Synthesis, cytotoxicity, and anti-inflammatory evaluation of 2-(furan-2-yl)-4-(phenoxy)quinoline derivatives. Part 4

Article abstract of DOI:10.1016/j.bmc.2006.02.039

A number of 2-(furan-2-yl)-4-phenoxyquinoline derivatives have been synthesized and evaluated for anti-inflammatory evaluation. 4-[(2-Furan-2-yl)quinolin-4-yloxy]benzaldehyde (8), with an IC₅₀ value of 5.0 μM against β-glucuronidase release, wa

Full text of DOI:10.1016/j.bmc.2006.02.039

Bioorganic & Medicinal Chemistry 14 (2006) 4373–4378
Synthesis, cytotoxicity, and anti-inflammatory evaluation of
2-(furan-2-yl)-4-(phenoxy)quinoline derivatives. Part 4
Yeh-Long Chen,a Yue-Ling Zhao,a Chih-Ming Lu,a
Cherng-Chyi Tzenga,* 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 26 January 2006; revised 20 February 2006; accepted 21 February 2006
Available online 9 March 2006
Abstract—A number of 2-(furan-2-yl)-4-phenoxyquinoline derivatives have been synthesized and evaluated for anti-inflammatory
evaluation. 4-[(2-Furan-2-yl)quinolin-4-yloxy]benzaldehyde (8), with an IC50 value of 5.0 lM against b-glucuronidase release,
was more potent than its tricyclic furo[2,3-b]quinoline isomer 3a (>30 lM), its 40-COMe counterpart 7 (7.5 lM), and its oxime
derivative 13a (11.4 lM) and methyloxime derivative 13b (>30 lM). For the inhibition of lysozyme release, however, oxime
derivative 12a (8.9 lM) and methyloxime derivative 12b (10.4 lM) are more potent than their ketone precursor 7 and their
respective tricyclic furo[2,3-b]quinoline counterparts 4a and 4b. Among them, 4-{4-[(2-furan-2-yl)-quinolin-4-yloxy]phenyl}but-
3-en-2-one (10) is the most active against lysozyme release with an IC50 value of 4.6 lM, while 8 is the most active against
b-glucuronidase release with an IC50 value of 5.0 lM. (E)-1-{3-[(2-Furan-2-yl)quinolin-4-yloxy]phenyl}ethanone oxime (11a) is
capable of inhibiting both lysozyme and b-glucuronidase release with IC50 values of 7.1 and 9.5 lM, respectively. For the inhi-
bition of TNF-a formation, 1-{3-[(2-furan-2-yl)quinolin-4-yloxy]phenyl}ethanone (6) is the most potent with an IC50 value of
2.3 lM which is more potent than genistein (9.1 lM). For the inhibitory activity of fMLP-induced superoxide anion generation,
11a (2.7 lM), 11b (2.8 lM), and 13b (2.2 lM) are three of the most active. None of above compounds exhibited significant
cytotoxicity.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
methyloxime 2b (Chart 1) exhibited cytotoxic activity
with mean GI50 values of 10.5, 6.85, and 20.6 lM,
respectively, while the mean GI50 values for their 4-
substituted counterparts 1b, 2c, and 2d are 4.36, 5.54,
and 5.99 lM, respectively.11 We have also synthesized
certain 9-anilinoacridine, 9-phenoxyacridine, 4-anilinof-
uro[2,3-b]quinoline, and 4-phenoxyfuro[2,3-b]quinoline
derivatives for anti-inflammatory evaluation.12–15 Some
Quinolin-4(1H)-one moiety is a characteristic compo-
nent of a large number of antibacterial and/or antican-
cer agents.1–5 The biological activity of these
quinolone derivatives depends not only on the bicyclic
heteroaromatic pharmacophore but also on the nature
of the peripheral substituents and their spatial relation-
ship. With a phenyl group appended on C-2 position of
quinolin-4(1H)-one, a number of 2-phenylquinolone
derivatives have been discovered to possess antimitotic
activity.6–8 Recently, we have synthesized certain 4-ani-
lino-2-phenylquinoline derivatives and their isomeric
4-anilino-2-(furan-2-yl)quinolines for anticancer evalua-
tion.9–11 Among them, 1-(3-{2-[(furan-2-yl)quino-
lin-4-yl]amino}phenyl)-ethanone 1a, its oxime 2a and
OR
3
3
N
O
4
4
Me
Me
HN
N
HN
N
O
O
2a 3-substituted, R = H
2b 3-substituted, R = Me
2c 4-substituted, R = H
2d 4-substituted, R = Me
1a 3-substituted
1b 4-substituted
Keywords: Quinoline; 2-(Furan-2-yl)-4-phenoxyquinoline; Anti-inflam-
matory activity.
*
Corresponding author. Tel.: +886 7 3121101 ext 6985; fax: +886 7
3125339; e-mail: tzengch@kmu.edu.tw
Chart 1. Structures of 4-anilino-2-(furan-2-yl)quinoline derivatives.
