臺灣博碩士論文加值系統

類固醇硫酸酯酶（steroid sulfatase, STS）之功能為調節雌酮硫酸鹽（estrone sulfate, E1S）轉化為雌激素酮（estrone, E1）及硫酸脫氫表雄酮（dehydroepiandrosterone sulfate, DHEAS）轉化為脫氫表雄酮（dehydroepiandrosterone, DHEA）的關鍵角色。類固醇硫酸酯酶一般存在於人類的組織與器官中。不過與正常細胞相較時，癌化的ERα+乳癌腫瘤之類固醇硫酸酯酶活性會大量表現。因此，抑制類固醇硫酸酯可間接降低誘導乳癌細胞增長的類固醇雌激素含量，達到治愈乳癌的效果。

先前的研究顯示香豆素胺基磺酸鹽類（coumarin-based sulfamates）的化合物可有效抑制類固醇硫酸酯酶的活性。因此在本研究中，我們設計合成了3-benzylaminocoumarin-7-O-sulfamates並對其進行構效關係的研究探討。首先以3-aminocoumarins與苯甲醛進行還原氨化反應得到一系列的3-benzylaminocoumarins，接著進行磺胺酰化反應得到最終產物，既3-benzylaminocoumarin-7-O-sulfamates。

3-benzylaminocoumarin-7-O-sulfamates的抑制活性及構效關係的探討直接以MCF-7乳癌細胞及純化後的人類胎盤類固醇硫酸酯酶進行，發現活性最佳者為3-(2,3-dimethoxybenzyl)aminocoumarin-7-O-sulfamate (28j)，其IC50為130 nM。為了更進一步了解化合物28j的結構限制，合成了3-(2,3- dimethoxyphenethyl)aminocoumarin-7-O-sulfamate（30）、3-(2,3-dimethoxy- benzamido)coumarin-7-O-sulfamate （32） 及3-(2,3-dimethoxybenzyl)-5-oxo-1,3,4,5- tetrahydrochromeno[3,4-c]pyridine-8-yl sulfamate （35）並測試其對於類固醇硫酸酯酶的抑制活性，發現以coumarin為核心之化合物中其3號位置衍生化可增加活性，但些微結構的修飾可能導致活性消失，針對coumarin 3號位置進行剛性結構修飾有助於維持其抑制活性。

Recent findings have shown that steroid sulfatase (STS) is a potential novel target for breast cancer treatment. STS plays a crucial role in the regulation of steroid hormone concentrations which is responsible for the conversion of estrone sulfate (E1S) to estrone (E1), as well as dehydroepiandrosterone sulfate (DHEAS) to dehydroepiandrosterone (DHEA). STS is present in several human tissues and organs. However, in contrast to normal tissues, STS enzyme activity in ERα-positive breast cancer tumors is overexpressed. Therefore, inhibition of STS is a new approach to abate estrogenic steroids that stimulate the proliferation and development of breast cancer.

Previous studies have shown that coumarin-based sulfamates are capable to inhibit STS enzyme activities. In this study, a series of 3-benzylaminocoumarin-7-O-sulfamate analogues were designed and synthesized. Reductive amination of 3-aminocoumarin and benzaldehydes, followed by NaBH3CN treatment, a series of 3-benzylamino coumarins were obtained. 3-benzylaminocoumarins were further subjected to sulfamoyl chloride in THF to give the desired 3-benzylaminocoumarin-7-O-sulfamate derivatives.

The inhibitiory activity of 3-benzylaminocoumarin-7-O-sulfamate derivatives 28a-q were tested directly with MCF-7 cells and purified STS enzyme which was extracted from human placenta. 3-(2,3-dimethoxybenzyl)aminocoumarin-7-O-sulfamate (28j) was found to have highest inhibition activity against STS (IC50 = 130 nM). In order to study conformation of compound 28j, 3-(2,3-dimethoxyphenethyl) aminocoumarin-7-O-sulfamate (30), 3-(2,3-dimethoxy-benzamido)coumarin-7-O- sulfamate (32) and 3-(2,3-dimethoxybenzyl)-5-oxo-1,3,4,5-tetrahydrochromeno[3,4-c] pyridine-8-yl sulfamate (35) were synthesized. Structure activity relationship (SAR) analysis revealed that in coumarin structure modification at 3-position improved inhibitory activity, however subtle change of substation moiety might cause activity loss. Structure with rigid modification at 3-position of coumarin derivatives could maintain STS inhibitory activity.

