因為我們的目標是通過使用Ugi四組分反應（Ugi 4-CR）來合成多種含硼類似物。這種目標產物物我們預計將使其具有一下四個關鍵特徵：（a）模擬di-peptide骨架的鹼性代謝過程（允許化合物通過POT途徑轉運）；（b）羰基組分（這將增加總體硼含量/分子）；（c）兩個硼酸基團（可以形成具有特殊親水性的硼酸-果糖複合物）；和（d）DOTA附屬物（允許Ugi-4CR類似物被放射性同位素標記，例如177Lu和111In）。這樣的一種設計思路可以讓我們的目標產物具有診斷與治療一體化的效果，最後我們通過合成含硼Ugi-4CR前體再與DOTA進行peptide coupling以合成多重含硼寡肽嘗試使用我們實驗室自己合成出的更為複雜的isocyanide進行合成，我們成功合成出了產物6（Fig 9），並且通過了MASS和NMR檢測。
我也希望可以引入氟原子以便提高我們的目標產物的代謝效率，所以我們設計並合成了以下兩種目標物4.5分別在我們的Ugi起始物中的acid或aldehyde中加入F官能基。

We aim to synthesize libraries of multiple boron-containing analogs by employing Ugi-four component reaction (Ugi 4-CR) (Scheme 1). These Ugi-4CR analogs would possess four key signatures: (a) a di-peptide skeleton that mimic basic metabolite (that allows the compound to be transported via POT pathway); (b) a carboranyl component (that would increase the overall boron-content/ molecule); (c) two boronic acids groups (that could form the boronic acid-fructose complex with exceptional hydrophilicity); and (d) a DOTA appendage (that allows the Ugi-4CR analogs to be labeled by radioactive isotopes, such as 177Lu and 111In).Such a design idea can make our target product have the effect of integration of diagnosis and treatment,
Finally, we synthesized the boron-containing ugi-4cr precursor and then combined it with dota to synthesize multiple boron-containing oligopeptides
We tried to use the more complex isocyanide synthesized by our own laboratory to synthesize. We successfully synthesized the product 6 (Fig. 9), and passed the mass and NMR test.
I also hope to introduce fluorine atoms to improve the metabolic efficiency of our target products, so we designed and synthesized the following two targets 4.5 to add f functional groups to acid or aldehyde in our UGI initiator respectively.

謝誌	I
主目錄	VIII
圖表目錄	X
Chapter 1 緒論	1
1-1研究動機	1
2-1研究目的	2
Chapter 2文獻回顧	4
2-1金屬螯合劑簡介	4
2-1.1鑭系金屬簡介	4
2-1.2鑭系金屬螯合劑發展簡介	5
2-1.3類似金屬螯合劑藥物介紹	7
2-2硼中子捕獲治療(Boron Neutron Capture Therapy, BNCT)	8
2-2.1硼中子捕獲治療(Boron Neutron Capture Therapy, BNCT)之簡介	8
2-2.2硼中子捕獲治療(Boron Neutron Capture Therapy, BNCT)之發展歷程	11
2-3診療一體化（theranostics）之簡介	13
Chapter 3結果與討論	14
3-1含硼Ugi多組分反應的研究與應用	14
3-2多重含硼寡肽之合成	16
3-2.1直接藉由Ugi反應合成含DOTA之多重含硼寡肽	16
3-2. 2通過酸保護的氨基酸修飾DOTA以進行Ugi反應合成多重含硼寡肽	20
3-2.3通過Boc保護的乙二胺修飾DOTA以進行Ugi反應合成多重含硼寡肽	23
3-2.4通過先合成含硼Ugi-4CR前體再與DOTA進行peptide coupling以合成多重含硼寡肽	25
3-2.5多重含硼寡肽的結論及應用延伸	29
3-2.6氟原子在藥物設計中的應用	30
Chapter 4實驗步驟	33
4.1 起始物	33
Chapter 6實驗藥品與實驗儀器	49
4.1使用藥品	49
4.2實驗儀器與測試方法	51
附錄一 光譜圖資料	52
附錄二 參考資料	59

圖表目錄
Figure 1 The structure of TTHA.DTPA and EDTA	5
Figure 2The structure of DOTA and TETA	6
Figure 3硼中子捕獲治療原理示意圖	8
Figure 4 Ugi多组分反应	15
Figure 5直接藉由Ugi反應合成含DOTA之多重含硼寡肽失败研究	19
Figure 6 产物4的水解反应	22
Figure 7 TFA去保护的副产物	27
Figure 8 目标产物	28
Figure 9 产物6	29
Figure 10 降血脂类的药物 Ezetimibe	31
Figure 11 两种含氟目标产物	32

Scheme 1. Synthesis of Dipeptidyl DOTA Boron-containing Analogs	3
Scheme 2直接藉由Ugi反應合成含DOTA之多重含硼寡肽	16
Scheme 3 通过酸保护的氨基酸修饰DOTA以进行Ugi反應合成多重含硼寡肽	20
Scheme 4 Boc保护的乙二胺与DOTA进行peptide coupling偶联	24
Scheme 5 合成含硼Ugi-4CR前体再与DOTA进行peptide coupling以合成多重含硼寡肽	26

Table 1直接藉由Ugi反應合成含DOTA之多重含硼寡肽反应尝试	18
Table 2酸保护的甘氨酸与DOTA进行peptide coupling偶联	21
Table 3 含硼Ugi-4CR前体合成的改进	27

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