0968-0896/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.02.039

4374
Y.-L. Chen et al. / Bioorg. Med. Chem. 14 (2006) 4373–4378
of them were found to be more potent than the calmod-
ulin inhibitor trifluoperazine, which inhibits the degran-
ulation and superoxide anion generation in neutrophils.
To explore more potent anti-inflammatory agents and to
establish structure–activity relationships, we described
herein the synthesis and anti-inflammatory evaluation
of 2-(furan-2-yl)-4-phenoxyquinoline derivatives whose
structures belong to isomers of 4-phenoxyfuro[2,3-
b]quinolines (Chart 2). Although 2-(furan-2-yl)quinoline
skeleton is not a system with three fused aromatic rings,
its third furan ring is appended at C(2), which can
accommodate itself in a virtually coplanar fashion to
the tricyclic furo[2,3-b]quinoline.16
NCI-H460, and SF-268) because highly cytotoxic agents
will hardly be developed as anti-inflammatory drug
candidates.
2. Chemistry
Preparation
of
2-(furan-2-yl)-4-phenoxyquinoline
derivatives is outlined in the Scheme 1. The known
4-chloro-2-(furan-2-yl)quinoline (5)11 was treated with
3-hydroxyacetophenone to afford 1-{3-[(2-furan-2-
yl)quinolin-4-yloxy]phenyl}ethanone (6), which was
then reacted with hydroxylamine or methylhydroxyl-
amine to give exclusively (E)-1-{3-[(2-furan-2-yl)-quino-
lin-4-yloxy]phenyl}ethanone oxime (11a) or its methyl
derivative 11b, respectively. Accordingly, compounds
7–10, respectively, were obtained from 5 by the treat-
ment with substituted phenols. Reaction of 7 and 8,
respectively, with NH2OH or NH2OMe provided their
respective (E)-oximes 12a, 13a and (E)-methyloximes
12b, 13b in a good overall yield. The configuration of
the oxime moiety was determined by through-space
nuclear Overhauser effect spectroscopy (NOESY) which
revealed coupling connectivity to CH3 protons. We have
also confirmed the configuration of the oxime and meth-
yloxime moieties by the 13C NMR spectra. The carbon
of CH3 which is syn to the OR0 moiety (E-form) shifted
upfield (d 11.86 ppm for (E)-11a, 12.49 for (E)-11b,
12.40 for (E)-12a, and 12.65 for (E)-12b), while that of
the anti isomer (Z-form) shifted downfield (d value of
CH3 is 11.50 ppm for the syn isomer and 18.75 ppm
for the anti isomer of butan-2-one oxime).17
Due to structural similarity between 2-(furan-2-yl)-4-
phenoxyquinolines and their isomeric 4-anilino-2-(fur-
an-2-yl)quinoline (Chart 1), newly synthesized
compounds were also evaluated for their cytotoxicity
against three representative cancer cell lines (MCF7,
OR
N
O
Me
R
O
O
O
N
O
N
4a R = H
4b R = Me
3a R = H
3b R = Me
Chart 2. Structures of 4-phenoxyfuro[2,3-b]quinoline derivatives.
O
Me
O
Cl
N
(i)
N
O
10
O
5
O
(i)
(i)
(i)
O
Me
R
O
Me
O
N
O
N
O
N
O
9
O
O
6
7 R = Me
8 R = H
(ii)
OR'
N
(ii)
Me
R
O
12a R = Me, R' = H
12b R = R' = Me
13a R = R' = H
O
N
OR'
N
13b R = H, R' = Me
O
N
11a R' = H
O
11b R' = Me
Scheme 1. Reagents and conditions: (i) 3- or 4-substituted phenol, K2CO3, acetone or THF in scaled bomb, 150 °C for 24 h (51–68%); (ii) NH2OR,
K2CO3, EtOH, reflux for 0.5 h (61–70%).

