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研究生:王耀賢
研究生(外文):Yao-Hsien Wang
論文名稱:5alpha-還原脢親和性標籤的合成
論文名稱(外文):The Synthesis of a Novel 5alpha-Reductase Photoaffinity Label
指導教授:簡偉明
指導教授(外文):Wai-Ming Kan
學位類別:碩士
校院名稱:國立成功大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:1999
畢業學年度:87
語文別:中文
論文頁數:92
中文關鍵詞:5alpha-還原脢睪固酮親和性標籤前列腺肥大
外文關鍵詞:5alpha-reductasetestosteroneaffinity labelbenign prostatic hyperplasia
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良性前列腺肥大(benign prostatic hyperplasia, BPH)在成年男性中佔有很高的罹患率。根據統計,男性在65歲以上約有50%的機率會得到前列腺肥大,由於科學發展及醫療技術的進步,人口老化是必然的趨勢。因此除非有預防的方法,否則得到此病的人數將一直增加。目前的治療方法主要是以減輕症狀為主,在良性前列腺肥大的致病過程中,5alpha-還原脢扮演一個很重要的角色。它能夠經由一個輔脢(NADPH)將睪固酮(T)還原成二氫睪固酮(DHT)。二氫睪固酮能使前列腺產生肥大的情形,另外在前列腺癌(prostate cancer)、青春痘(acne)、女性的多毛症(female hirsutism)及男性特徵的禿頭(male pattern baldness)中,5alpha-還原脢及二氫睪固酮的濃度在影響的組織中有升高的趨勢,因此發展5alpha-還原脢的抑制劑(5R inhibitor)可以對上述的疾病提供一個治療的方法。目前已經有5alpha-還原脢的抑制劑(finasteride, Proscar)問世,但對於5alpha-還原脢在體內的作用則還沒有清楚的瞭解。
目前已知有兩種5alpha-還原脢被發現出來,分別是第一型及第二型。由這兩型在體內的分佈及對5alpha-還原脢抑制劑的親和性(affinity)有明顯的差異性來看,它們和睪固酮結合的區域應該會有不同的性質。有學者利用photoaffinity labelling的方法,發現了5alpha-還原脢和NADPH的結合區域是由9個胺基酸所組成。因此,本實驗室對兩個主題感到很有興趣,一個是5alpha-還原脢和睪固酮的結合區域(binding domain),我們計畫以親和性標籤(affinity label)的方法來研究及找出5alpha-還原脢和睪固酮的結合區域。首先必須合成出一個化合物來作為5alpha-還原脢的親和性標籤(affinity label)。以化學合成的方法合成出中間體compound 9,利用compound 9可以合成出許多不同的親和性標籤,目前我們已先將compound 9打入兔子體內產生抗體,抗體可用來做為確定5alpha-還原脢和親和性標籤結合的偵測工具,而合成親和性標籤的工作則在繼續進行研究當中。
同時我們也進行篩選具有5alpha-還原脢抑制性的化合物,我們分別對compound Ⅰ、compound Ⅱ、compoundⅢ、compound Ⅳ進行初步的篩選。由實驗結果發現,除了compound Ⅱ沒有作用之外,其餘3種化合物都具有對5alpha-還原脢產生抑制作用的性質。由以上研究結果來看,能夠使我們對5alpha-還原脢和睪固酮結合區域的了解增加,同時對5alpha-還原脢的結構-功能關係(structure-function relationship)有更進一步的認識。另外,篩選具有5alpha-還原脢抑制性的化合物也能夠對5alpha-還原脢引起的疾病提供一個新的治療方向,幫助我們研發出新的治療藥物。

5alpha-Reductase serve an important function in many androgen-sensitive cells by converting the major circulating androgenic hormone, testosterone (T), into the more potent intracellular hormone, 5alpha-dihydrotestosterone (DHT). The quantity of this enzyme and DHT is elevated in the affected tissue of such conditions as benign prostatic hyperplasia (BPH), prostate cancer, acne, female hirsutism, and male pattern baldness. Inhibition of this enzyme might provide a means of therapy for these androgen-related disorders.
One of these diseases, BPH is a common disease among elderly male. Recent estimates suggest that 50% of males over the age of 65 will require a prostatectomy during the remainder of their lifetime, although the slow progress of the disease and the general acceptance of BPH as an inevitable consequence of aging. Surgery, particularly transurethral resection of the prostate (TURP), is effective in the treatment of BPH. It is generally accepted that two components contribute to symptomatic BPH: static component related to prostatic tissue mass and a dynamic component related to prostatic smooth muscle tone. Alpha1-adrenoceptor antagonists and 5alpha-reductase inhibitors have been suggested for BPH Treatment. However, only finasteride, a steroidal 5alpha-reductase inhibitors is clinical available. Up to now, the function of 5alpha-reductase is not clear.
Two 5alpha-reductase enzymes have been identified and cloned, 5alpha-reductase 1 and 5alpha-reductase 2. There are apparent difference on their tissue distribution and inhibition affinity. Identification of the domains that precipitate with the binding of substrate and cofactor and subsequent catalysis is an important step in understanding structure-function relationship in virtually any enzyme system. Thereby, we focus on two aspects. One is the testosterone domain of 5alpha-reductase, and the other is screening for new compounds with 5alpha-reductase inhibition activity.
Four compounds were tested for 5alpha-reductase inhibitory activity. Three of them, compound Ⅰ、compound Ⅲ、compound Ⅳshowed promising inhibitory activities. According to the enzyme kinetics results, we can design and synthesize novel inhibitors with more potent inhibition activity for clinical use. It may contribute to the development of the clinical treatment of disease related to 5alpha-reductase inhibitors.

致謝
中文摘要
英文摘要
縮寫簡索表
緒論 1
實驗材料與方法 10
結果 37
討論 46
參考文獻 51
圖表 62
自述

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