Synthesis and anti-inflammatory evaluation of 4-anilinofuro[2,3-b] quinoline and 4-phenoxyfuro[2,3-b]quinoline derivatives. Part 3

Article abstract of DOI:10.1016/j.bmc.2003.10.051

Mast cells, neutrophils and macrophages are important inflammatory cells that have been implicated in the pathogenesis of acute and chronic inflammatory diseases. To explore a novel anti-inflammatory agent, we have synthesized certain 4-anilinofuro[2,3-b]

Full text of DOI:10.1016/j.bmc.2003.10.051

Bioorganic & Medicinal Chemistry 12 (2004) 387–392
Synthesis and anti-inflammatory evaluation of
4-anilinofuro[2,3-b]quinoline and
4-phenoxyfuro[2,3-b]quinoline derivatives. Part 3
Yeh-Long Chen,a,* I-Li Chen,a Chih-Ming Lu,a Cherng-Chyi Tzeng,a
Lo-Ti Tsaob and Jih-Pyang Wangb
aFaculty of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung City 807, Taiwan
bDepartment of Education and Research, Taichung Veterans General Hospital, Taichung 407, Taiwan
Received 8 August 2003; accepted 27 October 2003
Abstract—Mast cells, neutrophils and macrophages are important inflammatory cells that have been implicated in the pathogenesis
of acute and chronic inflammatory diseases. To explore a novel anti-inflammatory agent, we have synthesized certain 4-anilino-
furo[2,3-b]quinoline and 4-phenoxyfuro[2,3-b]quinoline derivatives and evaluated their anti-inflammatory activities by reaction of
3,4-dichlorofuro[2,3-b]quinoline with appropriate Ar-NH2 or Ar-OH. Compounds 6a and 15 were proved to be more potent than
the reference inhibitor, mepacrine for the inhibition of rat peritoneal mast cell degranulation with IC50 values of 6.5 and 16.4 mM,
respectively. Compounds 2b, 6a, 10, and 15 also showed potent inhibitory activity (IC50=7.2–29.4 mM) for the secretion of lyso-
somal enzyme and b-glucuronidase from neutrophils. These results also indicated that oxime derivatives are more potent than the
respective ketone precursors (6aꢀ2a; 7aꢀ3), and the substituent such as Me at the oxime decreased inhibitory activity (6aꢀ6b;
7aꢀ7b). Among these derivatives, compound 6a showed the most potent activity with IC50 values of 6.5–11.6 mM for the inhibition
of mast cell degranulation and neutrophil degranulation.
# 2003 Elsevier Ltd. All rights reserved.
1. Introduction
vatives and evaluated their anti-inflammatory
activities.14,15 Recently, we have also synthesized certain
4-anilinofuro[2,3-b]quinoline derivatives from a natural
alkaloid, dictamnine, and evaluated their cytotoxi-
city.16,17 We were especially interested in the study of
furo[2,3-b]quinoline because it constitutes an important
group of bioactive natural products such as dictamnine,
acrophylline, confusameline, skimmianine, kokusagi-
nine, and haplopine.18ꢁ23 These alkaloids were found to
possess wide-ranging biological properties including
anti-allergic,18 anti-inflammatory,19 cytotoxic,20 anti-
platelet aggregation,21,22 and the voltage-gated potas-
sium channel blocking activities.23 Although the 4-
anilinofuro[2,3-b]quinoline ring belongs to the isosteric
isomer of 9-anilinoacridine, comparison on the biologi-
cal activities between these two rings have not been
explored. In continuation of our studies on 9-anilino-
acridine derivatives, we report herein the preparation
and anti-inflammatory activities of certain 4-anilino-
furo[2,3-b]quinoline derivatives. We have also synthe-
sized and evaluate a number of 4-phenoxyfuro[2,3-
b]quinoline derivatives for the establishment of anti-
inflammatory structure–activity relationships.
9-Aminoacridine has been used clinically as an anti-
septic drug. This tricyclic heterocycle may interact with
DNA through intercalation, thus disrupting DNA
replication.1,2 A large number of its derivatives have
been prepared and evaluated for biological activities.3ꢁ5
Two notable examples are mepacrine (quinacrine), the
acridine derivative to be clinically used as an anti-
malarial drug which also acts as a calmodulin inhibitor
to suppress the histamine secretion process in mast cell 6ꢁ9
and amsacrine (m-AMSA), an antileukemic agent.10ꢁ12
Certain 9-thioacridines have also been synthesized as
inhibitors of trypanothione reductase from Trypano-
soma cruzi, the causative agent of Chagas’ disease.13
Due to the biological versatility of acridine derivatives,
we have synthesized certain 9-anilinoacridine, 9-phe-
noxyacridine, and 4-phenoxyfuro[2,3-b]quinoline deri-
Keywords: Anti-inflammatory; 4-Anilinofuro[2,3-b]quinoline; 4-Phe-
noxyfuro[2,3-b]quinoline; Furo[2,3-b]quinoline.
* Corresponding author. Tel.: +886-7-312-1101x2249; fax: +886-7-
312-5339; e-mail: eloch@cc.kmu.edu.tw
0968-0896/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2003.10.051

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Y.-L. Chen et al. / Bioorg. Med. Chem. 12 (2004) 387–392
acid in EtOH/H2O (2:1) afforded 4-(3-chlorofuro[2,3-
b]quinolin-4-ylaminobenzoic acid (2b) in 57% yield.
