Synthesis and cytotoxicity evaluation of metal-chelator-bearing flavone, carbazole, dibenzofuran, xanthone, and anthraquinone

Article abstract of DOI:10.1002/hlca.200390078

2-(Aryloxymethyl)-5-benzyloxy-1-methyl-1H-pyridin-4-ones 8a-8g, 2-(aryloxymethyl)-5-hydroxy-4H-pyran-4-ones 9a-9g, and 2-(aryloxymethyl)-5-hydroxy-1-methyl-1H-pyridin-4-ones 10a-10g were prepared from the known 5-benzyloxy-2-(hydroxymethyl)pyran-4-one (3) in a good overall yield. These compounds were evaluated in vitro against a three-cell lines panel consisting of MCF7 (breast), NCI-H460 (lung), and SF-268 (CNS), and the active compounds passed on for evaluation in the full panel of 60 human tumor cell lines derived from nine cancer cell types. The results indicated that 5-hydroxy derivatives are more favorable than their corresponding 5-benzyloxy precursors (10a-10g vs. 8a-8g), and 1-methyl-1H-pyridin-4-ones are more favorable than their corresponding pyran-4(1H)-ones (10a-10g vs. 9a-9g). Among these three types of compounds, 2-(aryloxymethyl)-5-hydroxy-1-methyl-1H-pyridin-4-ones 10a-10g were the most cytotoxic; they inhibited the growth of almost all the cancer cells tested. On the contrary, compound 8a (a mean GI₅₀ = 27.8 μM), 8b (38.5), 8d (11.0), and 8e (30.5) are especially active against the growth of SK-MEL-5 (a melanoma cancer cell) with a GI₅₀ of <0.01, 5.65, 0.55, and 0.03 μM, respectively (cf. Table 2).

Full text of DOI:10.1002/hlca.200390078

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Helvetica Chimica Acta Vol. 86 (2003)
Synthesis and Cytotoxicity Evaluation of Metal-Chelator-Bearing Flavone,
Carbazole, Dibenzofuran, Xanthone, and Anthraquinone
by Yeh-Long Chen*, Po-Hsu Chen, Chao-Ho Chung, Kuang-Chieh Li, Haw-Yaun Jeng, and Cherng-Chyi Tzeng
School of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University,
Kaohsiung City 807, Taiwan
(phone: (886)7-3121101 ext 2249; fax: (886)7-3125339; e-mail: yeloch@cc.kmu.edu.tw)
2-(Aryloxymethyl)-5-benzyloxy-1-methyl-1H-pyridin-4-ones 8a 8g, 2-(aryloxymethyl)-5-hydroxy-4H-
pyran-4-ones 9a 9g, and 2-(aryloxymethyl)-5-hydroxy-1-methyl-1H-pyridin-4-ones 10a 10g were prepared
from the known 5-benzyloxy-2-(hydroxymethyl)pyran-4-one (3) in a good overall yield. These compounds were
evaluated in vitro against a three-cell lines panel consisting of MCF 7 (breast), NCI-H460 (lung), and SF-268
(CNS), and the active compounds passed on for evaluation in the full panel of 60 human tumor cell lines derived
from nine cancer cell types. The results indicated that 5-hydroxy derivatives are more favorable than their
corresponding 5-benzyloxy precursors (10a 10g vs. 8a 8g), and 1-methyl-1H-pyridin-4-ones are more
favorable than their corresponding pyran-4(1H)-ones (10a 10g vs. 9a 9g). Among these three types of
compounds, 2-(aryloxymethyl)-5-hydroxy-1-methyl-1H-pyridin-4-ones 10a 10g were the most cytotoxic; they
inhibited the growth of almost all the cancer cells tested. On the contrary, compound 8a (a mean GI50 ˆ 27.8 mm),
8b (38.5), 8d (11.0), and 8e (30.5) are especially active against the growth of SK-MEL-5 (a melanoma cancer
cell) with a GI50 of < 0.01, 5.65, 0.55, and 0.03 mm, respectively (cf. Table 2).
Introduction. 3-Hydroxy-4H-pyran-4-one and 3-hydroxy-1H-pyridin-4-one de-
rivatives have received increasing attention due to their biological activities, such as
orally active iron chelators, antioxidant, antibacterial, antitumor activities, and in
treatment of Parkinson×s disease [1 9]. The commercially available plant product,
kojic acid (1; 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one), isolated from fermen-
tative products of Aspergillus species, has been reported to inhibit tyrosinase via
chelation of its copper [10][11], which is indispensable for tyrosinase activity [12][13].
Recently, the nonproteinogenic amino acid mimosine (2; a-amino-3-hydroxy-4-oxo-
4H-pyridine-1-propanoic acid), derived from seeds of Leucaena leucocephala or
Mimosa pudica, has been reported to inhibit DNA synthesis in DNAviruses by altering
iron and ribonucleotide triphosphate metabolism [14][15]. A recent study showed that
mimosine (2) might block cell proliferation by multiple mechanisms in human lung
cancer cells [16]. Recently, we reported the preparation of alkylating a-methylidene-g-
butyrolactones linked to potential DNA-intercalating carriers such as flavone,
xanthone, carbazole, dibenzofuran, and anthraquinone, along with their evaluation
against 60 human cancer cell lines derived from nine cancer cell types. The results
indicated that these compounds inhibit not only leukemia but also certain solid-cancer
cell lines [17 19]. In continuation of our search for more potent anticancer agents, we
have linked metal-chelating 3-hydroxy-4H-pyran-4-one and 1-methyl-1H-pyridin-4-
one to these DNA-intercalating moieties for evaluation.
Results and Discussion.
