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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78946完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 梁碧惠 | zh_TW |
| dc.contributor.advisor | Pi-Hui Liang | en |
| dc.contributor.author | 張巧念 | zh_TW |
| dc.contributor.author | Chiao-Nien Chang | en |
| dc.date.accessioned | 2021-07-11T15:31:18Z | - |
| dc.date.available | 2024-02-28 | - |
| dc.date.copyright | 2018-10-11 | - |
| dc.date.issued | 2018 | - |
| dc.date.submitted | 2002-01-01 | - |
| dc.identifier.citation | 1. Stewart, B. W.; Wild, C. P., World Cancer Report 2014; International Agency for Research on Cancer: Lyon, France, 2014.
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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. J. Steroid Biochem. Mol. Biol. 2005, 94, 239-51. 31. Bubert, C.; Leese, M. P.; Mahon, M. F.; Ferrandis, E.; Regis-Lydi, S.; Kasprzyk, P. G.; Newman, S. P.; Ho, Y. T.; Purohit, A.; Reed, M. J.; Potter, B. V., 3,17-Disubstituted 2-Alkylestra-1,3,5(10)-trien-3-ol Derivatives: Synthesis, in Vitro and in Vivo Anticancer Activity. J. Med. Chem. 2007, 50, 4431-43. 32. Leese, M. P.; Leblond, B.; Smith, A.; Newman, S. P.; Di Fiore, A.; De Simone, G.; Supuran, C. T.; Purohit, A.; Reed, M. J.; Potter, B. V., 2-Substituted Estradiol Bis-sulfamates, Multitargeted Antitumor Agents: Synthesis, in Vitro SAR, Protein Crystallography, and in Vivo Activity. J. Med. Chem. 2006, 49, 7683-96. 34. Fischer, D. S.; Woo, L. W.; Mahon, M. F.; Purohit, A.; Reed, M. J.; Potter, B. 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M Rasmussen, L.; Zaveri, N.; Stenvang, J.; H Peters, R.; Lykkesfeldt, A., A Novel Dual-target Steroid Sulfatase Inhibitor and Antiestrogen: SR 16157, a Promising Agent for the Therapy of Breast Cancer. Breast Cancer Res. Treat. 2008, 106, 191-203. 39. Stanway, S. J.; Purohit, A.; Woo, L. W.; Sufi, S.; Vigushin, D.; Ward, R.; Wilson, R. H.; Stanczyk, F. Z.; Dobbs, N.; Kulinskaya, E.; Elliott, M.; Potter, B. V.; Reed, M. J.; Coombes, R. C., Phase I Study of STX 64 (667 Coumate) in Breast Cancer Patients: the First Study of a Steroid Sulfatase Inhibitor. Clin. Cancer Res. 2006, 12, 1585-92. 40. Woo, L. W. L.; Ganeshapillai, D.; Thomas Mark, P.; Sutcliffe Oliver, B.; Malini, B.; Mahon Mary, F.; Purohit, A.; Potter Barry, V. L., Structure–Activity Relationship for the First-in-Class Clinical Steroid Sulfatase Inhibitor Irosustat (STX64, BN83495). ChemMedChem 2011, 6, 2019-2034. 41. Hejaz, H. A.; Woo, L. W.; Purohit, A.; Reed, M. J.; Potter, B. V., Synthesis, in Vitro and in Vivo Activity of Benzophenone-Based Inhibitors of Steroid Sulfatase. Bioorg. Med. Chem. 2004, 12, 2759-72. 42. Ahmed, S.; James, K.; Owen, C. P.; Patel, C. K.; Patel, M., Novel Inhibitors of the Enzyme Estrone Sulfatase (ES). Bioorg. Med. Chem. Lett. 2001, 11, 841-844. 