目 錄
中文摘要……………………………………………………………………………… I
英文摘要……………………………………………………………………………… III
目錄…………………………………………………………………………………… V
圖目錄………………………………………………………………………………… VII
表目錄………………………………………………………………………………… VIII
途徑目錄……………………………………………………………………………… IX
縮寫對照表…………………………………………………………………………… X

第一章、 簡介…………………………………………………………………… 1
1.1 乳癌…………………………………………………………………. 1
1.1.1 何謂乳癌…………………………………………………. 1
1.1.2 乳癌的現況………………………………………………. 1
1.1.3 乳癌的病理………………………………………………. 4
1.1.4 乳癌的分期………………………………………………. 5
1.1.5 乳癌的發生………………………………………………. 7
1.1.6 乳癌的診斷………………………………………………. 9
1.1.7 乳癌的治療………………………………………………. 10
1.2 促使乳癌生成之賀爾蒙危險因子…………………………………. 17
1.3 致癌的雌激素………………………………………………………. 19
1.3.1 雌激素的代謝……………………………………………. 20
1.3.2 雌激素受體的信息傳遞途徑……………………………. 22
1.4 類固醇硫酸酯酶……………………………………………………. 25
1.4.1 何謂類固醇硫酸酯………………………………………. 25
1.4.2 類固醇硫酸酯酶的構造與位置…………………………. 25
1.4.3 類固醇硫酸酯酶的受質與功能…………………………. 26
1.4.4 類固醇硫酸酯酶的反應機制……………………………. 28
1.4.5 類固醇硫酸酯酶與乳癌…………………………………. 29
1.5 類固醇硫酸酯酶抑制劑的發展……………………………………. 31
1.5.1 類固醇胺基磺酸鹽類抑制劑……………………………. 31
1.5.1.1 Li與Ishida團隊……………………………….. 31
1.5.1.2 Nippon Organon………………………………... 32
1.5.1.3 Sterix Ltd……………………………………….. 32
1.5.1.4 Poirier團隊…………………………………….. 35
1.5.1.5 Numazawa團隊………………………………… 35
1.5.1.6 Lykkesfeldt與Peter團隊………………………. 36
1.5.2 非類固醇胺基磺酸鹽類抑制劑……………………..…... 37
1.5.2.1 Sterix Ltd…………………………………...…. 37
1.5.2.2 Ahmed團隊………………………………….... 39
1.5.2.3 Teikoku hormone……………………………… 40
1.5.2.4 Norvatis………………………………………... 40
1.5.2.5 Poirier團隊…………………………………… 41
1.5.2.6 Laboratoire Theramex………………………… 41
1.6 研究方向與目的……………………………………………………. 43
第二章、 結果與討論…………………………………………………………….… 45
2.1 化合實驗部份………………………………………………………. 45
2.1.1 化合物27a-q的合成……………………………………… 45
2.1.2 化合物28a-q的合成……………………………………… 48
2.1.3 化合物30的合成……………………………………….… 53
2.1.4 化合物32的合成……………………………………….… 55
2.1.5 化合物35的合成…………………………………………. 57
2.2 生物實驗部份………………………………………………………. 59
2.2.1 類固醇硫酸酯酶的受質塞選……………………………... 59
2.2.2 類固醇硫酸酯酶的抑制活性測試………………………... 62
2.2.3 化合物28j對類固醇硫酸酯酶的親合性測試…………… 68
2.3 電腦模擬部份………………………………………………………. 70
第三章、 結論………………………………………………………………………. 72
第四章、 實驗材料與方法…………………………………………………………. 73
4.1 人類胎盤類固醇硫酸酯酶的萃取與純化…………………………. 73
4.2 西方墨點法分析………………………………………………….… 75
4.3 MCF-7細胞培養…………………………………………………… 77
4.4 藥物對類固醇硫酸酯酶的抑制活性測試…………………………. 78
4.4.1 人類胎盤類固醇硫酸酯酶………………………………. 78
4.4.2 MCF-7 細胞…………………………………………….. 79
4.5 藥物對人類胎盤類固醇硫酸酯酶的親合性測試…………………. 80
4.6 一般化學實驗方法…………………………………………………. 81
4.7 合成步驟與化合物數據分析………………………………………. 84
第五章、 參考文獻…………………………………………………………………. 108
第六章、 附圖………………………………………………………………………. 125

1.Saunders, C., Jassal, Sunil. Chapter 13, Oxford: Oxford University Press, Breast cancer (1. ed.), 2009.
2.World Cancer Research Fund International, 2015.
3.SEER Stat Fact Sheets: Breast Cancer, National Cancer Institute, 2014.
4.World Cancer Report 2014, Chapter 5.2, World Health Organization, 2014.
5.Male Breast Cancer Treatment, National Cancer Institute, 2014.
6.World Cancer Report 2014, Chapter 1.1, World Health Organization, 2014.
7.衛生福利部國民健康署, 2015.
8.Fisher, E.R., Gregorio, R.M., Fisher, B., Redmond, C., Vellios, F., Sommers, S.C.The pathology of invasive breast cancer. Cancer, 1975, 36, 1-85.
9.Schröder, F. H., Hermanek, P., Denis, L., Fair, W. R., Gospodarowicz, M. K., Pavone-Macaluso, M. The TNM classification of prostate cancer. The Prostate, 1992, 21, 129-138.
10.https://www.everydayhealth.com.tw/article/8659
11.Hennessy, B. T., Smith, D. L., Ram, P. T., Lu, Y., Mills, G. B. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nature Reviews Drug Discovery, 2005, 4, 988-1004.
