Synthesis and Cytotoxic and Antiplatelet Activities of Dibenzofuran- and Carbazole-Substituted Oximes

Article abstract of DOI:10.1002/hlca.200490091

The dibenzofuran- and carbazole-substituted oximes or methyloximes 5-10 were prepared and evaluated for their cytotoxic and antiplatelet activities. These compounds were synthesized via alkylation of dibenzofuran-2-ol or 9H-carbazol-2-ol with α-halocarbonyl reagents, followed by reaction with NH₂OH or NH₂OMe (Scheme). A preliminary anticancer assay indicated that the oxime-type dibenzofuran derivatives 5 and 7a-d are active, while the corresponding oxime ethers 9h and 9c are inactive at the same concentration. Therefore, a H-bond-donating group seems to be crucial for cytotoxicity. Among the compounds tested, 2-[(dibenzo[b,d]-furan-2-yl)oxy]-1-(4-methoxyphenyl)ethan-1-one O-methyloxime (9c) exhibited potent inhibitory activity against platelet aggregation induced by arachidonic acid, with an IC₅₀ value of 14.87 μM, without being cytotoxic at a concentration of 100 μM.

Full text of DOI:10.1002/hlca.200490091

Helvetica Chimica Acta Vol. 87(2004)
983
Synthesis and Cytotoxic and Antiplatelet Activities of Dibenzofuran- and
Carbazole-Substituted Oximes
by Tai-Chi Wang*, I-Li Chen, and Daih-Huang Kuo
Department of Pharmacy, Tajen Institute of Technology, Pingtung, Taiwan
(phone: ‡886-8-7624004 ext. 316; fax: ‡886-8-7625308; e-mail: tcwang@ccsun.tajen.edu.tw)
and Chang-Hui Liao
Graduate Institute of Natural Products, Chang-Gung University, Tao-Yuan, Taiwan
The dibenzofuran- and carbazole-substituted oximes or methyloximes 5 10 were prepared and evaluated
for their cytotoxic and antiplatelet activities. These compounds were synthesized via alkylation of dibenzofuran-
2-ol or 9H-carbazol-2-ol with a-halocarbonyl reagents, followed by reaction with NH2OH or NH2OMe
(Scheme). A preliminary anticancer assay indicated that the oxime-type dibenzofuran derivatives 5 and 7a
d
are active, while the corresponding oxime ethers 9b and 9c are inactive at the same concentration. Therefore, a
H-bond-donating group seems to be crucial for cytotoxicity. Among the compounds tested, 2-[(dibenzo[b,d]-
furan-2-yl)oxy]-1-(4-methoxyphenyl)ethan-1-one O-methyloxime (9c) exhibited potent inhibitory activity
against platelet aggregation induced by arachidonic acid, with an IC50 value of 14.87 mm, without being cytotoxic
at a concentration of 100 mm.
1. Introduction. Although DNA intercalators exhibit a wide range of biological
activities, their anticancer properties have attracted the most attention [1 4].
Extensive SAR (structure/activity relationship) studies with DNA-intercalating
chromophores have revealed a positive correlation between the strength of reversible
DNA binding and cytotoxic potency [5 7]. Efforts to identify molecules with a greater
affinity for DNA have resulted in the development of −dimeric× intercalators, in which
two intercalating ligands are bridged by a central linkage [8 15]. Recently, we have
reported cytotoxic and antiplatelet evaluations of a-methylidene-g-butyrolactones
linked to potential DNA-intercalating carriers such as flavone, xanthone, carbazole
(CAR), and dibenzofuran (DBF) [16]. Among them, the dibenzofuran derivatives
were the most cytotoxic. The present report describes the preparation and cytotoxic
evaluation of selected dibenzofuran- and carbazole-substituted oximes and oxime
ethers. We expected the oximes (H-bond donors) and O-methyloximes (H-bond
acceptors) to form H-bonds with DNA during the intercalation process of the
carbazole and dibenzofuran moieties.
Certain dibenzofuran derivatives exhibit a great variety of biological effects,
including inhibition of the clotting activity of thrombin [17] and inhibition of serotonin
(5-hydroxytryptamine; 5 HT)-induced bradycardia in rats [18]. Therefore, the anti-
platelet activity of these dibenzofuran and carbazole derivatives has also been
evaluated in the hope to identify potential drug candidates that selectively inhibit either
platelet aggregation or growth of cancer cells.

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2. Results and Discussion. 2.1. Synthesis. The preparation of compounds 1 10 is
illustrated in the Scheme. Alkylation of dibenzo[b,d]furan-2-ol (DBFÀOH) with
chloroacetone under basic conditions gave the propan-2-one 1, which was treated with
NH2OH to afford exclusively the (E)-configured oxime 5 in 59% overall yield. The
configuration of the oxime moiety was determined by through-space nuclear-Over-
hauser-effect spectroscopy (NOESY), which revealed a coupling connectivity to the
Me H-atoms. Accordingly, 7a d were obtained in fairly good overall yields from
DBFÀOH and different bromomethyl ketones, followed by treatment of 3a d with
NH2OH. Compounds 7a d were found to be mostly (Z)-configured, with only trace
amounts of the (E)-isomers being present. The OCH2 C-atom of the (E)-oxime was
shifted downfield (dC 70.42 for (E)-5), while that of the (Z)-isomer was shifted upfield
(dC 59.47for ( Z)-7a) [19][20].