Accordingly, 4-[4-(3-chlorofuro[2,3-b]quinolin-4-ylami-
no)phenyl]- but-3-en-2-one (5) was prepared from N-[4-
(3-oxobut-1-enyl)phenyl]acetamide25 under the same
reaction condition. Preparation of 2a, 3, and 4 had been
described in our previously paper.16 Compounds 2a and
3 were reacted with hydroxylamine or methoxylamine,
respectively, in EtOH to give the corresponding oximes
6a, 7a and methyloximes 6b, 7b in 62–97% yield.
Preparation of 4-phenoxyfuro[2,3-b]quinolines 8–10 is
described in Scheme 2. Compound 1 was treated with 3-
hydroxyacetophenone to afford 1-[3-(3-chlorofuro[2,3-
b]quinolin-4yloxy)phenyl]ethanone (8) which was then
reduced with H2 in the presence of Lindlar catalyst to
give 1-[3-(furo[2,3-b]quinolin-4-yloxy)phenyl]ethanone
(10) in 69% yield. Reaction of 8 with hydroxylamine or
methoxylamine, respectively, in EtOH gave the corre-
sponding oximes 9a and methyloximes 9b in 87–90%
yield.
Scheme 1. (i) Substituted-anilines, EtOH-H2O (2:1 v/v), HCl, reflux;
(ii) R0ONH2, EtOH, reflux; (iii) N-[4-(3-oxobut-1-enyl)phenyl]aceta-
mide, EtOH–H2O (2:1) v/v), HCl, reflux.
4-(3-Chlorofuro[2,3 - b]quinolin - 4 - yloxy)benzaldehyde
and 4-hydroxy-
(11) was synthesized from
1
benzaldehyde, which was then reduced with Lindlar
catalyst and H2 to give 4-(furo[2,3-b]quinolin-4-yloxy)-
benzaldehyde (13) and [4-(furo[2,3-b]quinolin- 4-yloxy)-
phenyl]methanol (14) (Scheme 3). Accordingly, reaction
of 1 and 4-hydroxybenzylideneacetone afforded 12,
which was reduced to give 4-[4-(furo[2,3-b]quinolin-4-
yloxy)phenyl]butan-2-one (15) and 4-[4-(furo[2,3-b]-
quinolin-4-yloxy)phenyl]butan-2-ol (16).
3. Biological results and discussion
3.1. Mast cell degranulation
Scheme 2. (i) 3-Hydroxyacetophenone, EtOH–H2O (2:1 v/v), HCl,
reflux; (ii) RONH2, EtOH, reflux; (iii) H2, Lindlar catalyst, EtOH–
CH2Cl2 (1:1 v/v).
In the present study, assessment of inhibitory efficacy
with respect to mast cell degranulation was performed
by measuring the content of b-glucuronidase in super-
natant. As shown in Table 1, (E)-1-[3-(3-chlorofuro
[2,3-b]quinolin-4-ylamino)phenyl]ethanone oxime (7a)
demonstrated only a weak inhibitory activity (IC50
value of 35.8 mM) while (E)-1-[4-(3-chlorofuro[2,3-
b]quinolin-4-ylamino)phenyl]ethanone oxime (6a) (6.5
mM) and 4-[4-(furo[2,3-b]quinolin-4-yloxy)phenyl]butan-
2-one (15) (16.4 mM) exhibited more potent activity
than the reference inhibitor, mepacrine (20.6 mM).
These results also indicated that oxime derivatives are
more potent than the respective ketone precursors
(6aꢀ2a; 7aꢀ3) and the substituent such as Me at the
oxime decreased inhibitory activity (6aꢀ6b; 7aꢀ7b).
The resultht atcompound 15 was more potent than 13
suggested that the distance between furoquinoline and
the carbonyl group also play an important role.
Scheme 3. Reagents (i) 4-Hydroxybenzaldehyde, K2CO3, THF in a
sealed bomb; (ii) 4-Hydroxybenylideneacetone, K2CO3, acetone in a
sealed bomb; (iii) Lindlar catalyst, H2, MeOH-CH2Cl2 (1:1 v/v).