Preparation of the 2-(aryloxymethyl)-5-hydroxy-4H-
pyran-4-ones 9a 9g and 2-(aryloxymethyl)-5-hydroxy-1-methyl-1H-pyridin-4-ones

Helvetica Chimica Acta Vol. 86 (2003)
779
10a 10g is illustrated in the Scheme. The known 5-benzyloxy-2-(hydroxymethyl)-4H-
pyran-4-one (3) [20], obtained by benzylation of kojic acid (1), was treated with SOCl2
to afford 5-benzyloxy-2-(chloromethyl)-4H-pyran-4-one (5) in an overall yield of 70%.
Treatment of 3 with 40% aqueous MeNH2 gave 5-benzyloxy-2-(hydroxymethyl)-1-
methyl-1H-pyridin-4-one (4) [21], which was reacted with SOCl2 to give 5-benzyloxy-2-
(chloromethyl)-1-methyl-1H-pyridin-4-one (6). Condensation of 5 and 6 with Ar-
ylÀOH in the presence of K2CO3 and KI afforded 2-(aryloxymethyl)-5-benzyloxy-4H-
Scheme
O
O
X
O
HO
BnO
BnO
BnCl
SOCl2
OH
Cl
OH
KOH, EtOH
O
X
1
3 X = O
4 X = NCH3
5 X = O
6 X = NCH3
CH3NH2
O
O
BnO
20% HCl
AcOH
HO
Aryl-OH
K2CO3
O
O
X
X
Aryl
Aryl
7 X = O
8 X = NCH3
9 X = O
10 X = NCH3
O
O
O
N
H
O
c
b
a
O
O
O
O
e
f
d
O
O
g

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Helvetica Chimica Acta Vol. 86 (2003)
pyran-4-ones 7a 7g and their 1-methyl-1H-pyridin-4-one counterparts 8a 8g, respec-
tively, in a yield of 46 95%. Removal of Bn group was achieved with 20% aqueous
HCl, and the final products 9a 9g and 10a 10g respectively, were obtained in 60
96% yield.
The 4H-pyran-4-ones 9a 9g and the 1H-pyridin-4-ones 8a 8g and 10a 10g were
evaluated in vitro against a panel of three cell lines consisting of MCF 7 (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 was 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 compared to the untreated control cells.
Compounds that reduced the growth of any one of the cell lines to 32% or less
(negative numbers indicate cell kill) are passed on for evaluation in the full panel of 60
human tumor cell lines derived from nine cancer cell types (leukemia, non-small-cell
lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer,
prostate cancer, and breast cancer). For each compound, dose-response curves for each
cell line were measured at five different drug concentrations, and the concentration
causing 50% cell-growth inhibition (GI50) relative to the control was calculated [22].
Results from Table 1 indicated that, with the exception of compounds 8c, 8f, 8g, 9b, and
9e, all are active. Therefore, 5-OH derivatives are more favorable than their
Table 1. In vitro Anticancer Assayof 4 H-Pyran-4-one and 1H-Pyridin-4-one Derivatives
Compound
Growth percentages
NCI-H460 (Lung)
Mean GI50 (mm)a)
MCF 7 (Breast)
SF-268 (CNS)
7c
7d
8a
8b
8c
8d
8e
8f
8g
9a
9b
9c
9d
9e
9f
9g
10a
10b
10c
10d
10e
10f
10g
15
88
22
18
73
19
67
77
77
37
74
36
32
54
14
55
77
71
11
66
À 70
À 74
44
0
51
17
12
À 31
8
36
58.8
46.7
27.8
38.5
n.d.b)
11.0
30.5
n.d.
n.d.
13.7
n.d.
3.42
7.65
n.d.
43.2
82.6
3.81
1.84
0.35
0.68
4.61
0.38
0.27
À 3
63
46
13
85
72
À 58
À 70
86
38
À 88
À 72
93
À 6
118
12
À 59
À 79
41
À 66
3
17
31
À 36
À 76
18
11
À 76
À 77
5
0
À 20
À 41
À 10
10
8
11
11
17
a) Mean values over all 60 cancer cell lines tested. b) Not determined.

Helvetica Chimica Acta Vol. 86 (2003)
781
corresponding 5-benzyloxy precursors (10a 10g vs. 8a 8g), and 1-methyl-1H-pyridin-
4-ones are more favorable than the corresponding 4H-pyran-4-ones (10a 10g vs. 9a
9g). Among these metal-chelator-bearing intercalating agents, carbazole 10c, dibenzo-
furan 10d, xanthone 10f, and anthraquinone 10g exhibited most significant cytotoxicity,
with mean GI50 values in a range of 0.27 0.68 mm.
Although 2-(aryloxymethyl)-5-hydroxy-1-methyl-1H-pyridin-4-ones 10a 10g were
the most cytotoxic, they inhibited the growth of almost all the cancer cells tested
(Table 2). On the contrary, compounds 8a (a mean GI50 ˆ 27.8 mm), 8b (38.5), 8d (11.0),
and 8e (30.5) are especially active against the growth of SK-MEL-5 (a melanoma
cancer cell) with a GI50 of < 0.01, 5.65, 0.55, and 0.03 mm, respectively.
Table 2. Growth Inhibition (GI50 (mm)) of Melanoma Cancer Subpanels by4 H-Pyran-4-one and 1H-Pyridin-4-
one Derivatives
Compd.
MALME-3M
M14
SK-MEL-2
SK-MEL-5
UACC-257
UACC-62
7c
7d
8a
8b
8d
8e
9a
9c
9d
> 100
37.0
> 100
41.1
12.9
32.6
22.3
2.57
13.7
32.7
46.1
9.71
1.88
1.32
1.53
15.9
0.30
0.29
> 100
25.8
44.9
28.4
27.9
14.4
19.7
15.1
n.d.
n.d.
