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系統識別號 U0002-1307201815324600
中文論文名稱 四硼Ugi化合物之合成及其作為BNCT藥物之生物測試
英文論文名稱 The Synthesis of Tetra Boron-containing Ugi Analogous and their Biological Evaluation as the Potential BNCT Agent
校院名稱 淡江大學
系所名稱(中) 化學學系碩士班
系所名稱(英) Department of Chemistry
學年度 106
學期 2
出版年 107
研究生中文姓名 邱碩蓓
研究生英文姓名 Shuo-Bei Qiu
學號 606160017
學位類別 碩士
語文別 中文
口試日期 2018-06-29
論文頁數 174頁
口試委員 指導教授-潘伯申
委員-陳一瑋
委員-潘伯申
委員-黃俊誠
中文關鍵字 硼中子捕獲治療  多組成反應  生物測試 
英文關鍵字 BNCT  Boron  Multicomponent  Biological Evaluation 
學科別分類 學科別自然科學化學
中文摘要 利用Ugi Reaction合成四硼化合物(I)
本研究將對含硼異腈與其他含硼化合物之Ugi-4CR反應進行優化,並成功地以微波反應合成出9個含4個硼酯官能基之含硼雙胜肽化合物。這一系列的化合物,在單位分子含硼量較高,我們預期它在BNCT療程中會有所表現。
硼酯官能基之去保護(II)
本研究嘗試了三種將硼酯官能基去保護成硼酸化合物,將對這些方法進行討論,由於含硼化合物的純化不容易,希望能找出效率高、產率高的方法,提升含硼化合物的產量。
四硼化合物之生物測試(III)
我們將對本實驗室合成的含硼化合物、含硼果糖化合物、BNCT臨床用藥BPA做比較,藉由硼酸化合物會與DAHMI結合,在U2OS細胞的螢光圖中會發亮,可以得知含硼化合物聚集於細胞核,且透過螢光圖來看會比BPA來的亮,進一步利用流氏細胞儀來判斷這些進入細胞的含硼藥物進入細胞所發出的螢光量,並對這些研究做討論。
英文摘要 1. Synthesis of Tetra Boron-containing Ugi Analogous :
In this study, the Ugi-4CR reaction of boron-containing isocyanide with other boron-containing compounds was optimized, and nine boron-containing double peptiods containing four boronate esters functional groups were successfully synthesized by microwave reaction. These compounds could be potentially utilized in boron neutron capture therapy due to their high boron content.
2. Boronate Esters Functional Groups Deprotection :
In this study, we attempt three way to deprotect boronate esters functional groups into boronic acid compounds will be discussed. Since the purification of boron-containing compounds is not easy, it is hoped that high-efficiency, high-yield methods can be identified and boron-containing compounds can be improved yield.
3. Biological Evaluation of Tetra Boron Analogs :
We will compare boron-containing compounds, boron-containing fructose compounds synthesized in our laboratory, and BNCT clinically used BPA. By binding boronic acid compounds to DAHMI, they will glow in the fluorescence of U2OS cells. Gathered in the nucleus, and brighter than the BPA through the fluorescence chart, and further use of the rheometer to determine the amount of fluorescence of these boron-containing drugs entering the cells to enter the cell, and discuss these studies.
