Journal of Medicinal Chemistry
Brief Article
calcd for [M + Na]+ 317.11482; found 317.11606. Compounds 2−9
were similarly prepared.
Biology. Details of reporter assays, RT-PCR, Western blot, and
MTT assays were described in the SI. The t test was performed using
GraphPad Prism 5 software (San Diego, CA, USA). p < 0.05 was
considered statistically significant.
responsive element site recognized by androgen receptor. Proc. Natl.
Acad. Sci. U.S.A. 1997, 94, 5673−5678.
(8) Schaefer, J. S.; Zhang, M. Role of maspin in tumor metastasis and
angiogenesis. Curr. Mol. Med. 2003, 3, 653−658.
(9) Cher, M. L.; Biliran, H. R.; Bhagat, S.; Meng, Y. H.; Che, M. X.;
Lockett, J.; Abrams, J.; Fridman, R.; Zachareas, M.; Sheng, S. J. Maspin
expression inhibits osteolysis, tumor growth, and angiogenesis in a
model of prostate cancer bone metastasis. Proc. Natl. Acad. Sci. U.S.A.
2003, 100, 7847−7852.
(10) Zhou, J. M.; Geng, G. Y.; Wu, J. H. Synthesis and in vitro
characterization of ionone-based chalcones as novel antiandrogens
effective against multiple clinically relevant androgen receptor mutants.
Invest. New Drugs 2010, 28, 291−298.
(11) Luo, H. W.; Wu, B. J.; Wu, M. Y.; Yong, Z. G.; Niwa, M.; Hirata,
Y. Pigments from Salvia miltiorrhiza. Phytochemistry 1985, 24, 815−
817.
ASSOCIATED CONTENT
■
S
* Supporting Information
NMR analysis of TS-IIA, syntheses, NMR, and MS analyses of
1−10 and 11a−11i as well as AR, AR-v7, GR, PR, and maspin-
dependent reporter assays, RT-PCR and Western blot analyses,
and MTT assays of TS-IIA and its derivatives. This material is
(12) Lee, J.; Snyder, J. K. Ultrasound-promoted cycloadditions in the
synthesis of Salvia miltiorrhiza abietanoid o-quinones. J. Org. Chem.
1990, 55, 4995−5008.
(13) Hu, R.; Dunn, T. A.; Wei, S.; Isharwal, S.; Veltri, R. W.;
Humphreys, E.; Han, M.; Partin, A. W.; Vessella, R. L.; Isaacs, W. B.;
Bova, G. S.; Luo, J. Ligand-independent androgen receptor variants
derived from splicing of cryptic exons signify hormone-refractory
prostate cancer. Cancer Res. 2009, 69, 16−22.
(14) Taplin, M. E.; Manola, J.; Oh, W. K.; Kantoff, P. W.; Bubley, G.
J.; Smith, M.; Barb, D.; Mantzoros, C.; Gelmann, E. P.; Balk, S. P. A
phase II study of mifepristone (RU-486) in castration-resistant
prostate cancer, with a correlative assessment of androgen-related
hormones. BJU Int. 2008, 101, 1084−1089.
(15) Wang, X.; Morris-Natschke, S. L.; Lee, K. H. New developments
in the chemistry and biology of the bioactive constituents of Tanshen.
Med. Res. Rev. 2007, 27, 133−148.
(16) Hall, D. C.; Johnson-Pais, T. L.; Grubbs, B.; Bernal, R.; Leach,
R. J.; Padalecki, S. S. Maspin reduces prostate cancer metastasis to
bone. Urol. Oncol.: Semin. Orig. Invest. 2008, 26, 652−658.
AUTHOR INFORMATION
■
Corresponding Author
*Phone: (514) 340-8222. Fax (514) 340-8717. E-mail: jian.h.
ACKNOWLEDGMENTS
■
This work was supported in part by the Exchange Visit Awards
from the Fonds de la Recherche en Sante due Quebec and the
National Natural Science Foundation of China (J.W.) and the
Canadian Institutes of Health Research (J.W.). We thank Drs. J.
Luo (The John Hopkins University), L. D. Mayo (Indiana
University); S. Srivastava (Uniformed Services University), O.
Ogawa (Kyoto University), and L. N. Song (Columbia
University) for providing plasmids for this work.
ABBREVIATIONS USED
■
AR, androgen receptor; Bic, bicalutamide; CRPC, castration-
resistant prostate cancer; CS-FBS, charcoal-stripped fetal
bovine serum; DEX, dexamethasone; DHT, dihydrotestoster-
one; GR, glucocorticoid receptor; HRE, hormone responsive
element; LBD, ligand-binding domain; PR, progesterone
receptor; PSA, prostate-specific antigen; TS-IIA, tanshinone IIA
REFERENCES
■
(1) Taplin, M. E. Androgen receptor: role and novel therapeutic
prospects in prostate cancer. Expert Rev. Anticancer Ther. 2008, 8,
1495−1508.
(2) Attard, G.; Cooper, C. S.; de Bono, J. S. Steroid hormone
receptors in prostate cancer: a hard habit to break? Cancer Cell 2009,
16, 458−462.
(3) Yoshida, T.; Kinoshita, H.; Segawa, T.; Nakamura, E.; Inoue, T.;
Shimizu, Y.; Kamoto, T.; Ogawa, O. Antiandrogen bicalutamide
promotes tumor growth in a novel androgen-dependent prostate
cancer xenograft model derived from a bicalutamide-treated patient.
Cancer Res. 2005, 65, 9611−9616.
(4) Steketee, K.; Timmerman, L.; Ziel-van der Made, A. C.;
Doesburg, P.; Brinkmann, A. O.; Trapman, J. Broadened ligand
responsiveness of androgen receptor mutants obtained by random
amino acid substitution of H874 and mutation hot spot T877 in
prostate cancer. Int. J. Cancer 2002, 100, 309−317.
(5) Khamis, Z. I.; Iczkowski, K. A.; Sang, Q. X. Metastasis
suppressors in human benign prostate, intraepithelial neoplasia, and
invasive cancer: their prospects as therapeutic agents. Med. Res. Rev.
2011, DOI: 10.1002/med.20232.
(6) Pierson, C. R.; McGowen, R.; Grignon, D.; Sakr, W.; Dey, J.;
Sheng, S. Maspin is up-regulated in premalignant prostate epithelia.
Prostate 2002, 53, 255−262.
(7) Zhang, M.; Magit, D.; Sager, R. Expression of maspin in prostate
cells is regulated by a positive Ets element and a negative hormonal
975
dx.doi.org/10.1021/jm2015292 | J. Med. Chem. 2012, 55, 971−975