1.68
< 0.01
5.65
0.55
0.03
12.4
2.57
7.21
41.9
30.5
0.89
1.24
0.17
0.28
4.71
0.31
0.21
> 100
> 100
64.0
> 100
15.7
37.5
25.9
18.9
25.9
11.7
17.5
1.70
1.73
4.79
26.9
28.9
4.44
1.78
0.35
1.35
3.25
0.41
0.22
35.6
41.3
33.2
13.1
25.8
19.5
4.27
10.9
63.5
> 100
16.5
1.03
9.65
43.2
> 100
30.6
5.73
27.6
> 100
4.83
1.99
0.77
1.26
8.35
0.35
0.29
9f
9g
> 100
1.83
10a
10b
10c
10d
10e
10f
10g
1.46
0.24
0.53
5.13
0.53
0.28
5.04
3.25
4.06
40.7
0.32
0.31
Conclusions. Certain metal-chelator-bearing compounds were synthesized and
evaluated for their cytotoxicity. The preliminary results indicated 2-(aryloxymethyl)-5-
hydroxy-1-methyl-1H-pyridin-4-ones 10a 10g were the most cytotoxic. Among them,
carbazole 10c, dibenzofuran 10d, xanthone 10f, and anthraquinone 10g exhibited mean
GI50 values in a range of 0.27 0.68 mm. However, certain 2-(aryloxymethyl)-5-
benzyloxy-1-methyl-1H-pyridin-4 -ones 8 demonstrated selective cytotoxicity. Com-
pounds 8a (a mean GI50 ˆ 27.8 mm), 8b (38.5), 8d (11.0), and 8e (30.5) are especially
active against the growth of SK-MEL-5 (a melanoma cancer cell) with GI50 values of
< 0.01, 5.65, 0.55, and 0.03 mm, respectively.
Experimental Part
General. M.p.: Electrothermal IA9100 digital melting-point apparatus; uncorrected. TLC: silica gel 60 F-
254 plates from EM Laboratories, Inc.; detection by UV light (254 nm). NMR (1H and 13C) Spectra: Varian
Unity-400 or Varian Gemini-200 spectrometer, chemical shifts d in ppm with Me4Si as an internal standard

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Helvetica Chimica Acta Vol. 86 (2003)
(ˆ0 ppm), coupling constants J in Hz. Elemental analyses were carried out on a Heraeus CHN-O-Rapid
elemental analyzer, and results were within Æ 0.4% of calc. values.
5-Benzyloxy-2-(chloromethyl)-4H-pyran-4-one (5). To a suspension of 5-benzyloxy-2-(hydroxymethyl)-1-
methyl-1H-pyridin-4-one (3; 2.32 g, 10 mmol) at r.t. in Et2O (15 ml) was added SOCl2 (2 ml, 12.24 mmol), and
the mixture was stirred for 1 h. After treatment with H2O, more Et2O was added, and the org. layer was washed
with H2O, dried (Na2SO4), and concentrated at r.t. to give 5 (2.24 g, 89%). Pale yellow solid: M.p. 115 1178
([20]: 118 1208). 1H-NMR (DMSO): 4.67 (s, PhCH2); 4.96 (s, CH2Cl); 6.58 (s, HÀC(3)); 7.41 (m, 5 arom. H);
8.29 (s, HÀC(6)). 13C-NMR (DMSO): 41.21; 70.68; 114.54; 128.23; 128.34 (2 C); 128.54 (2 C); 136.03; 141.77;
146.93; 161.93; 173.15. Anal. calc. for C13H11O3Cl: C 62.29, H 4.42; found: C 62.33, H 4.53.
5-Benzyloxy-2-(chloromethyl)-1-methyl-1H-pyridin-4-one and 5-Benzyloxy-2-(chloromethyl)-1,4-dihydro-
1-methyl-4-oxopyridinium Chloride (6). Compound 6 was prepared from 4 [21] by the same procedure as
described for 5 in 73% yield. M.p. 179 1808. 1H-NMR (DMSO): 4.13 (s, MeN); 5.11 (s, CH2Cl); 5.23
(s, PhCH2); 7.40 7.50 (m, 5 arom. H); 7.55 (s, HÀC(3)); 8.77; 8.90 (s, HÀC(6)). 13C-NMR (DMSO) 40.33;
42.84; 71.59; 114.44; 128.28 (2 C); 128.58 (2 C); 132.74; 135.32; 145.46; 146.29; 162.50. Anal. calc. for
C14H14ClNO2: C 63.76, H 5.35, N 5.31; found: C 63.69, H 5.44, N 5.21.
General Procedure for Coupling of 5-Benzyloxy-2-(chloromethyl)-4H-pyran-2-one (5) and 5-Benzyloxy-2-
(chloromethyl)-1-methyl-1H-pyridin-4-one (6) with Heterocyclic Phenol Derivatives. A mixture of 5 (5 mmol)
or 6 (5 mmol), K2CO3 (0.69 g, 5 mmol), KI (50 mg), and corresponding heterocyclic phenol derivative
(5 mmol) in acetone (50 ml) was refluxed (monitored until the reactant disappeared by TLC). Evaporation of
the solvent gave a residue, which was poured into ice water (50 ml). The resulting solid was collected and
crystallized from EtOH.
3-[(5-Benzyloxy-4-oxo-4H-pyran-2-yl)methoxy]-2-phenyl-4H-[1]benzopyran-4-one (7a). Yield: 81%
(from 5 and 3-hydroxy-2-phenyl-4H-[1]benzopyran-4-one). M.p. 161 1638. 1H-NMR (CDCl3): 4.93 (s, PhCH2);
4.97 (s, CH2O); 6.33 (s, HÀC(3')); 7.22 (s, HÀC(6')); 7.36 (m, 5 arom. H); 7.43 7.56 (m, 5 arom H); 7.72
(m, arom. H); 7.93 (m, 2 arom. H); 8.25 (dd, J ˆ 8.0, 1.2, HÀC(5)). 13C-NMR (CDCl3): 69.35; 71.89; 115.44;
118.16; 124.01; 125.11; 125.80; 127.77 (2 C); 128.42 (2 C); 128.63; 128.71 (2 C); 128.87 (2 C); 130.38; 130.97;
133.91; 135.73; 138.69; 141.47; 147.06; 155.38; 157.00; 161.80; 174.35. Anal. calc. for C29H22O5: C 74.33, H 4.46;
found: C 74.06, H 4.48.