Scheme
Reaction of 2-[(dibenzofuran-2-yl)oxy]-1-(4-fluorophenyl)ethan-1-one (3b) and of
its 4-MeO counterpart 3c with NH2OMe provided the (Z)-configured O-methyloximes
9b and 9c, respectively. The same synthetic procedure was applied for the synthesis of
the carbazole derivatives of type 6, 8, and 10.
2.2. Cytotoxicity. All compounds were evaluated in vitro against a three-cell-line
panel, consisting of MCF 7(breast), NCI-H460 (lung), and SF-268 (CNS) [21]. The
results are shown in Table 1. All DBF-substituted oximes (5 and 7a d) were active, in
contrast to the O-methyloxime counterparts 9b and 9c, which were inactive at the same
concentration. Therefore, a H-bond-donating group seems to be crucial for cytotoxicity.

Helvetica Chimica Acta Vol. 87(2004)
985
Table 1. Primary Anticancer Assay of Dibenzofuran and Carbazole Derivatives. DBF, dibenzo[b,d]furan-2-yl;
CAR, 9H-carbazol-2-yl (see the Scheme).
Compound
Substituents
Growth [%]a)
GI50 [mm]b)c)
R
R'
R''
NCI-H460
(Lung)
MCF 7
(Breast)
SF-268
(CNS)
5
6
7a
7b
7c
7d
8a
8b
8c
8d
9b
9c
DBF
CAR
DBF
DBF
DBF
DBF
CAR
CAR
CAR
CAR
DBF
DBF
CAR
CAR
Me
Me
C6H5
4-F-C6H4
4-MeO-C6H4
[1,1'-Biphenyl]-4-yl
C6H5
H
H
H
H
H
H
H
H
H
0
99
0
1
0
0
1
0
5
1
59
108
17870
11
0
130
0
0
0
0
40.5
d
107n.d.
0
0
0
0
1
0
9
1
)
16.4
21.9
19.6
22.0
17.7
21.1
18.3
16.3
n.d.
À 1
3
4-F-C6H4
0
5
1
79
108
4-MeO-C6H4
[1,1'-Biphenyl]-4-yl
4-F-C6H4
4-MeO-C6H4
4-F-C6H4
H
Me
Me
6Me
Me
101
107n.d.
10b
10c
48.7
6753
4-MeO-C6H4
29.5
a) For details, see Exper. Part. b) Data obtained by the in vitro disease-oriented tumor-cell screen of NCI [22].
GI50 stands for −drug concentration causing 50% cell-growth inhibition×. c) Mean values over all cell lines (see
Exper. Part) tested. d) Not determined.
The active DBF compounds 5 and 7a d were evaluated in the full panel of 60
human-tumor-cell lines derived from nine types of cancer cells (leukemia, non-small-
cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer,
prostate cancer, and breast cancer; see Exper. Part). For each compound, dose-
response curves for each cell line were determined for five different drug concen-
trations, and the concentrations causing 50% cell-growth inhibition (GI50) relative to a
control were calculated [22]. As can be seen from Table 1, a Me group is inferior to a Ph
substituent (GI50 ˆ 40.5 vs. 16.4 mm for 5 vs. 7a). Comparable mean GI50 values for 7a
d indicated that cytotoxicity was not affected by para-substituents on the Ph ring. A
similar trend was observed for the carbazole (CAR) derivatives 6, 8a d, 10b, and 10c.
Here, 6 was inactive, and 10b and 10c exhibited weak cytotoxicities. Hence, 5 is more
cytotoxic than 6, which is in accordance with our previous finding that a-methylidene-
g-butyrolactone-containing dibenzofurans are more cytotoxic than their carbazole
counterparts [16]. However, the oxime-type DBF (7a d) and CAR (8a d) derivatives
exhibited similar cytotoxicities.
2.3. Antiplatelet Activity. The antiplatelet activities of compounds 5 10 were
evaluated in washed rabbit platelets (Table 2). Platelet aggregation was induced by
thrombin (Thr; 0.1 U/ml), arachidonic acid (AA; 200 mm), and collagen (Col; 10 mg/
ml), and the final drug concentration was 100 mm. All compounds were found to be
inactive against Thr-induced aggregation. With the exception of 7b and 8b, which
strongly inhibit Col-induced aggregation, most compounds exhibited only weak or

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Helvetica Chimica Acta Vol. 87(2004)
marginal inhibitory activities. However, 6, 7a, 7b, 8a c, 9b, 9c, and 10c were strongly
inhibiting the platelet aggregation induced by AA. Among them, 7b, 9c, and 10c were
the most-potent drugs with IC50 values of 14.43, 14.87, and 14.60mm, respectively. This
finding is promising, because 9c was found to be noncytotoxic at a concentration of
100 mm.
Table 2. Inhibition of Thrombin (Thr), Arachidonic Acid (AA), and Collagen (Col) Induced Platelet
Aggregation by Dibenzofuran- and Carbazol-Substituted Oximes or Oxime Ethers. Parameters: Thr, 0.1 U/ml;
AA, 200 mm; Col, 10 mg/ml; mean values for aggregation (Æ S.E.M, n ˆ 3 5) and inhibition (IC50) are given.
Aqueous DMSO mixtures (1.5, 5, 15, and 50% of DMSO) were used as the control group, and compounds were
tested at 4, 10, 20, 50, and 100 mm concentration.