12.Petrucelli, N., Daly, M. B., Feldman, G. L. BRCA1 and BRCA2 hereditary breast and ovarian cancer, 2013.
13.Jordan, V. C., Brodie, A. M. Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer. Steroids, 2007, 72, 7-25.
14.Holmes, M.D., Chen, W.Y., Feskanich, D., Kroenke, C.H., Colditz, G.A. Physical activity and survival after breast cancer diagnosis. JAMA, 2005, 25, 2479-2486.
15.Mangasarian, O.L., Street, W.N., Wolberg, W.H. Breast cancer diagnosis and prognosis via linear programming. Operations Research, 1995, 43, 570-577.
16.Fisher, B. Biological and clinical considerations regarding the use of surgery and chemotherapy in the treatment of primary breast cancer. Cancer, 1977, 40, 574-587.
17.Veronesi, U., Cascinelli, N., Mariani, L., Greco, M., Saccozzi, R., Luini, A., Marubini, E. Twenty-year follow-up of a randomized study comparing breast- conserving surgery with radical mastectomy for early breast cancer. New England Journal of Medicine, 2002, 347, 1227-1232.
18.Early Breast Cancer Trialists'' Collaborative Group. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. The Lancet, 2006, 366, 2087-2106.
19.Nelson, J. C., Beitsch, P. D., Vicini, F. A., Quiet, C. A., Garcia, D., Snider, H. C., Keleher, A. J. Four-year clinical update from the American Society of Breast Surgeons Mammo Site brachytherapy trial. The American Journal of Surgery, 2009, 198, 83-91.
20.Beitsch, P. D., Shaitelman, S. F., Vicini, F. A. Accelerated partial breast irradiation. Journal of Surgical Oncology, 2011, 103, 362-368.
21.Shapiro, C. L., Recht, A. Side effects of adjuvant treatment of breast cancer. New England Journal of Medicine, 2001, 344, 1997-2008.
22.McArthur, H. L., Hudis, C. A. Breast cancer chemotherapy. The Cancer Journal, 2007, 13, 141-147.
23.Early Breast Cancer Trialists'' Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. The Lancet, 2005, 365, 1687-1717.
24.Thürlimann, B., Keshaviah, A., Coates, A. S., Mouridsen, H., Mauriac, L., Forbes, J. F., Smith, I. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. The New England Journal of Medicine, 2005, 353, 2747-2757.
25.Farmer, H., McCabe, N., Lord, C. J., Tutt, A. N., Johnson, D. A., Richardson, T. B., Martin, N. M. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature, 2005, 434, 917-921.
26.Higgins, M. J., & Baselga, J. Targeted therapies for breast cancer. The Journal of Clinical Investigation, 2011, 121, 3797-3803.
27.Clemons, M., Goss, P. Estrogen and the risk of breast cancer. The New England Journal of Medicine, 2001, 344, 276-285.
28.Endogenous Hormones Breast Cancer Collaborative Group. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. Journal of the National Cancer Institute, 2003, 95, 1218-1226.
29.Onland-Moret, N. C., Kaaks, R., Van Noord, P. A. H., Rinaldi, S., Key, T., Grobbee, D. E., Peeters, P. H. M. Urinary endogenous sex hormone levels and the risk of postmenopausal breast cancer. British Journal of Cancer, 2003, 88, 1394-1399.
30.Missmer, S. A., Eliassen, A. H., Barbieri, R. L., Hankinson, S. E. Endogenous estrogen, androgen, and progesterone concentrations and breast cancer risk among postmenopausal women. Journal of the National Cancer Institute, 2004, 96, 1856-1865.
31.Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. The Lancet, 1997, 350, 1047-1059.
32.Fournier, A., Berrino, F., Riboli, E., Avenel, V., Clavel‐Chapelon, F. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. International Journal of Cancer, 2005, 114, 448-454.
33.Heiss, G., Wallace, R., Anderson, G. L., Aragaki, A., Beresford, S. A., Brzyski, R., Prentice, R. L. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA, 2008, 299, 1036-1045.
34.Prentice, R. L., Chlebowski, R. T., Stefanick, M. L., Manson, J. E., Pettinger, M., Hendrix, S. L., McTiernan, A. Estrogen plus progestin therapy and breast cancer in recently postmenopausal women. American Journal of Epidemiology, 2008, 167, 1207-1216.
35.Hofseth, L. J., Raafat, A. M., Osuch, J. R., Pathak, D. R., Slomski, C. A., Haslam, S. Z. Hormone Replacement Therapy with Estrogen or Estrogen plus Medroxyprogesterone Acetate Is Associated with Increased Epithelial Proliferation in the Normal Postmenopausal Breast 1. The Journal of Clinical Endocrinology & Metabolism, 1999, 84, 4559-4565.
36.Yue, W., Santen, R. J., Wang, J. P., Li, Y., Verderame, M. F., Bocchinfuso, W. P., Cavalieri, E. L. Genotoxic metabolites of estradiol in breast: potential mechanism of estradiol induced carcinogenesis. The Journal of Steroid Biochemistry and Molecular Biology, 2003, 86, 477-486.