Y.-L. Chen et al. / Bioorg. Med. Chem. 14 (2006) 4373–4378
4375
a,b
Table 1. IC50
derivatives against neutrophil degranulation
(lM) values of 2-(furan-2-yl)-4-phenoxyquinoline
3. Pharmacological results and discussion
3.1. Neutrophil degranulation
Compound
Neutrophil degranulationc
Lysozyme
b-Glucuronidase
Activation of neutrophils with 1 lM formyl-methionyl-
leucyl-phenylalanine (fMLP) in the presence of cytocha-
lasin B (5 lg/mL) evoked the release of 21.2% and
19.8% of lysozyme and b-glucuronidase, respectively, of
the initial cellular content. 4-[(2-Furan-2-yl)quinolin-4-
yloxy]benzaldehyde (8), with an IC50 value of 5.0 lM
against b-glucuronidase release, was more potent than
its tricyclic furo[2,3-b]quinoline isomer 3a (>30 lM), its
40-COMe counterpart 7 (7.5 lM), and its oxime deriva-
tive 13a (11.4 lM) and methyloxime derivative 13b
(>30 lM), and the calmodulin inhibitor, trifluoperazine
(17.0 lM) which inhibits the degranulation and superox-
ide anion generation in neutrophils.18,19 The same SAR
was observed in which 7 is more active against b-glucu-
ronidase release than its tricyclic furo[2,3-b]quinoline iso-
mer 3b (>30 lM), its meta-isomer 6 (>30 lM), and its
oxime derivative 12a (>30 lM) and methyloxime deriva-
tive 12b (>30 lM), and the double bond inserted deriva-
tive 10 (17.0 lM). For the inhibition of lysozyme
release, oxime derivative 12a (with an IC50 value of
8.9 lM) and methyloxime derivative 12b (10.4 lM) are
more potent than their ketone precursor 7 (>30 lM)
and their respective tricyclic furo[2,3-b]quinoline counter-
parts 4a (>30 lM) and 4b (>30 lM). The same SAR was
observed in which oxime derivative 11a (7.1 lM) was
more potent than its ketone precursor 6 (>30 lM) and
the positive trifluoperazine (8.3 lM). Insertion of a dou-
ble bond between phenyl group and the carbonyl moiety
led to more potent activity against lysozyme release but
less potent against b-glucuronidase release (10 vs 7). Sat-
uration of the double bond led to the decrease of both
activities (10 vs 9). Among them, 4-{4-[(2-furan-2-
yl)quinolin-4-yloxy]- phenyl}but-3-en-2-one (10) is the
most active against lysozyme release with an IC50 value
of 4.6 lM, while 8 is the most active against b-glucuroni-
dase release with an IC50 value of 5.0 lM. (E)-1-{3-[(2-
6
>30 (47.5 6.2)**
>30 (38.0 9.4)**
>30 (34.3 4.5)**
10.1 3.0
>30 (38.5 4.6)**
7.5 2.9
5.0 0.9
>30 (49.5 11.0)**
17.0 2.3
7
8
9
10
4.6 0.7
7.1 0.3
>30 (47.1 10.5)**
8.9 2.3
10.4 0.6
11a
11b
9.5 3.9
>30 (42.4 4.6)**
>30 (36.8 4.4)**
>30 (41.8 8.9)**
11.4 2.6
12a
12b
13a
13b
24.5 2.7
>30 (24.1 11.8)*
8.3 1.4
>30 (19.5 5.7)*
17.0 2.3
Trifluoperazine
a Values are means SE of at least three independent experiments.
b When 50% inhibition could not be reached at the highest concen-
tration, the percentage of inhibition is given in parentheses.
c Induced by fMLP (1 lM)/cytochalasin B (5 lg/mL).
* P < 0.05.
** P < 0.01.
Table 2. IC50 values of 2-(furan-2-yl)-4-phenoxyquinoline derivative
on TNF-a formation and nitric oxide production in RAW 264.7 cells
a
Compound
IC50 (lM)
TNF-a formationb
Nitric oxide productionb
6
2.3 0.3
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
ndd
7
8
9
10
>30
>30
11a
11b
>30
>30
12a
12b
>30
>30
13a
13b
>30
>30
Genistein
1400Wc
9.1 0.6
nd
7.2 2.5
a Values are means SE of at least three independent experiments.
b Induced by LPS (1 lg/mL).
Furan-2-yl)quinolin-4-yloxy]phenyl}ethanone
oxime
(11a) is capable of inhibiting both lysozyme and b-glucu-
ronidase release with IC50 values of 7.1 and 9.5 lM,
respectively (see Table 1).
c N-(3-Aminomethyl)benzylacetamidine 2HCl.
d Not determined.
of superoxide dismutase-inhibitable cytochrome
c
3.2. TNF-a release
reduction.20,21 As shown in Table 3, compounds 11a
and 11b had potent inhibitory effects on fMLP-induced
superoxide anion generation with IC50 values of 2.7 and
2.8 lM, respectively, while their para-substituted coun-
terparts 12a and 12b were inactive. The same SAR
was observed in which meta-COMe-substituted deriva-
tive 6 (6.7 lM) is more potent than its para-substituted
counterpart 7 (12.3 lM). The inhibitory activity of
fMLP-induced superoxide anion generation decreased
in the order of 13b (2.2 lM) > 8 (5.9 lM) > 7
(12.3 lM) indicates a methyloxime is more favorable
than an aldehyde which in turn is more favorable than
a ketone substituent at para-position of the phenoxy
moiety. The same SAR was observed in which meta-
methyloxime-substituted derivative 11b (2.8 lM) is
more potent than its ketone-substituted counterpart 6
(6.7 lM). Insertion of a double bond between phenyl
TNF-a, an early cytokine produced by activated macro-
phages, plays an essential role in pathological inflamma-
tory reactions. 1-{3-[(2-Furan-2-yl)quinolin-4-yloxy]-
phenyl}ethanone (6), with an IC50 value of 2.3 lM
against TNF-a formation in macrophage-like cell line
RAW 264.7, was more potent than positive genistein
(9.1 lM) and its congeners 7 – 13 which were inactive
(>30 lM) (Table 2).