Compound (100 mm)
Aggregation [%]
Thr
IC50 [mm]
AA
Col
AA
Col
Control
5
6
7a
7b
7c
7d
8a
8b
8c
8d
9b
9c
10b
10c
91.38 Æ 0.16
90.55 Æ 0.62
87.5 Æ 0.370
89.52 Æ 1.23
86.95 Æ 0.73a)
89.01 Æ8.13.9277
90.57 Æ 0.92
86.93 Æ 1.98
81.53 Æ 2.8b)
87.57 Æ 0.95
84.73 Æ 0.38c)
82.5 Æ 1.08a)
76.5 Æ 0.24a)
81.77 Æ 0.22a)
82.1 Æ 3.65a)
89.83 Æ 0.6791.4
91.54 Æ 1.13
Æ 0.38
90.33 Æ 1.11
54.93 Æ 1.45a)
22.4 Æ 1.84a)
3.72 Æ 3.04a)
59.4 Æ 13.1
a
)
34.77 Æ 0.19
39.73 Æ 6.98
14.43 Æ 2.33
107.53 Æ 3.4
65.12 Æ 3.45
35.19 Æ 5.34
0a)
0a)
Æ 2.29a)
83.76 Æ 1.54a)
91.25 Æ 0.73
15.2 Æ 0.08a)
0a)
0a)
27.9 Æ 5.2756.93
36.07 Æ 1.32
34.6 Æ 0.09
Æ 1.18
54.63 Æ 7.34
81.0 Æ 1.25
0a)
0a)
19.17 Æ 2.99a)
39.87 Æ 2.88a)
29.5 Æ 13.46a)
83.0 Æ 1.04a)
83.7 Æ 1.24a)
96.13 Æ 3.58
87.33 Æ 16.93
0a)
34.53 Æ 0.03
14.87 Æ 0.03
0a)
79.97 Æ 2.9c)
46.63 Æ 10.7a)
0a)
41.67 Æ 6.43
)
14.60 Æ 0.12
69.0 Æ 12.28
a
a) Significantly different from control value at P < 0.001. b) Significantly different from control value at P <
0.05. c) Significantly different from control value at P < 0.01.
3. Conclusions. A number of dibenzofuran- and carbazole-substituted oximes and
O-methyloximes have been synthesized and evaluated for their antiplatelet and
cytotoxic activities. A preliminary anticancer assay indicated that the methyloximes
were inactive (9b and 9c) or less active (10b and 10c) than their oxime counterparts (7b,
7c, 8b, and 8c), which indicates that a H-bond-donating group upon DNA-intercalation
of the dibenzofuran and carbazole moieties is more favorable than that of a H-bond-
accepting group. Compound 9c exhibited a potent inhibitory activity against platelet
aggregation induced by arachidonic acid, with an IC50 value of 14.87 mm, without being
cytotoxic at a concentration of 100 mm.
Experimental Part
General. TLC: precoated (0.2 mm) silica gel 60 F254 plates (EM Laboratories, Inc.); detection by UV light
(254 nm). M.p.: Electrothermal IA9100 digital melting-point apparatus; uncorrected. 1H-NMR spectra: Varian
Unity-400 or Varian Gemini-200 spectrometer (400 and 200 MHz, resp.), chemical shifts d in ppm rel. to SiMe4
as internal standard (ˆ0 ppm), coupling constants J in Hz. Elemental analyses were carried out on a Heraeus
CHN-O-Rapid elemental analyzer.

Helvetica Chimica Acta Vol. 87(2004)
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1-[(Dibenzo[b,d]furan-2-yl)oxy]propan-2-one (1). Dibenzo[b,d]furan-2-ol (1.84 g, 10 mmol), K2CO3
(1.38 g, 10 mmol), and anh. DMF (50 ml) were stirred at r.t. for 30 min. To this soln. was added chloroacetone1)
(0.92 g, 10 mmol) in DMF (10 ml) in one portion. The resulting mixture was stirred at r.t. for 24 h (TLC
monitoring) and then poured into ice-water (100 ml). The white solid thus obtained was collected and
recrystallized from Et2O to afford 1 (2.21 g, 92%). M.p. 80 818. 1H-NMR (CDCl3): 2.33 (s, Me); 4.64
(s, OCH2); 7.06 (dd J ˆ 8.8, 2.8, HÀC(3)); 7.38 (d, J ˆ 2.8, HÀC(1)); 7.48 (d, J ˆ 8.8, HÀC(4)); 7.31 7.91
(m, 4 arom. H). 13C-NMR (CDCl3): 26.62 (Me); 74.12 (CH2O); 105.10, 111.78, 112.38, 115.47, 120.62, 122.56,
124.16, 124.90, 127.38, 151.41, 154.02, 156.99 (arom. C); 205.82 (CˆO). Anal. calc. for C15H12O3 (240.25): C
74.99, H 5.03; found: C 74.82, H 4.96.