3.1.1. Neutrophil degranulation. Activation of neu-
trophils with 1 mM formyl-methionyl-leucyl-phenylala-
nine (fMLP) in the presence of cytochalasin B (5 mg/
mL) evoked the release of 21.2 and 19.8% of lysozyme
and b-glucuronidase, respectively, of the initial cellular
content. Compound 6a, with an IC50 value of 11.6 and
2. Chemistry
4-Anilinofuro[2,3-b]quinolines 2-7 were prepared as
described in Scheme 1. Reaction of the known 3,4-
dichlorofuro[2,3-b]quinoline (1)24 with 4-aminobenzoic

Y.-L. Chen et al. / Bioorg. Med. Chem. 12 (2004) 387–392
389
Table 1. IC50 (mM)a values of furo[2,3-b]quinoline derivatives against
mast cell and neutrophil degranulation
Table 2. IC50 values of furo[2,3-b]quinoline derivatives on TNF-a
formation
IC50 (mM)a,b
Compd
Mast cell degranulation Neutrophil degranulation
b-glucuronidaseb
Compd
Lysozymec b-glucuronidasec
RAW 264.7
N9
2a
2b
3
4
5
6a
6b
7a
7b
8
9a
9b
10
>30.0
>30.0
>30.0
>30.0
>30.0
>30.0
23.3Æ6.9
>30.0
>30.0
>30.0
>30.0
18.9Æ5.7
>30.0
>30.0
>30.0
2a
2b
3
4
5
6a
6b
7a
7b
8
9a
9b
10
>10.0
>30.0
>30.0
>30.0
>10.0
>10.0
>30.0
>30.0
>30.0
>30.0
>30.0
>30.0
>30.0
>30.0
>10.0
>30.0
>30.0
>30.0
0.42Æ0.12
>0.3
>30.0
>30.0
>30.0
>3.0
>1.0
>3.0
>3.0
>3.0
>30.0
1.7Æ0.1
>10.0
>10.0
>3.0
>10.0
>30.0
>30.0
>10.0
0.074Æ0.01
6.5Æ1.1
11.6Æ1.7
7.2Æ0.9
>30.0
>30.0
>30.0
>30.0
>30.0
35.8Æ1.1
>30.0
>30.0
>30.0
>30.0
>30.0
>30.0
>30.0
>30.0
>30.0
>30.0
>30.0
>30.0
>30.0
>30.0
>30.0
>30.0
29.4Æ2.0
26.1Æ5.9
11
12
13
14
>30.0
>30.0
>30.0
11
12
13
14
32.0Æ2.4
13.0Æ0.5
>30.0
9.3Æ1.2
>30.0
>30.0
14.0Æ1.2
>30.0
16.4Æ1.8
15
Mepacrine
Trifluoperazine
15
Dexamethasone
20.6Æ1.2
11.9Æ0.6
10.6Æ0.9
a Values are meansÆSE of at least three separate experiments.
b When compounds exhibited cytotoxicity at 30 mM, a lower concen-
tration was applied.
a Values are meansÆSE of at least three separate experiments.
b Induced by compound 48/80 (10 mg/mL).
c Induced by fMLP (1 mM)/cytochalasin B (5 mg/mL).
3.3. Preliminary cytotoxic evaluation
7.2 mM againstlysozyme and b-glucuronidase release,
respectively, was more potent than its positional isomer
7a and was comparable to the calmodulin inhibitor, tri-
fluoperazine (11.9 and 10.6 mM, respectively) which
inhibits the degradation and superoxide anion genera-
tion in neutrophils.26,27 4-(3-Chlorofuro[2,3-b]quinolin-
4-ylaminobenzoic acid (2b) with an IC50 value of 23.3
and 18.9 mM againstlysozyme and b-glucuronidase
release, respectively, was more potent than its acetyl
analogue 2a. In analogy to the inhibition of mast cell
degranulation, oxime derivatives are more potent than
the respective ketone precursors (6aꢀ2a), and the sub-
stituent such as Me at the oxime decreased inhibitory
activity (6aꢀ6b) and a longer distance between fur-
oquinoline and the carbonyl group was preferred
(12ꢀ11; 15ꢀ13). In addition, the inhibitory activity
was decreased by the reduction of carbonyl group to an
alcohol (13ꢀ14), but was increased by the reduction of
Cl at the 3-position (10ꢀ8). Compound 6a showed the
most potent activity with IC50 values of 7–12 mM for the
inhibition of neutrophil degranulation.
Nine furo[2,3-b]quinoline derivatives were selected for
evaluation in vitro against a three-cell line panel con-
sisting of MCF7 (Breast), NCI-H460 (Lung), and SF-
268 (CNS). In this protocol, each cell line is inoculated
and preincubated on a microtiter plate. Test agents are
then added at a single concentration (100 mM) and the
culture incubated for 48 h. End-point determinations
are made with alamar blue.28 Results for each test agent
are reported as the percent of growth of the treated cells
when compared to the untreated control cells. Com-
pounds which reduced the growth of any one of the cell
lines to 32% or less are considered to be cytotoxic.
Results indicated all of them, with the exception of
compound 5 which exhibited a weak inhibitory activity
on MCF7 cancer cell, are non-cytotoxic.
4. Conclusion
These results indicated that the anti-inflammatory
effects of furo[2,3-b]quinoline derivatives were medi-
ated, at least in part, through the suppression of chemi-
cal mediators released from mast cells, neutrophils and
macrophages, and the potential of these compounds to
be novel anti-inflammatory agents with no significant
cytotoxicity.
3.2. TNF-ꢀ release
TNF-a, an early cytokine produced by activated macro-
phages, plays an essential role in pathological inflam-
matory reactions. None of compounds 2–15 had similar
IC50 value as dexamethasone in the inhibition of TNF-a
formation in macrophage-like cell line RAW 264.7 and
microglial cell line N9 cells (the brain resident macro-
phages) (Table 2). However, (E)-1-[3-(3-chlorofuro[2,3-
b]quinolin-4-yloxy)phenyl]ethanone oxime (9a) showed
weak potency in N9 cells (IC50 values of 1.7 mM). The
results also confirm the conclusion above that the sub-
stituent such as Me at the oxime decreased inhibitory
activity (9aꢀ9b) (Table 2).
