本論文研究目的為以色胺酸為骨幹並改變硼頻那醇取代位置，製備5-硼頻那醇色胺酸衍生物，並進行生物活性驗證，期望可以提升含硼色胺酸衍生物之生物活性與水溶性，篩選出具有潛力之BNCT藥物，應用於硼中子捕獲治療研究。
本研究採取兩種合成方式製備5-硼頻那醇色胺酸衍生物，第一種以色胺酸主體架構已建立之5-溴色胺酸為起始物，經酯化並以t-boc保護可得產率93 %的triboc-5-d,l-bromo tryptophan methyl ester 7，再以Pd(0)催化劑將5號位溴基以硼頻那醇取代，得到產率95 %的triboc-5-d,l-boronopinacol tryptophan methyl ester 3 (TB-5-BT)，最後以TMSI試劑移除t-boc保護得到產率75 %的5-d,l-boronopinacol tryptophan methyl ester 4 (5-BT)，共三步驟反應，總產率為66 %。
第二種則是以色胺酸側鏈片段構築所需之乙醯胺為起始物，經與丙酮酸耦合得到產率55 %的2-(acetylamino)acrylic acid 8，再以碘甲烷進行SN2反應，得到產率93 %的methyl 2-acetamidoacrylate 9，並與5-溴吲哚進行Friedel-Crafts Alkylation得到產率85 %的N-acetyl-5-d,l-bromotryptophan methyl ester 10，最後以t-boc保護胺基與Pd(0)將溴基以硼頻那醇取代，得到產率57 %的diboc-N-acetyl-5-d,l-boronopinacol tryptophan methyl ester 5 (DBA-5-BT)，共五步驟反應，總產率為25 %。此外，同時以部分保護之N-acetyl-5-d,l-bromotryptophan methyl ester 10，直接以Pd(0)硼化得到N-acetyl-5-d,l-boronopinacol tryptophan methyl ester 6 (NA-5-BT)，其產率為65 %。
將濃度為1 nM – 100 uM的化合物3-6與BPA進行細胞毒殺實驗。綜合三種細胞 (U87-MG、LN229、3T3) 歸納並與BPA對照組比較，TB-5-BT 3與DBA-5-BT 5的毒性略低於BPA，而AZ-2,7-DBT 1、TB-6-BT 2、5-BT 4與NA-5-BT 6的毒性則略高於BPA。中子照射後之細胞存活率試驗結果，保護基存在的TB-5-BT 3與DBA-5-BT 5相較於標準藥物BPA，對U87-MG與LN229癌細胞株，降低20 %細胞存活率，而部分保護的5-BT 4與NA-5-BT 6，對LN229癌細胞株，則降低10 %細胞存活率，但對U87-MG癌細胞株，無毒殺作用。此外，中子照射對正常細胞不會造成傷害 (< 10 %)。
本研究成功製備5-硼頻那醇色胺酸衍生物TB-5-BT 3與DBA-5-BT 5，可有效降低細胞存活率 (10 – 20 %)，但仍需克服水溶性問題，未來研究方向或許可藉由脂質體包埋技術來改善水溶性，以及進一步以動物實驗驗證腫瘤治療效果。

The purpose of this thesis is to prepare a 5-boronopinacol tryptophan acid derivative by using tryptophan as the backbone and changing the substitution position of boronopinacol, and to verify the biological activity. It was expected to enhance the biological activity and water solubility of boron-containing tryptophan derivatives to screen out the potential BNCT drugs for boron neutron capture therapy research.
In this study, two synthetic methods were used to prepare 5-boronopinacol tryptophan derivatives. First, we used the 5-bromotryptophan as starting material, after esterification and protection with t-boc, a yield of 93% of triboc-5-d,l-bromo tryptophan methyl ester 7 was obtained, then replacing the bromine group at 5-position with boronopinacol through the Pd(0) catalysis, the triboc-5-d,l-boronopinacol tryptophan methyl ester 3 (TB-5-BT) in a yield of 95 % was obtained, finally, t-boc group was removed to obtain the 5-d,l-boronopinacol tryptophan methyl ester 4 (5-BT) in a yield of 75 %. A total 66 % of yield was obtained in three steps preparation.
