Design, synthesis and antitumor activities of novel 7-arylseleno-7-deoxydaunomycinone derivatives

Article abstract of DOI:10.1016/S0968-0896(02)00321-8

7-Arylseleno-7-deoxydaunomycinone derivatives 3a-e and 7-thiophenyl-7-deoxydaunomycinones (7 and 8) were synthesized and the antitumor activities of them were evaluated against human stomach cancer SGC-7901 and human leukaemia HL60. The cytotoxic assay sh

Full text of DOI:10.1016/S0968-0896(02)00321-8

Bioorganic & Medicinal Chemistry 10 (2002) 3899–3904
Design, Synthesis and Antitumor Activities of Novel 7-Arylseleno-
7
-deoxydaunomycinone Derivatives
Shu-Jia Zhang, Zheng-Ping Jia and Yan-Guang Wang*
Department of Chemistry, Zhejiang University, Hangzhou, 310027, China
Received 15 July 2002; accepted 22 July 2002
Abstract—7-Arylseleno-7-deoxydaunomycinone derivatives 3a–e and 7-thiophenyl-7-deoxydaunomycinones (7 and 8) were syn-
thesized and the antitumor activities of them were evaluated against human stomach cancer SGC-7901 and human leukaemia
HL60. The cytotoxic assay show that seleno daunomycinone derivatives are much better inhibitory activity than thiodaunomyci-
none and the structure–activity relationship was discussed. 7-Deoxydaunomycinone 4 was obtained when selenophenols were used
in excess and the possible mechanism was proposed.
#
2002 Elsevier Science Ltd. All rights reserved.
Introduction
the glycosidic oxygen analogue, which might produce
new molecules to be more accommodated in the minor
groove of DNA. Selenium now was recognized as an
essential nutriment and its deficiency can result in many
Daunorubicin (1a, R=H, DAU) and Doxorubicin (1b,
R=OH, DOX, Fig. 1) are clinically useful anthracycline
antitumor agents currently. However, their clinical uses
are hampered by a number of undesirable side effects,
8
,9
diseases in human body, such as cancer, cardiovas-
1
0
10
cular disease,
10
loss of immunocompetence,
viral
1
especially serious cardiotoxicity. The mechanism of
antibiotic action of DOX lies in its ability to intercalate
between adjacent DNAbase pairs causing topoisome-
infections and so on. On the other hand, selenium
can be a chemopreventive agent to remedy and retard
cancers. In this work, displacement of oxygen atom at
9
2
,3
rase II inhibition. DNAbinding data and the results
of biological testing point out that the groups linked at
C-7 and C-9 play an important role in the stabilization
of the cleavable ternary complex drug-DNA–topo-
isomerase II via specific contacts.2 The possible cova-
lent bindings between C-7 and various biological
nucleophiles have been sugessted as a root for the toxic
side effects of daunorubicin and doxorubicin. Many
efforts have been made to modify the anthracyclines and
try to develop analogues with high activity and low
toxicity, and most of them maintain the sugar moiety.
Several analogues with various leaving group have been
synthesized, and displacement of the 7-OH with O-, S-
C-7 of daunomycinone 2 with arylseleno group was
explored. 7-Arylseleno-daunomycinone derivatives were
synthesized and their antitumor activities were eval-
uated against human stomach cancer SGC-7901 and
human leukaemia HL60 in vitro. In order to compare
the antitumor activities of selenium and sulfur, we
also synthesized 7-thiophenyl-7-deoxydaunomycinone
analogues.
ꢀ4
5
6
Results and Discussion
Chemistry
7
and C-nucleophiles has been described. But the dis-
placement of 7-OH of daunomycinone by selenium
group has not been reported so far, and the replacement
of glycoside oxygen by selenium group might possibly
exhibit biological properties remarkably different from
Usually, the catalysts used to synthesize the selenide
from alcohol and selenols are acetic acid, trifluoroacetic
acid, boron-trifluoride etherate and so on. In our
experiment, trifluoroacetic acid (TFA), p-toluene-
sulfonic acid (p-TsOH), boron-trifluoride etherate, zinc
chloride, acetic acid and hydrochloride were used to
catalyze the synthesis of 7-arylseleno-7-deoxydauno-
mycinones 3 from daunomycinone 2 and selenophenols.