5. Experimental
5.1. General
TLC: precoated (0.2 mm) silica gel 60 F254 plates from
EM Laboratories, Inc.; detection by UV light (254 nm).
Mp: Electrothermal IA9100 digital melting-point appa-

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Y.-L. Chen et al. / Bioorg. Med. Chem. 12 (2004) 387–392
1
ratus; 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), coupling constants J in Hz. Elemental analyses
were carried outon a Heraeus CHN- O-Rapid elemental
analyzer, and results were withinÆ0.4% of calculated
values.
128.91, 130.01, 140.78, 142.24, 145.74, 146.44, 152.37,
.
160.72. Anal. calcd for C19H14ClN3O2 0.2HCl: C 63.55,
H 3.99, N 11.70; Found: C 63.94, H 4.28, N 11.33.
5.1.4. (E)-1-[4-(3-Chlorofuro[2,3-b]quinolin-4-ylamino)-
phenyl]ethanone O-methyloxime (6b). To a suspension
of 2a (103 mg, 0.30 mmol) in ethanol (16 mL) was
.
added 40% NH2Ome HCl aqueous (126 mg, 0.6 mmol).
The reaction mixture was stirred at room temperature
for 1 h (TLC monitoring), then concentrated in vacuo
to give a solid which was washed by H2O (20 mL) and
purified by FC (CH2Cl2) to give a white solid (102 mg,
5.1.1. 4-(3-Chlorofuro[2,3-b]quinolin-4-ylaminobenzoic
acid (2b). To a solution of 3,4-dichlorofuro[2,3-b]quin-
oline (1, 1.19 g, 5.00 mmol) and 4-aminobenzoic acid
(1.03 g, 7.50 mmol) in EtOH/H2O 2:1 (50 mL) was
added concentrated HCl until pH 6 resulted. The mix-
ture was refluxed for 18 h (TLC monitoring) and then
the solvent evaporated in vacuo to give a residual solid,
which was suspended in ice-water (250 mL) and neu-
tralized with 1 N NaOH solution. The resulting pre-
cipitate was collected by filtration, washed with H2O,
and then purified by flash column chromatography (FC,
silica gel CH2Cl2/MeOH 20:1) and recrystallized from
EtOH to give 2b (0.96 g, 57%). Mp 262–263ꢂC 1H
NMR (200 MHz, DMSO-d6): 6.86 (m, 2H-C(20, 60)),
7.59 (m, H-C(6)), 7.75 (m, 2H-C(30, 50)), 7.82 (m, H-
C(7)), 8.04 (dd, J=8.4, 0.8, H-C(8)), 8.22 (dd, J=8.6,
0.8, H-C(5)), 8.40 (s, H-C(2)), 9.45 (br s, NH), 12.65 (br
s, COOH). 13C NMR (50 MHz, DMSO-d6): 110.11,
111.05, 114.84, 121.70, 122.61, 123.73, 125.18, 128.65,
130.54, 131.31, 139.98, 143.37, 146.04, 150.73, 160.88,
167.43. HRMS (EI): calcd for C18H11ClN2O3: 338.0458.
Found: 338.0462.
ꢂ
1
93%). Mp 213–215 C. H NMR (200 MHz, CDCl3):
2.20 (s, Me), 3.98 (s, NOMe), 6.89 (m, 2H-C (20, 60)),
7.20 (br s, NH), 7.31 (m, H-C(6)), 7.55 (m, 2H-C(30, 50)),
7.68 (m, 2H-C(2, 7)), 7.82 (d, J=8.4, H-(8)), 8.08 (d,
J=8.4, H-C(5)). 13C NMR (50 MHz, CDCl3): 12.46,
61.86, 107.78, 110.13, 118.28 (2C), 119.88, 123.96,
124.45, 127.10 (2C), 128.92, 129.93, 130.95, 105.55,
141.75, 144.39, 146.58, 153.96, 160.57. Anal. calcd for
.
C20H16ClN3O2 0.3HCl: C 63.76, H 4.36, N 11.15;
Found: C 63.71, H 4.12, N 11.29.
5.1.5. (E)-1-[3-(3-Chlorofuro[2,3-b]quinolin-4-ylamino)-
phenyl]ethanone oxime (7a). This compound was
.
obtained from 3 and NH2OH HCl as described for 6a,
which was purified by FC (CH2Cl2/MeOH 100:1) in
93% yield. Mp. 250–252ꢂC. 1H NMR (200 MHz,
DMSO-d6): 2.08 (s, Me), 6.90 (m, H-C(60)), 7.13–7.26
(m, 3H-C(20, 40, 50)), 7.55 (m, H-C(6), 7.80 (m, H-C(7)),
8.01 (d, J=8.4, H-C(8)), 8.30 (m, 2H-C(2, 5)), 9.10 (br s,
NH), 11.11 (br s, NOH). 13C NMR (50 MHz, DMSO-
d6): 11.44, 108.51, 109.99, 113.33, 117.02, 118.24,
121.44, 123.53, 124.35, 128.29, 129.10, 130.08, 137.73,
141.27, 142.09, 145.79, 145.88, 152.66, 160.81. Anal.
calcd for C19H14ClN3O2: C 64.87, H 4.01, N 11.94;
Found: C 64.83, H 4.09, N 11.73.