Second, the acetamide, tryptophan side chain fragment, was used as starting material, after coupling with pyruvic acid, a yield of 55 % of 2-(acetylamino)acrylic acid 8 was obtained, then esterification via SN2 reaction to provide methyl 2-acetamidoacrylate 9 in 93 % of yield and react with 5-bromoindole via Friedel-Crafts alkylation to afford N-acetyl-5-d,l-bromotryptophan methyl ester 10 in 85 % of yield, finally, 5-boronopinacol tryptophan derivatives diboc-N-acetyl-5-d,l-boronopinacol tryptophan methyl ester (DBA-5-BT) was obtained in 57 % of yield via protecting by t-boc and Pd(0) catalysis. A total 25 % of yield was obtained in five steps preparation. Simultaneously, N-acetyl-5-d,l-boronopinacol tryptophan methyl ester 6 (NA-5-BT) was got through the Pd(0) borylation of partially protected N-acetyl-5-d,l-bromotryptophan methyl ester 10 in a yield of 65 %.
The MTT assay was carried out for compound 3-6 and BPA at a concentration of 1 nM – 100 uM. Comparing with BPA, TB-5-BT 3 and DBA-5-BT 5 are less toxic whereas AZ-2,7-DBT 1、TB-6-BT 2、5-BT 4 and NA-5-BT 6 are slightly or comparable toxicity than BPA. In the neutron irradiation experiment, compared with the standard drug BPA, TB-5-BT 3 and DBA-5-BT 5 could reduce cell viability by 20 % for U87-MG and LN229 cancer cell lines. The partially protected 5-BT 4 and NA-5-BT 6 could reduce cell viability by 10 % for LN229 cancer cell line but not for U87-MG cell line. Moreover, neutron irradiation does not cause damage to normal cells (< 10 %).
We have successfully developed 5-position boronopinacol substituted tryptophan derivatives TB-5-BT 3 and DBA-5-BT 5 that could reduce cell viability effectively (10 – 20 %), but still need to overcome the problem of water solubility. Future works will focus on the improvement of the water solubility by the liposome technique and evaluate the therapeutic effects in the animal model.

目錄
摘要 1
ABSTRACT 3
誌謝 4
全名縮寫對照表 5
1. 緒論 9
1.1癌症治療與體外放射治療 9
1.2硼中子捕獲治療 (BNCT) 10
1.2.1 硼中子捕獲治療(BNCT)之高標靶性的含硼藥物 11
1.2.2 含硼藥物發展現況 12
1.3腦瘤 13
1.3.1 腦瘤治療的方式 13
1.3.2 BNCT治療腦瘤 14
1.4血腦屏障 (Blood Brain Barrier, BBB) 15
1.5吲哚之雜環化學 15
1.5.1 吲哚之結構與其衍生物 15
1.5.2 吲哚雜環各原子之反應性比較 16
1.6研究動機 19
2. 結果與討論 22
2.1 5-硼頻那醇色胺酸衍生物之化學製備 22
2.1.1 以路徑一製備5-硼頻那醇色胺酸衍生物 24
2.1.2 以路徑二製備5-硼頻那醇色胺酸衍生物 28
2.2含硼色胺酸衍生物之活性分析 31
2.2.1 含硼色胺酸衍生物之細胞存活率分析 32
2.2.2 含硼色胺酸衍生物於不同細胞株之中子照射實驗 34
3. 實驗 36
3.1儀器設備與溶劑與試藥之一般處理 36
3.2實驗步驟與光譜數據 38
3.2.1 化學實驗 38
4. 結論 57
5. 附錄 58
5.1 以H3PO4嘗試移除Boc保護之質譜圖 58
5.2 嘗試以Nromal phase HPLC分離DL form之化合物3 60
5.3 化合物光譜、質譜與HPLC圖譜 63
6. 參考文獻 102

1. Alphandery, E., Glioblastoma Treatments: An Account of Recent Industrial Developments. Front. Pharmacol. 2018, 9, 879-910.
2. Weichselbaum, R. R.; Liang, H.; Deng, L. F.; Fu, Y. X., Radiotherapy and immunotherapy: a beneficial liaison? Nat. Rev. Clin. Oncol. 2017, 14 (6), 365-379.