論文目次 目錄
謝誌································································································I
中文摘要·························································································II
Abstract ························································································IV
目錄·····························································································VII
圖目錄···························································································IX
光譜目錄························································································XI
Chapter 1 緒論·················································································1
1.1 研究動機·····················································································1
1.2 硼化學簡介··················································································3
1.2.1 硼烷(Boranes) ············································································4
1.2.2 硼酸、硼酯(Boronic Acids and Boronate Esters) ··································5
1.2.3 硼酸鹽(Borates)··········································································7
1.3 含硼化合物之合成應用···································································7
1.3.1 Luche Reduction···········································································8
1.3.2 Suzuki-Miyaura Cross-Coupling Reaction············································9
1.3.3 Petasis Reaction ·········································································10
1.4 比較Peptoids 與Peptides 的差別······················································11
1.4.1 Peptoids 的介紹·········································································11
1.4.2 Peptides 的介紹·········································································13
1.5 含硼化合物在BNCT 上的應用························································15
1.5.1 BNCT 簡介··············································································15
1.5.2 BNCT 治療機制········································································17
1.5.3 BNCT 藥物介紹········································································18
Chapter 2 利用Ugi Reaction 合成多重含硼化合物···································20
2.1 多組成反應之介紹·······································································20
2.1.1 Ugi Reaction ·············································································22
2.1.2 Strecker Reaction········································································23
2.1.3 Hantzsch reaction········································································23
2.2 利用Ugi Reaction 合成含硼化合物···················································24
2.3 結果與討論················································································25
2.3.1 合成多重含硼化合物的優化條件···················································25
2.3.2 利用Ugi Reaction 合成多重含硼化合物··········································26
2.4 結論·························································································29
Chapter 3 硼酯官能基之去保護···························································30
3.1 硼酯官能基之去保護介紹······························································30
3.2 結果與討論················································································33
3.2.1 利用NaIO4 將硼酯官能基去保護··················································33
3.2.2 利用DEA 將硼酯官能基去保護····················································35
3.3 結論·························································································38
Chapter 4 硼酸化合物之生物測試························································39
4.1 硼酸化合物的發光團介紹······························································39
4.2 結果與討論················································································39
4.2.1 探討DAHMI 隨時間變化的螢光衰變·············································39
4.2.2 硼酸化合物與DAHMI 錯合的細胞螢光圖·······································42
4.2.3 含硼果糖化合物與DAHMI 錯合的細胞螢光圖·································48
4.2.4 經由流氏細胞儀測得含硼藥物濃度的比較·······································50
4.3 結論·························································································54
4.4 未來展望···················································································55
Chapter 5 實驗藥品與實驗儀器···························································56
5.1 使用藥品···················································································56
5.2 實驗儀器···················································································58
Chapter 6 實驗步驟··········································································59
6.1 多重含硼化合物之合成·································································59
6.1.1 硼酯起始物之合成(通用合成步驟A)···········································59
6.1.2 含硼甲醯胺化合物之合成····························································63
6.1.2.1 方法一··················································································63
6.1.2.2 方法二(通用合成步驟B)························································64
6.1.3 含異腈化合物之合成(通用合成步驟C)·········································68
