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

Article abstract of DOI:10.1016/S0968-0896(03)00439-5

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 an

Full text of DOI:10.1016/S0968-0896(03)00439-5

Bioorganic & Medicinal Chemistry 11 (2003) 3921–3927
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,a Chih-Ming Lu,a Cherng-Chyi Tzeng,a
Lo-Ti Tsaob and 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 IC50 values of 6.1, 5.9, 13.5, and 4.7 mM, respectively. Compounds 2c, 3b, 3c, and 5a
also showed potent inhibitory activity (IC50=4.3–18.3 mM) 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 IC50 vales
less then 10 mM. 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
9-Aminoacridine has been used clinically as an antiseptic
drug. This tricyclic heterocycle may interact with DNA
through intercalation, thus disrupting DNAreplication. 5,6
Alarge number of its derivatives have been prepared
and evaluated for biological activities.7ꢀ9 Two 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 cell10,11 and amsa-
crine (m-AMSA),12,13 an antileukemic agent.14ꢀ16 Cer-
tain 9-thioacridines have also been synthesized as
inhibitors of trypanothione reductase from Trypanosoma
cruzi, the causative agent of Chagas’ disease.17 Due 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.18 The 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
Mast cells play an important role in anaphylaxis and
inflammation. Avariety 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.1,2 Macrophages interact with other
immune cells and serves as central regulators of specific
immune response.3 Following 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.
*Corresponding author. Tel.: +886-7-312-1101x2249; fax: +886-7-
312-5339; e-mail: yeloch@cc.kmu.edu.tw
0968-0896/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0968-0896(03)00439-5

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Y.-L. Chen et al. / Bioorg. Med. Chem. 11 (2003) 3921–3927
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).
Chemistry
methoxyacridine (2b) in 57% yield. Accordingly, com-
pounds 2c–2e and 3c–3e were prepared from the
9-Phenoxyacridines 2a–2e and 3a–3e were prepared as
described in Scheme 1. Reaction of 9-chloro-4-
methoxyacridine (1b, R=4-OMe)21 with 4-hydroxy-
benzaldehyde afforded 9 - (4 - formylphenoxy) - 4 -
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,18 their 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 with 4-hydroxy-
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,
Figure 1.

