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研究生:涂源善
研究生(外文):Yuan Shan Tu
論文名稱:合成HP類緣化合物作為MAT之抑制劑以及細胞分化幫助劑
論文名稱(外文):Synthesis of Hemoregulatory Peptide(HP) Analogues
指導教授:郭盛助郭盛助引用關係
指導教授(外文):Sheng Chu Kuo
學位類別:博士
校院名稱:中國醫藥學院
系所名稱:藥物化學研究所
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:2000
畢業學年度:88
語文別:中文
論文頁數:56
中文關鍵詞:甲硫胺酸腺甘基轉移酵素HP類緣化合物人類血癌細胞分化
外文關鍵詞:methionine S-adenosyl transferaseMATHP analoguesHL-60 cellsdifferentiation
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本人為了尋找甲硫胺酸腺甘基轉移酵素(Methionine S-adenosyltransferase;MAT)新抑制劑與維他命A酸對HL-60人類血癌細胞誘導分化之加強劑,設計合成一系列HP類緣化合物(HP1~12)。標的化合物之合成係採用solid phase peptide synthesis 之方法而製備的。接著再根據表面薄層電漿共振技術 (SPR) 之原理設計出對於HL-60人類血癌細胞內之MAT酵素的活性抑制測試;其結果顯示出天然的HP類緣化合物PyroGlu-Glu-Glu-Cys-Lys-OH (HP1)及PyroGlu-Asp-Asp-Cys-Lys-OH (HP3)皆表現出最大的抑制活性。進一步,將HP1上的C-端-COOH集團改為-CONH2集團時,其抑制活性更甚於HP1。
經測試一系列HP類緣化合物對於HL-60人類血癌細胞所產生促進分化及抑制增殖能力的活性之後,建立了初步的結構與活性關係。同時發現所有的HP類緣化合物 (HP1~12)都具有明顯的活性,其中以PaA-Glu-Glu-
Cys-Lys-NH2 (HP12)活性最強且其促進維他命A酸誘導細胞活化能力相當於苯醋酸的50倍。
In my search for novel inhibitors of methionine S-adenosyl transferase(MAT)and potentiators of the activity of retinoic acid in inducing differentiation of HL-60 cells. A series of HP analogues(HP1~12)were designed. The solid phase peptide synthetic procedure was adopted for the preparation of these target peptides. Preliminary tests of their inhibitory effects on the MAT of HL-60 cells was performed according to the surface plasmon resonance(SPR)technology. Results indicate that PyroGlu-Glu-Glu-Cys-Lys-OH (HP1) and PyroGlu-Asp-Asp-Cys-Lys-OH(HP3) ,both being natural HP, displayed significant inhibitory effects. The synthetic HP6, obtained by converting the C-terminal-COOH of HP1 to-CONH2, demonstrated improved activity over HP1.
After testing the target peptides on HL-60 cells for differentiation and proliferation capability, a preliminary SAR was established.
All of the peptides (HP1~12) showed significant activity. Among them, PaA-Glu-Glu-Cys-Lys-NH2 (HP12) exhibited the highest activity with about 50 times the potency of phenylacetic acid in the potentiating activity of retinoic acid to induce cell differentiation.
封面
目錄
英文摘要
中文摘要
第一章 緒論
第一節 癌化學療法
第二節 癌細胞分化療法
(Ⅰ)傳統分化療法
(Ⅱ)新型分化療法劑概述
第三節 Peptide類分化幫助劑開發之重要意義
第四節 Peptide固相合成法(solid-phase peptide synthesis;SPPS)之簡介
(Ⅰ)Peptide固相合成法之特徵
(Ⅱ)固相合成法之基本操作
(Ⅲ)固相合成法之各種問題
第五節 研究動機與標的化合物之設計
第二章 材料與方法
第一節 固相peptide合成
(Ⅰ)材料與儀器
(Ⅱ)合成步驟之設計
第二節 MAT抑制活性之篩選試驗
(Ⅰ)材料與儀器
(Ⅱ)方法
第三節 細胞分化活性與增殖測試法
(Ⅰ)材料與儀器
(Ⅱ)方法
第三章 結果與討論
第一節 HP類緣化合物之合成
標的peptide合成實例(A)
標的peptide合成實例(B)
第二節 MAT抑制活性篩選
第三節 細胞分化活性與增殖測試
(Ⅰ)標的化合物(HP1~12)對HL-60人類血癌細胞生長之影響
(Ⅱ)標的化合物(HP1~12)對HL-60人類血癌細胞分化誘導效果
第四章 結論
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