1-[(9H-Carbazol-2-yl)oxy]propan-2-one (2). From 9H-carbazol-2-ol and chloroacetone, as described for 1:
1
92% yield. M.p. 179 1808. H-NMR (DMSO): 2.20 (s, Me); 4.87( s, OCH2); 6.79 (dd, J ˆ 8.8, 2.4, HÀC(3));
6.92 (d, J ˆ 2.4, HÀC(1)); 7.97 (d, J ˆ 8.8, HÀC(4)); 7.09 8.00 (m, 4 arom. H); 11.10 (s, NH). 13C-NMR
(DMSO): 26.32 (Me); 72.64 (CH2O); 95.53, 107.81, 110.64, 116.67, 118.58, 119.32, 120.93, 122.54, 124.28, 139.82,
140.88, 156.86 (arom. C); 204.64 (CˆO). Anal. calc. for C15H13NO2 (239.27): C 75.30, H 5.48, N 5.85; found: C
75.11, H 5.44, N 5.96.
2-[(Dibenzo[b,d]furan-2-yl)oxy]-1-(4-fluorophenyl)ethan-1-one (3b). From 2-bromo-1-(4-fluorophenyl)e-
than-1-one, as described for 1: 84% yield. M.p. 138 1398. 1H-NMR (CDCl3): 5.31 (s, OCH2); 7.11 (dd, J ˆ 8.8,
2.8, HÀC(3)); 7.45 (d, J ˆ 2.8, HÀC(1)); 7.47 (d, J ˆ 8.8, HÀC(4)); 7.16 8.11 (m, 8 arom. H). 13C-NMR
(CDCl3): 72.16 (CH2O); 105.69, 111.77, 112.30, 115.76, 115.93, 116.15, 120.65, 122.52, 124.21, 124.88, 127.34,
131.01, 131.11, 151.49, 154.23, 156.99, 164.88, 167.42 (arom. C); 193.42 (CˆO). Anal. calc. for C20H13FO3
(320.31): C 74.99, H 4.09; found: C 74.84, H 4.15.
2-[(Dibenzo[b,d]furan-2-yl)oxy]-1-(4-methoxyphenyl)ethan-1-one (3c). From 2-bromo-1-(4-methoxyphen-
yl)ethan-1-one, as described for 1: 93% yield. M.p. 143 1448. 1H-NMR (CDCl3): 3.88 (s, MeO); 5.31 (s, OCH2);
7.12 (dd, J ˆ 8.8, 2.4, HÀC(3)); 7.45 (d, J ˆ 2.4, HÀC(1)); 7.46 (d, J ˆ 8.8, HÀC(4)); 6.97 8.05 ( m, 8 arom. H).
13C-NMR (CDCl3): 55.50 (MeO); 71.98 (CH2O); 105.65, 111.72, 112.20, 114.03, 115.83, 120.66, 122.46, 124.29,
124.81, 127.24, 127.73, 130.59, 151.40, 154.44, 156.97, 164.07 (arom. C); 193.24 (CˆO). Anal. calc. for C21H16O4
(332.35): C 75.89, H 4.85; found: C 75.91, H 4.83.
1-([1,1×-Biphenyl]-4-yl)-2-[(dibenzo[b,d]furan-2-yl)oxy]ethan-1-one (3d). From 1-([1,1'-biphenyl]-4-yl)-2-
bromoethan-1-one, as described for 1: 79% yield. M.p. 185 1868. 1H-NMR (CDCl3): 5.40 (s, OCH2); 7.15
(dd, J ˆ 9.2, 2.8, HÀC(3)); 7.47 (d, J ˆ 2.8, HÀC(1)); 7.48 (d, J ˆ 9.2, HÀC(4)); 7.30 8.14 (m, 13 arom. H).
13C-NMR (CDCl3): 72.19 (CH2O); 105.75, 111.75, 112.27, 115.87, 120.67, 122.50, 124.28, 124.87, 127.28, 127.33,
127.46, 128.42, 128.83, 128.93, 129.01, 133.35 139.69, 146.61, 154.39, 157.00 (arom. C); 194.34 (CˆO). Anal. calc.
for C26H18O3 (378.42): C 82.52, H 4.79; found: C 82.22, H 4.86.
2-[(9H-Carbazol-2-yl)oxy]-1-(4-fluorophenyl)ethan-1-one (4b). From 9H-carbazol-2-ol and 2-bromo-1-(4-
1
fluorophenyl)ethan-1-one, as described for 1: 85% yield. M.p. 187 188 8. H-NMR (DMSO): 5.63 (s, OCH2);
6.84 (dd, J ˆ 8.4, 2.4, HÀC(3)); 6.98 (d, J ˆ 2.4, HÀC(1)); 7.97 (d, J ˆ 8.4, HÀC(4)); 7.09 8.18 (m, 8 arom. H);
11.08 (s, NH). 13C-NMR (DMSO): 70.54 (CH2O); 95.70, 108.02, 110.61, 115.82, 116.04, 116.64, 118.56, 119.31,
120.85, 122.54, 124.25, 130.99, 131.08, 131.29, 139.79, 140.85, 157.00, 164.08, 166.60 (arom. C); 193.67 (CˆO).
Anal. calc. for C20H14FNO2 (319.33): C 75.22, H 4.42, N 4.39; found: C 75.13, H 4.48, N 4.38.