Y.-L. Chen et al. / Bioorg. Med. Chem. 11 (2003) 3921–3927
3923
Table 1. IC50 (mM)a,b values of acridine and furo[2,3-b]quinoline derivatives against mast cell and neutrophil degranulation
Compd
Mast cell degranulation
Neutrophil degranulation
b-glucuronidasec
Lysozymed
b-glucuronidased
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
4
5a
5b
7
8a
20.7ꢁ0.7
6.1ꢁ0.2
>30.0 (44.8ꢁ3.1%)**
>30.0 (24.6ꢁ5.1%)
18.3ꢁ2.9
>30.0 (49.9ꢁ3.9%)**
>30.0 (42.9ꢁ0.8%)**
9.2ꢁ0.4
5.9ꢁ1.1
13.5ꢁ1.5
>30.0 (3.5ꢁ3.1%)
>30.0 (6.9ꢁ4.0%)
>30.0 (10.3ꢁ11.3%)
>30.0 (48.2ꢁ3.1%)**
15.2ꢁ2.0
>30.0 (ꢀ1.6ꢁ0.8%)
>30.0 (23.6ꢁ5.8%)*
>30.0 (32.4ꢁ1.5%)**
5.6ꢁ0.3
4.7ꢁ1.0
>30.0 (7.7ꢁ5.6%)
>30.0 (33.4ꢁ4.5%)*
>30.0 (17.2ꢁ1.2%)
>30.0 (13.4ꢁ1.7%)
>30.0 (48.4ꢁ2.9%)**
>30.0 (34.7ꢁ4.2%)**
>30.0 (29.5ꢁ7.6%)
21.0ꢁ0.4
4.3ꢁ0.8
>30.0 (25.1ꢁ6.2%)
>30.0 (15.4ꢁ6.1%)
23.7ꢁ0.6
>30.0 (33.3ꢁ4.8%)**
>30.0 (42.7ꢁ10.5%)**
>30.0 (26.7ꢁ0.6%)*
4.4ꢁ0.1
8.2ꢁ0.2
>30.0 (15.4ꢁ11.8%)
>30.0 (ꢀ0.9ꢁ1.1%)
>30.0 (17.6ꢁ0.9%)
>30.0 (0.8ꢁ2.0%)
>30.0 (9.9ꢁ1.4%)
>30.0 (0.1ꢁ3.4%)
>30.0 (27.9ꢁ5.0%)*
>30.0 (46.9ꢁ0.4%)**
>30.0 (9.6ꢁ2.9%)
>30.0 (32.6ꢁ3.2%)**
>30.0 (17.0ꢁ1.6%)
>30.0 (25.8ꢁ8.4%)**
>30.0 (18.4ꢁ2.2%)
28.0ꢁ4.4
>30.0 (5.9ꢁ2.8%)
>30.0 (33.5ꢁ4.0%)*
>30.0 (ꢀ23.3ꢁ1.6%)
>30.0 (35.9ꢁ5.6%)*
>30.0 (1.5ꢁ8.2%)
>30.0 (6.2ꢁ4.8%)
20.6ꢁ1.2
8b
9
10a
10b
Mepacrine
Trifluoperazine
11.9ꢁ0.6
10.6ꢁ0.9
aValues are meansꢁSE 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 (10 mg/mL).
dInduced by fMLP (1 mM)/cytochalasin B (5 mg/mL). *p <0.05, **p <0.01.
respectively. The configuration of the oxime moiety was
determined by through-space nuclear Overhauser effect
spectroscopy (NOESY) which revealed coupling con-
nectivity to CH3 protons. 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 to give 1-[4-(furo[2,3-b]quinolin-4-
yloxy)phenyl]ethanone oxime (10a) or its methyl
derivative 10b, respectively.
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 1 mM formyl-methionyl-
leucyl-phenylalanine (fMLP) in the presence of cytocha-
lasin B (5 mg/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
9.2 mM 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.23,24 The same
order was observed for (E)-9-[4-(3-oxobut-1-enyl)phe-
noxy]acridines in which 2-methoxy derivative 3c with an
IC50 value of 15.2 and 4.3 mM as compared to its 4-
methoxy isomer 3b with IC50 values of near 30 and
5.6 mM 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 IC50 values of 4–8 mM for
the inhibition of neutrophil degranulation.
Results and Discussion
Mast cell degranulation
In the present study, assessment of inhibitory efficacy
with respect to mast cell degranulation was performed
by measuring the content of b-glucuronidase in
supernatant. As shown in Table 1, 9-(4-formyl-
phenoxy)acridine (2a–2e) exhibited
a
significant
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 (IC50 values of 6.1,
5.9, 13.5 and 4.7 mM, 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
TNF-ꢀ release
TNF-a, an early cytokine produced by activated
macrophages, plays an essential role in pathological