37.Jefcoate, C. R., Liehr, J. G., Santen, R. J., Sutter, T. R., Yager, J. D., Yue, W., Naftolin, F. Tissue-specific synthesis and oxidative metabolism of estrogens. J Natl Cancer Inst Monogr, 2000, 27, 112.
38.Hayes, C. L., Spink, D. C., Spink, B. C., Cao, J. Q., Walker, N. J., Sutter, T. R. 17 beta-estradiol hydroxylation catalyzed by human cytochrome P450 1B1. Proceedings of the National Academy of Sciences, 1996, 93, 9776-9781.
39.Cavalieri, E. L., Devanesan, P., Bosland, M. C., Badawi, A. F., Rogan, E. G. Catechol estrogen metabolites and conjugates in different regions of the prostate of Noble rats treated with 4-hydroxyestradiol: implications for estrogen-induced initiation of prostate cancer. Carcinogenesis, 2002, 23, 329-333.
40.Mobley, J. A., Bhat, A. S., Brueggemeier, R. W. Measurement of oxidative DNA damage by catechol estrogens and analogues in vitro. Chemical Research In Toxicology, 1999, 12, 270-277.
41.Nutter, L. M., Wu, Y. Y., Ngo, E. O., Sierra, E. E., Gutierrez, P. L., Abul-Hajj, Y. J. An o-quinone form of estrogen produces free radicals in human breast cancer cells: correlation with DNA damage. Chemical Research in Toxicology, 1994, 7, 23-28.
42.Yue, T. L., Wang, X., Louden, C. S., Gupta, S., Pillarisetti, K., Gu, J. L., Feuerstein, G. Z. 2-Methoxyestradiol, an endogenous estrogen metabolite, induces apoptosis in endothelial cells and inhibits angiogenesis: possible role for stress-activated protein kinase signaling pathway and Fas expression. Molecular Pharmacology, 1997, 51, 951-962.
43.Devanesan, P., Todorovic, R., Zhao, J., Gross, M. L., Rogan, E. G., Cavalieri, E. L. Catechol estrogen conjugates and DNA adducts in the kidney of male Syrian golden hamsters treated with 4-hydroxyestradiol: potential biomarkers for estrogen-initiated cancer. Carcinogenesis, 2001, 22, 489-497.
44.Li, K. M., Todorovic, R., Devanesan, P., Higginbotham, S., Köfeler, H., Ramanathan, R., Cavalieri, E. L. Metabolism and DNA binding studies of 4-hydroxyestradiol and estradiol-3, 4-quinone in vitro and in female ACI rat mammary gland in vivo. Carcinogenesis, 2004, 25, 289-297.
45.Chakravarti, D., Mailander, P. C., Li, K. M., Higginbotham, S., Zhang, H. L., Gross, M. L., Rogan, E. G. Evidence that a burst of DNA depurination in SENCAR mouse skin induces error-prone repair and forms mutations in the H-ras gene. Oncogene, 2001, 20, 7945-7953.
46.Lavigne, J. A., Goodman, J. E., Fonong, T., Odwin, S., He, P., Roberts, D. W., Yager, J. D. The effects of catechol-O-methyltransferase inhibition on estrogen metabolite and oxidative DNA damage levels in estradiol-treated MCF-7 cells. Cancer Research, 2001, 61, 7488-7494.
47.Kong, L. Y., Szaniszlo, P., Albrecht, T., & Liehr, J. G. Frequency and molecular analysis of hprt mutations induced by estradiol in Chinese hamster V79 cells. International Journal of Oncology, 2000, 17, 1141-1150.
48.Samuni, A. M., Chuang, E. Y., Krishna, M. C., Stein, W., DeGraff, W., Russo, A., Mitchell, J. B. Semiquinone radical intermediate in catecholic estrogen-mediated cytotoxicity and mutagenesis: chemoprevention strategies with antioxidants. Proceedings of the National Academy of Sciences, 2003, 100, 5390-5395.
49.Tsutsui, T., Suzuki, N., Fukuda, S., Sato, M., Maizumi, H., McLachlan, J. A., Barrett, J. C. 17β-Estradiol-induced cell transformation and aneuploidy of Syrian hamster embryo cells in culture. Carcinogenesis, 1987, 8, 1715-1719.
50.Russo, J., Lareef, M. H., Balogh, G., Guo, S., & Russo, I. H. Estrogen and its metabolites are carcinogenic agents in human breast epithelial cells. The Journal of Steroid Biochemistry and Molecular Biology, 2003, 87, 1-25.
51.Newbold, R. R., Liehr, J. G. Induction of uterine adenocarcinoma in CD-1 mice by catechol estrogens. Cancer Research, 2000, 60, 235-237.
52.Turan, V. K., Sanchez, R. I., Li, J. J., Li, S. A., Reuhl, K. R., Thomas, P. E., Mesia-Vela, S. The effects of steroidal estrogens in ACI rat mammary carcinogenesis: 17β-estradiol, 2-hydroxyestradiol, 4-hydroxyestradiol, 16α-hydroxyestradiol, and 4-hydroxyestrone. Journal of Endocrinology, 2004, 183, 91-99.
