d
1
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.
2.24 (s, 3H, Me); 3.95 (s, 3H, NOMe); 7.60 (m, 1H, H-C(7));
7.72–7.84 (m, 6H, H-C(3, 8) and Ar-H); 8.00 (d, 1H, J = 8.4,
H-C(9)); 8.18 (d, 1H, J = 8.0, H-C(6)); 8.35 (d, 1H, J = 2.4,
H-C(2)); 11.58 (br s, 1H, NH); 15.68 (br s, 1H, HCl). 13C-
NMR (100 MHz, DMSO): d 12.21; 61.62; 107.29; 110.96;
113.10; 120.20 (2C); 120.92; 123.49; 125.38; 127.11 (2C);
129.42; 130.49; 133.57; 137.42; 146.72; 148.39; 153.48;
156.12. Anal. Calcd. for C20H17N3O2c1.2HCl: C 64.03, H
4.89, N 11.20; found: C 64.22, H 4.97, N 10.97.
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5.1.16. 5-[3-(Furo[3,2-c]quinolin-4-ylamino)phenyl]-5-
methyl-3-methylenedihydro-furan-2-one (16)
To a solution of 12 (151 mg, 0.5 mmol) in dry THF (30 ml),
activated Zn powder (85 mg, 0.75 mmol), hydroquinone
(3 mg), and ethyl 2-(bromomethyl)acrylate (260 mg,
0.75 mmol) were added. The mixture was refluxed under N2
for 2 h (TLC monitoring). After cooling, it was poured into
an ice-cold 5% HCl solution (150 ml) and extracted with
CH2Cl2 (3 × 100 ml). The combined CH2Cl2 extracts were
washed with H2O, dried (Na2SO4), and evaporated to give a
residual solid, which was purified by FC (n-hexane/AcOEt
3:1) and recrystallized from EtOH to give 16 (144 mg, 78%).
M.p.: 85–87 °C; 1H-NMR (200 MHz, CDCl3): d 1.79 (s, 3H,
Me); 3.20 (m, 2H, H-C(4′)); 5.66 (t, 1H, J = 2.4, C(3′)=CH);
6.29 (t, 1H, J = 2.4, C(3′)=CH); 6.79 (d, 1H, J = 2.0, H-C(3));
7.08 (ddd, 1H, J = 8.0, 1.6, 0.8 Hz,Ar-H); 7.42 (m, 2H, H-C(7)
and Ar-H); 7.61 (m, 1H, H-C(8)); 7.75 (d, 1H, J = 2.0 Hz,
H-C(2)); 7.89 (m, 4H, H-C(9), Ar-H and NH); 8.12 (dd, 1H,
J = 8.0, 1.4, H-C(6)). 13C-NMR (50 MHz, CDCl3): d 29.95;
42.71; 83.98; 104.27; 110.72; 115.01; 115.89; 118.41; 119.17;
119.74; 122.69; 123.66; 127.12; 128.67; 129.39; 135.04;
140.41; 144.01; 145.10; 145.51; 148.48; 156.74; 169.77.
HRMS (EI): Calcd. for C23H18N2O3: 370.1312; found:
370.1309.
5.1.17. 5-[4-(Furo[3,2-c]quinolin-4-ylamino)phenyl]-5-
methyl-3-methylenedihydro-furan-2-one (17)
Compound 17 was obtained from 13 as described for 16,
which was purified by FC (n-hexane/AcOEt 3:1) and recrys-