6-[(5-Benzyloxy-4-oxo-4H-pyran-2-yl)methoxy]-2-phenyl-4H-[1]benzopyran-4-one (7b). Yield: 94%
(from 5 and 6-hydroxy-2-phenyl-4H-[1]benzopyran-4-one). M.p. 222 2248. 1H-NMR (CDCl3): 4.94 (s, PhCH2);
5.09 (s, CH2O); 6.61 (s, HÀC(3')); 6.83 (s, HÀC(3)); 7.38 (m, 6 arom. H); 7.55 (m, 5 arom. H); 7.60
(s, HÀC(6')); 7.94 (m, 2 arom. H). 13C-NMR (CDCl3): 65.88; 71.99; 106.02; 106.96; 114.03; 120.16; 124.16;
124.60; 126.32 (2 C); 127.83 (2 C); 128.49; 128.75 (2 C); 129.02; 129.10 (2 C); 131.70; 135.64; 141.59; 147.36;
151.73; 154.81; 161.86; 163.57; 174.40; 178.01. Anal. calc. for C29H22O5: C 74.33, H 4.46; found: C 74.31, H 4.55.
5-Benzyloxy-2-{[(9H-carbazol-2-yl)oxy]methyl}-4H-pyran-4-one (7c). Yield: 86% (from 5 and 9H-
carbazol-2-ol). M.p. 196 1988. 1H-NMR (CDCl3): 4.86 (s, PhCH2); 5.05 (s, CH2O); 6.64 (s, HÀC(3')); 6.90
(m, 2 arom. H); 7.17 7.37 (m, 8 arom. H); 7.55 (s, HÀC(6)); 7.96 (m, 2 arom. H); 8.17 (br. s, NH). 13C-NMR
(CDCl3): 66.22; 71.99; 96.42; 108.19; 110.49; 114.11; 118.51; 119.71 (2 C); 121.28; 123.20; 125.06; 127.83 (2 C);
128.46; 128.73 (2 C); 135.69; 139.72; 140.55; 141.63; 147.31; 156.79; 162.76; 174.53. Anal. calc. for C25H19NO4: C
75.55, H 4.82, N 3.52; found: C 75.43, H 4.84, N 3.50.
5-Benzyloxy-2-{[(dibenzo[a,d]furan-2-yl)oxy]methyl}-4H-pyran-4-one (7d). Yield: 46% (from 5 and 2-
hydroxydibenzo[b,d]furan). M.p. 144 1468. 1H-NMR (CDCl3): 4.91 (s, PhCH2); 5.10 (s, CH2O); 6.62
(s, HÀC(3)); 7.07 (dd, J ˆ 8.8, 2.6, HÀC(3)); 7.26 7.53 (m, 10 arom. H); 7.59 (s, HÀC(6)); 7.89 (m, 1 arom.
H). 13C-NMR (CDCl3): 66.84; 72.00; 105.69; 111.86; 112.46; 114.15; 115.68; 120.66; 122.64; 124.09; 124.98;
127.52; 127.84 (2 C); 128.47; 128.73 (2 C); 135.69; 141.67; 147.31; 151.64; 153.77; 157.03; 162.59; 174.51. Anal.
calc. for C25H18O5: C 75.33, H 4.55; found: C 75.19, H 4.62.
5-Benzyloxy-2-[(9-oxo-9H-fluoren-2-yloxy)methyl]-4H-pyran-4-one (7e). Yield: 68% (from 5 and 2-
hydroxy-9H-fluoren-9-one). M.p. 205 2078. 1H-NMR (CDCl3): 4.85 (s, PhCH2); 5.08 (s, CH2O), 6.57
(s, HÀC(3)); 7.01 (dd, J ˆ 8.2, 2.6, HÀC(3')); 7.16 7.46 (m, 10 arom. H); 7.59 (m, HÀC(6), 1 arom. H).
13C-NMR (CDCl3): 65.80; 71.95; 109.86; 114.08; 119.86; 121.28; 121.63; 124.46; 127.80 (2 C); 128.31; 128.47;
128.72 (2 C); 134.21; 135.01; 135.60; 135.99; 138.36; 141.52; 144.40; 147.32; 158.56; 161.81; 174.31; 193.30. Anal.
calc. for C26H18O5 ¥ 0.5 H2O: C 74.46, H 4.56; found: C 74.32, H 4.41.
3-[(5-Benzyloxy-4-oxo-4H-pyran-2-yl)methoxy]-9H-xanthen-9-one (7f). Yield: 50% (from 5 and 3-
hydroxy-9H-xanthen-9-one). M.p. 178 1818. 1H-NMR (CDCl3): 4.93 (s, PhCH2); 5.08 (s, CH2O); 6.60
(s, HÀC(3')); 6.93 (m, 2 arom. H); 7.31 7.46 (m, 7 arom. H); 7.59 (s, HÀC(6')); 7.70 (m, 1 arom. H); 8.29
(m, 2 arom. H). 13C-NMR (CDCl3): 65.73; 71.92; 101.44; 113.01; 114.38; 116.74; 117.68; 121;82; 124.06; 126.63;

Helvetica Chimica Acta Vol. 86 (2003)
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127.76 (2 C); 128.44; 128.69 (2 C); 128.77; 134.52; 135.50; 141.53; 147.35; 156.12; 157.71; 161.05; 162.49; 174.17;
176.07. Anal. calc. for C26H18O6: C 73.23, H 4.25; found: C 73.02, H 4.28.
2-[(5-Benzyloxy-4-oxo-4H-pyran-2-yl)methoxy]anthraquinone (7g). Yield: 61% (from 5 and 2-hydroxy-
1
anthraquinone). M.p. 183 1848. H-NMR (DMSO): 4.93 (s, PhCH2); 5.30 (s, CH2O); 6.64 (s, HÀC(3')); 7.41
(m, 5 arom. H); 7.55 (m, 1 arom. H); 7.73 (s, HÀC(6')); 7.93 (m, 2 arom. H); 8.21 (m, 4 arom. H). 13C-NMR
(DMSO): 65.81; 70.59; 106.83; 111.14; 114.15; 121.44; 126.74; 126.79; 128.17 (2 C); 128.26; 128.47 (2 C); 129.65;
133.05; 133.09; 134.32; 134.72; 135.18; 136.01; 141.65; 146.95; 161.60; 162.10; 172.92; 181.38; 182.28. Anal. calc.
