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系統識別號 U0002-1807201816150800
中文論文名稱 硼中子捕獲療法中硼試劑的應用:藉由硫醇-馬來酰胺的點擊反應使硼酸鈉(BSH)與葉酸/生物素結合
英文論文名稱 Potential boron delivery agents for Boron Neutron Capture Therapy application: Sodium borocaptate(BSH) conjugated folic acid/biotin via thiol-maleimide "click" reaction
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 阮明忠
研究生英文姓名 MINH-TRUNG NGUYEN
學號 605185015
學位類別 碩士
語文別 英文
口試日期 2018-06-26
論文頁數 96頁
口試委員 指導教授-謝忠宏
委員-陳仁焜
委員-潘伯伸
委員-謝忠宏
中文關鍵字 硼中子捕獲治療  BSH  葉酸-共軛  生物素-共軛  馬來酰胺 
英文關鍵字 BNCT  BSH  Folate-conjugated  Biotin-conjugated  Maleimide 
學科別分類 學科別自然科學化學
中文摘要 硼中子捕獲治療(Boron neutron capture therapy BNCT)是一種用於局部侵入性惡性腫瘤的有效試劑,其中Sodium borocaptate (BSH)鈉硼硫醇金屬簇化物,是一個有效的藥物,但是其中卻包含部分的缺點,包括無法有效進入癌細胞之中,因此在此論文,我們選擇Folic acid葉酸與Biotin生物素維生素H做為引金屬試劑,試圖克服BSH本身的缺點,並期望應用在BNCT的治療上。
在本研究之中,我們合成出BSH非放射性20% 10B之試劑,並利用1-(2-Aminoethyl) maleimide與葉酸和生物素偶合,試圖利用其對硫醇的選擇性做為前驅藥物,利將BSH成功帶入細胞之中,而不需使用100% 10B之試劑。目前已能成功合成此二項前驅化合物,並測試其螢光指示劑之程度,同時也利用U2OS人骨肉瘤細胞測試其生物毒性,皆得到合理的成果,未來將應用在BNCT之中,使其有選擇性而可以避免100% 10B之鈉硼硫醇金屬簇化物。
英文摘要 Boron neutron capture therapy (BNCT) is a potential approach to treat cancer and Sodium borocaptate (BSH) has been used for BNCT application as a boron delivery agent. Even though, BSH were used in clinical trials, this agent till exhibits some disadvantage in the case of selective targeting of cancer cells and cellular uptake ability. Folic acid and biotin were considered as an excellent targeting ligand which can help to overcome the disadvantage of BSH in BNCT application. In this study, we prepared the natural sodium borocaptate (BSH) from natural abounded starting materials and we also successfully conjugated this potential BNCT agent with folic acid/biotin using 1-(2-Aminoethyl)maleimide as the short crosslinker.
Folic acid/biotin-conjugated BSH exhibited the potential boron delivery agent which decreased the cytotoxicity of BSH treatment effects on U2OS cell line. Interestingly, folate-conjugated products which showed two maleimide groups and it also exhibited the high fluorescence emission. Of these, this complex might provide a new strategy to enhance and also detect the boron accumulation. These observations offered two of new BSH delivery platforms which were described as a small molecule weight and highly targeting of cancer cells which could be used as starting material in further investigation.
論文目次 Contents
Acknowledgment I
Abstract III
Abbreviation V
Contents VIII
List of Figures XI
List of Tables XV
List of Schemes XVI
Chapter 1. Introduction 1
1.1. Boron Neutron Capture Therapy (BNCT) 1
1.2. Boron Delivery Agents 2
1.2.1. Boron 2
1.2.2. L- Boronophenylalanine (BPA) 5
1.2.3. Sodium borocaptate (BSH) 6
1.2.4. Improve BSH Uptake in Cancer Cells 7
1.3. Ligands and biomimetic strategies for targeted 11
1.3.1. Folate and folate receptor 11
1.3.2. Folate-based delivery application in BNCT 14
1.3.3. The blood-brain barrier (BBB) and the role of folate-based carrier 16
1.3.4. Biotin and biotin-specific uptake systems (B-SUS) 17
Chapter 2. Technical Approach 19
2.1. Preparation of compounds 19
2.1.1. Synthesis of [NEt3H]2[B12H12] 19
2.1.2. Synthesis of Na2[B12H12] 20
2.1.3. Synthesis of Sodium borocaptate Na2[B12H11SH] 20
2.1.4. Synthesis of Folic acid and Biotin conjugated BSH via Maleoylimide substituted 22
2.2. X-Ray crystallography 24
2.3. Bioactivity assessment 25
Chapter 3. Results and Discussions 27
3.1. Synthesis of BNCT agent: Sodium borocaptate (BSH) 27
3.1.1. Preparation of Na2[B12H12] from Na[BH4] and I2 27
3.1.2. Preparation Na2B12H11SH (BSH) from Na2[B12H12] and N-Methylbenzothiazole-2-thione 31
3.2. Synthesis of folate/biotin-conjugated BSH via carbonyl-reactive and sulfhydryl-reactive crosslinkers 37
3.2.1. Preparation of crosslinker, 1-(2-Aminoethyl)maleimide hydrochloride (C6H8N2O2.HCl) 37
3.2.2. Synthesis of folic acid-conjugated 1-(2-Aminoethyl)maleimide via carbonyl-reactive group 41
3.2.3. Synthesis of biotin-conjugated 1-(2-Aminoethyl)maleimide via carbonyl-reactive group 45
3.2.4. Synthesis of folate/biotin-conjugated BSH via “click” chemistry and its chemical properties 48
3.3. Fluorescence properties of conjugated products 56
3.3.1. Folate-conjugated 56
3.3.2. Biotin-conjugated products 58
3.4. Cytotoxicity 60
3.4.1. Cytotoxicity of BSH on U2OS cells 61
3.4.2. Cytotoxicity of FA-MAL and FA-MAL-BSH on U2OS cells 62
3.4.2. Cytotoxicity of BIO-MAL and BIO-MAL-BSH on U2OS cells 64
Conclusion 67
References 68
Appendix 11B NMR and 1H NMR spectra 80

