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研究生:毛志民
研究生(外文):Mao Chih-Min
論文名稱:COUMARIN等效性類似物的合成及生物活性評估
論文名稱(外文):SYNTHESIS AND BIOLOGICAL EVALUATION OF COUMARIN ISOSTERIC ANALOGUES
指導教授:徐令儀
指導教授(外文):Hsu Ling-Yih
學位類別:碩士
校院名稱:國防醫學院
系所名稱:藥學研究所
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:116
中文關鍵詞:生物等效基團等效性基團取代抗凝血劑整合酵素抑制劑整合酵素
外文關鍵詞:bioisostersisosteric alternativesanticoagulantsintegrase inhibitorsintegrasecoumarin
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鑑於coumarin類化合物具有抑制HIV-1 整合酵素(integrase)的功能;因此,本研究以bis- or tetra-coumarin(NSC 158393)類似物為前導化合物(lead compound),依其結構特性,設計一系列生物等效性(bioisosteric)類似物及其衍生物並進行其合成實驗,一共合成20個中間產物,36個終產物。
我們取其中23個化合物(T01至T23)進行抗凝血研究,發現化合物T01,T10,T11對collagen誘發凝集之作用有中等程度的抑制效果;與苯環之對位未經修飾的T06比較發現,若於連結物對位導入磺醯基或醯基等取代基,可增強對collagen誘發凝集作用之抑制效果。對整合酵素之抑制能力測試,將經由中華民國國防醫學院徐博士之藥物化學實驗室與法國巴黎的國家科學研究中心(CNRS)轄下Institute Gustave-Roussy的Dr. Auclair跨國合作,結果將於日後刊出。

Recently, coumarin analogues have been identified as effective inhibitors of HIV-1 integrase. Based on the structural feature of lead compound (NSC 158393) of HIV-1 integrase inhibitors, a series of bioisosteric analogues of coumarin has been designed and synthesized. We have prepared 20 intermediates and 36 final products.
Twenty three compounds(T01-T23) have been evaluated for the anticoagulant effect. Compounds T01, T10, T11 were shown moderately inhibitory activity against platelet aggregation induced by collagen. Structure-activity analysis indicated that a p-hydroxyl substition of the phenyl ring of the linker might increase inhibitory activity of platelet aggregation. The inhibitory activity of HIV integrase will be screened via a national cooperation between Dr. Auclair's Molecular Pharmacology Laboratory, Institute Gustave-Roussy, CNRS, France and Dr. Hsu's Medicinal Chemistry Laboratory, School of Pharmacy, National Defense Medical center, ROC. The results will be published elsewhere.

正文目錄
第一章 緒論5
第一節 研究背景6
壹、HIV感染之臨床藥物治療現況6
貳、整合簡介10
參、整合抑制劑之發展回顧12
第二節 研究方法21
壹、研究動機21
貳、合成反應概要29
第二章 材料與方法35
第一節 試劑、溶媒及原料35
第二節 重要儀器37
第三節 合成實驗39
壹、合成實驗部分39
貳、抗凝血活性評估部分94
第三章 結果95
第一節合成實驗95
第二節藥理實驗95
第四章 討論97
第一節合成實驗97
第二節藥理實驗106
第五章 結論107
第六章 參考文獻108
表目錄
表一、1999年現有治療HIV感染的藥物9
表二、由立體空間搜尋具抑制HIV-1整合活性的化合物16
表三、推敲四聚物(tetramer)之組成化合物18
表四、以苯環為coumarin的連接中心19
表五、檢視7-羥化對抑制效力的影響20
表六、檢視連接物對抑制強度的影響25
表七、Diarylsulfones25
表八、Sulfonic Acids and Sufonamides27
圖目錄
圖一、藥物的作用部位8
圖二、整合的反應機轉11
圖三、NSC 158393的分子結構15
圖四、Hydroxycoumarin雙體結構中可能的藥效基團15
圖五、藥效基團的空間距離15
圖六、Vitamin K Cycle22
圖七、coumarin類似物的修飾研究23
圖八、等效性基團取代的藥物設計24
圖九、標的化合物26
圖十、X2L-R+的結構28
圖十一、Alkylation of Guanine in DNA28
附圖一:化合物T03之1HNMR(DMSO-d6, 300 MHz)圖譜
附圖二:化合物T04之1HNMR(DMSO-d6, 300 MHz)圖譜
附圖三:化合物T08之1HNMR(DMSO-d6, 300 MHz)圖譜
附圖四:化合物T11之1HNMR(DMSO-d6, 300 MHz)圖譜
附圖五:化合物T14之1HNMR(DMSO-d6, 300 MHz)圖譜
附圖六:化合物T15之1HNMR(DMSO-d6, 300 MHz)圖譜
附圖七:化合物T16之1HNMR(DMSO-d6, 300 MHz)圖譜
附圖八:化合物T26之1HNMR(CDCl3, 300 MHz)圖譜
附圖九:化合物T30之1HNMR(DMSO-d6, 300 MHz)圖譜
附圖十:化合物T35之1HNMR(CDCl3, 300 MHz)圖譜
附圖十一:化合物T35之MS(FAB+)圖譜

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