3. Barth, R. F.; Vicente, M. G. H.; Harling, O. K.; Kiger, W. S.; Riley, K. J.; Binns, P. J.; Wagner, F. M.; Suzuki, M.; Aihara, T.; Kato, I.; Kawabata, S., Current status of boron neutron capture therapy of high grade gliomas and recurrent head and neck cancer. Radiat. Oncol. 2012, 7, 146-167.
4. Miyatake, S. I.; Kawabata, S.; Hiramatsu, R.; Kuroiwa, T.; Suzuki, M.; Kondo, N.; Ono, K., Boron Neutron Capture Therapy for Malignant Brain Tumors. Neurol. Med-Chir. 2016, 56 (7), 361-371.
5. Luderer, M. J.; de la Puente, P.; Azab, A. K., Advancements in Tumor Targeting Strategies for Boron Neutron Capture Therapy. Pharm. Res-Dordr. 2015, 32 (9), 2824-2836.
6. Barth, R. F.; Mi, P.; Yang, W. L., Boron delivery agents for neutron capture therapy of cancer. Cancer Commun. 2018, 38, 35-50.
7. Chandra, S.; Barth, R. F.; Haider, S. A.; Yang, W. L.; Huo, T. Y.; Shaikh, A. L.; Kabalka, G. W., Biodistribution and Subcellular Localization of an Unnatural Boron-Containing Amino Acid (Cis-ABCPC) by Imaging Secondary Ion Mass Spectrometry for Neutron Capture Therapy of Melanomas and Gliomas. Plos One 2013, 8 (9), 1-9.
8. Neumann, M.; Bergmann, M.; Gabel, D., Cell type selective accumulation of mercaptoundecahydro-closo-dodecaborate (BSH) in glioblastoma multiforme. Acta. Neurochir. 2003, 145 (11), 971-975.
9. Geier, E. G.; Schlessinger, A.; Fan, H.; Gable, J. E.; Irwin, J. J.; Sali, A.; Giacomini, K. M., Structure-based ligand discovery for the Large-neutral Amino Acid Transporter 1, LAT-1. P. Natl. Acad. Sci. USA. 2013, 110 (14), 5480-5485.
10. Kobayashi, H.; Ishii, Y.; Takayama, T., Expression of L-type amino acid transporter 1 (LAT1) in esophageal carcinoma. J. Surg. Oncol. 2005, 90 (4), 233-238.
11. Aihara, T.; Hiratsuka, J.; Morita, N.; Uno, M.; Sakurai, Y.; Maruhashi, A.; Ono, K.; Harada, T., First clinical case of boron neutron capture therapy for head and neck malignancies using F-18-BPA pet. Head Neck-J. Sci. Spec. 2006, 28 (9), 850-855.
12. Liberman, S. J.; Dagrosa, A.; Rebagliati, R. A. J.; Bonomi, M. R.; Roth, B. M.; Turjanski, L.; Castiglia, S. I.; Gonzalez, S. J.; Menendez, P. R.; Cabrini, R.; Roberti, M. J.; Batistoni, D. A., Biodistribution studies of boronophenylalanine-fructose in melanoma and brain tumor patients in Argentina. Appl. Radiat. Isotopes 2004, 61 (5), 1095-1100.
13. Khalil, A.; Ishita, K.; Ali, T.; Tjarks, W., N3-substituted thymidine bioconjugates for cancer therapy and imaging. Future Med. Chem. 2013, 5 (6), 677-692.
14. Altieri, S.; Balzi, M.; Bortolussi, S.; Bruschi, P.; Ciani, L.; Clerici, A. M.; Faraoni, P.; Ferrari, C.; Gadan, M. A.; Panza, L.; Pietrangeli, D.; Ricciardi, G.; Ristori, S., Carborane Derivatives Loaded into Liposomes as Efficient Delivery Systems for Boron Neutron Capture Therapy. Journal of Medicinal Chemistry 2009, 52 (23), 7829-7835.