List of Figures
Figure 1-1. Two clinical boron delivery agents for BNCT [1] 4
Figure 1-2. Folic acid structure. Blue and Red represent for pteroate and glutamate moiety, respectively 12
Figure 1-3. Structure of FRα bound to folic acid. 13
Figure 1-4. Folic acid affinities of FRa ligand-binding-pocket mutants. 14
Figure 1-5. The structure of Biotin.17
Figure 3-1. Crystal structure of Na2[B12H12].6[THF] and Na2[B12H12].4[THF]. Thermal ellipsoids are shown at the 50% probability level 29
Figure 3-2. 11B NMR and 1H NMR of Na2B12H12 and Na2B12H11SH in comparison 33
Figure 3-3. Crystal structure of Na2[B12H11SH] in packing complex with 18-crown-6-ether [C12H24O6], THF [C4H8O], and DMSO [C2H6OS]. Thermal ellipsoids are shown at the 50% probability level 36
Figure 3-4. 1H NMR spectra of 1-(2-Aminoethyl)maleimide (D2O), 300 MHz : 3.25-3.28 [2H, t, CH2], 3.85-3.89 [2H, t, CH2], 6.94 [2H, s, maleimide] 39
Figure 3-5. The crystal structure of 1-(2-Aminoethyl)maleimide hydrochloride 40
Figure 3-6. 1H NMR spectrum in the comparison between FA-conjugated product and Folic acid. 300Hz. D2O 43
Figure 3-7. ESI spectrum of FA-MAL with the main peak at 708.47 m/z which represents for [M+Na]+ ion and another at 686.27 which represents for [M+H]+ 44

Figure 3-8. 1H NMR spectrum in the comparison between Biotin-conjugated product and Biotin. 300Hz. D2O 47
Figure 3-9. ESI spectrum of BIO-MAL with the main peak at 389 m/z which represents for [M+Na]+ ion 48
Figure 3-10. 1H NMR in the comparison between folic acid/biotin-conjugated compounds 50
Figure 3-11. 11B NMR chemical shifts in the comparison between FA-MAL-BSH, BIO-MAL-BSH, and BSH. 600 Hz 51
Figure 3-12. ESI spectrum of BIO-MAL-BSH 52
Figure 3-13. ESI spectra of FA-MAL-BSH 52
Figure 3-14. Two parallel reactions of a succinimidyl thioether in solution [68] 53
Figure 3-15. Excitation and Emission spectra in the comparison between Folic acid with its conjugated products at 0.1 μM concentration in NaHCO3 and PBS solution. 57
Figure 3-16. Excitation and Emission spectra in the comparison between FA-MAL and FA-MAL adding BSH (the ratio is 1:1 molar). All compound was prepared at 0.1 μM concentration in NaHCO3 and PBS solution. 58
Figure 3-17. Excitation and Emission spectra of Biotin-conjugated products at 1 μM concentration which was prepared in DMSO 59
Figure 3-18. Excitation and emission spectra of Biotin-conjugated products at 1 μM concentration which was prepared in PBS solution 60
Figure 3-19. Effects of BSH with varying concentrations on the viability of U2OS cells after 24h. The results are the mean SE of 3 separate measurements. 61