5.1.2. 4-[4 - (3 - Chlorofuro[2,3 - b]quinolin - 4 - ylamino)-
phenyl]but-3-en-2-one (5). This compound was obtained
from 1 and N-[4-(3-oxobut-1-enyl)phenyl]acetamide as
described for 2b, which was purified by ꢂFC (CH2Cl2/
1
AcOEt20:1) in 48% yield. Mp 207–208 C. H NMR
(400 MHz, CDCl3): 2.36 (s, COMe), 6.62 (d, J=16.4,
CH¼CHCOMe), 6.93 (m, 2H-C(20, 60)), 7.31 (m, H-
C(6)), 7.46 (m, 2H-C(30, 60), CH¼CHCOMe and NH),
7.71 (m, 2H-C(2, 7)), 7.89 (d, J=8.0, H-C(8)), 8.13 (d,
J=8.4, H-C(5)). 13C NMR (100 MHz, CDCl3): 27.48,
108.36, 110.42, 118.41 (2C), 120.06, 124.25, 124.52,
125.46, 128.25, 128.74, 129.74 (2C), 130.50, 141.00,
141.64, 142.76, 145.55, 145.73, 160.02, 198.27. Anal.
calcd for C21H15ClN2O2: C 69.52, H 4.17, N 7.72;
Found: C 69.27, H 4.27, N 7.66.
5.1.6. (E)-1-[3-(3-Chlorofuro[2,3-b]quinolin-4-ylamino)-
phenyl]ethanone O-methyloxime (7b). This compound
.
.
was obtained from 3 and 40% NH2OMe HCl as descri-
bed for 6b, which was purified by FC (CH2Cl2) in 97%
yield. Mp 151–152 ꢂC. 1H NMR (200 MHz, DMSO-d6):
2.11 (s, Me), 3.87 (s, NOMe), 6.86 (m, H-C(60)), 7.17–
7.34 (m, 3H-C(20, 40, 50)), 7.54 (m, H-C(6)), 7.78 (m, H-
C(7)), 7.98 (d, J=8.4, H-C(8)), 8.30 (m, 2H-C(2, 5)),
9.13 (br s, NH). 13C NMR (50 MHz, DMSO-d6): 12.32,
61.46, 108.36, 109.92, 114.05, 117.06, 118.40, 121.30,
123.44, 124.26, 128.24, 129.08, 130.00, 136.68, 141.05,
142.02, 145.73, 145.84, 153.88, 160.77. Anal. calcd for
5.1.3. (E)-1-[4-(3-Chlorofuro[2,3-b]quinolin-4-ylamino)-
phenyl]ethanone oxime (6a). To a suspension of 2a (216
mg, 0.64 mmole) in ethanol (20 mL) was added
.
C20H16ClN3O2 0.1H2O: C 65.35, H 4.44, N 11.43;
Found: C 65.28, H 4.50, N 11.08.
.
NH2OH HCl (89 mg, 1.28 mmol). The reaction mixture
was stirred at room temperature for 1 h (TLC monitor-
ing), then concentrated in vacuo to give a solid which
was washed by H2O (20 mL), purified by FC (CH2Cl2–
AcOEt 20:1) and recrystallized from EtOH to give a
5.1.7. 1-[3-(3-Chlorofuro[2,3-b]quinolin-4-yloxy)phenyl]-
ethanone (8). A mixture of 1 (0.72 g, 3.0 mmol), K2CO3
(0.62 g, 4.5 mmol), and 3-hydroxyacetophenone (0.49 g,
3.6 mmol) in acetone (50 mL) was heated at 150 ꢂC for
20 h in a steel bomb. It was cooled, the solvent evapo-
rated in vacuo to give a residual solid, which was sus-
pended in ice-water (100 mL). The resulting precipitate
was collected by filtration, washed with H2O, and then
purified by FC (n-hexane/EtOAc 4:1) and recrystallized
from EtOH to give a white solid 8 (0.80 g, 79%). Mp
yellow solid (140 mg, 62%). Mp 219–220ꢂC. H NMR
1
(200 MHz, DMSO-d6): 2.10 (s, Me), 6.90 (m, 2H-C(20,
60)), 7.54 (m, 3H-C(6, 30, and 50)), 7.80 (m, H-C(7)), 8.01
(d, J=8.6, H-C(8)), 8.26 (d, J=8.4, H-C(5)), 8.34 (s, H-
C(2)), 9.16 (br s, NH), 10.93 (br s, NOH). 13C NMR
(50 MHz, DMSO-d6): 11.21, 109.08, 109.90, 115.86
(2C), 121.61, 123.47, 124.36, 126.38 (2C), 128.26,

Y.-L. Chen et al. / Bioorg. Med. Chem. 12 (2004) 387–392
391
168–169ꢂC. H NMR (200 MHz, CDCl3): 2.56 (s, Me),
195ꢂC. H NMR (200 MHz, CDCl3): 7.02 (m, 2H-C(20,
60)), 7.54 (m, H-C(6)), 7.76 (s, H-C(2)), 7.81 (m, H-
C(7)), 7.86 (m, 2H-C(30, 50)), 8.05 (dd, J=8.6, 1.6, H-
C(8)), 8.19 (d, J=8.6, H-C(5)), 9.93 (s, CHO). 13C
NMR (50 MHz, CDCl3): 109.85, 110.15, 116.04 (2C),
120.96, 121.81, 125.91,. 128.80, 130.79, 131.78, 132.19
(2C), 142.53, 146.77, 150.58, 161.15, 163,58, 190.51.