3.3. Superoxide formation
In the superoxide anion generation experiments, neutro-
phils were stimulated with fMLP (0.3 lM)/cytochalasin
B (5 lg/mL) or phorbol 12-myristate 13-acetate (PMA;
3 nM) for 10 min in the presence of cytochrome c, and
the superoxide anion generation was measured in terms

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Y.-L. Chen et al. / Bioorg. Med. Chem. 14 (2006) 4373–4378
a
Table 3. IC50 (lM) values of 2-(furan-2-yl)-4-phenoxyquinoline
derivatives against neutrophil superoxide formation
Table 4. Cytotoxicity of 2-(furan-2-yl)-4-phenoxyquinoline derivatives
Compound
Growth percentagea
Compound
Superoxide formation (nmol)
MCF7
(breast
cancer)
NCI-H460
(lung
cancer)
SF-268
(CNS
cancer)
Mean GI50
(lM)b,c
fMLPb
PMAc
6
6.7 0.6
12.3 0.1
5.9 0.9
5.9 1.1
11.3 1.6
2.7 0.7
2.8 0.8
>30
>30
>30
>30
>30
>30
>30
7
1a
1b
2a
2b
2c
11
2
1
1
17
19
10.5
4.36
6.85
20.6
5.54
5.99
ndd
nd
8
9
10
25
50
88
83
66
78
73
55
56
61
97
80
93
87
0
26
98
17
1
11a
11b
12a
12b
13a
13b
DPId
81
7.1 1.2
2d
6
17
38
49
78
28
37
40
90
44
55
80
111
46
>30
>30
>30
>30
7
66
91
17.5 1.1
2.2 0.4
1.3 0.2
8
nd
nd
7.2 2.2
1.4 0.7
9
85
39
11a
11b
12a
12b
13a
13b
nd
nd
41
a Values are means SE of at least three independent experiments.
b Induced by fMLP (0.3 lM)/cytochalasin B (5 lg/ml).
c Induced by PMA (3 nM).
114
62
nd
nd
94
114
nd
nd
d Diphenylene iodonium chloride.
a In this protocol, each cell line is inoculated and preincubated on a
microtiter plate. Test agents are then added at a single concentration
(100 lM) and the culture incubated for 48 h. End-point determina-
tions are made with alamar blue.23 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.
b Data obtained from NCI’s in vitro disease-oriented tumor cell
screen.24 GI50: drug molar concentration causing 50% cell growth
inhibition.
group and the carbonyl moiety does not enhance the
inhibitory effect (10 vs 7). Saturation of the double bond
led to the increase of inhibitory activity (9 > 10). Among
them, only 11b and 13b are active on the inhibitory effect
of PMA-induced superoxide anion generation in rat
neutrophils. Because fMLP and PMA activate NADPH
oxidase to produce superoxide anion through different
cellular signaling mechanisms.22 No appreciable effect
of 6–10, 11a, and 13a on PMA-induced response
suggests the involvement of PMA-independent signaling
pathway.
c Mean values over all 60 cell lines tested.
d Not determined.
3.4. Preliminary cytotoxic evaluation
idase release in neutrophils with IC50 values of 5.0 and
7.5 lM, respectively, while their respective tricyclic 4-
phenoxyfuro[2,3-b]quinoline isomers 3a and 3b were
inactive (>30 lM) indicating that the 2-(furan-2-yl)quin-
oline skeleton is more favorable than the tricyclic
furo[2,3-b]quinoline heterocycle to be developed as
anti-inflammatory agents. The same SAR was observed
for the inhibition of lysozyme release in which 2-(furan-
2-yl)quinolines 12a and 12b are potent inhibitors, while
their respective furo[2,3-b]quinoline counterparts 4a and
4b are inactive. These results are interesting because
none of the synthesized (2-furan-2-yl)-4-phenoxyquino-
line derivatives exhibited significant cytotoxicity.
All the synthesized (2-furan-2-yl)quinoline derivatives
were evaluated in vitro against a 3-cell line panel consist-
ing 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 lM) and the culture
incubated for 48 h. End-point determinations are made
with alamar blue.23 Results for each test agent were
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 considered to be cytotoxic. According
to these criteria, 4-phenoxy derivative 6, its oxime 11a
and methyloxime 11b are considered as non-cytotoxic
(Table 4). However, strong cytotoxicity demonstrated
by their respective 4-anilino counterparts 1a, 2a, and 2b
indicated that the bridged atom between quinoline and
phenyl group is crucial in which the nitrogen is more
favorable than the oxygen. The same SAR was observed
in which oxygen-bridged compounds 7, 12a, and 12b are
non-cytotoxic, while their respective nitrogen-bridged
counterparts 1b, 2c, and 2d are cytotoxic agents.
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). All chromatographic separations were per-
formed using silica gel (Merck 60 230–400 mesh). Mp:
Electrothermal IA9100 melting point apparatus; uncor-
rected. 1H and 13C NMR spectra: Varian-Unity-400
spectrometer at 400 and 100 MHz, chemical shifts d in
ppm with SiMe4 as an internal standard (=0 ppm), cou-
pling constants J in Hz. Elemental analyses were carried
4. Conclusion
(2-Furan-2-yl)-4-phenoxyquinoline derivatives 7 and 8
exhibited potent inhibitory activities against b-glucuron-

Y.-L. Chen et al. / Bioorg. Med. Chem. 14 (2006) 4373–4378
4377
out on a Heraeus CHN-O-Rapid elemental analyzer,
and results were within 0.4% of calculated values.