6.1.4 多重含硼化合物之合成(通用合成步驟D)·····································72
6.2 硼酯官能基之去保護····································································93
6.2.1 方法一(通用合成步驟E)··························································93
6.2.2 方法一(通用合成步驟F)··························································104
6.3 含硼果糖化合物之合成································································108
附錄一光譜資料··············································································109
附錄二參考資料··············································································171


圖目錄
Figure 1.1 市售含硼藥物的結構.................................................................................1
Figure 1.2 含peptide 結構的藥物...............................................................................2
Figure 1.3 Diborane 的結構.........................................................................................4
Figure 1.4 硼烷化合物的結構.....................................................................................4
Figure 1.5 硼酸與硼酯的結構.....................................................................................5
Figure 1.6 硼酸化合物的相對pKa .............................................................................6
Figure 1.7 三氟硼酸鹽的結構.....................................................................................7
Figure 1.8 (a) peptides 與(b) peptoids 之構型..........................................................11
Figure 1.9 oligomers of n-substituded glycine ...........................................................11
Figure 1.10 胰島素的二維結構.................................................................................13
Figure 1.11 蘇胺酸蛋白酶抑制劑.............................................................................14
Figure 1.12 熱中子與10-B之反應機制....................................................................17
Figure 1.13 BNCT 藥物結構.....................................................................................18
Figure 1.14 Phenylalanine 的結構.............................................................................19
Figure 2.1 (a)Linear approach;(b)Convergent Approach;(c)Multicomponent Approach .....................................................................................................................20
Scheme 1.1 Petasis reaction ........................................................................................10
Scheme 1.2 Mannicih Raeaction .................................................................................10
Scheme 1.3 peptoids 合成方法..................................................................................12
Scheme 1.4 利用Ugi reaction 合成peptoids.............................................................12
Scheme 1.5 peptides 合成方法..................................................................................14
Scheme 2.1 Ugi 多組成反應......................................................................................22
Scheme 2.2 Ugi 多組成反應之反應機構..................................................................22
Scheme 2.3 Strecker 多組成反應..............................................................................23
Scheme 2.4 Hantzsch 多組成反應.............................................................................23
Scheme 2.5 Westcott 等人合成出的含有硼酸之Ugi 化合物..................................24
Scheme 3.1 硼酯官能基的去保護.............................................................................31
Scheme 3.2 4-Formylphenylboronate ester 去保護示意圖.......................................36
Scheme 3.3 硼酯isocyanide 在溫和條件下去保護..................................................37
Scheme 3.4 比較NaIO4 與DEA 將硼酯化合物去保護的差別..............................37
Scheme 4.1 含硼化合物與DAHMI 錯合示意圖.....................................................40
Scheme 4.2 硼酸化合物與fructose 錯合示意圖......................................................48
Scheme 4.3 硼酸化合物與DAHMI 錯合UV 光譜.................................................50
Table 2.1 合成多重含硼化合物的優化條件............................................................25
Table 2.2 合成多重含硼化合物................................................................................28
Table 3.1 硼酸化合物................................................................................................34
Table 4.1 DAHMI 隨時間變化的螢光衰變測試.....................................................41
Table 4.2 僅有硼酸化合物進入U2OS 的細胞螢光圖............................................42
Table 4.3 僅有DAHMI 進入U2OS 的細胞螢光圖.................................................42
Table 4.4 單硼化合物進入U2OS 的細胞螢光圖....................................................44
Table 4.5 四硼化合物進入U2OS 的細胞螢光圖....................................................46
Table 4.6 硼酸化合物與含硼果糖化合物的細胞螢光圖........................................49
Table 4.7 硼酸化合物與含硼果糖化合物的流式細胞圖........................................52
Table 4.8 硼酸化合物與含硼果糖化合物的螢光量比較.........................................53

光譜目錄
附圖1 化合物S1 之1H-NMR (300 MHz, CDCl3)..................................................109
附圖2 化合物S2 之1H-NMR (300 MHz, CDCl3)..................................................109
附圖3 化合物S3 之1H-NMR (300 MHz, CDCl3)..................................................110
附圖4 化合物S4 之1H-NMR (300 MHz, CDCl3)..................................................110