for C27H18O6: C 73.97, H 4.14; found: C 73.77, H 4.16.
5-Benzyloxy-1-methyl-2-{[(4-oxo-2-phenyl-4H-[1]benzopyran-3-yl)oxy]methyl}-1H-pyridin-4-one (8a).
Yield: 68% (from 6 and 3-hydroxy-2-phenyl-4H-[1]benzopyran-4-one). M.p. 113 1158. 1H-NMR (DMSO):
3.58 (s, MeN); 4.96 (s, PhCH2); 4.98 (s, CH2O); 6.10 (s, HÀC(3)); 7.36 (m, 5 arom. H); 7.46 (s, HÀC(6)); 7.54
(m, 4 arom. H); 7.82 (m, 4 arom. H); 8.14 (dd, J ˆ 8.0, 1.6, HÀC(5')). 13C-NMR (DMSO): 39.71; 69.18; 70.51;
118.23; 118.50; 123.45; 125.03; 125.32; 127.86; 127.94 (2 C); 128.30 (2 C); 128.44 (2 C); 128.50 (2 C); 129.14;
130.09; 130.96; 134.31; 137.06; 138.18; 142.81; 147.60; 154.86; 156.81; 171.18; 173.72. Anal. calc. for C29H23NO5: C
74.83, H 4.98, N 3.01; found: C 74.87, H 5.04, N 3.12.
5-Benzyloxy-1-methyl-2-{[(4-oxo-2-phenyl-4H-[1]benzopyran-6-yl)oxy]methyl}-1H-pyridin-4-one (8b).
Yield: 76% (from 6 and 6-hydroxy-2-phenyl-4H-[1]benzopyran-4-one). M.p. 1788 (dec). 1H-NMR (CDCl3):
3.63 (s, MeN); 4.94 (s, PhCH2); 5.19 (s, CH2O); 6.64 (s, HÀC(3)); 6.83 (s, HÀC(3')); 7.04 (s, HÀC(6)); 7.31
7.65 (m, 11 arom. H); 7.92 (m, 2 arom. H). 13C-NMR (DMSO) 40.60; 66.85; 71.85; 106.43; 106.88; 111.99;
119.04; 120.14; 123.82; 124.59; 126.26 (2 C); 127.84 (2 C); 128.06; 128.53 (2 C); 129.06 (2 C); 129.44; 131.59;
131.69; 136.67; 142.22; 148.39; 154.67; 163.53; 173.19; 177.90. Anal. calc. for C29H23NO5: C 74.83, H 4.98, N 3.01;
found: C 74.82, H 4.91, N 3.09.
5-Benzyloxy-2-{[(9H-carbazol-2-yl)oxy]methyl}-1-methyl-1H-pyridin-4-one (8c). Yield: 59% (from 6 and
1
9H-carbazol-2-ol). M.p. 1728 (dec). H-NMR (DMSO): 3.72 (s, MeN); 5.02 (s, PhCH2); 5.16 (s, CH2O); 6.46
(s, HÀC(3)); 6.89 (dd, J ˆ 8.8, 2.4, HÀC(3')); 7.11 (m, 2 arom. H); 7.28 7.45 (m, 7 arom. H); 7.71 (s, HÀC(6));
8.01 (m, 2 arom. H); 11.20 (br. s, NH). 13C-NMR (DMSO) 39.92; 65.84; 70.56; 96.11; 108.09; 110.70; 117.02;
118.64; 118.87; 119.44; 120.78; 121.02; 112.49; 124.42; 127.91; 128.02 (2 C); 128.35 (2 C); 129.38; 137.07; 139.88;
140.82; 143.98; 156.54; 171.36. Anal. calc. for C26H22N2O3: C 76.08, H 5.40, N 6.82; found: C 76.02, H 5.44, N 6.74.
5-Benzyloxy-2-{[(dibenzo[b;d]furan-2-yl)oxy]methyl}-1-methyl-1H-pyridin-4-one (8d). Yield: 73% (from
6 and dibenzo[b,d]furan-2-ol). M.p. 193 1958. 1H-NMR (CDCl3): 3.64 (s, MeN); 4.90 (s, PhCH2); 5.17
(s, CH2O); 6.60 (s, HÀC(3)); 7.02 (m, HÀC(6), HÀ(3')); 7.29 7.57 (m, 10 arom. H); 7.90 (d, J ˆ 7.2, HÀC(4')).
13C-NMR (CDCl3): 40.70; 67.81; 71.78; 105.53; 111.76; 112.40; 115.55; 119.24; 120.62; 122.61; 123.97; 124.92;
127.48; 127.80 (2 C); 128.02; 128.49 (2 C) ; 129.40; 136.65; 142.80; 148.32; 151.51; 153.55; 156.92; 173.15. Anal.
calc. for C26H21NO4: C 75.90, H 5.14, N 3.40; found: C 75.84, H 5.21, N 3.39.