2-[(9H-Carbazol-2-yl)oxy]-1-(4-methoxyphenyl)ethan-1-one (4c). From 9H-carbazol-2-ol and 2-bromo-1-
(4-methoxyphenyl)ethan-1-one, as described for 1: 91% yield. M.p. 162 1638. 1H-NMR (DMSO): 3.86
(s, MeO); 5.56 (s, OCH2); 6.83 (dd, J ˆ 8.8, 2.4, HÀC(3)); 6.96 (d, J ˆ 2.4, HÀC(1)); 7.97 (d, J ˆ 8.8, HÀC(4));
7.08 8.08 (m, 8 arom. H); 11.08 (s, NH). 13C-NMR (DMSO): 55.61 (MeO); 70.36 (CH2O); 95.62, 108.08,
110.60, 114.09, 116.55, 118.55, 119.29, 120.84, 122.60, 124.22, 127.42, 130.32, 139.77, 140.88, 157.15, 163.58
(arom. C); 193.30 (CˆO). Anal. calc. for C21H17NO3 (331.36): C 76.12, H 5.17, N 4.23; found: C 76.12, H 5.26, N
4.25.
1-([1,1×-Biphenyl]-4-yl)-2-[(9H-carbazol-2-yl)oxy]ethan-1-one (4d). From 9H-carbazol-2-ol and 1-([1,1'-
biphenyl]-4-yl)-2-bromoethan-1-one, as described for 1: 93% yield. M.p. 223 2248. 1H-NMR (DMSO): 5.68
(s, OCH2); 6.87( dd, J ˆ 8.8, 2.4, HÀC(3)); 7.01 (d, J ˆ 2.4, HÀC(1)); 7.99 (d, J ˆ 8.8, HÀC(4)); 7.10 8.18
(m, 13 arom. H); 11.10 (s, NH). 13C-NMR (DMSO): 70.63 (CH2O); 95.68, 108.06, 110.63, 116.61, 118.56, 119.32,
120.88, 122.57, 124.25, 127.04, 128.52, 128.70, 129.14, 133.30, 138.83, 139.79, 140.90, 145.15, 157.07 (arom. C);
194.55 (CˆO). Anal. calc. for C26H19NO2 (377.43): C 82.74, H 5.07, N 3.71; found: C 82.66, H 5.17, N 3.72.
1
)
Systematic name: 1-chloropropan-2-one.

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Helvetica Chimica Acta Vol. 87(2004)
(E)-1-[(Dibenzo[b,d]furan-2-yl)oxy]propan-2-one Oxime (5). To a soln. of 1 (0.24 g, 1 mmol) in EtOH
(20 ml) was added a soln. of NH2OH ¥ HCl (0.14 g, 2 mmol) in EtOH (2 ml). The mixture was heated at reflux
for 24 h (TLC monitoring) and evaporated to a white solid, which was purified by flash chromatography (FC;
silica gel; CH2Cl2/hexane 1:1) and recrystallization (Et2O/hexane 1:1): 0.16 g (63%). M.p. 129 1308. 1H-NMR
(DMSO): 1.90 (s, Me); 4.66 (s, OCH2); 7.15 (dd, J ˆ 8.8, 2.6, HÀC(3)); 7.61 (d, J ˆ 8.8, HÀC(4)); 7.78 (d, J ˆ 2.6,
HÀC(1)); 7.34 8.12 (m, 4 arom. H); 10.96 (s, NOH). 13C-NMR (DMSO): 11.52 (Me); 70.42 (CH2O); 105.96,
111.62, 112.09, 116.03, 121.10, 122.76, 123.76, 124.11, 127.52, 150.25, 152.01, 154.47, 156.14 (arom. C and CˆN).
Anal. calc. for C15H13NO3 (255.27): C 70.58, H 5.13, N 5.49; found: C 70.66, H 5.24, N 5.45.
(E)-1-[(9H-Carbazol-2-yl)oxy]propan-2-one Oxime (6). From 2, as described for 5: 67% yield. M.p. 229
2308. 1H-NMR (DMSO): 1.89 (s, Me); 4.64 (s, OCH2); 6.81 (dd, J ˆ 8.8, 2.4, HÀC(3)); 7.02 (d, J ˆ 2.4,
HÀC(1)); 7.97 (d, J ˆ 8.8, HÀC(4)); 7.09 8.00 (m, 4 arom. H); 10.93, 11.13 (2s, NOH and NH). 13C-NMR
(DMSO): 11.49 (Me); 69.80 (CH2O); 95.84, 108.20, 110.60, 116.59, 118.53, 119.29, 120.87, 122.54, 124.24, 139.79,
140.87, 152.26, 157.27 (arom. C and CˆN). Anal. calc. for C15H14N2O2 (254.28): C 70.85, H 5.55, N 11.02; found:
C 70.85, H 5.56, N 10.98.
(Z)-2-[(Dibenzo[b,d]furan-2-yl)oxy]-1-phenylethan-1-one Oxime (7a). From 3a, as described for 5: 69%
yield. M.p. 139 1408. 1H-NMR (DMSO): 5.37( s, OCH2); 7.09 (dd, J ˆ 8.8, 2.0, HÀC(3)); 7.59 (d, J ˆ 8.8,
HÀC(4)); 7.80 (d, J ˆ 2.0, HÀC(1)); 7.39 8.10 (m, 9 arom. H); 11.96 (s, NOH). 13C-NMR (DMSO): 59.47
(CH2O); 105.41, 111.66, 112.13, 115.51, 121.07, 122.80, 123.75, 124.15, 126.36, 127.56, 128.29, 128.85, 134.39,
150.26, 152.82, 154.26, 156.15 (arom. C and CˆN). Anal. calc. for C20H15NO3 (317.34): C 75.70, H 4.76, N 4.41;
found: C 75.59, H 4.82, N 4.42.
