Brief Articles
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 23 5819
g) was added to a solution of 4 in triglyme (15 mL), and the
Acknowledgment. This investigation was sup-
ported by grant CA 17625 from National Cancer Insti-
tute awarded to K. H. Lee, and by the National Science
Council of Republic of China and National Research
Institute of Chinese Medicine.
mixture was heated to reflux for 3 days to furnish compound
5
(1.4 g). To a solution of 5 in anhydrous dichloromethane (20
mL) was added a solution of boron tribromide in dichloro-
methane (1.0 M, 24 mL) dropwise at 0 °C. The mixture was
heated to reflux and stirred for 3 h to give the desired naphthol
intermediate 6 (1.2 g) after silica gel chromatography. The
1
total yield over four steps (2 f 6) was 70%. mp 93-94 °C; H
References
NMR (CDCl
3
) δ 2.67 (s, 3H), 5.30 (s, 1H), 6.83 (d, J ) 7.5 Hz,
1
H), 7.31-7.41 (m, 3H), 7.58 (d, J ) 8.4 Hz, 1H), 8.06 (d, J )
(
1) Labrie, F.; Labrie, C.; B e´ langer, A.; Simard, J.; Gauthier, S.; Luu-
The, V.; et al. EM-652 (SCH 57068), a third generation SERM
acting as pure antiestrogen in the mammary gland and en-
dometrium. J. Steroid Biochem. Mol. Biol. 1999, 69, 51-84.
8
.1 Hz, 1H).
Synthesis of 4-Hydroxy-7-methyl-benzo[h]chromen-2-
one (7). The mixture of 5-methyl-1-naphthol (6) (1.0 g, 6.33
mmol), malonic acid (658 mg, 6.33 mmol), and PPA (10 g) was
heated at 75 °C for 3 h. After the reaction, ice-water was
added to the black residue. The solid was filtered, dissolved
(2) Jordan, V. C.; Gradishar, W. J. Molecular mechanisms and
future uses of antiestrogens. Mol. Aspects Med. 1997, 18, 187-
2
47.
(
3) Slamon, D. J.; Godolphin, W.; Jones, L. A., et al. Studies of the
HER-2/neu proto-oncogene in human breast and ovarian cancer.
Science 1989, 244, 707-712.
2 3
in 10% Na CO solution, and stirred overnight. The basic
solution was filtered, and the filtrate was acidified with 2 N
HCl solution until the pH was about 4. The precipitate was
(
4) Kinoshita, Y.; Chen, S. Induction of aromatase (CYP19) expres-
sion in breast cancer cells through a nongenomic action of
estrogen receptor R. Cancer Res. 2003, 63, 3546-3555.
then filtered and purified by silica gel chromatography to yield
1
7
(620 mg, 43%) as a yellow solid. mp 223-225 °C; H NMR
(
DMSO-d
6
) δ 2.69 (s, 3H), 5.70 (s, 1H), 7.57-7.61 (m, 2H), 7.86
d, J ) 9.0 Hz, 1H), 7.92 (d, J ) 9.0 Hz, 1H), 8.23 (d, J ) 7.5
(5) Dhingra, K. Antiestrogens-tamoxifen, SERMs and beyond.
Invest. New Drugs 1999, 17, 285-311.
(
(
(
(
(
6) Ryu, S. Y.; Lee, C. O.; Choi, S. U. In vitro cytotoxicity of
Hz, 1H), 12.8 (br s, 1H).
tanshinones from Salvia miltiorrhiza. Planta Med. 1997, 63,
Synthesis of Neo-tanshinlactone (1). To a solution of 7
3
39-342.
(
50 mg, 0.22 mmol) in toluene (8 mL) was added a mixture of
7) Wu, W.-L.; Chang, W.-L.; Chen, C.-F. Cytotoxic activities of
tanshinones against human carcinoma cell lines. Am. J. Chin.
Med. 1991, 19, 207-216.
4
HOAc (66 mg, 1.1 mmol) and NH OAc (80 mg, 1.1 mmol) in
EtOH (2 mL) and chloroacetone (103 mg, 1.1 mmol). The
mixture was refluxed 24 h. After cooling, the mixture was
8) Cao, E.-H.; Liu, X.-Q.; Wang, J.-J.; Xu, N.-F. Effect of natural
antioxidant tanshinone II-A on DNA damage by lipid peroxida-
tion in liver cells. Free Radic. Biol. Med. 1996, 20, 801-806.
9) Honda, G.; Koezuka, Y.; Tabata, M. Isolation of an antidermato-
phytic substance from the root of Salvia miltiorrhiza. Chem.