5-Benzyloxy-1-methyl-2-{[(9-oxo-9H-fluoren-2-yl)oxy]methyl}-1H-pyridin-4-one (8e). Yield: 54% (from 6
and 2-hydroxy-9H-fluoren-9-one). M.p. 216 2178. 1H-NMR (DMSO): 3.69 (s, MeN); 5.01 (s, PhCH2); 5.19
(s, CH2O); 6.41 (s, HÀC(3)); 7.26 7.45 (m, 8 arom. H); 7.57 (m, 2 arom. H); 7.69 (s, HÀC(6)); 7.73 (m, 2 arom.
H). 13C-NMR (DMSO): 40.59; 65.81; 70.54; 110.48; 116.91; 120.56; 121.57; 122.42; 123.98; 127.87; 127.96 (2 C);
128.31 (2 C); 128.41; 129.41; 133.39; 135.04; 135.51; 137.02; 137.21; 143.35; 144.13; 147.50; 158.71; 171.28; 192.81.
Anal. calc. for C27H21NO4: C 76.58, H 5.00, N 3.31; found: C 76.58, H 5.03, N 3.36.
5-Benzyloxy-1-methyl-2-{[(9-oxo-9H-xanthen-3-yl)oxy]methyl}-1H-pyridin-4-one (8f). Yield: 94% (from
6 and 3-hydroxy-9H-xanthen-9-one). M.p. 204 2068. 1H-NMR (DMSO): 3.71 (s, MeN); 5.02 (s, PhCH2); 5.31
(s, CH2O); 6.45 (s, HÀC(3)); 7.19 (dd, J ˆ 9.0, 2.0, HÀC(2')); 7.33 7.88 (m, arom. H); 8.17 (m, 7 arom. H).
13C-NMR (DMSO): Anal. calc. for C27H21NO5: C 73.79, H 4.82, N 3.19; found: C 73.80, H 4.88, N 3.12.
2-[(5-Benzyloxy-1,4-dihydro-1-methyl-4-oxopyridin-2-yl)methoxy]anthraquinone (8g). Yield: 87% (from 6
and 2-hydroxyanthraquinone). M.p. 229 2318. 1H-NMR (DMSO): 3.71 (s, MeN); 5.02 (s, PhCH2); 5.36
(s, CH2O); 6.45 (s, HÀC(3')); 7.33 7.78 (m, 8 arom. H); 7.93 (m, 2 arom. H); 8.20 (m, 3 arom. H). 13C-NMR
(DMSO): 40.52; 65.91; 70.48; 106.32; 111.21; 117.14; 121.49; 126.62; 126.69; 127.09; 127.81; 127.89 (2 C); 128.25
(2 C); 129.39; 129.47; 133.00; 134.19; 134.61; 135.06; 136.95; 142.81; 147.52; 162.06; 171.21; 181.27; 182.22. Anal.
calc. for C28H21NO5: C 74.49, H 4.69, N 3.10; found: C 74.50, H 4.76, N 3.11.
General Procedure for Removal of the Protecting Group. A suspension of the (5-benzyloxy-4-oxo-4H-
pyran-2-yl)methoxy derivative 7 (3 mmol) or the corresponding (5-benzyloxy-1-methyl-4-oxo-1,4-dihydropyr-
idin-2-yl)methoxy derivative 8 (3 mmol) in AcOH (15 ml) was treated with 20% HCl (15 ml), and the mixture
was heated at reflux for 8 34 h (monitored by TLC). After evaporation of the AcOH, the residue was
suspended in H2O (30 ml). The resulting precipitate was filtered and washed with H2O. The crude product was
crystallized from EtOH.

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Helvetica Chimica Acta Vol. 86 (2003)
3-[(5-Hydroxy-4-oxo-4H-pyran-2-yl)methoxy)]-2-phenyl-4H-[1]benzopyran-4-one (9a). Yield: 81% (from
7a). M.p. 149 1528. 1H-NMR (DMSO) 4.96 (s, CH2O); 6.37 (s, HÀC(3')); 7.55 (m, 4 arom. H); 7.47 7.87
(m, HÀC(6'), 2 arom. H); 7.98 (m, 2 arom. H); 8.13 (m, 1 arom. H); 9.10 (br. s, OH). 13C-NMR (DMSO):
69.38; 113.33; 118.51; 123.43; 124.99; 125.25; 128.41 (2 C); 128.54 (2 C); 130.06; 130.93; 134.28; 138.75; 139.52;
145.82; 154.82; 156.07; 161.75; 173.50; 173.58. Anal. calc. for C21H14O6: C 69.61, H 3.89; found: C 69.63, H 3.92.
6-[(5-Hydroxy-4-oxo-4H-pyran-2-yl)methoxy]-2-ph enyl-4H-[1]benzopyran-4-one (9b). Yield: 94% (from
7b). M.p. 245 2478. 1H-NMR (DMSO) 5.16 (s, CH2O); 6.61 (s, HÀC(3')); 7.04 (s, HÀC(3)); 7.57 (m, 5 arom.
H); 7.81 (m, 1 arom. H); 8.10 (m, 2 arom. H); 8.15 (s, HÀC(6')); 9.26 (br. s, OH). 13C-NMR (DMSO) 65.86;
106.13; 106.29; 112.62; 120.35; 123.64; 123.93; 126.24 (2 C); 129.04 (2 C); 131.04; 131.72; 139.90; 145.98; 150.77;
154.69; 161.92; 162.41; 173.58; 176.69. Anal. calc. for C21H14O6: C 69.61, H 3.89; found: C 69.64, H 3.95.