3924
Y.-L. Chen et al. / Bioorg. Med. Chem. 11 (2003) 3921–3927
Table 2. IC50 values of acridine and furo[2,3-b]quinoline derivatives
on TNF-a formation
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.
Compd
IC50 (mM)a,b
RAW 264.7
N9
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
4
5a
5b
7
8a
>30.0 (17.2ꢁ3.3%)*
>10.0 (27.2ꢁ2.6%)
>10.0 (18.8ꢁ7.9%)
29.1ꢁ1.9
>3.0 (19.9ꢁ3.8%)*
>10.0 (34.5ꢁ7.1%)**
>10.0 (29.9ꢁ5.3%)*
9.3ꢁ2.8
>30.0 (40.5ꢁ3.4%)**
>30.0 (ꢀ15.7ꢁ4.1%)**
>10.0 (35.2ꢁ10.8%)*
>3.0 (33.1ꢁ14.2%)*
>3.0 (39.0ꢁ9.2%)**
>30.0 (37.8ꢁ7.9%)**
>10.0 (47.2ꢁ3.1%)
>10.0 (44.9ꢁ2.0%)**
>30.0 (7.2ꢁ0.8%)
>30.0 (ꢀ46.5ꢁ11.9%)*
>30.0 (2.4ꢁ3.4%)
>30.0 (27.3ꢁ2.5%)
>30.0 (ꢀ14.1ꢁ0.8%)
>30.0 (ꢀ11.0ꢁ4.3%)
>30.0 (11.1ꢁ4.6%)
0.42ꢁ0.12
>10.0 (22.3ꢁ6.9%)
8.7ꢁ0.3
>10.0 (44.4ꢁ1.4%)**
>3.0 (3.4ꢁ12.0%)
>3.0 (9.7ꢁ3.9%)
>10.0 (42.8ꢁ3.0%)**
0.8ꢁ0.3
Experimental
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 melt-
ing-point apparatus; uncorrected. 1H 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 out on a Heraeus
CHN-O-Rapid elemental analyzer, and results were
withinꢁ0.4% of calculated values.
>3.0 (40.1ꢁ3.1%)**
>3.0 (39.3ꢁ1.2%)**
>30.0 (9.4ꢁ7.8%)
>10.0 (ꢀ19.3ꢁ2.0%)
>3.0 (ꢀ31.1ꢁ2.0%)**
>3.0 (28.6ꢁ11.7%)*
>10.0 (47.7ꢁ1.3%)**
>3.0 (14.0ꢁ2.5%)
0.074ꢁ0.01
8b
9
10a
10b
Dexamethasone
aValues are meansꢁSE 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.
General procedure for coupling of substituted-phenols
with 9-chloroacridine or 4-chlorofuro[2,3-b]quinoline de-
rivatives
inflammatory reactions. None of compounds 2–10 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
macrophages) (Table 2). However, compound 2d
showed weak potency in RAW 264.7 (IC50 values of
29.1 mM), and 2d and 3a exhibited moderate potency in
N9 cells (IC50 values of 9.3 and 8.7 mM, 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.
Amixture of the substituted-phenols (3 mmol), K CO3
2
(0.62 g, 4.5 mmol), and corresponding substituted-9-
chloroacridine (1, 3 mmol) or 3,4-dichlorofuro[2,3-
b]quinoline (6, 3 mmol) in THF (50 mL) or acetone
(50 mL) was heated at 150 ꢂC for 20 h 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 ꢂC.
1H NMR (200 MHz, 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
(50 MHz, 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,
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
(100 mM) and the culture incubated for 48 h. 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.
155.42,
163.12,
.
191.39.
Anal.
calcd
for
C21H15NO3 0.2H2O: C 75.76, H 4.54, N 4.21; found: C
75.90, H 4.65, N 4.19.
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 ꢂC. 1H NMR (200 MHz,
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 (50 MHz, DMSO-d6): 55.54, 96.93, 116.08 (2C),
119.33, 120.18, 121.22, 125.90, 126.94, 129.54, 129.72,