53.Yager, J. D. Endogenous estrogens as carcinogens through metabolic activation. J Natl Cancer Inst Monogr, 2000, 27, 67-73.
54.Webb, P., Nguyen, P., Valentine, C., Lopez, G. N., Kwok, G. R., McInerney, E., Kushner, P. J. The estrogen receptor enhances AP-1 activity by two distinct mechanisms with different requirements for receptor transactivation functions. Molecular Endocrinology, 1999, 13, 1672-1685.
55.Levin, E. R. Bidirectional signaling between the estrogen receptor and the epidermal growth factor receptor. Molecular Endocrinology, 2003, 17, 309-317.
56.Demonacos, C. V., Karayanni, N., Hatzoglou, E., Tsiriyiotis, C., Spandidos, D. A., Sekeris, C. E. Mitochondrial genes as sites of primary action of steroid hormones. Steroids, 1996, 61, 226-232.
57.Sekeris, C. E. The mitochondrial genome: a possible primary site of action of steroid hormones. In vivo (Athens, Greece), 1989, 4, 317-320.
58.Aronica, S. M., Kraus, W. L., Katzenellenbogen, B. S. Estrogen action via the cAMP signaling pathway: stimulation of adenylate cyclase and cAMP-regulated gene transcription. Proceedings of the National Academy of Sciences, 1994, 91, 8517-8521.
59.Song, R. X. D., McPherson, R. A., Adam, L., Bao, Y., Shupnik, M., Kumar, R., Santen, R. J. Linkage of rapid estrogen action to MAPK activation by ERα-Shc association and Shc pathway activation. Molecular Endocrinology, 2002, 16, 116-127.
60.Santen, R. J., Song, R. X., McPherson, R., Kumar, R., Adam, L., Jeng, M. H., Yue, W. The role of mitogen-activated protein (MAP) kinase in breast cancer. The Journal of Steroid Biochemistry and Molecular Biology, 2002, 80, 239-256.
61.Razandi, M., Pedram, A., Greene, G. L., Levin, E. R. Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ERα and ERβ expressed in Chinese hamster ovary cells. Molecular Endocrinology, 1999, 13, 307-319.
62.Razandi, M., Pedram, A., Levin, E. R. Plasma membrane estrogen receptors signal to antiapoptosis in breast cancer. Molecular Endocrinology, 2000, 14, 1434-1447.
63.Pettersson, K., Gustafsson, J. Å. Role of estrogen receptor beta in estrogen action. Annual Review of Physiology, 2001, 63, 165-192.
64.Monje, P., & Boland, R. Subcellular distribution of native estrogen receptor α and β isoforms in rabbit uterus and ovary. Journal of Cellular Biochemistry, 2001, 82, 467-479.
65.Stoica, G. E., Franke, T. F., Moroni, M., Mueller, S., Morgan, E., Iann, M. C., Stoica, A. Effect of estradiol on estrogen receptor-α gene expression and activity can be modulated by the ErbB2/PI3-K/Akt pathway. Oncogene, 2003, 22, 7998-8011.
66.Stengel, C., Newman, S. P., Day, J. M., Tutill, H. J., Reed, M. J., Purohit, A. Effects of mutations and glycosylations on STS activity: a site-directed mutagenesis study. Molecular and Cellular Endocrinology, 2008, 283, 76-82.
67.Miki, Y., Nakata, T., Suzuki, T., Darnel, A. D., Moriya, T., Kaneko, C., Sasano, H. Systemic distribution of steroid sulfatase and estrogen sulfotransferase in human adult and fetal tissues. The Journal of Clinical Endocrinology & Metabolism, 2002, 87, 5760-5768.
68.Reed, M. J., Purohit, A., Woo, L. W. L., Newman, S. P., & Potter, B. V. Steroid sulfatase: molecular biology, regulation, and inhibition. Endocrine Reviews, 2005, 26, 171-202.
69.Ghosh, D. Human sulfatases: a structural perspective to catalysis. Cellular and Molecular Life Sciences, 2007, 64, 2013-2022.
70.Hernandez-Guzman, F. G., Higashiyama, T., Pangborn, W., Osawa, Y., Ghosh, D. Structure of human estrone sulfatase suggests functional roles of membrane association. Journal of Biological Chemistry, 2003, 278, 22989-22997.
71.Pasqualini, J. R., Chetrite, G., Blacker, C., Feinstein, M. C., Delalonde, L., Talbi, M., & Maloche, C. Concentrations of estrone, estradiol, and estrone sulfate and evaluation of sulfatase and aromatase activities in pre-and postmenopausal breast cancer patients. The Journal of Clinical Endocrinology & Metabolism, 1996, 81, 1460-1464.
72.Ruder, H. J., Loriaux, L., Lipsett, M. B. Estrone sulfate: production rate and metabolism in man. Journal of Clinical Investigation, 1972, 51, 1020.