2-{[(9H-Carbazol-2-yl)oxy]methyl}-5-hydroxy-4H-pyran-4-one (9c). Yield: 76% (from 7c). M.p. 185
1878. 1H-NMR ((D6)DMSO): 5.10 (s, CH2O); 6.59 (s, HÀC(3)); 6.86 (dd, J ˆ 8.6, 2.2, HÀC(3')); 7.06 (d, J ˆ
2.4, HÀC(1')); 7.13 (m, 1 arom. H); 7.27 (m, 2 arom. H); 7.42 (d, J ˆ 8.0, HÀC(4)); 8.00 (m, 2 arom. H); 8.14
(s, HÀC(6')); 9.23 (br. s, OH); 11.17 (br. s, NH). 13C-NMR ((D6)DMSO): 65.66; 95.85; 107.88; 110.58; 112.35;
116.92; 118.52; 119.32; 120.94; 122.35; 124.32; 128.36; 139.76; 140.69; 145.94; 156.42; 162.68; 173.57. Anal. calc.
for C18H13NO4: C 70.35, H 4.26, N 4.56; found: C 70.38, H 4.21, N 4.54.
2-{[(Dibenzo[b,d]furan-2-yl)oxy]methyl}-5-hydroxy-4H-pyran-4-one (9d). Yield: 88% (from 7d). M.p.
184 1868. 1H-NMR ((D6)DMSO): 5.12 (s, CH2O); 6.62 (s, HÀC(3)); 7.22 (dd, J ˆ 9.0, 2.8, HÀC(3')); 7.40
(m, 1 arom. H); 7.53 (m, 1 arom. H); 7.67 (m, 2 arom. H); 7.86 (d, J ˆ 2.8, HÀC(1')); 8.16 (m, HÀC(6), 1 arom.
H); 9.25 (br. s, OH). 13C-NMR (CDCl3): 66.26; 106.02; 111;72; 112.32; 112.50; 116.02; 121.24; 122.89; 123.71;
124.24; 127.70; 139.93; 146.04; 150.52; 153.80; 156.20; 162.53; 173.71. Anal. calc. for C18H12O5: C 70.13, H 3.92;
found: C 70.08, H 3.98.
5-Hydroxy-2-{[(9-oxo-9H-fluoren-2-yl)oxy]methyl}-4H-pyran-4-one (9e). Yield 65% (from 7e). M.p.
216 2188. 1H-NMR (DMSO): 5.12 (s, CH2O); 6.59 (s, HÀC(3)); 7.27 (m, 3 arom. H); 7.57 (m, 2 arom. H); 7.71
(m, 2 arom. H); 8.14 (s, HÀC(6)); 9.30 (br. s, OH). 13C-NMR ((D6)DMSO): 65.71; 110.24; 112.54; 120.47;
121.23; 122.37; 123.90; 128.35; 133.31; 134.99; 135.43; 137.13; 139.88; 144.00; 145.96; 158.63; 161.96; 173.58;
192.68. Anal. calc. for C19H12O5: C 71.25, H 3.78; found: C 71.26, H 3.82.
3-[(5-Hydroxy-4-oxo-4H-pyran-2-yl)methoxy]-9H-xanthen-9-one (9f). Yield 95% (from 7f). M.p. 251
2538. 1H-NMR (DMSO): 5.23 (s, CH2O); 6.65 (s, HÀC(3')); 7.16 (dd, J ˆ 8.6, 2.4, HÀC(2)); 7.31 (d, J ˆ 2.4,
HÀC(4)); 7.48 (m, 1 arom. H); 7.63 (d, J ˆ 8.6, HÀC(1)); 7.86 (m, 1 arom. H); 8.16 (m, HÀC(6'), 2 arom. H);
9.30 (br. s, OH). 13C-NMR (DMSO) 65.89; 101.67; 112.82; 113.78; 115.53; 117.84; 121.09; 124.32; 125.82; 127.76;
135.07; 139.97; 146.03; 155.53; 157.24; 161.34; 162.83; 173.56; 174.84. Anal. calc. for C19H12O6: C 67.86, H 3.60;
found: C 67.76, H 3.68.
2-[(5-Hydroxy-4-oxo-4H-pyran-2-yl)methoxy]anthraquinone (9g). Yield 91% (from 7g). M.p. 237 2388.
1H-NMR (DMSO): 5.28 (s, CH2O); 6.64 (s, HÀC(3')); 7.55 (dd, J ˆ 8.4, 2.6, HÀC(3)); 7.70 (d, J ˆ 2.6,
HÀC(1)); 7.92 (m, 2 arom. H); 8.15 (s, HÀC(6')); 8.18 (m, 3 arom. H); 9.30 (br. s, OH). 13C-NMR (DMSO)
65.92; 111.08; 112.89; 121.36; 126.65; 126.73; 127.15; 129.56; 132.99; 133.02; 134.22; 134.63; 135.12; 140.03;
146.10; 161.46; 162.08; 173.62; 181.29; 182.20. Anal. calc. for C20H12O6: C 68.97, H 3.47; found: C 68.95, H 3.49.
5-Hydroxy-1-methyl-2-{[(4-oxo-2-phenyl-4H-[1]-benzopyran-3yl)oxy]methyl}-1H-pyridin-4-one (10a).
Yield: 73% (from 8e). M.p. 185 1868. 1H-NMR (DMSO): 3.88 (br. s, OH); 4.02 (s, MeN); 5.24 (s, CH2O);
7.38 (s, HÀC(3)); 7.58 (m, 4 arom. H); 7.88 (m, 4 arom. H); 8.15 (dd, J ˆ 8.0, 1.4, HÀC(5')); 8.23 (s, HÀC(6)).
13C-NMR (DMSO) 42.84; 68.27; 113.75; 118.59; 123.42; 125.02; 125.43; 128.49 (2 C); 128.66 (2 C); 129.92;
131.14; 133.02; 134.47; 138.50; 144.04; 144.64; 154.91; 156.67; 160.12; 173.69. Anal. calc. for C22H17NO5 ¥ 0.2 H2O:
C 69.73, H 4.62, N 3.70; found: C 69.62, H 4.64, N 3.66.