*
5
Corresponding author. Tel.:+86-571-879-51512; fax:+86-571-879-
1512; e-mail: xianfeng@css.zju.edu.cn
0
968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(02)00321-8

3900
S.-J. Zhang et al. / Bioorg. Med. Chem. 10 (2002) 3899–3904
ppm with a coupling constant of 2.4–3.6 Hz. According
5
,11
to literature reports
and comparing with the J (H-7,
d 5.31 ppm, J=3.8 Hz) of daunomycinone 2, the con-
figuration of 3a–f was determined as 7S-configuration.
Interestingly, when the molar ratio of 2 to selenophenols
.
was 1:1 catalyzed by BF OEt and ZnCl , the products 3
3
2
2
were obtained mainly. When selenophenols exceeds 2 by
–3 times, however, 7-deoxydaunomycinone 4 was the
2
main product at room temperature for 30 min. But at
first 5 min reaction, 3 was detected on TLC. On the
other hand, pure 3a (7S configuration) was tested in the
Figure 1. Structures of daunorubicin and doxorubicin.
.
presence of BF OEt in CH Cl , 4 was not found but 5
2
3
2
2
As a result, trifluoroacetic acid, in dichloromethane at
room temperature for 3 h, was the most potent and
convenient catalyst for this reaction. The synthetic
approach catalyzed by trifluoroacetic acid was depicted
in Scheme 1. The experimental results, catalyzed by
trifluoroacetic acid and other catalysts, are listed in
Tables 1 and 2, respectively.
(7R-isomer, H-7, d 4.98 ppm, dd, J=8.5, 6.1 Hz) was
obtained mainly (Scheme 2).
At same time, benzyl alcohol and 1,4-dihydroxy-anthra-
quinone 6 were reacted with excessive selenophenol cat-
.
alyzed by BF OEt in CH Cl , benzyl phenyl selenide
3
2
2
2
was gained (identified by GC–MS) and 6 remained
unchanged (Scheme 3). The above experiments sug-
gested that selenophenol could not be a reducer to
reduce quinone directly and the formation of 4 is related
to the structure of daunomycinone. It is known that
selenium has reductive properties and anthraquinone is
Displacement of 7-OH group in compound 2 should
exist in formation of two isomers, that is, 7S and 7R
configurations. In reaction conditions described above,
only one isomer was obtained. The NMR spectra of
compound 3a–f show: H-7 as doublet at d 4.87–4.95
Scheme 2.
Scheme 1.
Table 1. Experimental results of the synthesis of compound 3a–e
catalyzed by TFA
ꢁ
Compd
Ar
Yield (%)
Mp ( C)
3a
3b
3c
3d
3e
3f
C
6
H
5
64.1
70.2
71.7
58.2
78.3
74.8
187–188.5
173–175
167–170
177.5–181
168.5–169.5
96—99
p-MeC
p-MeOC
o-ClC
m-MeC
Naphthyl
6
H
4
6
H
4
6
H
4
6
H
4
Scheme 3.
Table 2. Experimental results catalyzed by other catalysts
ꢁ
Cat.
Solvent
Time
Temp ( C)
Yield (%)
Product
TFACH
p-TsOH
2
2
2
2
Cl
Cl
Cl
Cl
2
2
2
2
3 h
5 h
15 min
1 h
20 min
rt
rt
rt
64.1
61.8
49.8
58.7
51.2
3a (only)
3a (only)
3a (main)
3a (only)
3a (main)
CH
CH
CH
3
BF .OEt
2
ꢀ15
ZnCl
AcOH
HCl
2
Cl(CH
2
)
2
Cl
80
Unreacted
Unreacted

S.-J. Zhang et al. / Bioorg. Med. Chem. 10 (2002) 3899–3904
3901
Scheme 4.
an oxidant. It has been reported that anthracyclines
could form an anthracycline radical in the body and this
is the main reason why anthracyclines are cardio-
toxic. On the basis of the reports, we propose the
following mechanism for the formation of 4 (Scheme 4).
Further confirmation of this mechanism is under way.