(Z)-2-[(Dibenzo[b,d]furan-2-yl)oxy]-1-(4-fluorophenyl)ethan-1-one Oxime (7b). From 3b, as described
for 5: 83% yield. M.p. 160 1618. 1H-NMR (DMSO): 5.37( s, OCH2); 7.08 (dd, J ˆ 8.8, 2.4, HÀC(3)); 7.59
(d, J ˆ 8.8, HÀC(4)); 7.79 (d, J ˆ 2.4, HÀC(1)); 7.21 8.10 (m, 8 arom. H); 11.98 (s, NOH). 13C-NMR (DMSO):
59.50 (CH2O); 105.44, 111.68, 112.16, 115.13, 115.35, 115.51, 121.08, 122.81, 123.75, 124.16, 127.59, 128.55, 128.62,
130.81, 130.84, 150.29, 152.08, 154.16, 156.16, 161.24, 163.69 (arom. C and CˆN). Anal. calc. for C20H14FNO3
(335.33): C 71.64, H 4.21, N 4.18; found: C 71.24, H 4.32, N 4.03.
(Z)-2-[(Dibenzo[b,d]furan-2-yl)oxy]-1-(4-methoxyphenyl)ethan-1-one Oxime (7c). From 3c, as described
for 5: 63% yield. M.p. 133 1348. 1H-NMR (DMSO): 3.77 (s, MeO); 5.33 (s, OCH2); 7.09 (dd, J ˆ 8.8, 2.4,
HÀC(3)); 7.59 (d, J ˆ 8.8, HÀC(4)); 7.80 (d, J ˆ 2.4, HÀC(1)); 6.95 8.10 (m, 8 arom. H); 11.73 (s, NOH).
13C-NMR (DMSO): 55.10 (MeO); 59.39 (CH2O); 105.35, 111.66, 112.13, 113.74, 115.51, 121.05, 122.80, 123.77,
124.15, 126.77, 127.56, 127.71, 150.23, 152.32, 154.28, 156.15, 159.80 (arom. C and CˆN). Anal. calc. for
C21H17NO4 (347.36): C 72.61, H 4.93, N 4.03; found: C 72.60, H 4.98, N 3.92.
(Z)-1-([1,1'-Biphenyl]-4-yl)-2-[(dibenzo[b,d]furan-2-yl)oxy]ethan-1-one Oxime (7d). From 3d, as de-
1
scribed for 5: 81% yield. M.p. 174 1758. H-NMR (DMSO): 5.38 (s, OCH2); 7.11 (dd, J ˆ 8.8, 2.4, HÀC(3));
7.59 (d, J ˆ 8.8, HÀC(4)); 7.82 (d, J ˆ 2.4, HÀC(1)); 7.35 8.10 (m, 13 arom. H); 12.01 (s, NOH). 13C-NMR
(DMSO): 59.41 (CH2O); 105.44, 111.69, 112.21, 115.57, 121.10, 122.84, 123.78, 124.21, 126.59, 126.92, 127.62,
127.68, 128.97, 133.45, 139.44, 140.49, 150.30, 152.50, 154.31, 156.18 (arom. C and CˆN). Anal. calc. for
C26H19NO3 (393.43): C 79.37, H 4.87, N 3.56; found: C 79.40, H 4.93, N 3.53.
(Z)-2-[(9H-Carbazol-2-yl)oxy]-1-phenylethan-1-one Oxime (8a). From 4a, as described for 5: 60% yield.
M.p. 187 188 8. 1H-NMR (DMSO): 5.35 (s, OCH2); 6.74 (dd, J ˆ 8.4, 2.4, HÀC(3)); 7.04 (d, J ˆ 2.4, HÀC(1));
7.93 (d, J ˆ 8.4, HÀC(4)); 7.08 7.98 (m, 9 arom. H); 11.16, 11.92 (2s, NOH and NH). 13C-NMR (DMSO): 59.13
(CH2O); 95.29, 107.85, 110.60, 116.59, 118.53, 119.28, 120.88, 122.52, 124.22, 126.44, 128.24, 128.80, 134.39,
139.77, 140.90, 153.20, 157.04 (arom. C and CˆN). Anal. calc. for C20H16N2O2 (316.35): C 75.93, H 5.10, N 8.86;
found: C 75.91, H 5.13, N 8.76.
(Z)-2-[(9H-Carbazol-2-yl)oxy]-1-(4-fluorophenyl)ethan-1-one Oxime (8b). From 4b, as described for 5:
67% yield. M.p. 189 1908. 1H-NMR (DMSO): 5.35 (s, OCH2); 6.73 (dd, J ˆ 8.4, 2.0, HÀC(3)); 7.03 (d, J ˆ 2.0,
HÀC(1)); 7.93 (d, J ˆ 8.4, HÀC(4)); 7.09 7.98 (m, 8 arom. H); 11.15, 11.94 (2s, NOH and NH). 13C-NMR
(DMSO): 59.19 (CH2O); 95.33, 107.84, 110.61, 115.07, 115.30, 116.65, 118.56, 119.29, 120.92, 122.52, 124.27,
128.61, 128.70, 130.81, 130.84, 139.79, 140.90, 152.47, 156.92, 161.23, 163.67 (arom. C and CˆN). Anal. calc. for
C20H15FN2O2 (334.34): C 71.85, H 4.52, N 8.38; found: C 71.87, H 4.56, N 8.31.
