Synthesis and anti-inflammatory evaluation of 9-phenoxyacridine and 4-phenoxyfuro[2,3-b]quinoline derivatives. Part 2.

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 9-phenoxyacridine and 4-phenoxyfuro[2,3-b]quinoline derivatives and evaluated their anti-inflammatory activities. The title compounds were synthesized by reaction of either 9-chloroacridine or 3,4-dichlorofuro[2,3-b]quinoline with appropriate Ar-OH and their anti-inflammatory activities were studied on inhibitory effects on the activation of mast cells, neutrophils and macrophages. Four 9-(4-formylphenoxy)acridine derivatives 2b-2e were proved to be more potent than the reference inhibitor, mepacrine for the inhibition of rat peritoneal mast cell degranulation with IC(50) values of 6.1, 5.9, 13.5, and 4.7 microM, respectively. Compounds 2c, 3b, 3c, and 5a also showed potent inhibitory activity (IC(50)=4.3-18.3 microM) for the secretion of lysosomal enzyme and beta-glucuronidase from neutrophils. In addition, 2d, 3a, and 4 inhibited TNF-alpha formation from the N9 cells (the brain resident macrophages) with IC(50) vales less then 10 microM. These results indicated that acridine derivatives exhibited more potent anti-inflammatory activities than their respective furo[2,3-b]quinoline counterparts (4 vs 9; 5a vs 10a; 5b vs 10b).

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Synthesis and Anti-Inflammatory Evaluation of 9-Phenoxyacridine
and 4-Phenoxyfuro[2,3-b]quinoline Derivatives. Part 2
Yeh-Long Chen,a,* I-Li Chen,aChih-Ming Lu,aCherng-Chyi Tzeng,a
Lo-Ti Tsaoband Jih-Pyang Wangb
aSchool 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 17 April 2003; accepted 19 June 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 9-phenoxy-
acridine and 4-phenoxyfuro[2,3-b]quinoline derivatives and evaluated their anti-inflammatory activities. The title compounds were
synthesized by reaction of either 9-chloroacridine or 3,4-dichlorofuro[2,3-b]quinoline with appropriate Ar–OH and their anti-
inflammatory activities were studied on inhibitory effects on the activation of mast cells, neutrophils and macrophages. Four 9-(4-
formylphenoxy)acridine derivatives 2b–2e were proved to be more potent than the reference inhibitor, mepacrine for the inhibition
of rat peritoneal mast cell degranulation with IC50values of 6.1, 5.9, 13.5, and 4.7mM, respectively. Compounds 2c, 3b, 3c, and 5a
also showed potent inhibitory activity (IC50=4.3–18.3mM) for the secretion of lysosomal enzyme and b-glucuronidase from neu-
trophils. In addition, 2d, 3a, and 4 inhibited TNF-a formation from the N9 cells (the brain resident macrophages) with IC50vales
less then 10mM. These results indicated that acridine derivatives exhibited more potent anti-inflammatory activities than their
respective furo[2,3-b]quinoline counterparts (4 vs 9; 5a vs 10a; 5b vs 10b).
# 2003 Elsevier Ltd. All rights reserved.
Introduction
Mast cells play an important role in anaphylaxis and
inflammation. A variety of inflammatory mediators are
secreted from mast cell during cell activation. Activated
neutrophils release lysosomal enzymes which are cap-
able of proteolytic disruption of healthy tissue in a
number of disease states such as pulmonary emphy-
sema, rheumatoid arthritis, arteriosclerosis, and glo-
merulonephritis.1,2Macrophages interact with other
immune cells and serves as central regulators of specific
immune response.3Following the activation of macro-
phages, tumor necrosis factor-a (TNF-a) was generated
which mediated wide variety pathologic states such as
lethal septic shock, rheumatoid arthritis, and cachexia.4
Thus, a therapeutic agent which inhibits the activation
of inflammatory cells and the following release of
inflammatory mediators may be useful for the treatment
of these inflammatory conditions.
9-Aminoacridine has been used clinically as an antiseptic
drug. This tricyclic heterocycle may interact with DNA
throughintercalation,thusdisruptingDNAreplication.5,6
A large number of its derivatives have been prepared
and evaluated for biological activities.7?9Two notable
examples are mepacrine (quinacrine), the acridine deri-
vative to be clinically used as an anti-malarial drug
which also acts as a calmodulin inhibitor to suppress the
histamine secretion process in mast cell10,11and amsa-
crine (m-AMSA),12,13an antileukemic agent.14?16Cer-
tain 9-thioacridines have also been synthesized as
inhibitors of trypanothione reductase from Trypanosoma
cruzi, the causative agent of Chagas’ disease.17Due to the
biological versatility of acridine derivatives, we have syn-
thesized certain 9-anilinoacridine and 9-phenoxyacridine
derivatives (Fig. 1) and evaluated their anti-inflamma-
tory activities.18The present report describes the influ-
ence of substituents with respect to anti-inflammatory
activities of 9-phenoxyacridine derivatives. To further
explore the structure–activity relationships, the acridine
skeleton of certain 9-phenoxyacridines was replaced
with its bioisosteric furo[2,3-b]quinoline ring which con-
stitutes an important group of bioactive natural products
such as dictamnine, robustine, and haplopine.19,20
0968-0896/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0968-0896(03)00439-5
Bioorganic & Medicinal Chemistry 11 (2003) 3921–3927
*Corresponding author. Tel.: +886-7-312-1101x2249; fax: +886-7-
312-5339; e-mail: yeloch@cc.kmu.edu.tw

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Chemistry
9-Phenoxyacridines 2a–2e and 3a–3e were prepared as
describedinScheme1.