In order to compare the antitumor activity of selenium
and sulfur analogues, we synthesized 7-thiophenyl-7-
deoxydaunomycinone 7 and 8 from daunomycinone 2
4
,12
.
and thiophenol catalyzed by CF COOH and BF OEt ,
3
3
2
respectively. In contrast to seleno derivatives, 7S- and
7R-thiophenyl-7-deoxydaunomycinone were both
obtained at any time, but 4 was not found even though
the thiophenol was added in excess, probably because
the reductive power of selenium is stronger than sulfur.
The ratio of 7S (7):7R (8) was 2:1 from the reaction
Because boron-trifluoride etherate and zinc chloride are
stronger Lewis acid than trifluoroacetic acid and
p-toluenesulfonic acid, arylseleno group of 3 can not
leave in the presence of TFAand p-TsOH as catalysts at
room temperature, so main product was 3 no matter if
the selenophenols were excessive or not.
catalyzed by CF COOH (Scheme 5).
3
Biological Activity
The conversion from 3a to 5 can be explained from the
half-chair conformation of ring Ain 3a and 5 (Fig. 2).
Selenophenyl group in 3a was in the axial position,
whereas it was in the equatorial orientation in 5. Com-
pound 5, a thermodynamically controlled product, is more
stable than 3a, so 5 was obtained after a long time reaction.
In another experiment conducted, after 6 h reaction of
daunomycinone and selenophenol catalyzed by TFAat
room temperature, compound 5 can be detected.
Compounds 3a–e, 7 and 8 were assayed for cytotoxicity
by using cells of human stomach cancer SGC-7901 and
human leukaemia HL60. Results are expressed in terms
of inhibitory activity (IC , mg/mL) obtained by the
5
0
MTT method. The results are listed in Table 3.
As shown in Table 3, seleno daunomycione derivatives
showed inhibitory activity on the human stomach can-
cer SGC-7901 and the human leukaemia HL60, but
lesser extent than DAU. Among compounds tested,
7-phenylselenodaunomycinone 3a and 7-(o-chloro-
phenylseleno)daunomycinone 3d were found to be
highly cytotoxic against human stomach cancer, and
7-(p-methylphenylseleno)daunomycinone 3c was found
to be highly cytotoxic against human leukaemia HL60.
On the other hand, seleno derivatives 3a–e are much
more potent than the thio analogues 7 and 8 regarding
tested tumor cells, and the quinone radical intermediate
4A or 4B probably are the key reason on this fact.
Seleno derivatives might form quinone radical inter-
mediate 4A or 4B to intercalate between DNAbase
Figure 2. The conformation of 3a and 5.
Table 3. Cytotoxicities of new compounds 3a–e, 7 and 8 against
tumor cells
a
IC50 (mg/mL)
Compd
Ar
SGC-7901b
HL60c
3
3
3
3
3
6
6
a
b
c
d
e
C
6
H
5
21.7
34.5
91.8
23.8
68.2
58.7
36.8
76.1
p-MeC
p-MeOC
o-ClC
m-CH
6
H
4
6
H
4
6
H
4
3
C
6
H
4
63.6
51.2
A
B
—
—
—
>100
>100
0.23
>100
>100
DAU
0.08
aActivity against tumor cells was measured by MTT-microculture
tetrazolium assay.
b
SGC-7901, human stomach cancer.
HL60, human leukemia.
c
Scheme 5.

3902
S.-J. Zhang et al. / Bioorg. Med. Chem. 10 (2002) 3899–3904
pairs causing cytotoxicity, whereas thio derivatives do
not have this ability. Further studies on the antitumor
abilities of sulfur and selenium are under way.
(CH ). Anal. calcd for C H O Se: C, 60.34; H, 4.13.
3
Found: C, 60.37; H, 4.11.
27 22
7
7-(4-Methylphenylseleno)-7-deoxydaunomycinone (3b). A
mixture of daunomycinone 2 (34 mg, 0.08), selenophe-
nol (15 mg, 0.09 mmol) and trifluoroacetic acid (0.5 mL)
was dissolved in dichloromethane and stirred for 3 h to
give 33 mg of 3b (70.2%) as a red powder. IR: 3441,
Conclusion
We have completed the synthesis and cytotoxic assay of
novel 7-arylseleno-7-deoxydaunomycinone derivatives
and 7-thiophenyl-7-deoxydaunomycinone analogues
derived from daunomycinone. All synthesized seleno
derivatives exhibited antitumor activities against human
stomach cancer SGC-7901 and human leukaemia HL60.