附圖5 化合物S5 之1H-NMR (300 MHz, CDCl3)..................................................111
附圖6 化合物S6 之1H-NMR (300 MHz, CDCl3)..................................................111
附圖7 化合物S7 之1H-NMR (300 MHz, CDCl3)..................................................112
附圖8 化合物S8 之1H-NMR (300 MHz, CDCl3)..................................................112
附圖9 化合物S9 之1H-NMR (300 MHz, CDCl3)..................................................113
附圖10 化合物S10 之1H-NMR (300 MHz, CDCl3)..............................................113
附圖11 化合物S11 之1H-NMR (300 MHz, CDCl3) .............................................114
附圖12 化合物S12 之1H-NMR (300 MHz, CDCl3)..............................................114
附圖13 化合物S13 之1H-NMR (300 MHz, CDCl3)..............................................115
附圖14 化合物S14 之1H-NMR (300 MHz, CDCl3)..............................................115
附圖15 化合物S15 之1H-NMR (300 MHz, CDCl3)..............................................116
附圖16 化合物S16 之1H-NMR (300 MHz, CDCl3)..............................................116
附圖17 化合物S17 之1H-NMR (300 MHz, CDCl3)..............................................117
附圖18 化合物S18 之1H-NMR (300 MHz, CDCl3)..............................................117
附圖19 化合物S19 之1H-NMR (300 MHz, CDCl3)..............................................118
附圖20 化合物S20 之1H -NMR (600 MHz, CDCl3).............................................118
附圖21 化合物S20 之13C -NMR (150 MHz, CDCl3)...........................................119
附圖22 化合物S20 之11B -NMR (192.5 MHz, CDCl3)........................................119
附圖23 化合物S21 之1H -NMR (600 MHz, CDCl3).............................................120
附圖24 化合物S21 之13C -NMR (150 MHz, CDCl3)...........................................120
附圖25 化合物S21 之11B -NMR (192.5 MHz, CDCl3)........................................121
附圖26 化合物S22 之1H -NMR (600 MHz, CDCl3).............................................121
附圖27 化合物S22 之13C -NMR (150 MHz, CDCl3)...........................................122
附圖28 化合物S22 之11B -NMR (192.5 MHz, CDCl3)........................................122
附圖29 化合物S23 之1H -NMR (600 MHz, CDCl3).............................................123
附圖30 化合物S23 之13C -NMR (150 MHz, CDCl3)...........................................123
附圖31 化合物S23 之11B -NMR (192.5 MHz, CDCl3)........................................124
附圖32 化合物A1 之1H -NMR (600 MHz, CDCl3) .............................................124
附圖33 化合物A1 之13C -NMR (150 MHz, CDCl3) ............................................125
附圖34 化合物A1 之11B -NMR (192.5 MHz, CDCl3) .........................................125

附圖35 化合物A1 之HRMS (ESI, positive ion) [M + H]+.....................................126
附圖36 化合物A2 之1H -NMR (600 MHz, CDCl3) .............................................126
附圖37 化合物A2 之13C -NMR (150 MHz, CDCl3) ............................................127
附圖38 化合物A2 之11B -NMR (192.5 MHz, CDCl3) .........................................127
附圖39 化合物A2 之HRMS (ESI, positive ion) [M + H]+.....................................128
附圖40 化合物A3 之1H -NMR (600 MHz, CDCl3) .............................................128
附圖41 化合物A3 之13C -NMR (150 MHz, CDCl3) ............................................129
附圖42 化合物A3 之11B -NMR (192.5 MHz, CDCl3) .........................................129
附圖43 化合物A3 之HRMS (ESI, positive ion) [M + H]+.....................................130
附圖44 化合物A4 之1H -NMR (600 MHz, CDCl3) .............................................130
附圖45 化合物A4 之13C -NMR (150 MHz, CDCl3) ...........................................131
附圖46 化合物A4 之11B -NMR (192.5 MHz, CDCl3) ........................................131
附圖47 化合物A4 之HRMS (ESI, positive ion) [M + H]+....................................132
附圖48 化合物A5 之1H -NMR (600 MHz, CDCl3) .............................................132
附圖49 化合物A5 之13C -NMR (150 MHz, CDCl3) ............................................133
附圖50 化合物A5 之11B -NMR (192.5 MHz, CDCl3) .........................................133
附圖51 化合物A5 之HRMS (ESI, positive ion) [M + H]+.....................................134
附圖52 化合物A6 之1H -NMR (600 MHz, CDCl3) .............................................134
附圖53 化合物A6 之13C -NMR (150 MHz, CDCl3) ............................................135
附圖54 化合物A6 之11B -NMR (192.5 MHz, CDCl3) .........................................135
附圖55 化合物A6 之HRMS (ESI, positive ion) [M + H]+.....................................136
附圖56 化合物A7 之1H -NMR (600 MHz, CDCl3) .............................................136
附圖57 化合物A7 之13C -NMR (150 MHz, CDCl3) ............................................137
附圖58 化合物A7 之11B -NMR (192.5 MHz, CDCl3) .........................................137
附圖59 化合物A7 之HRMS (ESI, positive ion) [M + H]+.....................................138
附圖60 化合物A8 之1H -NMR (600 MHz, CDCl3) .............................................138
附圖61 化合物A8 之13C -NMR (150 MHz, CDCl3) ............................................139
附圖62 化合物A8 之11B -NMR (192.5 MHz, CDCl3) .........................................139
附圖63 化合物A8 之HRMS (ESI, positive ion) [M + H]+.....................................140