Anal. calcd for C18H10ClNO3: C 66.78, H 3.11, N 4.33;
Found: C 66.63, H 3.14, N 4.34.
1
1
7.08 (m, H-C(60)), 7.41 (dd, J=8.2, 7.8, H-C(50)), 7.51
(m, 2H-C(20, 6)), 7.67 (m, H-C(40)), 7.73 (s, H-C(2)),
7.79 (m, H-C(7)), 8.08 (dd, J=8.4, 1.2, H-C(8)), 8.17 (d,
J=8.4, H-C(5)). 13C NMR (50 MHz, CDCl3): 26.72,
109.90, 114.82, 120.15, 121.20, 122.04, 123.15, 123.46,
125.70, 128.69, 130.13, 130.62, 138.96, 142.26, 146.75,
151.53, 159.50, 161.22, 197.18. Anal. calcd for
C19H12ClNO3: C 67.56, H 3.58, N 4.15; Found: C 67.52,
H 3.63, N 4.13.
5.1.12. 4-[4-(3-Chlorofuro[2,3-b]quinolin-4-yloxy)phenyl]-
but-3-en-2-one (12). This compound was obtained from
1 and 4-hydroxybenzylideneacetone in acetone as
described for 8, which was purified by FC (CH2Cl2) in
87% yield. Mp 185–186ꢂC. 1H NMR (200 MHz, CDCl3):
2.36 (s, Me), 6.61 (d, J=16.0, CH¼CH(C¼O)Me), 6.91
(m, 2H-C(20, 60)), 7.42–7.56 (m, 3H-C(30, 50, 6) and
CH¼CH(C¼O)Me), 7.73 (s, H-C(2)), 7.79 (m, H-C(7)),
8.07 (dd, J=8.0, 1.0, H-C(8)), 8.17 (d, J=8.6, H-C(5)).
13C NMR (50 MHz, CDCl3): 27.50, 109.97, 110.17,
116.12 (2C), 121.18, 122.05, 125.75, 126.27, 128.73,
129.39, 130.15 (2C), 130.65, 142.42, 146.78,
151.45, 160.88, 161.24, 198.16. Anal. calcd for
5.1.8. (E) - 1 - [3 - (3 - Chlorofuro[2,3 - b]quinolin-4-yloxy)-
phenyl]ethanone oxime (9a). This compound was
.
obtained from 8 and NH2OH HCl as described for 6a,
which was purified by FC (CH2Cl2/EtoAc 20:1) in 90%
yield. Mp 181–183 ꢂC. 1H NMR (400 MHz, DMSO-d6):
2.11 (s, Me), 7.00 (m, H-C(60)), 7.23 (m, H-C(20)), 7.37
(m, 2H-C(40, 50)), 7.62 (m, H-C(6)), 7.88 (m, H-C(7)),
8.04 (dd, J=8.4, 0.8, H-C(8)), 8.13 (d, J=8.4, H-C(5)),
8.55 (s, H-C(2)), 11.25 (s, NOH). 13C NMR (100 MHz,
DMSO-d6): 11.46, 108.56, 110.16, 111.63, 115.83,
120.57, 120.72, 121.87, 126.01, 128.35, 130.22, 130.81,
138.89, 144.19, 146.07, 150.88, 152.22, 158.89, 160.83.
Anal. calcd for C19H13ClN2O3: C 64.69, H 3.71, N 7.94;
Found: C 64.33, H 3.86, N 7.60.
.
C21H14ClNO3 0.1H2O: C 68.99, H 3.91, N 3.83; Found:
C 38.92, H 3.93, N 3.75.
5.1.9. (E)-1-[3-(3-Chlorofuro[2,3-b]quinolin-4-yloxy)-
phenyl]ethanone O-methyloxime (9b). This compound
5.1.13. 4-(Furo[2,3-b]quinolin-4-yloxy)benzaldehyde (13)
and [4-(furo[2,3-b]quinolin-4-yloxy)phenyl]methanol (14).
Hydrogenation of 11 as described for 10, which was
purified by FC (CH2Cl2) to give 13 (23% yield) and 14
(34% yield).
.
was obtained from 8 and 40% NH2OMe HCl as descri-
bed for 6b, which was purified by FC (CH2Cl2) in 87%
yield. Mp 137–139ꢂC. 1H NMR (200 MHz, CDCl3):
2.18 (s, Me), 3.97 (s, NOMe), 6.73 (m, H-C(60)), 7.25
(dd, J=8.4, 8.0, H-C(50)), 7.38 (m, 2H-C(20, 40)), 7.51
(m, H-C(6)), 7.72 (s, H-C(2)), 7.79 (m, H-C(7)), 8.14 (m,
H-C(5, 8)). 13C NMR (50 MHz, CDCl3): 12.67, 62.04,
110.19, 113.63, 115.70, 120.78, 121.42, 122.43, 125.58,
128.62, 129.78, 130.58, 138.78, 142.11, 142.72, 146.79,
152.08, 153.81, 159.38, 161.35. Anal. calcd for
C20H15ClN2O3: C 65.49, H 4.12, N 7.64; Found: C
65.28, H 4.17, N 7.47.