The cytotoxicity data suggest that the seleno derivatives
are much more potent than the thio analogues.
1
1695, 1618, 1538; H NMR: 14.04 (1H, s, OH), 13.40
(1H, s, OH), 8.07 (1H, d, J=7.6 Hz, ArH), 7.77 (1H, t,
J=7.8 Hz, ArH), 7.65 (2H, d, J=7.8 Hz, ArH), 7.38
(1H, d, J=8.2 Hz, ArH), 7.14 (2H, d, J=7.8 Hz, ArH),
4.91 (1H, d, J=2.7 Hz, H-7), 4.09 (3H, s, OCH ), 3.20
3
(1H, dd, J=18.7, 1.3 Hz, H-10e), 3.01 (1H, d, J=18.7
Hz, H-10a), 2.48 (1H, dd, J=14.8, 5.0 Hz, H-8e), 2.45
(
1H, d, J=14.8 Hz, H-8a), 2.40 (3H, s, CH ), 2.36 (3H,
3
1
3
s, CH3); C NMR: 211.79 (C¼O), 187.17 (C¼O),
1
1
86.64 (C¼O), 161.26 (C-4), 155.91 (C-6), 155.84 (C-
Experimental
1), 139.20 (C-2), 137.27 (C-6a), 135.89 (C), 135.48
Melting point was determined on a YANACO melting
point apparatus and uncorrected. Infrared (IR) spectra
were taken on a Nicolet 230 FT-IR spectrophotometer.
Elemental analyses were performed on Carlo Elba 1106
(2ꢂCH), 133.51 (C-12a), 130.99 (C-10a), 129.48 (2CH),
128.48 (C), 121.31 (C-4a), 119.91 (C-3), 118.59 (C-1),
111.30 (C-5a), 110.78 (C-11a), 77.02 (C-9), 56.91
(OCH ), 35.59 (C-7), 35.02 (C-8), 33.18 (C-10), 24.76
3
1
13
instrument. H and C NMR spectra were recorded on
AVANCE DMX500 using CDCl . Chemical shifts were
(CH ), 21.56 (CH ). Anal. calcd for C H O Se: C,
3
3
28 24
7
60.98; H, 4.39. Found: C, 61.02; H, 4.36.
3
reported at d values in parts per million (ppm) and
coupling constants (J) are given in hertz (Hz). MS
spectra were recorded on ESQUIRE-LC-00075.
7-(4-Methoxyphenylseleno)-7-deoxydaunomycinone (3c).
Amixture of daunomycinone 2 (42 mg, 0.11 mmol),
selenophenol (20 mg, 0.11 mmol) and trifluoroacetic
acid (0.5 mL) was dissolved in dichloromethane and
stirred for 3 h to give 43 mg of 3c (71.7%) as a red
1
General experimental procedure for the synthesis of 7-
arylseleno-7-deoxydaunomycinone 3. To a solution of 2
in CH Cl (10 mL) was added selenophenols (1 equiv) and
powder. IR: 3433, 1695, 1617, 1583; H NMR: 14.07
(1H, s, OH), 13.40 (1H, s, OH), 8.03 (1H, d, J=7.7 Hz,
ArH), 7.78 (1H, t, J=8.2 Hz, ArH), 7.68 (1H, d, J=8.7
Hz, ArH), 7.39 (1H, d, J=8.3 Hz, ArH), 6.85 (1H, d,
J=8.7 Hz, ArH), 4.87 (1H, d, J=2.4 Hz, H-7), 4.60
(1H, s, OH-9), 4.10 (3H, s, OCH ), 3.81 (3H, s, OCH ),
2
2
CF COOH 0.5 mL, stirred at room temperature for 3 h,
3
monitored by TLC. The reaction mixture quenched into
water, washed with saturated NaHCO , water, extrac-
3
3
3
ted with CH Cl (3ꢂ25 mL). The organic phase was
3.18 (1H, d, J=18.7 Hz, H-10e), 3.01 (1H, d, J=18.7
1
2
2
3
dried with anhydrous Na SO and then evaporated in
2
Hz, H-10a), 2.46 (2H, m, H-8), 2.40 (3H, s, CH3);
C
4
vacuum. The residue was purified by silica gel column
chromatography eluting with hexane/ dichloromethane/
acetate ester (4:4:1) and 3 was obtained in moderate to
high yield.