73.Ghosh, D. Human sulfatases: a structural perspective to catalysis. Cellular and Molecular Life Sciences, 2007, 64, 2013-2022.
74.Aka, J. A., Mazumdar, M., Chen, C. Q., Poirier, D., Lin, S. X. 17β-hydroxysteroid dehydrogenase Type 1 stimulates breast cancer by dihydrotestosterone inactivation in addition to estradiol production. Molecular Endocrinology, 2010, 24, 832-845.
75.Haynes, B. P., Straume, A. H., Geisler, J., A''Hern, R., Helle, H., Smith, I. E., Dowsett, M. Intratumoral estrogen disposition in breast cancer. Clinical Cancer Research, 2010, 16, 1790-1801.
76.Utsumi, T., Yoshimura, N., Takeuchi, S., Ando, J., Maruta, M., Maeda, K., Harada, N. Steroid sulfatase expression is an independent predictor of recurrence in human breast cancer. Cancer Research, 1999, 59, 377-381.
77.Evans, T. R., Rowlands, M. G., Law, M., Coombes, R. C. Intratumoral oestrone sulphatase activity as a prognostic marker in human breast carcinoma. British Journal of Cancer, 1994, 69, 555.
78.Utsumi, T., Yoshimura, N., Maruta, M., Takeuchi, S., Ando, J., Maeda, K., Harada, N. Significance of steroid sulfatase expression in human breast cancer. Breast Cancer, 1999, 6, 298-300.
79.Howarth, N. M., Purohit, A., Reed, M. J., & Potter, B. V. Estrone sulfamates: potent inhibitors of estrone sulfatase with therapeutic potential. Journal of Medicinal Chemistry, 1994, 37, 219-221.
80.Li, P. K., Pillai, R., Young, B. L., Bender, W. H., Martino, D. M., Lin, F. T. Synthesis and biochemical studies of estrone sulfatase inhibitors. Steroids, 1993, 58, 106-111.
81.Dibbelt, L., Li, P. K., Pillai, R., Knuppen, R. Inhibition of human placental sterylsulfatase by synthetic analogs of estrone sulfate. The Journal of Steroid Biochemistry and Molecular Biology, 1994, 50, 261-266.
82.Woo, L. L., Lightowler, M., Purohit, A., Reed, M. J., Potter, B. V. Heteroatom- substituted analogues of the active-site directed inhibitor estra-1,3,5(10)-trien-17- one-3-sulphamate inhibit estrone sulphatase by a different mechanism. The Journal of Steroid Biochemistry and Molecular Biology, 1996, 57, 79-88.
83.Li, P. K., Murakata, C., Akinaga, S. U.S. Patent No. 6,288,050. Washington, DC: U.S. Patent and Trademark Office. 2001.
84.Ishida, H., Nakata, T., Suzuki, M., Shiotsu, Y., Tanaka, H., Sato, N., Li, P. K. A novel steroidal selective steroid sulfatase inhibitor KW-2581 inhibits sulfated-estrogen dependent growth of breast cancer cells in vitro and in animal models. Breast Cancer Research and Treatment, 2007, 106, 215-227.
85.Jinbo, Y., & Inoue, Y. Novel estradiol derivatives. PCT Int Appl WO, 2000053620. 2000.
86.Reed, J. E., Woo, L. L., Robinson, J. J., Leblond, B., Leese, M. P., Purohit, A., Potter, B. V. 2-Difluoromethyloestrone 3-O-sulfamate, a highly potent steroid sulfatase inhibitor. Biochemical and Biophysical Research Communications, 2004, 317, 169-175.
87.Nussbaumer, P., Billich, A. Steroid sulfatase inhibitors. Medicinal Research Reviews, 2004, 24, 529-576.
88.Leese, M. P., Leblond, B., Newman, S. P., Purohit, A., Reed, M. J., Potter, B. V. Anti-cancer activities of novel D-ring modified 2-substituted estrogen-3- O-sulfamates. The Journal of Steroid Biochemistry and Molecular Biology, 2005, 94, 239-251.
89.Potter, B. V. L., Reed, M. J. Oestrogen-17-sulfamates as inhibitors of steroid sulfatase. PCT Int. Appl. WO, 2002016392. 2002.
90.Leese, M. P., Leblond, B., Smith, A., Newman, S. P., Di Fiore, A., De Simone, G., Potter, B. V. 2-Substituted estradiol bis-sulfamates, multitargeted antitumor agents: synthesis, in vitro SAR, protein crystallography, and in vivo activity. Journal of Medicinal Chemistry, 2006, 49, 7683-7696.
91.Fischer, D. S., Woo, L. L., Mahon, M. F., Purohit, A., Reed, M. J., & Potter, B. V. D-ring modified estrone derivatives as novel potent inhibitors of steroid sulfatase. Bioorganic & Medicinal Chemistry, 2003, 11, 1685-1700.
92.Fischer, D. S., Chander, S. K., Woo, L. L., Fenton, J. C., Purohit, A., Reed, M. J., Potter, B. V. Novel D-ring modified steroid derivatives as potent, non-estrogenic, steroid sulfatase inhibitors with in vivo activity. The Journal of Steroid Biochemistry and Molecular Biology, 2003, 84, 343-349.