152.76, 153.58, 162.23, 208.62. Anal. Calcd for
C23H19NO3: C, 77.28; H, 5.37; N, 3.92. Found: C,
77.00; H, 5.43; N, 3.85.
5.1.1. 1-{3-[(2-Furan-2-yl)quinolin-4-yloxy]phenyl}etha-
none (6). A mixture of 4-chloro-2-(furan-2-yl)quinoline11
(5, 0.46 g, 2 mmol), 4-hydroxyacetophenone (0.27 g,
2 mmol), K2CO3 (0.41 g, 3 mmol), and acetone
(60 mL) was heated in a sealed steel bomb at 150 °C
for 24 h (TLC monitoring). The resulting mixture was
evaporated under reduced pressure and then H2O
(100 mL) was added. The precipitate was collected,
washed with H2O, and purified by flash column chroma-
tography (FC, silica gel; MeOH/CH2Cl2 = 1/20) to give
6 (0.44 g, 67%). Mp 109–111 °C. 1H NMR (CDCl3):
2.63 (3H, s, COCH3), 6.51 (1H, dd, J = 3.6, 1.8 Hz, 40-
H), 6.98 (1H, s, 3-H), 7.13 (1H, dd, J = 3.6, 0.8 Hz,
Ar-H), 7.39–7.63 (4H, m, Ar-H), 7.71–7.93 (3H, m,
Ar-H), 8.12 (1H, m, 5-H), 8.28 (1H, m, 8-H). 13C
NMR (CDCl3): 26.70, 100.85, 110.18, 112.20, 120.53,
121.55, 122.15, 125.34, 125.48, 125.93, 129.00, 130.55,
130.65, 139.39, 143.90, 149.74, 149.91, 153.34, 154.92,
161.71, 196.92. Anal. Calcd for C21H15NO3: C, 76.57;
H, 4.60; N, 4.25. Found: C, 76.47; H, 4.83; N, 4.10.
5.1.5. 4-{4-[(2-Furan-2-yl)quinolin-4-yloxy]phenyl}but-3-
en-2-one (10). Obtained from 5 and 4-hydroxybenzylide-
neacetone as described for 6 in 57% yield. Mp 126–
128 °C. H NMR (CDCl3): 2.35 (3H, s, COCH3), 6.51
1
(1H, dd, J = 3.4, 2.0 Hz, 40-H), 6.63 (1H, d, J = 16.0
Hz, CH@CH(C@O)CH3), 6.95 (1H, s, 3-H), 7.06–7.13
(3H, m, 50-, ArH), 7.29 (2H, m, ArH), 7.43–7.54 (3H,
m, 30-, 6-H, and CH@CH(C@O)CH3), 7.72 (1H, m, 7-
H), 8.03 (1H, d, J = 8.6 Hz, 5-H), 8.31 (1H, m, 8-H).
13C NMR (CDCl3): 27.86, 100.42, 108.51, 110.19,
112.22, 120.71, 120.91 (2C), 121.65, 125.84, 128.38,
130.19 (2C), 130.44, 138.38, 143.77, 144.09, 149.58,
150.14, 152.24, 153.79, 162.33, 198.68. Anal. Calcd for
C23H17NO3: C, 77.73; H, 4.82; N, 3.94. Found: C,
77.59; H, 4.79; N, 3.64.
5.1.6.
(E)-1-{3-[(2-Furan-2-yl)quinolin-4-yloxy]phen-
yl}ethanone oxime (11a). To a suspension of 6 (0.17 g,
0.5 mmol) in EtOH (10 mL) were added NH2OHÆHCl
(0.18 g, 2.5 mmol) and potassium carbonate (0.16 g,
1.3 mmol). The reaction mixture was refluxed for 2 h
(TLC monitoring). After cooling, the solvent was re-
moved in vacuo and the residue was suspended in ice
water (20 mL). The precipitate obtained was collected
and crystallized from MeOH to give 11a (0.12 g, 70 %).
Mp 186–187 °C. 1H NMR (CDCl3): 2.28 (3H, s,
N@CCH3), 6.52 (1H, dd, J = 3.8, 1.8 Hz, 40-H), 7.01
(1H, s, 3-H), 7.20 (2H, m, 30-, Ar-H), 7.45–7.62 (5H,
m, 50-, 6-, Ar-H), 7.76 (1H, m, 7-H), 8.11 (1H, d,
J = 8.0 Hz, 5-H), 8.31 (1H, dd, J = 8.4, 1.4 Hz, 8-H),
10.44 (1H, br s, NOH).13C NMR (CDCl3): 11.86,
100.62, 110.25, 112.10, 118.40, 120.45, 121.10, 121.55,
123.12, 125.76, 128.06, 130.05, 130.63, 139.45, 143.83,
149.25, 149.90, 152.32, 152.85, 154.33, 162.14. Anal.