NMR: 211.89 (C¼O), 187.18 (C¼O), 186.65 (C¼O),
161.26 (C-4), 160.46 (C), 156.02 (C-6), 155.86 (C-11),
137.87 (2CH), 137.41 (C-2), 135.93 (C), 135.74 (C),
135.70 (C-12a), 135.58 (C-10a), 121.28 (C-4a), 119.92
(
C-3), 118.50 (C-1), 115.02 (2ꢂCH), 111.31 (C-5a),
7
-Phenylseleno-7-deoxydaunomycinone (3a). Amixture
of daunomycinone 2 (41 mg, 0.1 mmol), selenophenol
16 mg, 0.11 mmol) and trifluoroacetic acid (0.5 mL)
110.67 (C11a), 77.02 (C-9), 56.95 (OCH ), 56.54
3
(OCH ), 36.08 (C-7), 34.65 (C-8), 33.20 (C-10), 24.80
3
(
(CH ). Anal. calcd for C H O Se: C, 59.27; H, 4.26.
28 24
3
8
was dissolved in dichloromethane and stirred for 3 h to
give 35.5 mg of 3a (64.1%) as a red powder. IR: 3444,
Found: C, 59.23; H, 4.23.
1
1
(
695, 1617, 1583; H NMR: 14.02 (1H, s, OH), 13.40
1H, s, OH), 8.03 (1H, d, J=7.7 Hz, ArH), 7.77 (3H, m,
7-(2-Chlorophenylseleno)-7-deoxydaunomycinone (3d). A
mixture of daunomycinone 2 (55 mg, 0.14 mmol), sele-
nophenol (27 mg, 0.14 mmol) and trifluoroacetic acid
(0.5 mL) was dissolved in dichloromethane and stirred
for 3 h to give 46 mg of 3d (58.2%) as a red powder. IR:
ArHArH), 7.39 (1H, d, J=8.4 Hz, ArH), 7.34 (3H, m,
ArH), 4.95 (1H, d, J=3.7 Hz, H-7), 4.43 (1H, s, OH-9),
4
3
5
.09 (3H, s, OCH ), 3.19 (1H, d, J=18.7 Hz, H-10e),
3
1
.01 (1H, d, J=18.7 Hz, H-10a), 2.55 (1H, dd, J=14.7,
.2 Hz, H-8e), 2.49 (1H, d, J=14.7 Hz, H-8a), 2.39 (3H,
3433, 1708, 1617, 1538; H NMR: 13.77 (1H, s, OH),
13.36 (1H, s, OH), 7.98 (1H, d, J=7.65 Hz, ArH), 7.79
(1H, d, J=7.4 Hz, ArH), 7.74 (1H, t, J=8.0 Hz, ArH),
7.45 (1H, d, J=7.8 Hz, ArH), 7.34 (1H, d, J=8.2 Hz,
ArH), 7.26 (1H, m, ArH), 7.19 (1H, m, ArH), 4.94 (1H,
d, J=2.4 Hz, H-7), 4.10 (1H, s, OH-9), 4.05 (3H, s,
OCH3), 3.15 (1H, d, J=18.6 Hz, H-10e), 3.01 (1H, d,
J=18.6 Hz, H-10a), 2.67 (2H, m, H-8), 2.40 (3H, s,
1
3
s, CH3); C NMR: 211.69 (C¼O), 187.21 (C¼O),
1
1
86.70 (C¼O), 161.28 (C-4), 155.98 (C-6), 155.93 (C-
1), 137.49 (C-2), 135.93 (C-6a), 135.80 (C), 135.42
(
(
(
(
2ꢂCH), 133.42 (C-12a), 131.47 (C-10a), 129.38
2ꢂCH), 128.59 (C), 121.22 (C-4a), 119.94 (C-3), 118.53
C-1), 111.32 (C-5a), 110.70 (C-11a), 77.01 (C-9), 56.95