Y.-L. Chen et al. / Bioorg. Med. Chem. 11 (2003) 3921–3927
3925
131.06, 131.42, 132.24 (2C), 147.11, 148.01, 151.30,
157.37, 162.83, 191.40. Anal. calcd for
C21H15NO3 0.1H2O: C 76.17, H 4.57, N 4.23; found: C
76.15, H 4.81, N 4.14.
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-(6-Chloro - 2 - methoxyacridin - 9 - yloxy)benzaldehyde
(2d). This compound was obtained from 4-hydroxy-
benzaldehyde and 6,9-dichloro-2-methoxyacridine,
which was purifiedꢂ by FC (hexane/AcOEt 3:1) in 54%
4-[4-(6-Chloro-2-methoxyacridin-9-yloxy)phenyl]but-3-
en-2-one (3d). This compound was obtained from
4-hydroxybenzylideneacetone
and
6,9-dichloro-2-
methoxyacridine, which was purified by FC (hexane/
AcOEt 3:1) and recrystallized from EtOH in 68% yield.
1
yield. Mp 148–150 C. H NMR (200 MHz, 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 (50 MHz, 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.
Mp 183–185 ꢂC. H NMR (200 MHz, DMSO-d6): 2.29
1
(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 (50 MHz, 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 C21H14ClNO3 0.1H2O: C 68.99, H 3.91, N
3.83; found: C 68.90, H 4.27, N 3.62.
.
calcd for C24H18ClNO3 0.3H2O: C 70.43, H 4.58, N
3.42; found: C 70.48, H 4.60, N 3.18.
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/
4-[4-(2-Chloroacridin-9-yloxy)phenyl]but-3-en-2-one (3e).
This compound was obtained from 4-hydroxy-
benzylideneacetone and 2,9-dichloro-2-methoxyacridine,
which was purified by FC (hexane/AcOEt 3:1) in 54%
yield. Mp 180–182 ꢂC. 1H NMR (200 MHz, CDCl3):
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
(100 MHz, 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,
AcOEt 3:1) in 53% yield. Mp 172–173 ꢂC. H NMR
1
(400 MHz, 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 (100 MHz, 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, 191.38. Anal. calcd for
.
C20H12ClNO2 0.2H2O: C 71.20, H 3.65, N 4.15; found:
C 71.10, H 3.92, N 3.87.
4-[4-(4-Methoxyacridin-9-yloxy)phenyl]but-3-en-2-one
(3b). This compound was obtained from 4-hydroxy-
benzylideneacetone and 9-chloro-4-methoxyacridine,
which was purified by FC (hexane/AcOEt 1:1) and
recrystallized from EtOH in 30% yield. Mp 188–190 ꢂC.
1H NMR (400 MHz, 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 (100 MHz, 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,
153.61,
160.73,
.
198.19.
Anal.
calcd
for
C23H16ClNO2 0.1H2O: C 73.54, H 4.30, N 3.73; found:
C 73.32, H 4.38, N 3.69.
1-[4-(3-Chlorofuro[2,3 - b]quinolin - 4 - yloxy)phenyl]etha-
none (7). This compound was obtained from
4-hydroxyacetophenoe and 6, which was purifiedꢂby FC
1
(hexane/AcOEt 4:1) in 66% yield. Mp 230–232 C. H
NMR (400 Hz, 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 (100 MHz,
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.
.
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 and 9-chloro-2-methoxyacridine,
which was purified by FC (hexane/AcOEt 2:1) in 36%
(E)-1-[4-(3-Chlorofuro[2,3-b]quinolin-4-yloxy)phenyl]-
ethanone oxime (8a). To a suspension of 7 (50 mg,
0.15 mmol) in ethanol (10 mL) was added NH2OH HCl
yield. Mp 160–161 ꢂC. H NMR (400 MHz, DMSO-d6):
1
.
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 (100 MHz, DMSO-d6): 27.18, 55.52, 97.13, 116.03
(2C), 119.55, 120.35, 121.45, 125.85, 126.32, 126.77,
(21 mg, 0.3 mmol). The reaction mixture was stirred at
room temperature for 30 min (TLC monitoring), then
concentrated in vacuo to give a solid which was washed
by H2O (20 mL) and purified by FC (CH2Cl2–AcOEt
20:1ꢂ) to give a white solid (48 mg, 90%). Mp 206–
1
208 C. H NMR (200 MHz, DMSO-d6): 2.12 (s, Me),
6.99 (m, 2H-C(20, 60)), 7.61 (m, 3H-C(30, 50, 6)), 7.88

3926
Y.-L. Chen et al. / Bioorg. Med. Chem. 11 (2003) 3921–3927
(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 (50 MHz, 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,
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 (50 MHz, 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, 163.22. Anal. calcd for
.
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
(50 mg, 0.15 mmol) in ethanol (10 mL) was added 40%
C20H16N2O3 0.1H2O: C 71.89, H 4.89, N 8.38; found: C
71.87, H 5.03, N 8.14.
.
NH2OMe HCl aqueous (63 mg, 0.3 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 pale-yellow solid (50 mg, 90%). Mp
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.
140–141 ꢂC. H NMR (200 MHz, CDCl3): 2.19 (s, Me),
1
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 (50 MHz, 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, 0.34 g, 1 mmol) in MeOH–CH2Cl2
(1=1, 100 mL) was hydrogenated for 3 h (TLC monitor-
ing) under H2 with Lindlar catalyst (0.34 g). 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 ꢂC. 1H NMR (400 MHz, DMSO-d6): 2.59 (s,
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 (100 MHz, 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
References and Notes
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(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 ꢂC. 1H NMR (200 MHz,
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,
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J=2.6, H-C(2)), 8.06 (d, J=8.4, H-C(8)), 8.32 (d,
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124.85, 127.45 (2C), 127.87, 130.01, 133.86, 145.40,
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.
C19H14N2O3 0.4H2O: C 70.10, H 4.58, N 8.60; found: C
70.24, H 4.73, N 8.41.
(E)-1-[4-(Furo[2,3-b]quinolin-4-yloxy-phenyl]ethanone O-
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aqueous as described for 8b: 75% yield. Mp 149–151 ꢂC.
1H NMR (200 MHz, CDCl3): 2.26 (s, Me), 4.02 (s,

Y.-L. Chen et al. / Bioorg. Med. Chem. 11 (2003) 3921–3927
3927
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