43. Woo, L. W. L.; Jackson, T.; Putey, A.; Cozier, G.; Leonard, P.; Acharya, K. R.; Chander, S. K.; Purohit, A.; Reed, M. J.; Potter, B. V. L., Highly Potent First Examples of Dual Aromatase−Steroid Sulfatase Inhibitors Based on a Biphenyl Template. J. Med. Chem. 2010, 53, 2155-2170. 44. 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. J. Steroid Biochem. Mol. Biol. 2003, 87, 141-8. 45. Nussbaumer, P.; Lehr, P.; Billich, A., 2-Substituted 4-(Thio)chromenone 6-O-Sulfamates: Potent Inhibitors of Human Steroid Sulfatase. J. Med. 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C.; Synthesis and Biological Evaluation of Coumarin-7-Sulfamate with Ring Expansion at 3, 4-position as Steroid Sulfatase Inhibitors. M.S. Thesis, National Taiwan University, September 2017. 60. Chaki, H.; Kotsubo, H.; Tanaka, T.; Aikawa, Y.; Hirono, S.; Shiozawa, S. Novel Bensophenone Derivatives or Salts Thereof. Patent WO/2003/042150, May 22, 2003. 61. Trottier, A.; Maltais, R.; Ayan, D.; Barbeau, X.; Roy, J.; Perreault, M.; Poulin, R.; Lague, P.; Poirier, D., Insight into the Mode of Action and Selectivity of PBRM, a Covalent Steroidal Inhibitor of 17beta-hydroxysteroid Dehydrogenase Type 1. Biochem. Pharmacol. 2017, 144, 149-161. | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78946 | - |
| dc.description.abstract | 類固醇硫酸酯酶(steroid sulfatase, STS)為雌激素生合成中的關鍵酵素，催化雌酮硫酸鹽(estrone sulfate, E1S)和硫酸脫氫表雄酮(dehydroepiandrosterone sulfate, DHEAS)轉化為具雌激素活性之雌激素酮(estrone, E1)和脫氫表雄酮(dehydroepiandrosterone, DHEA)。而在雌激素受體陽性型(ER+)乳癌組織中，類固醇硫酸酯酶過度表現引起雌激素濃度升高，誘導癌細胞增生並抑制細胞凋亡。因此，抑制類固醇硫酸酯酶的活性可以降低類固醇雌激素水平，繼而減緩乳房腫瘤的生長。
Irosustat (STX-64, 32c)為首個進入臨床2期試驗的類固醇硫酸酯酶抑制劑，具有香豆素胺基磺酸(coumarin-based sulfamate)骨架，其臨床試驗因副作用而中止。基於STX-64與類固醇硫酸酯酶的分子模擬研究，我們保留了其香豆素-7-胺基磺酸骨架，設計並合成了一系列的芐基衍生物。先前的研究發現，香豆素3號位芐基衍生物如3-(2,3-dimethoxybenzyl)-aminocoumarin-7-sulfamate (52c)對STS具有良好活性。進一步，將香豆素3、4號位擴環以增加平面性，其芐基衍生物如化合物55b對人類胎盤類固醇硫酸酯酶具有理想的抑制活性和分配係數(Log P)值。因此，本研究將針對這個系列進行更深入的構效關係探討。 結果顯示，增加苯環對位的親脂性可以提升對STS的抑制效果，異丙基修飾的化合物60e對人類胎盤及MCF-7細胞類固醇硫酸酯酶之IC50分別為0.25 nM及0.38 μM。苯環的間位含有氯亦可以增加抑制活性，而苯環鄰位修飾甲基的化合物(60d)活性最強，對人類胎盤及MCF-7細胞類固醇硫酸酯酶之IC50分別為0.15 nM及3.31 μM。這些化合物具可以應用於乳癌之荷爾蒙療法，未來將於(ER+)乳癌動物模型中進一步測試。 | zh_TW |
| dc.description.abstract | Steroid sulfatase (STS) plays a major role in estrogen biosynthesis that catalyzes the conversion of inactive estrone 3-sulfate (E1S) to estrogenic estrone (E1) and dehydroepiandrosterone sulfate (DHEAS) to dehydroepiandrosterone (DHEA). The STS is overexpressed in estrogen receptor-positive (ER+) breast cancer which causes estrogen levels raising, resulting in cell proliferation and anti-apoptosis. Therefore, inhibition of STS is a promising approach to reduce estrogenic steroid level which in turn halts breast tumorigenesis.