methoxyacridine (1b, R=4-OMe)21with 4-hydroxy-
benzaldehyde afforded 9 - (4 - formylphenoxy) - 4 -
Reactionof9-chloro-4-
methoxyacridine (2b) in 57% yield. Accordingly, com-
pounds 2c–2e and 3c–3e were prepared from the
respective substituted 9-chloroacridine under the same
reaction conditions. Although the synthesis and anti-
inflammatory evaluation of 2a, 3a, 4, 5a, and 5b had
been described in our previously paper,18their anti-
inflammatory activities are also included in this report
for comparison.
Preparation of 4-phenoxyfuro[2,3-b]quinolines 7–10 is
described in Scheme 2. The known 3,4-dichlorofuro[2,3-
b]quinoline(6)22
was treated
acetophenone to afford 1-[4-(3-chlorofuro[2,3-b]quin-
olin-4yloxy)phenyl]ethanone (7) which was then reacted
with hydroxylamine or methylhydroxylamine to give
(E) - 1 - [4 - (3 - chlorofuro[2,3 - b]quinolin4 - yloxy)-
phenyl]ethanone oxime (8a) or its methyl derivative 8b,
with 4-hydroxy-
Figure 1.
Scheme 1. Reagents: (i) 4-hydroxybenzaldehyde, K2CO3, THF in a sealed bomb; (ii) 4-hydroxybenzylideneacetone, K2CO3, acetone in a sealed bomb.
Scheme 2. Reagents: (i) 4-hydroxyacetophenone, K2CO3, THF in a sealed bomb; (ii) NH2OH HCl or 40% NH2OMe HCl, EtOH; (iii) Lindlar
catalyst, H2, MeOH–CH2Cl2(1:1).
3922Y.-L. Chen et al./Bioorg. Med. Chem. 11 (2003) 3921–3927

Page 3

respectively. The configuration of the oxime moiety was
determined by through-space nuclear Overhauser effect
spectroscopy (NOESY) which revealed coupling con-
nectivity to CH3protons. Hydrogenative reduction of 7
in the presence of Lindlar catalyst gave 1-[4-(furo[2,3-
b]quinolin-4-yloxy)phenyl]ethanone (9) in 53% yield,
which was then reacted with hydroxylamine or methyl-
hydroxylamine togive
yloxy)phenyl]ethanoneoxime
derivative 10b, respectively.
1-[4-(furo[2,3-b]quinolin-4-
(10a) or itsmethyl
Results and Discussion
Mast cell degranulation
In the present study, assessment of inhibitory efficacy
with respect to mast cell degranulation was performed
bymeasuring thecontent
supernatant. Asshown
phenoxy)acridine(2a–2e)
inhibition of mast cell activation while its (E)-9-[4-(3-
oxo-but-1-enyl)phenoxy]acridine counterparts (3a–3e)
were ineffective. Compounds 2b–2e (IC50values of 6.1,
5.9, 13.5 and 4.7mM, respectively) were more potent
while 2a was equipotent to the reference inhibitor,
mepacrine. These results also indicated that the sub-
stituent such as OMe and Cl at the acridine enhanced
inhibitory activity (2b–2e vs 2a). The result that com-
pounds 3a–3e exerted weak inhibition, suggesting that
the distance between acridine and the carbonyl group
also play an important role. Although the inhibitory
activity of 4 and 9 was comparable, the acridine deriva-
tives are more potent than their respective furo[2,3-
b]quinoline counterparts (5a vs 10a; 5b vs 10b). For the
of
Table
exhibited
b-glucuronidase
1,9-(4-formyl-
a significant
in
in
furo[2,3-b]quinoline-4-yloxy)phenyl]ethanone deriva-
tives, substituent such as Cl at C-3 position decreased
the inhibitory activity (7 vs 9; 8b vs 10b) with an excep-
tion of 8a, which is more active than its 3-unsubstituted
counterpart, 10a.
Neutrophil degranulation
Activation of neutrophils with 1mM formyl-methionyl-
leucyl-phenylalanine (fMLP) in the presence of cytocha-
lasin B (5mg/mL) evoked the release of 21.2 and 19.8%
of lysozyme and b-glucuronidase, respectively, of the
initial cellular content. 4-(2-Methoxyacridin-9-yloxy)-
benzaldehyde (2c), with an IC50 value of 18.3 and
9.2mM against lysozyme and b-glucuronidase release,
respectively, was more potent than its 4-methoxy isomer
2b and was comparable to the calmodulin inhibitor, tri-
fluoperazine which inhibits the degradation and super-
oxide anion generation in neutrophils.23,24The same
order was observed for (E)-9-[4-(3-oxobut-1-enyl)phe-
noxy]acridines in which 2-methoxy derivative 3c with an
IC50value of 15.2 and 4.3mM as compared to its 4-
methoxy isomer 3b with IC50 values of near 30 and
5.6mM against lysozyme and b-glucuronidase release,
respectively. In analogy to the inhibition of mast cell
degranulation, the acridine derivatives are more active
inhibitors than their respective furo[2,3-b]quinoline
counterparts (4 vs 9; 5a vs 10a). Compound 5a showed
the most potent activity with IC50values of 4–8mM for
the inhibition of neutrophil degranulation.