Calcd for C21H16N2O3Æ0.3H2O: C, 72.10; H, 4.79; N,
8.01. Found: C, 72.24; H, 4.90; N, 7.93.
5.1.2. 1-{4-[(2-Furan-2-yl)quinolin-4-yloxy]phenyl}etha-
none (7). Obtained from 5 and 4-hydroxyacetophenone
as described for 6 in 65% yield. Mp 156–157 °C. 1H
NMR (CDCl3): 2.65 (3H, s, COCH3), 6.54 (1H, dd,
J = 3.2, 1.6 Hz, 40-H), 7.13 (1H, s, 3-H), 7.27 (3H,
m, 30-H, Ar-H), 7.54 (2H, m, 50-, 6-H), 7.77 (1H, m,
7-H), 8.08 (2H, m, Ar-H), 8.21 (2H, m, 5-, 8-H).
13C NMR (CDCl3): 26.55, 102.08, 110.93, 112.40,
115.77, 120.08 (2C), 120.60, 121.59, 126.20, 128.73,
130.52, 130.89 (2C), 130.95, 134.16, 144.23, 149.69,
158.80, 196.65. Anal. Calcd for C21H15NO3: C,
76.57; H, 4.60; N, 4.25. Found: C, 76.41; H, 4.64;
N, 4.27.
5.1.3.
4-[(2-Furan-2-yl)quinolin-4-yloxy]benzaldehyde
(8). Obtained from 5 and 4-hydroxybenzaldehyde in
THF as described for 6 in 51% yield. Mp 107–
109 °C. 1H NMR (CDCl3): 6.54 (1H, dd, J = 3.2,
1.6 Hz, 40-H), 7.18 (2H, m, 3-, 30-H), 7.33 (2H, m,
Ar-H), 7.54 (2H, m, 50-, 6-H), 7.77 (1H, m, 7-H),
8.00 (2H, m, Ar-H), 8.17 (2H, m, 5-, 8-H), 10.04
(1H, s, CHO). 13C NMR (CDCl3): 102.32, 112.34,
112.78 (2C), 116.42, 120.56, 121.68, 122.41, 126.64,
127.46, 129.83, 131.52, 132.02, 132.28 (2C), 133.60,
144.48, 144.73, 159.81, 190.64. Anal. Calcd for
C20H13NO3: C, 76.17; H, 4.16; N, 4.44. Found: C,
76.03; H, 4.34; N, 4.33.
5.1.7.
(E)-1-{3-[(2-Furan-2-yl)quinolin-4-yloxy]phen-
yl}ethanone O-methyloxime (11b). Obtained from 6 and
NH2OMeÆHCl as described for 11a: 66% yield. Mp
1
63–64 °C. H NMR (CDCl3): 2.24 (3H, s, N@CCH3),
3.99 (3H, s, NOCH3), 6.51 (1H, dd, J = 3.6, 1.6 Hz, 40-
H), 6.99 (1H, s, 3-H), 7.09 (1H, d, J = 3.6 Hz, 30-H),
7.21 (1H, ddd, J = 7.6, 2.6, 1.2 Hz, Ar-H), 7.44–7.64
(5H, m, 50-, 6-, Ar-H), 7.74 (1H, m, 7-H), 8.11 (1H, d,
J = 8.4 Hz, 5-H), 8.30 (1H, dd, J = 8.4, 1.0 Hz, 8-
H).13C NMR (CDCl3): 12.49, 62.08, 100.76, 110.01,
112.10, 118.60, 120.65, 121.36, 121.67, 123.12, 125.74,
129.04, 130.14, 130.44, 139.19, 143.78, 149.80, 150.01,
153.43, 153.61, 154.65, 162.00. Anal. Calcd for
C22H18N2O3Æ0.3H2O: C, 72.62; H, 5.16; N, 7.70. Found:
C, 72.73; H, 5.06; N, 7.82.
5.1.4. 4-{4-[(2-Furan-2-yl)quinolin-4-yloxy]phenyl}butan-
2-one (9). Obtained from 5 and 4-hydroxybenzylacetone
as described for 6 in 52% yield. Mp 137–138 °C. 1H
NMR (CDCl3): 2.18 (3H, s, COCH3), 2.82, 2.94 (4H,
two m, CH2CH2CO), 6.51 (1H, dd, J = 3.4, 2.0 Hz, 40-
H), 6.98 (1H, s, 3-H), 7.14 (3H, m, 30-, ArH), 7.28
(2H, m, ArH), 7.51 (2H, m, 50-, 6- H), 7.73 (1H, m, 7-
H), 8.011 (1H, d, J = 8.6 Hz, 5-H), 8.29 (1H, m, 8-H).
13C NMR (CDCl3): 29.13, 30.04, 44.98, 100.55, 110.06,
112.10, 120.68, 120.88 (2C), 121.69, 125.68, 128.93,
130.05 (2C), 130.41, 138.30, 143.77, 149.66, 149.93,
5.1.8.