5-Hydroxy-1-methyl-2-{[(4-oxo-2-phenyl-4H-6-yl)oxy]methyl}-1H-pyridin-4-one (10b). Yield: 75% (from
8f). M.p. 263 2668. 1H-NMR (DMSO): 3.86 (br. s, OH); 4.10 (s, MeN); 5.52 (s, CH2O); 7.07 (s, HÀC(3)); 7.56
(s, HÀC(3')); 7.63 (m, 5 arom. H); 7.86 (d, J ˆ 9.0, HÀC(8')); 8.12 (m, 2 arom. H); 8.39 (s, HÀC(6)). 13C-NMR
(DMSO): 42.86; 65.08; 106.28; 106.98; 112.39; 120.55; 123.75; 124.11; 126.36 (2 C); 129.16 (2 C); 131.11; 131.88;
133.16; 144.56 (2 C); 151.08; 154.49; 160.64; 162.55; 176.80. Anal. calc. for C22H17NO5: C 70.39, H 4.56, N 3.73;
found: C 70.36, H 4.68, N 3.77.
2-{[(9H-Carbazol-2-yl)oxy]methyl}-5-hydroxy-1-methyl-1H-pyridin-4-one (10c). Yield: 68% (from 8h).
M.p. 198 1998. 1H-NMR (DMSO): 3.85 (br. s, OH); 4.04 (s, MeN); 5.41 (s, CH2O); 7.13 7.48 (m, 6 arom. H);
8.03 (m, 2 arom. H); 8.25 (s, HÀC(6)); 11.27 (br. s, NH). 13C-NMR (DMSO): 42.30; 65.01; 96.33; 107.83; 110.68;
112.46; 118.59; 119.41; 121.00; 122.32; 124.44; 128.43; 131.86; 139.87; 140.71; 144.76; 144.90; 156.12; 161.86.
Anal. calc. for C19H16N2O3 ¥ 0.5H2O: C 69.29, H 5.20, N 8.50; found: C 69.21, H 5.28, N 8.47.

Helvetica Chimica Acta Vol. 86 (2003)
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2-{[(Dibenzo[b,d]furan-2-yl)oxy]methyl}-5-hydroxy-1-methyl-1H-pyridin-4-one (10d). Yield: 86% (from
8i). M.p. 107 1098. 1H-NMR (DMSO): 4.07 (s, MeN); 4.15 (br. s, OH); 5.44 (s, CH2O); 7.19 7.17 (m, 7 arom.
H); 8.15 (m, 1 arom. H); 8.29 (s, HÀC(6)). 13C-NMR (DMSO): 42.46; 65.65; 106.39; 111.78; 112.43; 116.26;
121.27; 122.97; 123.68; 124.30; 127.81; 128.50; 128.65; 132.05; 144.83; 150.70; 153.52; 156.24; 161.91. Anal. calc.
for C19H15NO4: C 71.02, H 4.71, N 4.36; found: C 69.98, H 4.80, N 4.26.
5-Hydroxy-1-methyl-2-{[(9-oxo-9H-fluoren-2-yl)oxy]methyl}-1H-pyridin-4-one (10e). Yield: 72% (from
1
8j). M.p. 248 2518. H-NMR (DMSO): 3.75 (br. s, OH); 4.05 (s, MeN); 5.45 (s, CH2O); 7.34 (m, 3 arom. H);
7.47 (s, HÀC(3)); 7.57 (m, 2 arom. H); 7.75 (m, 2 arom. H); 8.34 (s, HÀC(6)). 13C-NMR (DMSO): 42.80; 65.01;
110.64; 112.18; 120.69; 121.66; 122.55; 124.05; 128.58; 133.07; 133.40; 135.14; 135.60; 137.60; 144.04; 144.50;
144.65; 158.40; 160.69; 192.79. Anal. calc. for C20H15NO4 ¥ 0.8H2O: C 69.07, H 4.81, N 4.03; found: C 69.11, H
4.86, N 4.08.
5-Hydroxy-1-methyl-2-{[(9-oxo-9H-xanthen-3-yl)o xy]methyl}-1H-pyridin-4-one (10f). Yield: 95% (from
8k). M.p. 257 2598. 1H-NMR (DMSO): 3.85 (br. s, OH); 4.08 (s, MeN); 5.57 (s, CH2O); 7.24 (dd, J ˆ 8.8, 2.2,
HÀC(2')); 7.45 8.21 (m, 7 arom. H); 8.37 (s, HÀC(6)). 13C-NMR (DMSO): 43.18; 65.42; 102.45; 107.09;
112.33; 114.31; 116.15; 118.21; 121.47; 124.79; 126.23; 128.22; 133.57; 135.56; 144.42; 144.80; 155.91; 157.64;
162.79; 175.22. Anal. calc. for C20H15NO5: C 68.76, H 4.33, N 4.01; found: C 68.71, H 4.33, N 4.06.
2-[(1,2-Dihydro-5-hydroxy-1-methyl-4-oxopyridin-2-yl)methoxy]anthraquinone (10g). Yield: 83% (from
8l). M.p. 2128 (dec). 1H-NMR (DMSO): 3.75 (br. s, OH); 4.08 (s, MeN); 5.61 (s, CH2O); 7.47 (s, HÀC(3')); 7.63
(dd, J ˆ 8.8, 2.6, HÀC(3)); 7.83 (d, J ˆ 2.6, HÀC(1)); 7.94 (m, 2 arom. H); 8.22 (m, 3 arom. H); 8.32
(s, HÀC(6')). 13C-NMR (DMSO): 43.05; 65.40; 107.09; 111.78; 112.99; 121.78; 127.02; 127.07; 127.71; 129.94;
133.07; 133.32; 134.62; 135.03; 135.46; 144.17; 145.07; 161.47; 162.05; 181.63; 182.55. Anal. calc. for C21H15NO5: C
69.80, H 4.18, N 3.88; found: C 69.72, H 4.22, N 3.91.
Financial support of this work by the National Science Council of the Republic of China (NSC 90-2113-M-
037-014) 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.
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Received October 18, 2002