TNF-? release
TNF-a, an early cytokine produced by activated
macrophages, plays an essential role in pathological
Table 1.IC50(mM)a,bvalues of acridine and furo[2,3-b]quinoline derivatives against mast cell and neutrophil degranulation
CompdMast cell degranulationNeutrophil degranulation
b-glucuronidasec
Lysozymed
b-glucuronidased
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
4
5a
5b
7
8a
8b
9
10a
10b
Mepacrine
Trifluoperazine
20.7?0.7
6.1?0.2
5.9?1.1
13.5?1.5
4.7?1.0
>30.0 (7.7?5.6%)
>30.0 (33.4?4.5%)*
>30.0 (17.2?1.2%)
>30.0 (13.4?1.7%)
>30.0 (48.4?2.9%)**
>30.0 (34.7?4.2%)**
>30.0 (29.5?7.6%)
21.0?0.4
>30.0 (5.9?2.8%)
>30.0 (33.5?4.0%)*
>30.0 (?23.3?1.6%)
>30.0 (35.9?5.6%)*
>30.0 (1.5?8.2%)
>30.0 (6.2?4.8%)
20.6?1.2
>30.0 (44.8?3.1%)**
>30.0 (24.6?5.1%)
18.3?2.9
>30.0 (3.5?3.1%)
>30.0 (6.9?4.0%)
>30.0 (10.3?11.3%)
>30.0 (48.2?3.1%)**
15.2?2.0
>30.0 (25.1?6.2%)
>30.0 (15.4?6.1%)
23.7?0.6
8.2?0.2
>30.0 (15.4?11.8%)
>30.0 (?0.9?1.1%)
>30.0 (17.6?0.9%)
>30.0 (0.8?2.0%)
>30.0 (9.9?1.4%)
>30.0 (0.1?3.4%)
>30.0 (27.9?5.0%)*
>30.0 (49.9?3.9%)**
>30.0 (42.9?0.8%)**
9.2?0.4
>30.0 (?1.6?0.8%)
>30.0 (23.6?5.8%)*
>30.0 (32.4?1.5%)**
5.6?0.3
4.3?0.8
>30.0 (33.3?4.8%)**
>30.0 (42.7?10.5%)**
>30.0 (26.7?0.6%)*
4.4?0.1
>30.0 (46.9?0.4%)**
>30.0 (9.6?2.9%)
>30.0 (32.6?3.2%)**
>30.0 (17.0?1.6%)
>30.0 (25.8?8.4%)**
>30.0 (18.4?2.2%)
28.0?4.4
11.9?0.610.6?0.9
aValues are means?SE of at least three separate experiments.
bWhen 50% inhibition could not be reached at the highest concentration, the % of inhibition is given in parentheses.
cInduced by compound 48/80 (10mg/mL).
dInduced by fMLP (1mM)/cytochalasin B (5mg/mL). *p <0.05, **p <0.01.
Y.-L. Chen et al./Bioorg. Med. Chem. 11 (2003) 3921–39273923

Page 4

inflammatory reactions. None of compounds 2–10 had
similar IC50value 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
macrophages) (Table 2). However, compound 2d
showed weak potency in RAW 264.7 (IC50values of
29.1mM), and 2d and 3a exhibited moderate potency in
N9 cells (IC50values of 9.3 and 8.7mM, respectively).
The results also confirm the conclusion above that the
acridine derivatives exhibited a better potency for the
inhibition of TNF-a formation than their respective
furo[2,3-b]quinoline counterparts (4 vs 9; 5a vs 10a; 5b
vs 10b) (Table 2). Compound 4 was among the most
potent inhibitor in N9 cells.
Preliminary cytotoxic evaluation
Two furo[2,3-b]quinoline derivatives, 7 and 9, were
selected for evaluation 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
inoculated and preincubated on a microtiter plate. Test
agents are then added at a single concentration
(100mM) and the culture incubated for 48h. End-point
determinations are made with sulforhodamine B, a
protein-binding dye. 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 cyto-
toxic. The growth percentages over MCF7, NCI-
H460, and SF-268 cells are: 91, 74, 96, respectively,
for compound 7 and 86, 46, 66, respectively, for
compound 9. These results showed both compounds
to be non-cytotoxic.
Conclusion
These results indicated that the anti-inflammatory
effects of acridine and furo[2,3-b]quinoline derivatives
were mediated, at least in part, through the suppression
of chemical mediators released from mast cells, neu-
trophils and macrophages, and the potential of these
compounds to be novel anti-inflammatory agents with
no significant cytotoxicity.