Irosustat (STX-64, 32c), a coumarin-based sulfamate, was the first potent STS inhibitor to enter phase II trial but which was halted. Inspired by the docking investigation of STX-64 and STS, a series of STS inhibitors with coumarin skeleton were designed and synthesized. In was found earlier that 3-benzylaminocoumarin-7- sulfamate (52c) was capable of inhibiting STS activity, and a series of substituents at adjacent phenyl ring were synthesized and evaluated. Moreover, ring expansion at 3,4-position of coumarin resulted in compound 55b which displayed improved inhibitory activity against STS of both human placenta and MCF-7 cells, and it also showed good partition coefficient (Log P). Intensive investigation on this series were then conducted. In this study, conformational restricted derivatives with hydrophobic group at para-position of phenyl ring (60e) had IC50 of 0.25 nM and 0.38 μM against STS of human placenta and MCF-7 cell line, respectively. The phenyl ring bearing meta-chloro substituents enhanced inhibitory activity and the ortho-methyl substituted derivative 60d was the most potent compound with an IC50 value of 0.15 nM and 3.31 μM in STS of placental microsome and MCF-7 cell line, respectively. These compounds are potential agents for breast cancer as adjuvant endocrine therapy (AET), which will be tested in animal model of (ER+) breast cancer in the future. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T15:31:18Z (GMT). No. of bitstreams: 1 ntu-107-R05423024-1.pdf: 10944371 bytes, checksum: 3fa92459bcb486bd9aa9381e52dc823f (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
謝誌 ii 中文摘要 iii Abstract v 縮寫對照表 x 圖目錄 xiii 表目錄 xv 第一章、簡介 1 1.1 乳癌 1 1.1.1 流行病學 1 1.1.2 乳癌危險因子 4 1.1.3 乳癌分類 5 1.2 雌激素 7 1.2.1 雌激素造成乳癌之機轉 7 1.2.2 雌激素生合成 11 1.2.3 荷爾蒙療法藥物 13 1.3 類固醇硫酸酯酶 15 1.3.1 類固醇硫酸酯酶與乳癌 15 1.3.2 類固醇硫酸酯酶之構造 15 1.3.3 類固醇硫酸酯酶之受質與功能 17 1.3.4 類固醇硫酸酯酶之作用機轉 18 1.4 類固醇硫酸酯酶抑制劑之發展 19 1.4.1 類固醇胺基磺酸類抑制劑 19 1.4.2 非類固醇胺基磺酸類抑制劑 24 第二章、研究方向與目的 32 2.1 研究動機 32 2.2研究策略 33 2.1.1 雙環香豆素胺基磺酸芐基衍生物 33 2.1.2 三環及四環香豆素胺基磺酸芐基衍生物 36 第三章、結果與討論 37 3.1 化學合成 37 3.1.1 三環香豆素芐基胺基磺酸60a-p 37 3.1.2雙環香豆素芐基胺基磺酸67a-d 45 3.2 生物分析 54 3.2.1 類固醇硫酸酯酶之純化 54 3.2.1 類固醇硫酸酯酶之酵素動力學探討 55 3.2.2 類固醇硫酸酯酶的抑制活性測試 57 3.2.3 化合物60d與類固醇硫酸酯酶之親和性測試 61 3.3 電腦模擬 63 第四章、結論 67 第五章、實驗材料與方法 69 5.1 生物分析 69 5.1.1 材料與器材 69 5.1.2 人類胎盤類固醇硫酸酯酶之萃取及純化 70 5.1.3 人類胎盤類固醇硫酸酯酶濃度測定 70 5.1.4 人類胎盤類固醇硫酸酯酶膠體電泳分析 71 5.1.5 人類胎盤類固醇硫酸酯酶Km測試 72 5.1.6 MCF-7細胞培養 72 5.1.7 藥物對類固醇硫酸酯酶的抑制活性測試 73 5.2 化學合成 75 5.2.1 反應試劑 75 5.2.2 實驗儀器 75 5.2.3 Compounds preparation 77 References 111 Appendix I | - |
| dc.language.iso | zh_TW | - |
| dc.title | 合成香豆素-7-胺基磺酸衍生物作為類固醇硫酸酯酶抑制劑及其用於荷爾蒙依賴型乳癌治療之活性評估 | zh_TW |
| dc.title | Synthesis and Biological Evaluation of Coumarin-7-Sulfamate Derivatives as Steroid Sulfatase Inhibitors for the Treatment of Hormone-Dependent Breast Cancer | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 106-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 王光昭;陳基旺;忻凌偉;蔡耿彰 | zh_TW |
| dc.contributor.oralexamcommittee | ;;; | en |
| dc.subject.keyword | 荷爾蒙受體陽性型乳癌,荷爾蒙療法,類固醇硫酸酯?抑制劑,香豆素-7-胺基磺酸, | zh_TW |
| dc.subject.keyword | hormone receptor-positive breast cancer,adjuvant endocrine therapy,STS,steroid sulfatase inhibitor,coumarin-7-sulfamate, | en |
| dc.relation.page | 213 | - |
| dc.identifier.doi | 10.6342/NTU201803636 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2018-08-16 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 藥學研究所 | - |
| dc.date.embargo-lift | 2028-12-31 | - |
| 顯示於系所單位： | 藥學系 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-106-2.pdf 目前未授權公開取用 | 10.69 MB | Adobe PDF |
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