15. Theodoropoulos, D.; Rova, A.; Smith, J. R.; Barbu, E.; Calabrese, G.; Vizirianakis, I. S.; Tsibouklis, J.; Fatouros, D. G., Towards boron neutron capture therapy: The formulation and preliminary in vitro evaluation of liposomal vehicles for the therapeutic delivery of the dequalinium salt of bis-nido-carborane. Bioorg. Med. Chem. Lett. 2013, 23 (22), 6161-6166.
16. Pardridge, W. M., Drug delivery to the brain. J. Cerebr. Blood. F. Met. 1997, 17 (7), 713-731.
17. Achilli, C.; Grandi, S.; Ciana, A.; Guidetti, G. F.; Malara, A.; Abbonante, V.; Cansolino, L.; Tomasi, C.; Balduini, A.; Fagnoni, M.; Merli, D.; Mustarelli, P.; Canobbio, I.; Balduini, C.; Minetti, G., Biocompatibility of functionalized boron phosphate (BPO4) nanoparticles for boron neutron capture therapy (BNCT) application. Nanomed-Nanotechnol. 2014, 10 (3), 589-597.
18. Stupp, R.; Mason, W. P.; van den Bent, M. J.; Weller, M.; Fisher, B., Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New. Engl. J. Med. 2005, 352 (10), 987-996.
19. Hatanaka, H.; Nakagawa, Y., Clinical-Results of Long-Surviving Brain-Tumor Patients Who Underwent Boron Neutron-Capture Therapy. Int. J. Radiat. Oncol. 1994, 28 (5), 1061-1066.
20. Ishiwata, K.; Shiono, M.; Kubota, K.; Yoshino, K.; Hatazawa, J.; Ido, T.; Honda, C.; Ichihashi, M.; Mishima, Y., A Unique Invivo Assessment of 4-[B-10]Borono-L-Phenylalanine in Tumor-Tissues for Boron Neutron-Capture Therapy of Malignant Melanomas Using Positron Emission Tomography and 4-Borono-2-[F-18]Fluoro-L-Phenylalanine. Melanoma. Res. 1992, 2 (3), 171-179.
21. Liu, H. Y. B.; Brugger, R. M.; Greenberg, D. D.; Rorer, D. C.; Hu, J. P.; Hauptman, H. M., Enhancement of the Epithermal Neutron Beam Used for Boron Neutron-Capture Therapy. Int. J. Radiat. Oncol. 1994, 28 (5), 1149-1156.
22. Miyatake, S. I.; Tamura, Y.; Kawabata, S.; Iida, K.; Kuroiwa, T.; Ono, K., Boron neutron capture therapy for malignant tumors related to meningiomas. Neurosurgery 2007, 61 (1), 82-90.
23. Miyatake, S. I.; Kawabata, S.; Yokoyama, K.; Kuroiwa, T.; Michiue, H.; Sakurai, Y.; Kumada, H.; Suzuki, M.; Maruhashi, A.; Kirihata, M.; Ono, K., Survival benefit of Boron neutron capture therapy for recurrent malignant gliomas. J. Neuro-Oncol. 2009, 91 (2), 199-206.
24. Kabalka, G. W.; Shaikh, A. L.; Barth, R. F.; Huo, T. Y.; Yang, W. L.; Gordnier, P. M.; Chandra, S., Boronated unnatural cyclic amino acids as potential delivery agents for neutron capture therapy. Appl. Radiat. Isotopes 2011, 69 (12), 1778-1781.
25. He, T. Y.; Musah, R. A., Evaluation of the Potential of 2-Amino-3-(1,7-dicarba-closo-dodecaboranyl-1-thio) propanoic Acid as a Boron Neutron Capture Therapy Agent. Acs. Omega. 2019, 4 (2), 3820-3826.
26. Daneman, R.; Prat, A., The Blood-Brain Barrier. Csh. Perspect. Biol. 2015, 7 (1), a020412.
27. Geldenhuys, W. J.; Mohammad, A. S.; Adkins, C. E.; Lockman, P. R., Molecular determinants of blood-brain barrier permeation. Therapeutic delivery 2015, 6 (8), 961-71.