Experimental
General. TLC: precoated (0.2mm) silica gel 60 F254
plates from EM Laboratories, Inc.; detection by UV
light (254nm). Mp: Electrothermal IA9100 digital melt-
ing-point apparatus; uncorrected.
spectra: Varian-Unity-400 spectrometer at 400 and
100MHz or Varian-Gemini-200 spectrometer at 200
and 50MHz, chemical shifts d in ppm with SiMe4as an
internal standard (=0ppm), coupling 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.
1H and
13C NMR
General procedure for coupling of substituted-phenols
with 9-chloroacridine or 4-chlorofuro[2,3-b]quinoline de-
rivatives
A mixture of the substituted-phenols (3mmol), K2CO3
(0.62g, 4.5mmol), and corresponding substituted-9-
chloroacridine (1, 3mmol) or 3,4-dichlorofuro[2,3-
b]quinoline (6, 3mmol) in THF (50mL) or acetone
(50mL) was heated at 150?C for 20h in a steel bomb. It
was cooled, filtered, concentrated, washed well with
water, and purified by flash column chromatography
(FC, silica gel).
4-(4-Methoxyacridin - 9 - yloxy)benzaldehyde (2b). This
compound was obtained from 4-hydroxybenzaldehyde
and 9-chloro-4-methoxyacridine, which was purified by
FC (hexane/AcOEt 2:1) in 57% yield. Mp 194–196?C.
1H NMR (200MHz, DMSO-d6): 4.07 (s, 4-OMe), 7.06
(m, 2H-C(30, 50)), 7.24 (m, H-C(3)), 7.50 (m, 2 arom H),
7.62 (m, 1 arom H), 7.91 (m, 2H-C(20, 60) and 1 arom
H), 8.29 (d, J=8.8, H-C(5)), 9.89 (s, CHO).13C NMR
(50MHz, DMSO-d6): 55.78, 107.80, 112.88, 115.96
(2C), 118.27, 119.37, 120.33, 121.51, 127.23, 129.98,
130.63, 131.39, 132.22 (2C), 142.95, 148.57, 152.88,
155.42,163.12, 191.39.
C21H15NO3.0.2H2O: C 75.76, H 4.54, N 4.21; found: C
75.90, H 4.65, N 4.19.
Anal. calcdfor
4-(2 - Methoxyacridin- 9-yloxy)benzaldehyde (2c). This
compound was obtained from 4-hydroxybenzaldehyde
and 9-chloro-2-methoxyacridine, which was purified by
FC (hexane/AcOEt 3:1) and recrystallized from EtOH
in 23% yield. Mp 145–147?C.
DMSO-d6): 3.78 (s, 2-OMe), 7.06 (m, 2H-C(30, 50), and 1
arom H), 7.58 (m, 2 arom H), 7.88 (m, 2H-C(20, 60) and
2 arom H), 8.20 (m, 2H-C(4, 5)), 9.90 (s, CHO).13C
NMR (50MHz, DMSO-d6): 55.54, 96.93, 116.08 (2C),
119.33, 120.18, 121.22, 125.90, 126.94, 129.54, 129.72,
1H NMR (200MHz,
Table 2.
on TNF-a formation
IC50values of acridine and furo[2,3-b]quinoline derivatives
CompdIC50(mM)a,b
RAW 264.7 N9
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
4
5a
5b
7
8a
8b
9
10a
10b
Dexamethasone
>30.0 (17.2?3.3%)*
>10.0 (27.2?2.6%)
>10.0 (18.8?7.9%)
29.1?1.9
>30.0 (40.5?3.4%)**
>30.0 (?15.7?4.1%)**
>10.0 (35.2?10.8%)*
>3.0 (33.1?14.2%)*
>3.0 (39.0?9.2%)**
>30.0 (37.8?7.9%)**
>10.0 (47.2?3.1%)
>10.0 (44.9?2.0%)**
>30.0 (7.2?0.8%)
>30.0 (?46.5?11.9%)*
>30.0 (2.4?3.4%)
>30.0 (27.3?2.5%)
>30.0 (?14.1?0.8%)
>30.0 (?11.0?4.3%)
>30.0 (11.1?4.6%)
0.42?0.12
>3.0 (19.9?3.8%)*
>10.0 (34.5?7.1%)**
>10.0 (29.9?5.3%)*
9.3?2.8
>10.0 (22.3?6.9%)
8.7?0.3
>10.0 (44.4?1.4%)**
>3.0 (3.4?12.0%)
>3.0 (9.7?3.9%)
>10.0 (42.8?3.0%)**
0.8?0.3
>3.0 (40.1?3.1%)**
>3.0 (39.3?1.2%)**
>30.0 (9.4?7.8%)
>10.0 (?19.3?2.0%)
>3.0 (?31.1?2.0%)**
>3.0 (28.6?11.7%)*
>10.0 (47.7?1.3%)**
>3.0 (14.0?2.5%)
0.074?0.01
aValues are means?SE of at least three separate experiments.
bWhen 50% inhibition could not be reached at the highest concen-
tration, the % of inhibition is given in parentheses. *p <0.05,
**p <0.01.
3924 Y.-L. Chen et al./Bioorg. Med. Chem. 11 (2003) 3921–3927

Page 5

131.06, 131.42, 132.24 (2C), 147.11, 148.01, 151.30,
157.37, 162.83,191.40.