93.Foster, P. A., Newman, S. P., Chander, S. K., Stengel, C., Jhalli, R., Woo, L. L., Purohit, A. In vivo efficacy of STX213, a second-generation steroid sulfatase inhibitor, for hormone-dependent breast cancer therapy. Clinical Cancer Research, 2006, 12, 5543-5549.
94.Woo, L. L., Fischer, D. S., Sharland, C. M., Trusselle, M., Foster, P. A., Chander, S. K., Reed, M. J. Anticancer steroid sulfatase inhibitors: synthesis of a potent fluorinated second-generation agent, in vitro and in vivo activities, molecular modeling, and protein crystallography. Molecular Cancer Therapeutics, 2006, 7, 2435-2444.
95.Poirier, D., Ciobanu, L. C., Bérubé, M. A multidetachable sulfamate linker successfully used in a solid-phase strategy to generate libraries of sulfamate and phenol derivatives. Bioorganic & Medicinal Chemistry Letters, 2002, 12, 2833-2838.
96.Ciobanu, L. C., Martel, C., Labrie, F., Poirier, D. Inhibition of estrone sulfate-induced uterine growth by potent nonestrogenic steroidal inhibitors of steroid sulfatase. Cancer Research, 2003, 63, 6442-6446.
97.Ciobanu, L. C., Boivin, R. P., Luu-The, V., Poirier, D. 3β-Sulfamate Derivatives of C19 and C21 Steroids Bearing at-Butylbenzyl or a Benzyl Group: Synthesis and Evaluation as Non-estrogenic and Non-androgenic Steroid Sulfatase Inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry, 2003, 18, 15-26.
98.Numazawa, M., Tominaga, T., Watari, Y., Tada, Y. Inhibition of estrone sulfatase by aromatase inhibitor-based estrogen 3-sulfamates. Steroids, 2006, 71, 371-379.
99.Rasmussen, L. M., Zaveri, N. T., Stenvang, J., Peters, R. H., Lykkesfeldt, A. E. A novel dual-target steroid sulfatase inhibitor and antiestrogen: SR 16157, a promising agent for the therapy of breast cancer. Breast Cancer Research and Treatment, 2007, 106, 191-203.
100.Malini, B., Purohit, A., Ganeshapillai, D., Woo, L. W. L., Potter, B. V., Reed, M. J. Inhibition of steroid sulphatase activity by tricyclic coumarin sulphamates. The Journal of Steroid Biochemistry and Molecular Biology, 2000, 75, 253-258.
101.Stanway, S. J., Purohit, A., Woo, L. L., Sufi, S., Vigushin, D., Ward, R., Elliott, M. Phase I study of STX 64 (667 Coumate) in breast cancer patients: the first study of a steroid sulfatase inhibitor. Clinical Cancer Research, 2006, 12, 1585-1592.
102.Reed, M.J., Potter, B.V.L. Compounds that inhibit oestrone sulphatase and/or aromatase and methods for making and using. US patent 6506792. Washington, DC: U.S. Patent and Trademark Office. 2003.
103.Hejaz, H. A., Woo, L. L., Purohit, A., Reed, M. J., Potter, B. V. Synthesis, in vitro and in vivo activity of benzophenone-based inhibitors of steroid sulfatase. Bioorganic & Medicinal Chemistry, 2004, 12, 2759-2772.
104.Bubert, C., Woo, L. W., Sutcliffe, O. B., Mahon, M. F., Chander, S. K., Purohit, A., Potter, B. V. Synthesis of aromatase inhibitors and dual aromatase steroid sulfatase inhibitors by linking an arylsulfamate motif to 4-(4H-1,2,4-triazol-4- ylamino) benzonitrile: SAR, crystal structures, in vitro and in vivo activities. ChemMedChem, 2008, 3, 1708-1730.
105.Wood, P. M., Woo, L. L., Labrosse, J. R., Trusselle, M. N., Abbate, S., Longhi, G., Potter, B. V. Chiral aromatase and dual aromatase-steroid sulfatase inhibitors from the letrozole template: synthesis, absolute configuration, and in vitro activity. Journal of Medicinal Chemistry, 2008, 51, 4226-4238.
106.Woo, L. L., Jackson, T., Putey, A., Cozier, G., Leonard, P., Acharya, K. R., Potter, B. V. Highly potent first examples of dual aromatase-steroid sulfatase inhibitors based on a biphenyl template. Journal of Medicinal Chemistry, 2010, 53, 2155-2170.
107.Ahmed, S., James, K., Owen, C. P., Patel, C. K., Patel, M. Novel inhibitors of the enzyme estrone sulfatase (ES). Bioorganic & Medicinal Chemistry Letters, 2001, 11, 841-844.
108.Owen, C., James, K., Sampson, L., Ahmed, S. Synthesis and biochemical evaluation of some novel benzoic acid based esters as potential inhibitors of oestrone sulphatase. Journal of Pharmacy and Pharmacology, 2003, 55, 85-93.