附圖64 化合物A9 之1H -NMR (600 MHz, CDCl3) .............................................140
附圖65 化合物A9 之13C -NMR (150 MHz, CDCl3) ............................................141
附圖66 化合物A9 之11B -NMR (192.5 MHz, CDCl3) .........................................141
附圖67 化合物A9 之HRMS (ESI, positive ion) [M + H]+.....................................142
附圖68 化合物A10 之1H -NMR (600 MHz, CDCl3) ...........................................142
附圖69 化合物A10 之13C -NMR (150 MHz, CDCl3) ..........................................143
附圖70 化合物A10 之11B -NMR (192.5 MHz, CDCl3) .......................................143

附圖71 化合物A10 之HRMS (ESI, positive ion) [M + H]+...................................144
附圖72 化合物A11 之1H -NMR (600 MHz, CDCl3) ...........................................144
附圖73 化合物A11 之13C -NMR (150 MHz, CDCl3) ..........................................145
附圖74 化合物A11 之11B -NMR (192.5 MHz, CDCl3) .......................................145
附圖75 化合物A11 之HRMS (ESI, positive ion) [M + H]+ ..................................146
附圖76 化合物B1 之1H -NMR (600 MHz, CD3OD) ............................................146
附圖77 化合物B1 之13C -NMR (150 MHz, CD3OD) ..........................................147
附圖78 化合物B1 之11B -NMR (192.5 MHz, CD3OD) .......................................147
附圖79 化合物B1 之HRMS (ESI, positive ion) [M + H]+ ....................................148
附圖80 化合物B2 之1H -NMR (600 MHz, CD3OD) ............................................148
附圖81 化合物B2 之13C -NMR (150 MHz, CD3OD) ..........................................149
附圖82 化合物B2 之11B -NMR (192.5 MHz, CD3OD) .......................................149
附圖83 化合物B2 之HRMS (ESI, positive ion) [M + H]+ ....................................150
附圖84 化合物B3 之1H -NMR (600 MHz, CD3OD) ............................................150
附圖85 化合物B3 之13C -NMR (150 MHz, CD3OD) ..........................................151
附圖86 化合物B3 之11B -NMR (192.5 MHz, CD3OD) .......................................151
附圖87 化合物B3 之HRMS (ESI, positive ion) [M + H]+ ....................................152
附圖88 化合物B4 之1H -NMR (600 MHz, CD3OD) ............................................152
附圖89 化合物B4 之13C -NMR (150 MHz, CD3OD) ..........................................153
附圖90 化合物B4 之11B -NMR (192.5 MHz, CD3OD) .......................................153
附圖91 化合物B4 之HRMS (ESI, positive ion) [M + H]+ ....................................154
附圖92 化合物B5 之1H -NMR (600 MHz, CD3OD) ............................................154
附圖93 化合物B5 之13C -NMR (150 MHz, CD3OD) ..........................................155
附圖94 化合物B5 之11B -NMR (192.5 MHz, CD3OD) .......................................155
附圖95 化合物B5 之HRMS (ESI, positive ion) [M + H]+ ....................................156
附圖96 化合物B6 之1H -NMR (600 MHz, CD3OD) ............................................156
附圖97 化合物B6 之13C -NMR (150 MHz, CD3OD) ..........................................157
附圖98 化合物B6 之11B -NMR (192.5 MHz, CD3OD) .......................................157
附圖99 化合物B6 之HRMS (ESI, positive ion) [M + H]+ ....................................158
附圖100 化合物B7 之1H -NMR (600 MHz, CD3OD) ..........................................158
附圖101 化合物B7 之13C -NMR (150 MHz, CD3OD) ........................................159
附圖102 化合物B7 之11B -NMR (192.5 MHz, CD3OD) .....................................159
附圖103 化合物B7 之HRMS (ESI, positive ion) [M + H]+ ..................................160
附圖104 化合物B8 之1H -NMR (600 MHz, CD3OD) ..........................................160
附圖105 化合物B8 之13C -NMR (150 MHz, CD3OD) ........................................161
附圖106 化合物B8 之11B -NMR (192.5 MHz, CD3OD) .....................................161

附圖107 化合物B8 之HRMS (ESI, positive ion) [M + H]+ ..................................162
附圖108 化合物B9 之1H -NMR (600 MHz, CD3OD) ..........................................162
附圖109 化合物B9 之13C -NMR (150 MHz, CD3OD) ........................................163
附圖110 化合物B9 之11B -NMR (192.5 MHz, CD3OD)......................................163
附圖111 化合物B9 之HRMS (ESI, positive ion) [M + H]+ ..................................164
附圖112 化合物B10 之1H -NMR (600 MHz, CD3OD).........................................164
附圖113 化合物B10 之13C -NMR (150 MHz, CD3OD) ......................................165
附圖114 化合物B10 之11B -NMR (192.5 MHz, CD3OD)....................................165
附圖115 化合物B10 之HRMS (ESI, positive ion) [M + H]+ ................................166
附圖116 化合物D1 之1H -NMR (300 MHz, CD3OD) .........................................166
附圖117 化合物B11 之1H -NMR (600 MHz, CD3OD).........................................167
附圖118 化合物B11 之13C -NMR (150 MHz, CD3OD).......................................167
附圖119 化合物B11 之11B -NMR (192.5 MHz, CD3OD)....................................168
附圖120 化合物D2 之1H -NMR (300 MHz, CD3OD) .........................................168
附圖121 化合物B12 之1H -NMR (300 MHz, CD3OD) ........................................169
附圖122 化合物D3 之1H -NMR (300 MHz, CD3OD) .........................................169
附圖123 化合物C1 之11B -NMR (192.5 MHz, D2O).........................................170
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