C21H15NO3.0.1H2O: C 76.17, H 4.57, N 4.23; found: C
76.15, H 4.81, N 4.14.
Anal.calcd for
4-(6-Chloro - 2 - methoxyacridin - 9 - yloxy)benzaldehyde
(2d). This compound was obtained from 4-hydroxy-
benzaldehyde and6,9-dichloro-2-methoxyacridine,
which was purified by FC (hexane/AcOEt 3:1) in 54%
yield. Mp 148–150?C.1H NMR (200MHz, DMSO-d6):
3.79 (s, 2-OMe), 7.11 (m, 2H-C(30, 50) and 1 arom H),
7.61 (m, 2 arom H), 7.92 (m, 2H-C(20, 60) and 1 arom
H), 8.15 (d, J=9.4, H-C(4)), 8.26 (d, J=1.8, H-C(5)),
9.92 (s, CHO).13C NMR (50MHz, DMSO-d6): 55.61,
97.08, 116.16 (2C), 117.96, 120.37, 123.51, 126.59,
127.21, 127.66, 131.30, 131.54, 132.24 (2C), 134.50,
147.84, 147.90, 151.78, 157.59, 162.70, 191.43. Anal.
calcd for C21H14ClNO3.0.1H2O: C 68.99, H 3.91, N
3.83; found: C 68.90, H 4.27, N 3.62.
4-(2-Chloroacridin-9-yloxy)benzaldehyde (2e). This com-
pound was obtained from 4-hydroxybenzaldehyde and
2,9-dichloroacridine, which was purified by FC (hexane/
AcOEt 3:1) in 53% yield. Mp 172–173?C.1H NMR
(400MHz, DMSO-d6): 7.12 (m, 2H-C(30, 50)), 7.65 (m, 1
arom H), 7.88–7.98 (m, 2H-C(20, 60) and 3 arom H),
8.01 (d, J=2.0, H-C(1)), 8.28 (m, 2H-C(4, 5)), 9.92 (s,
CHO).13C NMR (100MHz, DMSO-d6): 116.05 (2C),
119.36, 119.62, 119.98, 121.68, 127.51, 129.60, 131.36,
131.47, 131.53, 131.79, 131.88, 132.21 (2C), 148.04,
150.04,152.59, 162.91,
C20H12ClNO2.0.2H2O: C 71.20, H 3.65, N 4.15; found:
C 71.10, H 3.92, N 3.87.
191.38.Anal. calcdfor
4-[4-(4-Methoxyacridin-9-yloxy)phenyl]but-3-en-2-one
(3b). This compound was obtained from 4-hydroxy-
benzylideneacetoneand 9-chloro-4-methoxyacridine,
which was purified by FC (hexane/AcOEt 1:1) and
recrystallized from EtOH in 30% yield. Mp 188–190?C.
1H NMR (400MHz, DMSO-d6): 2.28 (s, COMe), 4.05
(s, 4-OMe), 6.60 (d, J=16.4, H-C(300)), 6.81 (m, 2H-
C(20, 60)), 7.25 (m, 3 arom H), 7.53 (m, 2H-C(30, 50) and
H-C(400)), 7.69 (m, 1 arom H), 7.81 (dd, J=8.4, 1.2, H-
C(8)), 7.94 (dd, J=8.8, 1.2, H-C(1)), 8.21 (dd, J=8.0,
1.2, H-C(5)).13C NMR (100MHz, DMSO-d6): 27.12,
56.24, 112.34, 115.86 (2C), 117.15, 118.32, 120.57,
121.13, 121.25, 124.09, 125.35, 125.74, 130.40 (2C),
131.87, 133.10, 140.68, 143.58, 147.85, 159.90, 176.60,
197.82. Anal. calcd for C24H19NO3.0.3H2O: C 76.90, H
5.11, N 3.74; found: C 76.50, H 5.44, N 3.54.
4-[4-(2-Methoxyacridin-9-yloxy)phenyl]but-3-en-2-one
(3c). This compound was obtained from 4-hydroxy-
benzylideneacetone and9-chloro-2-methoxyacridine,
which was purified by FC (hexane/AcOEt 2:1) in 36%
yield. Mp 160–161?C.1H NMR (400MHz, DMSO-d6):
2.31 (s, COMe), 3.80 (s, 4-OMe), 6.69 (d, J=16.4, H-
C(300)), 6.96 (m, 2H-C(20, 60)), 7.17 (d, J=2.8, H-C(1)),
7.59 (m, 2 arom H and H-C(400)), 7.69 (m, 2H-C(30, 50)),
7.82 (m, 1 arom H), 7.95 (dd, J=8.4, 1.2, H-C(8)), 8.17
(d, J=9.6, H-C(4)), 8.21 (d, J=8.8, 1.2, H-C(5)).13C
NMR (100MHz, DMSO-d6): 27.18, 55.52, 97.13, 116.03
(2C), 119.55, 120.35, 121.45, 125.85, 126.32, 126.77,
129.26, 129.53, 129.70, 130.64 (2C), 131.41, 142.38,
147.13, 148.06, 151.84, 157.24, 160.15, 197.98. Anal.
calcd for C24H19NO3: C 78.03, H 5.18, N 3.79; found: C
78.20, H 5.18, N 3.63.