1
3
OCH ), 36.69 (C-7), 35.30 (C-8), 33.14 (C-10), 24.72
3
CH3); C NMR: 211.05 (C¼O), 187.10 (C¼O), 186.56

S.-J. Zhang et al. / Bioorg. Med. Chem. 10 (2002) 3899–3904
3903
ꢁ
1279, 1212, 1078, 1033; H NMR: 14.12 (1H, s, OH),
13.36 (1H, s, OH), 8.04 (1H, d, J=7.6 Hz, ArH),
7.78 (1H, t, J=8.3 Hz, ArH), 7.69 (2H, m, ArH),
7.39 (4H, m, ArHArH), 5.05 (1H, s, OH-9), 4.92 (1H,
(
1
1
(
3
C¼O), 161.24 (C-4), 156.27 (C-6), 156.02 (C-11),
7. Mp 182–185 C; IR: 3381, 1699, 1616, 1584, 1421,
1
38.49 (C-2), 138.31 (C-6a), 136.73 (CH), 135.90 (C),
35.77 (CH), 133.35 (C-12a), 132.71 (C-10a), 129.73
CH), 129.45 (CH), 127.33 (C), 121.27 (4a), 119.90 (C-
), 118.47 (C-1), 111.22 (C-5a), 110.50 (C-11a), 76.76
C-9), 56.93 (OCH ), 36.39 (C-7), 34.75 (C-8), 32.97 (C-
(
d, J=4.2 Hz, H-7), 4.09 (3H, s, OCH ), 3.27 (1H,
3
3
1
5
0), 24.47 (CH ). Anal. calcd for C H O SeCl: C,
3
6.71; H, 3.70. Found: C, 56.73; H, 3.66.
dd, J=18.9, 1.6 Hz, H-10e), 3.03 (1H, d, J=18.9 Hz,
H-10a), 2.41 (3H, s, CH ), 2.33 (1H, d, J=14.8 Hz,
27 21
7
3
1
3
H-8e), 2.21 (1H, dd, J=14.8, 5.0 Hz, H-8a);
C
7-(3-Methylphenylseleno)-7-deoxydaunomycinone (3e). A
mixture of daunomycinone 2 (51 mg, 0.13 mmol), sele-
nophenol (22 mg, 0.13 mmol) and trifluoroacetic acid
NMR: 212.0 (C¼O), 187.0 (C¼O), 186.65 (C¼O),
161.04 (C-4), 155.73 (C-6), 155.60 (C-11), 135.60 (C-
2), 134.73 (C-6a), 134.46 (C), 134.01 (C-12a), 133.49
(2ꢂCH), 129.372 (2ꢂCH), 128.58 (CH), 121.02 (C-
4a), 119.72 (C-3), 118.40 (C-1), 111.26 (C-5a), 110.93
(
for 3 h to give 55 mg of 3e (78.3%) as a red powder.: IR:
0.5 mL) was dissolved in dichloromethane and stirred
1
3
1
447, 1695, 1617, 1582; H NMR: 14.00 (1H, s, OH),
3.33 (1H, s, OH), 7.96 (1H, d, J=7.6 Hz, ArH), 7.23
(C-11a), 76.79 (C-9), 56.72 (OCH ), 42.00 (C-7), 33.32
3
(C-8), 32.67 (C-10), 24.73 (CH ). Anal. calcd for
3
(
1H, t, J=8.0 Hz, ArH), 7.57 (1H, s, ArH), 7.53 (1H, d,
J=7.6 Hz, ArH), 7.34 (1H, d, J=8.3 Hz, ArH), 7.21
1H, q, J=7.6 Hz, ArH), 7.14 (1H, d, J=7.5 Hz, ArH),
.91 (1H, d, J=3.6 Hz, H-7), 4.06 (3H, s, OCH ), 3.18
C H O S: C, 66.11; H, 4.52. Found: C, 66.08; H,
7
4.57.