(Z)-2-[(9H-Carbazol-2-yl)oxy]-1-(4-methoxyphenyl)ethan-1-one Oxime (8c). From 4c, as described for 5:
72% yield. M.p. 174 1758. 1H-NMR (DMSO): 3.76 (s, MeO); 5.32 (s, OCH2); 6.74 (dd, J ˆ 8.8, 2.0, HÀC(3));
7.03 (d, J ˆ 2.0, HÀC(1)); 7.93 (d, J ˆ 8.8, HÀC(4)); 6.92 7.98 (m, 8 arom. H); 11.15, 11.70 (2s, NOH and NH).
13C-NMR (DMSO): 55.03 (MeO); 59.01 (CH2O); 95.19, 107.78, 110.53, 113.61, 116.48, 118.47, 119.19, 120.80,
122.46, 124.14, 126.70, 127.71, 139.69, 140.83, 152.62, 156.99, 159.69 (arom. C and CˆN). Anal. calc. for
C21H18N2O3 (346.38): C 72.82, H 5.24, N 8.09; found: C 72.51, H 5.35, N 7.98.

Helvetica Chimica Acta Vol. 87(2004)
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(Z)-1-([1,1×-Biphenyl]-4-yl)-2-[(9H-carbazol-2-yl)oxy]ethan-1-one Oxime (8d). From 4d, as described for
1
5: 64% yield. M.p. 195 1968. H-NMR (DMSO): 5.38 (s, OCH2); 6.77 (dd, J ˆ 8.8, 2.4, HÀC(3)); 7.06 (d, J ˆ
2.4, HÀC(1)); 7.94 (d, J ˆ 8.8, HÀC(4)); 7.08 7.99 (m, 8 arom. H); 11.16, 11.97(2 s, NOH and NH). 13C-NMR
(DMSO): 59.07(CH 2O); 95.27, 107.82, 110.55, 116.58, 118.49, 119.23, 120.85, 122.48, 124.18, 126.45, 126.53,
126.92, 127.61, 128.90, 133.42, 139.41, 139.76, 140.37, 140.87, 152.79, 157.03 (arom. C and CˆN). Anal. calc. for
C26H20N2O2 (392.45): C 79.57, H 5.14, N 7.14; found: C 79.57, H 5.20, N 7.12.
(Z)-2-[(Dibenzo[b,d]furan-2-yl)oxy]-1-(4-fluorophenyl)ethan-1-one O-Methyloxime (9b). To a soln. of 3b
(0.32 g, 1 mmol) in EtOH (20 ml) was added a soln. of NH2OMe ¥ HCl (0.17g, 2 mmol) in EtOH (2 ml). The
mixture was heated at reflux for 24 h (TLC monitoring) and evaporated to a crude oil, which was purified by FC
(silica gel; CH2Cl2/hexane 1:1): 0.25 g (72%). M.p. 167 1688. 1H-NMR (DMSO): 4.04 (s, MeO); 5.34
(s, OCH2); 7.06 (dd, J ˆ 8.8, 2.8, HÀC(3)); 7.59 (d, J ˆ 8.8, HÀC(4)); 7.79 (d, J ˆ 2.8, HÀC(1)); 7.20 8.13
(m, 8 arom. H). 13C-NMR (DMSO): 60.09 (CH2O); 62.28 (MeO); 97.67, 105.45, 111.66, 112.21, 115.12, 115.55,
121.09, 122.85, 123.69, 124.16, 127.61, 128.97, 129.13, 129.67, 129.73, 150.35, 153.18, 154.01, 156.16, 160.31, 165.22
(arom. C and CˆN). Anal. calc. for C21H16FNO3 (349.36): C 72.20, H 4.62, N 4.01; found: 72.18, H 4.70, N 4.04.
(Z)-2-[(Dibenzo[b,d]furan-2-yl)oxy]-1-(4-methoxyphenyl)ethan-1-one O-Methyloxime (9c). From 3c, as
described for 9b: 69% yield. M.p. 95 968. 1H-NMR (DMSO): 3.76 (s, MeO); 4.01 (s, MeON); 5.29 (s, OCH2);
7.05 (dd, J ˆ 9.2, 2.8, HÀC(3)); 7.58 (d, J ˆ 9.2, HÀC(4)); 7.75 (d, J ˆ 2.8, HÀC(1)); 6.94 8.10 (m, 8 arom. H).
13C-NMR (DMSO): 55.15 (MeO); 59.92 (CH2O); 62.05 (MeON); 105.35, 111.67, 112.19, 113.80, 115.58, 121.07,
122.83, 123.73, 124.15, 125.59, 127.59, 128.14, 150.31, 153.37, 154.15, 156.16, 160.23 (arom. C and CˆN). Anal.
calc. for C22H19NO4 (361.39): C 73.12, H 5.30, N 3.88; found: C 73.52, H 5.20, N 3.56.
(Z)-2-[(9H-Carbazol-2-yl)oxy]-1-(4-fluorophenyl)ethan-1-one O-Methyloxime (10b). From 4b, as de-
scribed for 9b: 72% yield. M.p. 180 1818. 1H-NMR (DMSO): 4.04 (s, MeO); 5.33 (s, OCH2); 6.70 (dd, J ˆ 8.6,
2.2, HÀC(3)); 6.98 (d, J ˆ 2.2, HÀC(1)); 7.93 (d, J ˆ 8.6, HÀC(4)); 7.07 8.00 (m, 8 arom. H); 11.16 (s, NH).