4-[4-(6-Chloro-2-methoxyacridin-9-yloxy)phenyl]but-3-
en-2-one (3d). This compound was obtained from
4-hydroxybenzylideneacetone
methoxyacridine, which was purified by FC (hexane/
AcOEt 3:1) and recrystallized from EtOH in 68% yield.
Mp 183–185?C.1H NMR (200MHz, DMSO-d6): 2.29
(s, COMe), 3.78 (s, 4-OMe), 6.68 (d, J=16.4, H-C(300)),
6.96 (m, 2H-C(20, 60)), 7.13 (d, J=2.4, H-C(1)), 7.54–
7.71 (m, 2H-C(30, 50), H-C(00) and 2 arom H), 7.95 (d,
J=9.2, H-C(8)), 8.13 (d, J=9.6, H-C(4)), 8.24 (d,
J=1.8, H-C(5)).13C NMR (50MHz, CDCl3): 27.52,
55.58, 97.29, 116.07 (2C), 118.53, 120.90, 123.28, 126.60,
127.57, 128.21, 129.26, 130.27 (2C), 131.34, 135.54,
142.22, 148.50, 152.67, 157.74, 160.47, 198.16. Anal.
calcd for C24H18ClNO3.0.3H2O: C 70.43, H 4.58, N
3.42; found: C 70.48, H 4.60, N 3.18.
and 6,9-dichloro-2-
4-[4-(2-Chloroacridin-9-yloxy)phenyl]but-3-en-2-one (3e).
Thiscompoundwas obtained
benzylideneacetone and 2,9-dichloro-2-methoxyacridine,
which was purified by FC (hexane/AcOEt 3:1) in 54%
yield. Mp 180–182?C.
2.36 (s, COMe), 6.61 (d, J=16.2, H-C(300)), 6.87 (m, 2H-
C(20, 60)), 7.42–7.54 (m, 2H-C(30, 50), H-C(400) and 1
arom H), 7.71 (dd, J=9.4, 2.4, H-C(3)), 7.81 (m, 1 arom
H), 8.03 (m, 2 arom H), 8.25 (m, 2H-C(4, 5)).13C NMR
(100MHz, DMSO-d6): 27.52, 116.04 (2C), 120.68,
122.28, 126.28, 126.80, 129.36, 129.85, 130.30 (2C),
130.96, 131.47, 132.06, 132.29, 142.23, 148.60, 150.50,
153.61, 160.73,198.19.
C23H16ClNO2.0.1H2O: C 73.54, H 4.30, N 3.73; found:
C 73.32, H 4.38, N 3.69.
from4-hydroxy-
1H NMR (200MHz, CDCl3):
Anal.calcdfor
1-[4-(3-Chlorofuro[2,3 - b]quinolin - 4 - yloxy)phenyl]etha-
none(7).Thiscompound
4-hydroxyacetophenoe and 6, which was purified by FC
(hexane/AcOEt 4:1) in 66% yield. Mp 230–232?C.1H
NMR (400Hz, CDCl3): 2.57 (s, COMe), 6.94 (m, 2H-
C(20, 60)), 7.53 (ddd, J=8.8, 6.8, 1.6, H-C(6)), 7.75 (s,
H-C(2)), 7.80 (ddd, J=8.8, 6.8, 1.6, H-C(7)), 7.94 (m,
2H-C(30, 50)), 8.06 (ddd, J=8.8, 1.6, 0.8, H-C(8)), 8.18
(ddd, J=8.8, 1.6, 0.8, H-C(5)).13C NMR (100MHz,
CDCl3): 26.40, 109.91, 110.18, 115.42 (2C), 121.06,
121.91, 125.84, 128.75, 130.71, 130.85 (2C), 132.30,
142.41, 146.76, 151.16, 161.18, 162.63, 196.47. Anal.
calcd for C19H12ClNO3: C 67.56, H 3.58, N 4.15; found:
C 67.48, H 3.58, N 4.12.
wasobtainedfrom
(E)-1-[4-(3-Chlorofuro[2,3-b]quinolin-4-yloxy)phenyl]-
ethanone oxime (8a). To a suspension of 7 (50mg,
0.15mmol) in ethanol (10mL) was added NH2OH.HCl
(21mg, 0.3mmol). The reaction mixture was stirred at
room temperature for 30min (TLC monitoring), then
concentrated in vacuo to give a solid which was washed
by H2O (20mL) and purified by FC (CH2Cl2–AcOEt
20:1) to give a white solid (48mg, 90%). Mp 206–
208?C.1H NMR (200MHz, DMSO-d6): 2.12 (s, Me),
6.99 (m, 2H-C(20, 60)), 7.61 (m, 3H-C(30, 50, 6)), 7.88
Y.-L. Chen et al./Bioorg. Med. Chem. 11 (2003) 3921–3927 3925

Page 6

(ddd, J=8.6, 6.8, 1.2, H-C(7)), 8.02 (d, J=8.6, H-C(8)),
8.13 (d, J=8.4, H-C(5)), 8.55 (s, H-C(2)), 11.14 (s,
NOH).13C NMR (50MHz, DMSO-d6): 11.44, 108.57,
110.22, 115.28 (2C), 120.68, 121.80, 125.94, 127.37 (2C),
128.36, 130.72, 131.86, 144.15, 146.11, 150.78, 152.09,
159.28, 160.86. Anal. calcd for C19H13ClN2O3.0.1H2O:
C 64.36, H 3.75, N 7.90; found: C 64.24, H 3.82, N 7.66.