Pharm. Bull. 1988, 36, 408-411.
diluted with H
2
O and extracted with EtOAc. The organic layer
was dried over Na
2
4
SO , filtered, and evaporated. The residue
was purified by column chromatography to give 1 (35 mg, 60%)
as a white solid. The spectroscopic data of synthetic compound
1
were identical with those of the natural product 1.
In Vitro Anticancer Assay. All stock cultures were
(10) Onitsuka, M.; Fujiu, M.; Shinma, N.; Maruyama, H. B. New
platelet aggregation inhibitors from Tan-Shen; radix of Salvia
miltiorrhiza Bunge. Chem. Pharm. Bull. 1983, 31, 1670-1675.
1
8
grown in T-25 flasks. Freshly trypsinized cell suspensions were
seeded in 96-well microtiter plates at densities of 1500-7500
cells per well with compounds added from DMSO-diluted stock.
After 3 days in culture, attached cells were fixed with cold 50%
trichloroacetic acid and then stained with 0.4% sulforhodamine
B (SRB). The absorbency at 562 nm was measured using a
microplate reader after solubilizing the bound dye. The mean
ED50 is the concentration of agent that reduces cell growth by
(
11) Lin, H. C.; Ding, H. Y.; Chang, W. L. Two new fatty diterpenoids
from Salvia miltiorrhiz. J. Nat. Prod. 2001, 64, 648-650.
12) Ryu, S. Y.; Lee, C. O.; Choi, S. U. Inhibition of mast cell
degranulation by tanshinones from the roots of Salvia miltior-
rhiza. Planta Med. 1999, 65, 654-655.
(
(
13) Luo, H.-W.; Ji, J.; Wu, M.-Y.; Yong, Z.-G.; Niwa, M.; and Hirata,
Y. Tanshinlactone, a novel seco-abietanoid from Salvia miltior-
rhiza. Chem. Pharm. Bull. 1986, 34, 3166-3168.
(
14) Suh, Y.-G.; Shin, D.-Y.; Min, K. H.; Hyun, S.-S.; Jung, J.-K.; Seo,
S.-Y. Facile construction of the oxaphenalene skeleton by peri
ring closure, formal synthesis of Mansonone F. Chem. Commun.
2000, 1203-1204.
5
0% under the experimental conditions and is the average
from at least three independent determinations that were
reproducible and statistically significant (Figure 2). The fol-
lowing human tumor cell lines were used in the assay: A549
(
15) Mayer, P.; Alibert, S.; Brunel, P.; Imbert, T. Synthesis of benzo-
[
de]chromene analogue of Efaroxan. Heterocycles 2000, 55, 387-
(non small cell lung cancer), MCF-7 (estrogen receptor positive
3
92.
breast cancer), ZR-75-1 (estrogen receptor positive breast
cancer), MDA-MB-231 (estrogen receptor negative breast
cancer), HS 587-T (estrogen receptor negative breast cancer),
SK-BR-3 (HER-2-overexpressing breast cancer), A431 (EGFR-
overexpressing skin cancer), LN-CaP (AR-dependent prostate
cancer), SW620 (colon cancer), PC-3 (prostate cancer), KB
(
16) Kamijo, H.; Takido, T.; Nakazawa, T.; Itabashi, K.; Seno, M.
Synthesis of 3-hydroxy-1H-phenalen-1-ones from methylthio-
naphthalenes with malonic acids. Nippon Kagaku Kaishi 1993,
11, 1257-1262.
(17) Risitano, F.; Grassi, G.; Foti, F.; Bilardo, C. A convenient
synthesis of furo[3,2-c]coumarins by a tandem alkylation/in-
tramolecular aldolization reaction. Tetrahedron Lett. 2001, 42,
(
nasopharyngeal carcinoma), KB-VIN (vincristine-resistant KB
3
503-3505.
subline). All cell lines were obtained from the Lineberger
(
18) Nakanishi, Y.; Chang, F.-R.; Liaw, C.-C.; Wu, Y.-C.; Bastow, K.
F.; Lee, K.-H. Acetogenins as selective inhibitors of the human
ovarian 1A9 tumor cell line. J. Med. Chem. 2003, 46, 3185.
Comprehensive Cancer Center (UNC-CH) or from ATCC
(
Rockville, MD) and were cultured in RPMI-1640 medium
supplemented with 25 mM HEPES, 0.25% sodium bicarbonate,
0% fetal bovine serum, and 100 µg/mL kanamycin.
1
JM040112R