(E)-1-{4-[(2-Furan-2-yl)quinolin-4-yloxy]phen-
yl}ethanone oxime (12a). Obtained from 7 and NH2O-
HÆHCl as described for 11a: 65% yield. Mp 249–
250 °C. 1H NMR (CDCl3): 2.34 (3H, s, N@CCH3),
6.56 (1H, dd, J = 3.6, 1.4 Hz, 40-H), 7.06 (1H, s, 3-H),
7.19 (1H, d, J = 3.6 Hz, 30-H), 7.25 (2H, m, Ar-H),

4378
Y.-L. Chen et al. / Bioorg. Med. Chem. 14 (2006) 4373–4378
7.57 (2H, m, 50-, 6-H), 7.75–7.84 (3H, m, 7-, Ar-H), 8.10
(1H, d, J = 8.8 Hz, 5-H), 8.33 (1H, dd, J = 8.4, 1.4 Hz,
8-H), 10.81 (1H, br s, NOH). 13C NMR (CDCl3):
12.40, 101.19, 111.44, 112.94, 121.05, 121.34 (2C),
122.36, 126.70, 127.95, 128.68 (2C), 131.73, 135.40,
144.96, 150.41, 152.42, 152.91, 155.10, 155.23, 163.18.
Anal. Calcd for C21H16N2O3Æ0.3H2O: C, 72.10; H,
4.79; N, 8.01. Found: C, 72.05; H, 4.74; N, 8.01.
edged. 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.
References and notes
1. Fang, K. C.; Chen, Y. L.; Sheu, J. Y.; Wang, T. C.; Tzeng,
C. C. J. Med. Chem. 2000, 43, 3809.
2. Chen, Y. L.; Fang, K. C.; Sheu, J. Y.; Hsu, S. L.; Tzeng,
C. C. J. Med. Chem. 2001, 44, 2374.
3. Tzeng, C. C.; Chen, Y. L. Chin. Pharm. J. 2002, 54, 229.
4. Sheu, J. Y.; Chen, Y. L.; Tzeng, C. C.; Hsu, S. L.;
Fang, K. C.; Wang, T. C. Helv. Chim. Acta 2003, 86,
2481.
5. Zhao, Y. L.; Chen, Y. L.; Sheu, J. Y.; Chen, I. L.; Wang,
T. C.; Tzeng, C. C. Bioorg. Med. Chem. 2005, 13, 3921.
6. Chen, K.; Kuo, S. C.; Hsieh, M. C.; Mauger, A.; Lin,
C. M.; Hamel, E.; Lee, K. H. J. Med. Chem. 1997, 40,
3049.
5.1.9.
(E)-1-{4-[(2-Furan-2-yl)quinolin-4-yloxy]phen-
yl}ethanone O-methyloxime (12b). Obtained from 7 and
NH2OMeÆHCl as described for 11a: 68% yield. Mp
111–112 °C. 1H NMR (CDCl3): 2.28 (3H, s, N@CCH3),
4.03 (3H, s, NOCH3), 6.52 (1H, dd, J = 3.6, 1.6 Hz, 40-
H), 7.03 (1H, s, 3-H), 7.14 (1H, d, J = 3.6 Hz, 30-H),
7.22 (2H, m, Ar-H), 7.52 (2H, m, 50-, 6-H), 7.72–7.80
(3H, m, 7-, Ar-H), 8.12 (1H, d, J = 8.4 Hz, 5-H), 8.28
(1H, dd, J = 8.4, 1.4 Hz, 8-H). 13C NMR (CDCl3):
12.65, 62.04, 100.90, 110.27, 112.21, 120.62, 120.81
(2C), 121.70, 125.86, 128.07 (2C), 128.93, 130.62,
133.99, 143.96, 149.66, 149.95, 153.38, 153.80, 155.23,
161.92. Anal. Calcd for C22H18N2O3: C, 73.72; H,
5.07; N, 7.82. Found: C, 73.67; H, 5.20; N, 7.68.
7. Nakamura, S.; Kozuka, M.; Bastow, K. F.; Tokuda, H.;
Nishino, H.; Suzuki, M.; Tatsuzaki, J.; Natschke, S. L.
M.; Kuo, S. C.; Lee, K. H. Bioorg. Med. Chem. 2005, 13,
4396.
5.1.10. (E)-4-[(2-Furan-2-yl)quinolin-4-yloxy]benzalde-
hyde oxime (13a). Obtained from 8 and NH2OHÆHCl
as described for 11a: 61% yield. Mp 201–202 °C. 1H
NMR (CDCl3): 6.53 (1H, dd, J = 3.6, 2.0 Hz, 40-H),
7.06 (1H, s, 3-H), 7.18 (1H, d, J = 3.6 Hz, 30-H), 7.25
(2H, m, Ar-H), 7.55 (2H, m, 50-, 6-H), 7.73 (2H, m,
Ar-H), 7.78 (1H, m, 7-H), 8.10 (1H, d, J = 8.8 Hz, 5-
H), 8.20 (1H, s, N@CH), 8.30 (1H, dd, J = 8.4, 1.2 Hz,
8-H), 10.80 (1H, br s, NOH). 13C NMR (CDCl3):
101.21, 110.72, 112.54, 120.76, 121.29 (2C), 121.91,
126.23, 128.27, 129.06 (2C), 130.38, 131.15, 144.33,
148.86, 149.57, 150.23, 153.01, 155.59, 162.25. Anal.