2
7
22
(
4
ꢁ
1
8: Mp 96–98 C; IR: 3482, 1713, 1616, 1584, 1411, 1285,
3
(
1H, dd, J=18.6, 1.0 Hz, H-10e), 2.95 (1H, d, J=18.6
Hz, H-10a), 2.52 (1H, dd, J=14.8, 5.1 Hz, H-8e), 2.46
1H, d, J=14.8 Hz, H-8a), 2.40 (3H, s, CH ), 2.38 (1H,
1212, 1067; H NMR: 14.00 (1H, s, OH), 13.57 (1H, s,
OH), 8.03 (1H, d, J=7.6 Hz, ArH), 7.77 (1H, t, J=8.1
Hz, ArH), 7.39 (3H, m, ArH+ArH), 7.30 (3H, m,
ArH), 5.01 (1H, dd, J=8.0, 4.7 Hz, H-7), 4.09 (3H, s,
(
3
1
3
s, CH3); C NMR: 211.89 (C¼O), 187.10 (C¼O),
1
86.62 (C¼O), 161.26 (C-4), 155.95 (C-6), 155.86
OCH ), 3.72 (1H, s, OH-9), 3.04 (1H, dd, J=18.9, 2.3
3
(
(
(
(
(
C-11), 139.22 (C-2), 137.30 (C-6a), 135.89 (C), 135.73
C), 133.59 (C-12a), 132.36 (CH), 130.99 (C-10a), 129.44
CH), 129.18 (CH), 128.85 (C), 121.31 (C-4a), 119.89
C-3), 118.54 (C-1), 111.29 (C-5a), 110.69 (C-11a), 77.10
Hz, H-10e), 2.69 (1H, d, J=18.9 Hz, H-10a), 2.57 (1H,
dd, J=14.8, 4.7 Hz, H-8e), 2.32 (4H, m, CH +H-8a);
3
1
3
C NMR: 210.02 (C¼O), 187.09 (C¼O), 186.74
(C¼O), 161.09 (C-4), 155.57 (C-6), 155.20 (C-11),
137.47 (C-2), 135.72 (C-6a), 153.53 (C), 134.94 (C),
134.36 (2ꢂCH), 133.30 (C), 129.01 (2ꢂCH), 128.54
(CH), 121.17 (C-4a), 119.72 (C-3), 118.42 (C-1), 111.73
C-9), 56.93 (OCH ), 35.51 (C-7), 34.98 (C-8), 33.15 (C-
3
1
C H O Se: C, 60.98; H, 4.39. Found: C, 60.95; H,
0), 24.79 (CH ), 21.55 (CH ). Anal. calcd for
3 3
2
8
24
7
4
.39.
(C-5a), 111.04 (C-11a), 78.06 (C-9), 56.74 (OCH ), 39.43
3
(C-7), 38.53 (C-8), 30.90 (C-10), 24.02 (CH ). Anal.
3
7
-Naphthylseleno-7-deoxydaunomycinone (3f). Amix-
calcd for C H O S: C, 66.11; H, 4.52. Found: C,
27 22 7
ture of daunomycinone 2 (33 mg, 0.083 mmol), seleno-
phenol (17 mg, 0.084 mmol) and trifluoroacetic acid (0.5
mL) was dissolved in dichloromethane and stirred for 3
66.13; H, 4.56.
7R-Selenophenyl-7-deoxydaunomycinone (5). To a solu-
tion of 2 (96 mg, 0.24 mmol) in CH Cl (15 mL) was
added thiophenol (73.8 mg, 0.24 mmol) and BF .OEt
0.5 mL, stirred at room temperature for 8 h, monitored
by TLC. The reaction mixture quenched into water,
washed with saturated NaHCO , water, extracted with
3
h to give 36 mg of 3f (74.8%) as a red powder. IR: 3461,
1
2
2
1
(
710, 1613, 1582; H NMR: 14.00 (1H, s, OH), 13.26
1H, s, OH), 8.29 (1H, d, J=8.3 Hz, ArH), 8.03 (1H, d,
3
2
J=7.7 Hz, ArH), 7.88 (3H, m, ArH), 7.78 (1H, t, J=8.1
Hz, ArH), 7.58 (2H, m, ArH), 7.43 (1H, d, J=7.7 Hz,
ArH), 7.39 (1H, d, J=8.4 Hz, ArH), 4.91 (1H, d, J=3.6
CH Cl (3ꢂ25 mL). The organic phase was dried with
2
2
Hz, H-7), 4.06 (3H, s, OCH ), 3.18 (1H, dd, J=18.6, 1.0
3
anhydrous Na SO and then evaporated in vacuum.