(E)-1-[4-(3-Chlorofuro[2,3-b]quinolin-4-yloxy)phenyl]-
ethanone O-methyloxime (8b). To a suspension of 7
(50mg, 0.15mmol) in ethanol (10mL) was added 40%
NH2OMe.HCl aqueous (63mg, 0.3mmol). The reaction
mixture was stirred at room temperature for 1h (TLC
monitoring), then concentrated in vacuo to give a solid
which was washed by H2O (20mL) and purified by FC
(CH2Cl2) to give a pale-yellow solid (50mg, 90%). Mp
140–141?C.1H NMR (200MHz, CDCl3): 2.19 (s, Me),
3.97 (s, OMe), 6.88 (m, 2H-C(20, 60)), 7.50 (m, H-C(6)),
7.60 (m, 2H-C(30, 50)), 7.73 (s, H-C(2)), 7.78 (m, H-
C(7)), 8.08 (d, J=8.4, H-C(8)), 8.17 (d, J=8.6, H-C(5)).
13C NMR (50MHz, CDCl3): 12.56, 61.91, 110.16,
110.34, 115.52 (2C), 121.37, 122.31, 125.62, 127.76 (2C),
128.70, 130.61, 131.54, 142.19, 146.80, 151.92, 153.78,
159.99, 161.32. Anal. calcd for C20H15ClN2O3.0.1H2O:
C 65.17, H 4.15, N 7.59; found: C 65.13, H 4.18, N 7.31.
1-[4-(Furo[2,3-b]quinolin-4-yloxy)phenyl]ethanone (9). A
solution of 1-[4-(3-chlorofuro[2,3-b]quinolin-4-yloxy)-
phenyl]ethanone (7, 0.34g, 1mmol) in MeOH–CH2Cl2
(1=1, 100mL) was hydrogenated for 3h (TLC monitor-
ing) under H2with Lindlar catalyst (0.34g). The reac-
tion mixture was filtered and the filtrate concentrated in
vacuo to give a residual solid, which was purified by FC
(n-hexane–EtOAc 2:1) to give 9 (0.16 g, 53%). Mp 195–
196?C.
COMe), 6.21 (d, J=2.8, H-C(3)), 7.32 (m, 2H-C(20, 60)),
7.62 (ddd, J=8.4, 6.8, 1.2, H-C(6)), 7.85 (ddd, J=8.4,
6.8, 1.2, H-C(7)), 8.07 (m, 4H-C(30, 50, 2, 8)), 8.23 (ddd,
J=8.4, 1.6, 0.4, H-C(5)).13C NMR (100MHz, DMSO-
d6): 26.65, 103.29, 108.70, 118.24 (2C), 119.14, 121.69,
125.13, 128.02, 130.05, 130.84 (2C), 133.22, 145.51,
146.97, 151.49, 159.88, 162.90, 196.56. Anal. calcd for
C19H13NO3.0.1H2O: C 74.80, H 4.36, N 4.59; found: C
74.83, H 4.30, N 4.53.
1H NMR (400MHz, DMSO-d6): 2.59 (s,
(E)-1-[4 -(Furo[2,3-b]quinolin-4-yloxy)phenyl]ethanone
oxime (10a). From 9 and NH2OH.HCl as described for
8a: 91% yield. Mp 195–197?C.1H NMR (200MHz,
DMSO-d6): 2.19 (s, Me), 5.91 (d, J=2.8, H-C(3)), 7.29
(m, 2H-C(20, 60)), 7.62 (m, H-C(6)), 7.77 (m, 2H-C(30,
50)), 7.84 (ddd, J=8.4, 6.8, 1.4, H-C(7)), 7.99 (d,
J=2.6, H-C(2)), 8.06 (d, J=8.4, H-C(8)), 8.32 (d,
J=8.4, H-C(5)).
11.48, 103.41, 107.28, 118.84, 119.19 (2C), 121.88,
124.85, 127.45 (2C), 127.87, 130.01, 133.86, 145.40,
146.21, 152.09, 152.83, 156.26, 62.99. Anal. calcd for
C19H14N2O3.0.4H2O: C 70.10, H 4.58, N 8.60; found: C
70.24, H 4.73, N 8.41.
13C NMR (50MHz, DMSO-d6):
(E)-1-[4-(Furo[2,3-b]quinolin-4-yloxy-phenyl]ethanone O-
methyloxime (10b). From 9 and 40% NH2OMe.HCl
aqueous as described for 8b: 75% yield. Mp 149–151?C.