13C-NMR (DMSO): 59.96 (CH2O); 62.63 (MeO); 95.57, 108.11, 110.91, 115.37, 115.81, 116.99, 118.86, 119.61,
121.24, 122.76, 124.60, 129.30, 129.47, 129.93, 129.99, 140.05, 141.10, 153.90, 157.00, 160.57, 165.48 (arom. C and
CˆN). Anal. calc. for C21H17FN2O2 (348.37): C 72.40, H 4.92, N 8.04; found: C 72.42, H 4.97, N 8.00.
(Z)-2-[(9H-Carbazol-2-yl)oxy]-1-(4-methoxyphenyl)ethan-1-one O-Methyloxime (10c). From 4c, as de-
scribed for 9b: 67% yield. M.p. 154 1558. 1H-NMR (DMSO): 3.76 (s, MeO); 4.02 (s, MeON); 5.29 (s, OCH2);
6.71 (dd, J ˆ 8.4, 2.0, HÀC(3)); 7.00 (d, J ˆ 2.0, HÀC(1)); 7.93 (d, J ˆ 8.4, HÀC(4)); 6.93 7.98 (m, 8 arom. H);
11.17( s, NH). 13C-NMR (DMSO): 55.16 (MeO); 59.53 (CH2O); 62.12 (MeON); 95.21, 107.87, 110.63, 113.77,
116.64, 118.58, 119.32, 120.95, 122.51, 124.28, 125.56, 128.21, 139.77, 140.87, 153.81, 156.89, 160.20 (arom. C and
CˆN). Anal. calc. for C22H20N2O3 (360.41): C 73.32, H 5.59, N 7.77; found: C 73.21, H 5.61, N 7.73.
Antiplatelet Evaluation. The following materials were used: collagen (type 1, bovine Achilles tendon; Sigma
Chemical Co.) was homogenized in 25 mm AcOH and stored (1 mg/ml) at À708. Arachidonic acid (AA),
EDTA (−ethylenediamine tetraacetate×), and bovine serum albumin were purchased from Sigma and dissolved
in CHCl3. For the determination of cell growth rel. to a control, each cell line was inoculated and pre-incubated
on a microtiter plate. Test agents (100 mm) were then added, and the culture was incubated for 48 h. End-point
determinations were made with alamar blue [21]. Compounds that reduced the growth of any one of the cell
lines to 32% or less (negative numbers in Table 2 indicate cell kill) were passed on for evaluation in the full
panel of 60 cell lines over a fivefold-logarithmic dose range. Theses cell lines were: 1) leukemia (CCRF-CEM,
HL-60 (TB), K-562, MOLT-4, PRMI-8226, and SR); 2) non-small-cell lung cancer (A549/ATCC, EKVX, HOP-
62, HOP-92, NCI-H226, NCI-H23, NCI-H322M, and NCI-H522); 3) colon cancer (COLC 205, HCC-2998,
HCT-116, HCT-15, HT29, KM12, and SW-620); 4) CNS cancer (SF-268, SF-295, SF-539, SNB-19, SNB-75, and
U251); 5) melanoma (LOX IMVI, MALME-3M, M14, SK-MEL-2, SK-MEL-28, SK-MEL-5, and UACC-257);
6) ovarian cancer (IGROV1, OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, and SK-OV-3); 7) renal cancer
(786 0, A498, ACHN, CAKI-1, RXF 393, SN12C, TK-10, and UO-31); 8) prostate cancer (PC-3 and DU-145);
and 9) breast cancer (MCF 7, MCF 7/ADR-RES, MDA-MB-231/ ATCC, HS 578T, MDA-MB-435, MDA-N and
T-47D).
Platelet Aggregation. Blood was collected from the rabbit marginal ear vein, anticoagulated with EDTA
(6 mm) and centrifuged for 10 min at 90 g at r.t. Platelet suspensions were prepared from the plasma according
to the washing procedures described in [23]. Platelet numbers were determined with a Coulter-ZM counter and
adjusted to 3 Â 108 platelets/ml. The platelet pellets were suspended in Tyrode×s soln. of the following
composition (mm): NaCl (136.8), KCl (2.8), NaHCO3 (11.9), MgCl2 (2.1), NaH2PO4 (0.33), CaCl2 (1.0), and
glucose (11.2), containing bovine serum albumin (0.35%). The platelet suspension was stirred at 1200 rpm, and
aggregation was measured at 378 by the turbidimetric method, as described by O×Brien [24], using a Payton
Lumi aggregometer (model 600B). To eliminate solvent effects, the final conc. of DMSO was fixed at 0.5%.

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Helvetica Chimica Acta Vol. 87(2004)
Percentage of aggregation was calculated using the absorbance of a platelet suspension as 0% aggregation, and
the absorbance of Tyrode×s soln. as 100% aggregation.
Financial support of this work by the National Science Council of the Republic of China is gratefully
acknowledged. We also thank the National Cancer Institute (NCI) of the U.S.A. for anticancer screenings, and
the National Center for High-Performance Computing for providing computer resources and chemical-database
services.
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Received October 24, 2003