Compound 13. Mp 129–131ꢂC. H NMR (200 MHz,
1
CDCl3): 6.16 (d, J=2.6, H-C(3)), 7.22 (m, 2H-C(20,
60)), 7.55 (m, H-C(6)), 7.61 (d, J=2.6, H-C(2)), 7.79
(m, H-C(7)), 7.94 (m, 2H-C(30, 50)), 8.18 (d, J=8.4,
H-C(8)), 8.25 (dd, J=8.6, 1.0, H-C(5)), 10.00 (s,
CHO). 13C NMR (50 MHz, CDCl3): 103.43, 108.97,
118.67 (2C), 119.70, 121.87, 125.19, 128.21, 130.26,
132.08 (2C), 132.82, 145.65, 145.90, 152.11, 161.38,
.
5.1.10. 1-[3-(Furo[2,3-b]quinolin-4-yloxy)phenyl]ethanone
(10). A solution of 8 (0.23 g, 0.68 mmol) in MeOH–
CH2Cl2 (1/1, 60 mL) was hydrogenated for 1 h (TLC
monitoring) under H2 with Lindlar catalyst (0.23 g).
The reaction mixture was filtered and the filtrate con-
centrated in vacuo to give a residual solid, which was
purified by FC (n-hexane–EtOAc 2:1) to give 10 (0.14 g,
69%). Mp 132–133 ꢂC. 1H NMR (200 MHz, CDCl3):
2.60 (s, Me), 5.81 (d, J=2.6, H-C(3)), 7.36 (m, H-C(60)),
7.51 (d, J=2.6, H-C(2)), 7.57 (m, 2H-C(50, 6)), 7.76–
7.89 (m, 3H-C(20, 40, 7)), 8.18 (d, J=8.2, H-C(8)), 8.37
(dd, J=8.4, 1.2, H-C(5)). 13C NMR (50 MHz, CDCl3):
26.74, 103.53, 107.32, 118.84, 119.31, 122.04, 123.86,
124.84, 127.86, 130.21, 130.40, 139.13, 144.82, 145.57,
152.16, 153.56, 156.56, 163.05, 196.82. Anal. calcd for
163.02, 190.45. Anal. calcd for C18H11NO3 0.1H2O: C
74.28, H 3.88, N 4.81; Found: C 74.32, H 4.23, N 4.76.
ꢂ
1
Compound 14. Mp 163–164 C. H NMR (400 MHz,
DMSO-d6): 4.57 (d, J=5.6, CH2OH), 5.32 (t, J=5.6,
OH), 5.66 (d, J=2.8, H-C(3)), 7.27 (m, 2H-C(20, 60)),
7.45 (m, 2H-C(30, 50)), 7.62 (m, H-C(6)), 7.83 (m, H-
C(7)), 7.93 (d, J=2.8, H-C(2)), 8.04 (d, J=8.0, H-C(8)),
8.36 (dd, J=8.4, 0.8, H-C(5)). 13C NMR (100 MHz,
DMSO-d6): 62.27, 103.44, 106.40, 118.61, 119.52 (2C),
121.95, 124.66, 127.77, 128.27 (2C), 129.96, 139.91,
145.34, 145.66, 153.63, 154.46, 163.06. Anal. calcd for
.
C18H13NO3 0.1H2O: C 73.76, H 4.54, N 4.78; Found: C
73.63, H 4.61, N 4.74.
.
C19H13NO3 0.1H2O: C 74.80, H 4.36, N 4.59; Found: C
74.80, H 4.43, N 4.55.
5.1.14. 4-[4-(Furo[2,3-b]quinolin-4-yloxy)phenyl]butan-2-
one (15) and 4-[4-(furo[2,3-b]quinolin-4-yloxy)phenyl]-
butan-2-ol (16). Hydrogenation of 12 as described for
10, which was purified by FC to give 15 (eluting with
CH2Cl2/EtOAc 20:1 and 21% yield) and 16 (eluting
with CH2Cl2/EtOAc 4:1 and 28% yield).
5.1.11. 4-(3-Chlorofuro[2,3-b]quinolin-4-yloxy)benzalde-
hyde (11). This compound was obtained from 1 and 4-
hydroxybenzaldehyde in THF as described for 8, which
was purified by FC (CH2Cl2) in 72% yield. Mp 194–

392
Y.-L. Chen et al. / Bioorg. Med. Chem. 12 (2004) 387–392
Compound 15. Mp 113–115ꢂC. H NMR (200 MHz,
DMSO-d6): 2.12 (s, Me), 2.84 (br s,
4. McConnaughie, A. W.; Jenkins, T. C. J. Med. Chem.
1995, 38, 3488.