1H NMR (200MHz, CDCl3): 2.26 (s, Me), 4.02 (s,
OMe), 5.86 (d, J=2.8, H-C(3)), 7.16 (m, 2H-C(20, 60)),
7.49 (d, J=2.6, H-C(2)), 7.55 (ddd, J=8.4, 6.8, 1.0, H-
C(6)), 7.74 (m, 2H-C(30, 50)), 7.78 (ddd, J=8.4, 6.8,
1.0, H-C(7)), 8.16 (d, J=8.4, H-C(8)), 8.38 (d,
J=8.4, H-C(5)).13C NMR (50MHz, CDCl3): 12.56,
62.04, 103.95, 107.28, 119.42 (3C), 122.22, 124.71,
127.84 (2C), 127.88, 130.13, 133.59, 144.57, 145.65,
153.53,153.92, 156.88,
C20H16N2O3.0.1H2O: C 71.89, H 4.89, N 8.38; found: C
71.87, H 5.03, N 8.14.
163.22.Anal.calcd for
Acknowledgements
Financial support of this work by the National Science
Council of the Republic of China (NSC 91-2113-M-037-
013)isgratefully acknowledged.
NationalCancerInstitute
States fortheanticancer
National Center for High-Performance Computing
for providingcomputer
database services.
We
of
also
the
thank
United
and
(NCI)
screenings the
resourcesand chemical
References and Notes
1. Menninger, H.; Putzier, R.; Mohr, W.; Weissinghage, D.;
Tillmann, K. J. Rheumatol. 1980, 39, 145.
2. Hyers, T. M.; Fowler, A. A. Fed. Proc. Fed. Am. Soc. Exp.
Biol. 1986, 45, 25.
3. Solbach, W.; Moll, H.; Rollinghoff, M. Immunol. Today
1991, 12, 4.
4. Beutler, G.; Cerami, A. A. Annu. Rev. Biochem. 1988, 57,
505.
5. Wakelin, L. P. G.; Adams, A.; Denny, W. A. J. Med.
Chem. 2002, 45, 894.
6. Bailly, C.; Denny, W. A.; Mellor, L. E.; Wakelin, L. P. G.;
Waring, M. J. Biochemistry 1992, 31, 3514.
7. Gamage, S. A.; Tepsiri, N.; Wilairat, P.; Wojcik, S. J.;
Figgitt, D. P.; Ralph, R. K.; Denny, W. A. J. Med. Chem.
1994, 37, 1486.
8. McConnaughie, A. W.; Jenkins, T. C. J. Med. Chem. 1995,
38, 3488.
9. 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.
10. Amellal, M.; Landry, Y. Br. J. Pharmacol. 1983, 80, 365.
11. Chakravarty, N.; Nielsen, E. H. Agents Actions 1986, 18,
65.
12. Yu, N.; Maciejewski-Lenoir, D.; Bloom, F. E.; Magis-
tretti, P. J. Mol. Pharmacol. 1995, 48, 550.
13. Romanelli, F.; Fillo, S.; Isidori, A.; Conte, D. Life Sci.
1997, 61, 557.
14. Denny, W. A.; Cain, B. F.; Hansch, G. J.; Panthana-
nickal, A.; Leo, A. J. Med. Chem. 1982, 25, 276.
15. Atwell, G. J.; Cain, B. F.; Seelye, R. N. J. Med. Chem.
1972, 15, 611.
16. Zwelling, L. A.; Michaels, S.; Erickson, L. C.; Ungerlei-
der, R. S.; Nichols, M.; Kohn, K. W. Biochemistry 1981, 20,
6553.
17. Bonse, S.; Santelli-Rouvier, C.; Barbe, J.; Krauth-Siegel,
R. L. J. Med. Chem. 1999, 42, 5448.
18. Chen, Y.-L.; Lu, C.-M.; Chen, I.-L.; Tsao, L.-T.; Wang,
J.-P. J. Med. Chem. 2002, 45, 4689.
3926 Y.-L. Chen et al./Bioorg. Med. Chem. 11 (2003) 3921–3927

Page 7

19. Zhao, W.; Wolfender, J. L.; Hostettmann, K.; Xu, R.;
Qin, G. Phytochemistry 1998, 47, 7.
20. Chen, I. S.; Wu, Y. C.; Lin, I. L.; Seki, H.; Ko, F. N.;
Teng, C. M. Phytochemistry 1994, 36, 237.
21. Su, T.-L.; Chen, C.-H.; Huang, L.-F.; Chen, C.-H.; Basu,
M.K.; Zhang, X.-G.;Chou, T.-C. J.Med. Chem. 1999, 42, 4741.
22. Tuppy, H.; Bohm, F. Monatsh. Chem. 1956, 87, 720.
23. Merrill, J. E.; Benveniste, E. N. Trends Neurosci. 1996, 19,
331.
24. Monks, A.; Scuderio, D.; Skehan, P.; Shoemaker, R.;
Paull, K.; Vistica, D.; Hose, C.; Langlay, J.; Cronise, P.; Vai-
gro-Wolff, A. J. Natl. Cancer Inst. 1991, 83, 757.
Y.-L. Chen et al./Bioorg. Med. Chem. 11 (2003) 3921–39273927