Calcd for C20H14N2O3Æ0.3H2O: C, 71.54; H, 4.39; N,
8.34. Found: C, 71.48; H, 4.54; N, 7.96.
8. Lai, Y. Y.; Huang, L. J.; Lee, K. H.; Xiao, Z.; Bastow, K.
F.; Yamori, T.; Kuo, S. C. Bioorg. Med. Chem. 2005, 13,
265.
9. Zhao, Y. L.; Chen, Y. L.; Chang, F. S.; Tzeng, C. C. Eur.
J. Med. Chem. 2005, 40, 792.
10. Chen, Y. L.; Huang, C. J.; Huang, Z. Y.; Tseng, C. H.;
Chang, F. S.; Yang, S. H.; Lin, S. R.; Tzeng, C. C. Bioorg.
Med. Chem. 2006, 14, in press.
11. Zhao, Y. L.; Chen, Y. L.; Tzeng, C. C.; Chen, I. L.; Wang,
T. C.; Han, C. H. Chem. Biodiver. 2005, 2, 205.
12. Chen, Y. L.; Lu, C. M.; Chen, I. L.; Tsao, L. T.; Wang, J.
P. J. Med. Chem. 2002, 45, 4689.
13. Chen, Y. L.; Chen, I. L.; Lu, C. M.; Tzeng, C. C.; Tsao, L.
T.; Wang, J. P. Bioorg. Med. Chem. 2003, 11, 3921.
14. Chen, Y. L.; Chen, I. L.; Lu, C. M.; Tzeng, C. C.; Tsao, L.
T.; Wang, J. P. Bioorg. Med. Chem. 2004, 12, 387.
15. Kuan, Y. H.; Lin, R. H.; Tsao, L. T.; Chen, Y. L.; Tzeng,
C. C.; Wang, J. P. Biochem. Pharmacol. 2005, 70, 901.
16. Atwell, G. J.; Bos, C. D.; Baguley, B. C.; Denny, W. A. J.
Med. Chem. 1988, 31, 1048.
5.1.11. (E)-4-[(2-Furan-2-yl)quinolin-4-yloxy]benzalde-
hyde O-methyloxime (13b). Obtained from 8 and NH2O-
MeÆHCl as described for 11a: 63% yield. Mp 122–
1
123 °C. H NMR (CDCl3): 4.00 (3H, s, NOCH3), 6.52
17. Silverstein, R. M.; Webster, F. X. 13C NMR Spectrom-
etry. In Spectrometric Identification of Organic Com-
pounds; Rose, N., Ed.; John Wiley: New York, 1998; pp
217–249.
18. Smith, R. J.; Bowman, B. J.; Iden, S. S. Immunology 1981,
44, 677.
19. Ochs, D. L.; Reed, P. W. Biochem. Biophys. Res. Commun.
1981, 102, 958.
20. Market, M.; Andrew, P. C.; Babior, B. M. Methods
Enzymol. 1984, 105, 358.
(1H, dd, J = 3.4, 1.8 Hz, 40-H), 7.05 (1H, s, 3-H), 7.17
(1H, d, J = 3.4 Hz, 30-H), 7.22 (2H, m, Ar-H), 7.52
(2H, m, 50-, 6-H), 7.68–7.79 (3H, m, 7-, Ar-H), 8.11
(1H, s, N@CH), 8.14 (1H, d, J = 8.0 Hz, 5-H), 8.27
(1H, dd, J = 8.6, 1.2 Hz, 8-H). 13C NMR (CDCl3):
62.13, 101.08, 110.47, 112.26, 120.58, 121.08 (2C),
121.67, 125.97, 128.86, 129.00 (2C), 129.61, 130.73,
144.05, 147.48, 149.86, 150.14, 153.22, 155.77, 161.80.
Anal. Calcd for C21H16N2O3: C, 73.23; H, 4.69; N,
8.14. Found: C, 73.28; H, 4.74; N, 8.06.
21. Wang, J. P.; Tsao, L. T.; Raung, S. L.; Lin, P. L.; Lin, C.
N. Free Radic. Biol. Med. 1999, 26, 580.
22. Segal, A. W.; Abo, A. Trends Biochem. Sci. 1993, 18, 43.
23. Gray, G. D.; Wickstrom, E. Biotechniques 1996, 21, 780.
24. Monks, A.; Scuderio, D.; Skehan, P.; Shoemaker, R.;
Paull, K.; Vistica, D.; Hose, C.; Langlay, J.; Cronise, P.;
Vaigro-Wolff, A.; Gray-Goodrich, M.; Campbell, H.;
Mayo, J.; Boyd, M. J. Natl. Cancer Inst. 1991, 83, 757.
Acknowledgments
Financial support of this work by the National Science
Council of the Republic of China is gratefully acknowl-