Figure 3-20. Effects of FA-MAL with varying concentrations on the viability of U2OS cells after 24h. The results are the mean SE of 3 separate measurements. 62
Figure 3-21. Effects of FA-MAL-BSH with varying concentrations on the viability of U2OS cells after 24h. The results are the mean SE of 3 separate measurements.63
Figure 3-22. Effects of BIO-MAL with varying concentrations on the viability of U2OS cells after 24h. The results are the mean SE of 3 separate measurements. 64
Figure 3-23. Effects of BIO-MAL-BSH with varying concentrations on the viability of U2OS cells after 24h. The results are the mean SE of 3 separate measurements. 65
Figure 0-1. 11B NMR spectrum of Na2[B12H12] in D2O solvent, 600 MHz 80
Figure 0-2. 11B NMR spectrum of Na2[B12H11SH] in D2O solvent, 600 MHz 81
Figure 0-3. 11B NMR spectrum of FA-MAL-BSH in DMSO d6 solvent, 600 MHz 82
Figure 0-4. 11B NMR spectrum of BIO-MAL-BSH in DMSO d6 solvent, 600 MHz 83
Figure 0-5. 1H NMR spectrum of Na2[B12H12] in D2O solvent, 300 MHz 84
Figure 0-6. 1H NMR spectrum of Na2[B12H11SH] in D2O solvent, 300 MHz 85
Figure 0-7. 1H NMR spectrum of FA-MAL-BSH in DMSO d6 solvent, 600 MHz 86
Figure 0-8. 1H NMR spectrum of BIO-MAL-BSH in DMSO d6 solvent, 600 MHz 87

Figure 0-9. 1H NMR spectrum of Boc-Ethylenediamine in CDCl3 solvent, 300 MHz88
Figure 0-10. 1H NMR spectrum of N-Boc-2-Maleimidoethylamine in CDCl3 solvent, 300 MHz 89
Figure 0-11. 1H NMR spectrum of 1-(2-Aminoethyl)- maleimide hydrochloride in CD3OD d4 solvent, 300 MHz 90
Figure 0-12. 1H NMR spectrum of Folic acid in DMSO d6 solvent, 300 MHz . 91
Figure 0-13. 1H NMR spectrum of FA-MAL in DMSO d6 solvent, 300 MHz . 92
Figure 0-14. 1H NMR spectrum of FA-MAL in DMSO d6 solvent, 600 MHz . 93
Figure 0-15. 1H NMR spectrum of Biotin in DMSO d6 solvent, 300 MHz 94
Figure 0-16. 1H NMR spectrum of BIO-MAL in DMSO d6 solvent, 300 MHz 95
Figure 0-17. 1H NMR spectrum of BIO-MAL in DMSO d6 solvent, 600 MHz 96

List of Tables
Table 1-1. Boron isotopes [8] 3
Table 3-1. 11B NMR and 1H NMR data of Na2B12H12 in D2O, 600 MHz 28
Table 3-2. Crystallographic parameters of Na2[B12H12] in two different packing complex with THF 30
Table 3-3. Crystal structure data of Na2[B12H12] in the comparison between of two complexes 31
Table 3-4. 11B NMR and 1H NMR data of Na2B12H11SH in D2O, 600 MHz 33
Table 3-5. Crystallographic parameters of Na2[B12H11SH] in packing complex with 18-crown-6-ether [C12H24O6], THF [C4H8O], and DMSO [C2H6OS] 35
Table 3-6. Crystal structure data of Na2[B12H11SH] in complex with 18-crown-6-ether [C12H24O6], THF [C4H8O], and DMSO [C2H6OS] 36
Table 3-7. Crystal structure data of 1-(2-Aminoethyl)maleimide hydrochloride 40
Table 3-8. Crystallographic parameters of 1-(2-Aminoethyl)maleimide hydrochloride 41
Table 3-9. Comparison 11B NMR data between Na2B12H11SH, FA-MAL-BSH, BIO-MAL-BSH in D2O, DMSO-d6, 600 MHz 51
Table 3-10. Some physical and chemical properties of BSH and Folic acid/Biotin-conjugated compounds 54
Table 3-11. Comparison IC50 of Folic acid-conjugated compounds in effect on U2OS cells viability 63
Table 3-12. Comparison IC50 of Biotin-conjugated compounds in effect on U2OS cells viability 65

List of Schemes
Scheme 3-1. The N-methyl benzothiazole-2-thione routes to synthesize BSH. [54] 32
Scheme 3-2. Maleimide thiols reaction [64]37
Scheme 3-3. Synthesis of 1-(2-Aminoethyl)maleimide hydrochloride [58] [59] [60] [61] 38
Scheme 3-4. Synthesis of folic acid-conjugated 1-(2-Aminoethyl)maleimide via carbonyl-reactive group 43
Scheme 3-5. Synthesis of Biotin-conjugated 1-(2-Aminoethyl)maleimide using DMSO as the solvent, DMAP and TEA as an organic base, NHS and DCC as the additive reagent in activated step 46
Scheme 3-6. Synthesis of Biotin-conjugated 1-(2-Aminoethyl)maleimide using DMF as the solvent and NHS, DCC as the additive reagent in activated step 46
Scheme 3-7. Preparation of Folate-conjugated BSH via “click” chemistry 49
Scheme 3-8. Preparation of Biotin-conjugated BSH via “click” chemistry 49
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