臺灣博碩士論文加值系統

BPA（4-dihydroxyborylphenylalanine）在日本進行GBM患者BNCT治療已有不錯的成效；11C-ACBC（1-amino-cyclobutane carboxylic acid） PET對腦腫瘤的攝取優於18F-FDG，且在1992年已證實腦腫瘤細胞與其他正常細胞對1-[11C]ACBC之吸收比例高達10：1。本研究之目的是希望能取其兩者在臨床試驗結果之優點，因此為了發展硼中子捕獲治療在肝癌的治療而選擇1-amino-3- (4-boronophenyl) cyclobutane carboxylic acid，乃一含ACBC結構且與BPA類似之藥物。
此含硼胺基酸化合物之合成程序共有七個步驟，且每一個步驟之實驗條件及方法亦有詳盡的討論。整個合成程序的主要關鍵在於第一、二步驟，其反應之試劑在進行反應的過程中對水分子相當敏感，易造成反應不完全及產率過低的現象；在最後第六、七步驟經由Bucherer-Strecker反應即可得最終產物，該反應本身亦有產率的的限制。以上所有合成程序中的中間產物化合物乃至最終產物皆經由氫核磁共振及碳核磁共振予以鑑定確認。
經由最後純化過程所得之最終產物，由台北榮總及中興大學著手進行肝癌治療的動物試驗，期望此一含硼胺基酸化合物可做為未來肝癌的硼中子捕獲治療藥物。

Clinical trials of BNCT for the treatment of glioblastoma and melanoma using 4-dihydroxyborylphenylalanine (BPA) as the boron compound have proven to be efficacious. In 1992, the 11C labeled 1-amino-cyclobutanecarboxylic acid (ACBC) for diagnosing brain tumors by PET imaging has been evidenced to be more accurate than 18F-FDG, being with tumor-to-normal tissue uptake ratio up to 10:1. In this study, 1-amino-3-(4-boronophenyl) cyclobutane carboxylic acid, a BPA analogue , with a moiety of ACBC structure, was synthesized and developed as a BNCT drug for treatment of brain and liver tumors.
The synthetic process involves 7 steps. The optimal condition for each step has been closely investigated. The key synthetic procedure is pertinent to the initial two steps. The reaction may become incomplete and lead to a low product-yield if existence of moisture. In addition, the last two steps involve Bucherer-Strecker reaction; the reactivity is inherently limited, resulting in a low product-yield. The final product, 1-amino-3-(4-boronophenyl) cyclobutane carboxylic acid was purified via a silica gel column chromatography. The intermediate and final products were identified by 1H-NMR and 13C-NMR.
The efficacy of the boron-contained amino acid for treatment of either brain tumor or liver tumor is being assessed by animal tests at National Chung Hsing University and Taipei Veterans General Hospital. It is anticipated that this boronated amino acid compound be efficacious as a BNCT agent in the future.

摘要----------------------------------------------------------Ⅰ
Abstract -----------------------------------------------------Ⅱ
謝誌----------------------------------------------------------Ⅳ
目錄----------------------------------------------------------Ⅵ
壹、 緒論-------------------------------------------------1
（一） 前言-------------------------------------------------1
（二） 中子捕獲核種的發展-----------------------------------2
（三） 硼中子捕獲治療的基本原理-----------------------------4
（四） 研究方向及目的---------------------------------------6
貳、 實驗部分---------------------------------------------8
（一） 儀器和材料-------------------------------------------8
（二） 化合物之基本資料------------------------------------10
（三） 實驗步驟--------------------------------------------13
參、 結果與討論------------------------------------------21
（一）〔2+2〕環化加成反應製備化合物2-------------------------21
(二）脫氯還原反應製備化合物3---------------------------------23
（三）保護基反應製備化合物4-----------------------------------26
（四）取代反應製備化合物5-------------------------------------28
（五）去保護基反應製備化合物6---------------------------------31
（六）Bucherer-Strecher 反應製備化合物7-----------------------33
（七）開環反應製備化合物8-------------------------------------35
肆、 結論------------------------------------------------36
伍、 參考資料--------------------------------------------37
附圖表--------------------------------------------------------41
總流程圖------------------------------------------------------41
表一、不同核種的熱中子捕獲截面積------------------------------42
表二、不同組織內元素的熱中子捕獲截面積
和所佔之組織百分比--------------------------------------------42
圖一、化合物3之氫核磁共振光譜圖-------------------------------43
圖二、化合物3之碳核磁共振光譜圖-------------------------------44
圖三、化合物4之氫核磁共振光譜圖-------------------------------45
圖四、化合物4之碳核磁共振光譜圖-------------------------------46
圖五、化合物5之氫核磁共振光譜圖-------------------------------47
圖六、化合物5之碳核磁共振光譜圖-------------------------------48
圖七、化合物6之氫核磁共振光譜圖-------------------------------49
圖八、化合物6之碳核磁共振光譜圖-------------------------------50
圖九、化合物7之氫核磁共振光譜圖-------------------------------51
圖十、化合物7之碳核磁共振光譜圖-------------------------------52
圖十一、化合物8之氫核磁共振光譜圖-----------------------------53
圖十二、化合物8之碳核磁共振光譜圖-----------------------------54

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