1
5. Gamage, S. A.; Figgitt, D. F.; Wojcik, S. J.; Ralph, R. K.;
Ransijn, A.; Mauel, J.; Yardley, V.; Snowdon, D.; Croft,
S. L.; Denny, W. A. J. Med. Chem. 1997, 40, 2634.
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8. Yu, N.; Maciejewski-Lenoir, D.; Bloom, F. E.; Magis-
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CH2CH2(C¼O)Me), 5.62 9d, J=2.6, H-C(3)), 7.21 (m,
2H-C(20, 60)), 7.35 (m, 2H-C(30, 50)), 7.61 (m, H-C(6)),
7.82 (m, H-C(7)), 7.92 (d, J=2.6, H-C(2)), 8.03 (d,
J=8.6, H-C(8)), 8.34 (dd, J=8.4, 0.8, H-C(5)). 13C
NMR (50 MHz, DMSO-d6): 28.38, 29.70, 44.09, 103.32,
106.26, 118.51, 119.66 (2C), 121.87, 124.55, 127.68,
129.87, 129.93 (2C), 138.54, 145.26, 145.55, 153.61,
153.82, 162.99, 207.48. Anal. calcd for C21H17NO3: C
76.12, H 5.17, N 4.23; Found: C 75.92, H 5.30, N 4.20.
10. Denny, W. A.; Cain, B. F.; Hansch, G. J.; Panthana-
nickal, A.; Leo, A. J. Med. Chem. 1982, 25, 276.
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1972, 15, 611.
12. Zwelling, L. A.; Michaels, S.; Erickson, L. C.; Ungerlei-
der, R. S.; Nichols, M.; Kohn, K. W. Biochemistry 1981,
20, 6553.
13. Bonse, S.; Santelli-Rouvier, C.; Barbe, J.; Krauth-Siegel,
R. L. J. Med. Chem. 1999, 42, 5448.
14. Chen, Y.-L.; Lu, C.-M.; Chen, I.-L.; Tsao, L.-T.; Wang,
J.-P. J. Med. Chem. 2002, 45, 4689.
15. Chen, Y.-L.; Chen, I.-L.; Lu, C.-M.; Tzeng, C.-C.; Tsao,
L.-T.; Wang, J.-P. Bioorg. Med. Chem. 2003, 11, 3921.
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2003, 55, 49.
17. Chen, I.-L.; Chen, Y.-L.; Tzeng, C.-C. Helv. Chim. Act.
2002, 85, 2214.
1
Compound 16. Pale-yellow oil. H NMR (200 MHz,
DMSO-d6): 1.11 (d, J=6.0, Me), 1.66 (m,
CH2CH2CH(OH)Me), 2.70 (m, CH2CH2CH(OH)Me),
3.63 (m, –CH2CH2CH(OH)Me), 4.51 (d, J=5.0, OH),
5.61 (d, J=2.8, H-C(3)), 7.22 (m, 2H-C(20, 60)), 7.33 (m,
2H-C(30, 50)), 7.61 (m, H-C(6)), 7.82 (m, H-C(7)), 7.92
(d, J=2.8, H-C(2)), 8.03 (dd, J=8.4, 1.2, H-C(8)), 8.35
(dd, J=8.4, 1.4, H-C(5)). 13C NMR (50 MHz, DMSO-
d6): 23.63, 30.88, 40.90, 65.16, 103.36, 106.21, 118.55,
119.77 (2C), 121.95, 124.61, 127.73, 129.63, 129.99 (2C),
139.93, 145.31, 145.56, 153.64, 153.78, 163.06. Anal.
.
calcd for C21H19NO3 0.2H2O: C 74.85, H 5.80, N 4.16;
Found: C 75.15, H 6.08, N 3.97.
18. Huang, A.-C.; Lin, T.-P.; Kuo, S.-C.; Wang, J.-P. J. Nat.
Prod. 1995, 58, 117.
19. Chang, C.-P.; Lin, T.-P.; Wang, J.-P.; Kuo, S.-C. Chin.
Pharm. J. 2001, 53, 239.
Acknowledgements
Financial support of this work by the National
Science Council of the Republic of China (NSC 91-
2113-M-037-013) is gratefully acknowledged. We also
thank National Cancer Institute (NCI) of the United
States for the anticancer screenings and the National
Center for High-Performance Computing for providing
computer resources and chemical database services.
20. Setzer, W. N.; Setzer, M. C.; Schmidt, J. M.; Moriarity,
D. M.; Vogler, B.; Reeb, S.; Holmes, A. M.; Haber, W. A.
Planta Med. 2000, 66, 493.
21. Chen, K.-S.; Chang, Y.-L.; Teng, C.-H.; Chen, C.-F.; Wu,
Y.-C. Planta Med. 2000, 66, 80.
22. Chen, I.-S.; Chen, H.-F.; Cheng, M.-J.; Chang, Y.-L.;
Teng, C.-M.; Tsutomu, I.; Chen, J.-J.; Tsai, I.-L. J. Nat.
Prod. 2001, 64, 1143.
23. Butenschon, I.; Moller, K.; Hansel, W. J. Med. Chem.
2001, 44, 1249.
24. Tuppy, H.; Bohm, F. Monatsh. Chem. 1956, 87, 720.
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References and notes
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