109.Patel, C. K., Owen, C. P., Ahmed, S. Inhibition of estrone sulfatase (ES) by alkyl and cycloalkyl ester derivatives of 4-[(aminosulfonyl)oxy] benzoic acid. Bioorganic & Medicinal Chemistry Letters, 2004, 14, 605-609.
110.Owen, C. P., Patel, M., Patel, C. K., Cartledge, T., Ahmed, S. Synthesis and in vitro biochemical evaluation of a series of compounds as potential inhibitors of estrone sulfatase (ES) and the role of pKa in both the synthesis and the inhibitory activity of the potential inhibitors. Letters in Drug Design & Discovery, 2007, 4, 394-398.
111.Okada, M., Nakagawa, T., Iwashita, S., Takegawa, S., Fujii, T., Koizumi, N. Development of novel steroid sulfatase inhibitors: I. Synthesis and biological evaluation of biphenyl-4-O-sulfamates. The Journal of Steroid Biochemistry and Molecular Biology, 2003, 87, 141-148.
112.Saito, T., Kinoshita, S., Fujii, T., Bandoh, K., Fuse, S., Yamauchi, Y., Horiuchi, T. Development of novel steroid sulfatase inhibitors: II. TZS-8478 potently inhibits the growth of breast tumors in postmenopausal breast cancer model rats. The Journal of Steroid Biochemistry and Molecular Biology, 2004, 88, 167-173.
113.Nussbaumer, P., Winiski, A. P., Billich, A. Estrogenic potential of 2-alkyl-4-(thio) chromenone 6-O-sulfamates: potent inhibitors of human steroid sulfatase. Journal of Medicinal Chemistry, 2003, 46, 5091-5094.
114.Nussbaumer, P., Bilban, M., Billich, A. 4, 4′-Benzophenone-O,O′-disulfamate: a potent inhibitor of steroid sulfatase. Bioorganic & Medicinal Chemistry Letters, 2002, 12, 2093-2095.
115.Ciobanu, L. C., Luu-The, V., Poirier, D. Nonsteroidal compounds designed to mimic potent steroid sulfatase inhibitors. The Journal of Steroid Biochemistry and Molecular Biology, 2002, 80, 339-353.
116.Fournier, D., Breuil, P. A., Poirier, D. Synthesis of aryl sulfamate and phenol small peptide derivatives using a multidetachable sulfamate linker strategy. Peptides for Youth, 2009, 219-220.
117.Lafay, J., Rondot, B., Carniato, D., Bonnet, P., Clerc, T., Shields, J., Duranti, E. U.S. Patent No. 7,476,691. Washington, DC: U.S. Patent and Trademark Office. 2009.
118.Maltais, R., Poirier, D. Steroid sulfatase inhibitors: a review covering the promising 2000-2010 decade. Steroids, 2011, 76, 929-948.
119.Nussbaumer, P., Billich, A. Steroid sulfatase inhibitors. Medicinal Research Reviews, 2004, 24, 529-576.
120.Demkowicz, S., Daśko, M., Kozak, W., Krawczyk, K., Witt, D., Masłyk, M., Rachon, J. Synthesis and biological evaluation of fluorinated 3‐phenylcoumarin‐7‐O‐sulfamate derivatives as steroid sulfatase inhibitors. Chemical Biology & Drug Design, 2016, 87, 233-238.
121.Lo, Y. S., Nolan, J. C., Shamblee, D. A. U.S. Patent No. 5,192,785. Washington, DC: U.S. Patent and Trademark Office. 1993.
122.Reed, M. J., Potter, B. V. U.S. Patent No. 6,083,978. Washington, DC: U.S. Patent and Trademark Office. 2000.
123.De Vos, F., Dumont, F., Santens, P., Slegers, G., Dierckx, R. A., De Reuck, J. Synthesis of two dopamine D4 receptor ligands: 11C labelled chromeno [3,4-c] pyridin‐5‐ones. Journal of Labelled Compounds and Radiopharmaceuticals, 2000, 43, 989-996.
124.Chiba, M., Pang, K. S. Effect of protein binding on 4-methylumbelliferyl sulfate desulfation kinetics in perfused rat liver. Journal of Pharmacology and Experimental Therapeutics, 1993, 266, 492-499.
125.Pasqualini, J. R., Schatz, B., Varin, C., Nguyen, B. L. Recent data on estrogen sulfatases and sulfotransferases activities in human breast cancer. The Journal of Steroid Biochemistry and Molecular Biology, 1992, 41, 323-329.
126.Gauthier, R., Vigneault, N., Bleau, G., Chapdelaine, A., Roberts, K. D. Solubilization and partial purification of steroid sulfatase of human placenta. Steroids, 1978, 31, 783-798.
127.Van der Loos, C. M., Van Breda, A. J., Van den Berg, F. M., Walboomers, J. M. M., Jöbsis, A. C. Human placental steroid sulphatase purification and monospecific antibody production in rabbits. Journal of Inherited Metabolic Disease, 1984, 7, 97-103.