2 4
Hz, H-10e), 2.95 (1H, d, J=18.6 Hz, H-10a), 2.52 (1H,
dd, J=14.8, 5.1 Hz, H-8e), 2.46 (1H, d, J=14.8 Hz, H-
The residue was isolated by silica gel column chroma-
tography eluting with hexane/dichloromethane/acetate
ester (5:5:1) to give 5 (51.6 mg, 40.7%) as a red powder.
Mp 73–75 C; IR: 3443, 1696, 1617, 1583; H NMR:
14.05 (1H, s, OH), 13.36 (1H, s, OH), 8.00 (1H, d,
J=7.54 Hz, ArH), 7.75 (1H, t, J=8.0 Hz, ArH), 7.42
(2H, d, J=7.0 Hz, ArH), 7.36 (2H, m, ArH+ArH),
7.25 (2H, m, ArH), 4.98 (1H, dd, J=8.5, 6.1 Hz, H-7),
8
positive): 611 (M+Na) . Anal. calcd for C H O Se:
a), 2.40 (3H, s, CH ), 2.38 (1H, s, CH ); MS (ESIsource,
3 3
+
ꢁ
1
3
1
24
7
C, 63.38; H, 4.12. Found: C, 63.41; H, 4.14.
7S- and 7R-thiophenyl-7-deoxydaunomycinone (7, 8). To
a solution of 2 (155 mg, 0.4 mmol) in CH Cl (15 mL)
2
2
was added thiophenol (59 mg, 0.54 mmol) and
CF COOH 1 mL, stirred at room temperature for 36 h,
4.08 (3H, s, OCH ), 3.68 (1H, s, OH-9), 2.93 (1H, dd,
3
J=16.2, 2.7 Hz, H-10e), 2.50 (1H, dd, J=15.4, 5.9 Hz,
H-8e), 2.32 (2H, m, H-10a+H-8a), 2.20 (3H, OCH );
3
monitored by TLC. The reaction mixture quenched into
water, washed with saturated NaHCO , water, extrac-
3
1
3
C NMR: 210.39 (C¼O), 187.28 (C¼O), 186.73
3
ted with CH Cl (3ꢂ25 mL). The organic phase was
(C¼O), 161.31 (C-4), 155.75 (C-6), 155.61 (C-11),
139.43 (C-2a), 137.28 (2ꢂCH), 136.00 (C-6a), 135.74
(C), 134.08 (C-12a), 131.84 (C-10a), 129.43 (C), 129.26
(2ꢂCH), 123.51 (C-4a), 119.89 (C-3), 118.56 (C-1),
111.72 (C-5a), 110.89 (C-11a), 78.13 (C-9), 56.96
2
2
dried with anhydrous Na SO and then evaporated in
2
4
vacuum. The residue was isolated by silica gel column
chromatography eluting with hexane/dichloromethane/
acetone (6:6:1) to give 7 (75 mg) as a red powder and 8
(
39 mg) as a red powder with 57.9% total yield.
(OCH ), 38.87 (C-7), 32.39 (C-8), 31.07 (C-10), 24.15
3

3904
S.-J. Zhang et al. / Bioorg. Med. Chem. 10 (2002) 3899–3904
(
Found: C, 60.38; H, 4.09.
CH ). Anal. calcd for C H O Se: C, 60.34; H, 4.13.
7
Acknowledgements
3
27 22
We would like to thank Mr. Yuan-Jiang Pang in the
Department of Chemistry for the NMR measurements.
Antitumor test procedures in vitro
Human stomach cancer SGC-7901. 200 mL SGC-7901
4
cell suspensions (5ꢂ10 cells/mL) were dispensed into
References and Notes
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After 56 h culture with the agents, the cells were incu-
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3
4
4
4
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6
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4
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(
250 mg/mL) for anther 4 h. Then, the plate was cen-
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2
9
1
1
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(
ELISA) plate reader (Dynatech MR4000). Analysis of
the relationship between measured A540 and number of
viable HL60 cells indicated that cell densities at
4
4
2
.5ꢂ10 ꢃ80ꢂ10 cells/mL gave rise to a detectable
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(