28. Peura, L.; Malmioja, K.; Huttunen, K.; Leppanen, J.; Hamalainen, M.; Forsberg, M. M.; Rautio, J.; Laine, K., Design, Synthesis and Brain Uptake of LAT1-Targeted Amino Acid Prodrugs of Dopamine. Pharm. Res-Dordr. 2013, 30 (10), 2523-2537.
29. Pian, K. L. H.; Westerberg, H. G. M.; van Megen, H. J. G. M.; den Boer, J. A., Sumatriptan (5-HT1D receptor agonist) does not exacerbate symptoms in obsessive compulsive disorder. Psychopharmacology 1998, 140 (3), 365-370.
30. Splitstoser, J. C.; Dillehay, T. D.; Wouters, J.; Claro, A., Early pre-Hispanic use of indigo blue in Peru. Sci. Adv. 2016, 2 (9), e1501623.
31. Li, Z.; Li, Q. Q.; Qin, J. G., Some new design strategies for second-order nonlinear optical polymers and dendrimers. Polym. Chem-Uk. 2011, 2 (12), 2723-2740.
32. Chen, L.; Zou, Y. X., Recent progress in the synthesis of phosphorus-containing indole derivatives. Org. Biomol. Chem. 2018, 16 (41), 7544-7556.
33. Quin, L. D.; Tyrell, J. A., Fundamentals of heterocyclic chemistry: importance in nature and in the synthesis of pharmaceuticals. 1st ed.; John Wiley & Sons: Hoboken, New Jersey, 2010, 170-171.
34. Lakhdar, S.; Westermaier, M.; Terrier, F.; Goumont, R.; Boubaker, T.; Ofial, A. R.; Mayr, H., Nucleophilic reactivities of indoles. J. Org. Chem. 2006, 71 (24), 9088-9095.
35. Olah, G. A.; Tashiro, M.; Kobayash.S, Mechanism of Electrophilic Aromatic Substitution - Orgn. Abstr. Pap. Am. Chem. S. 1970, 240-248.
36. Sainsbury, M., Heterocyclic chemistry. Royal society of chemistry: 2001; Vol. 8, 97-98
37. Leitch, J. A.; Bhonoah, Y.; Frost, C. G., Beyond C2 and C3: Transition-Metal-Catalyzed C-H Functionalization of Indole. Acs. Catal. 2017, 7 (9), 5618-5627.
38. Huang, Z.; Kwon, O.; Huang, H. Y.; Fadli, A.; Marat, X.; Moreau, M.; Lumb, J. P., A Bioinspired Synthesis of Polyfunctional Indoles. Angew. Chem. Int. Edit. 2018, 57 (37), 11963-11967.
39. Feng, Y.; Holte, D.; Zoller, J.; Umemiya, S.; Simke, L. R.; Baran, P. S., Total Synthesis of Verruculogen and Fumitremorgin A Enabled by Ligand-Controlled C-H Borylation. J. Am. Chem. Soc. 2015, 137 (32), 10160-10163.
40. Joule, J. A.; Mills, K., Heterocyclic chemistry at a glance. 2 ed.; John Wiley & Sons: Toronto, 2012, 21.
41. Miyaura, N.; Suzuki, A., Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chem. Rev. 1995, 95 (7), 2457-2483.
42. Katritzky, A. R.; Ramsden, C. A.; Joule, J. A.; Zhdankin, V. V., Handbook of heterocyclic chemistry. 3rd ed.; Elsevier: Amsterdam, 2010.
43. Salisbury, T. B.; Arthur, S., The Regulation and Function of the L-Type Amino Acid Transporter 1 (LAT1) in Cancer. Int. J. Mol. Sci. 2018, 19 (8), 2373-2383.
44. Verhoeven, J.; Hulpia, F.; Kersemans, K.; Bolcaen, J.; De Lombaerde, S.; Goeman, J.; Descamps, B.; Hallaert, G.; Van den Broecke, C.; Deblaere, K.; Vanhove, C.; Van der Eycken, J.; Van Calenbergh, S.; Goethals, I.; De Vos, F., New fluoroethyl phenylalanine analogues as potential LAT1-targeting PET tracers for glioblastoma. Sci. Rep-Uk. 2019, 9, 2878-2901.
45. Herholz, K., Brain Tumors: An Update on Clinical PET Research in Gliomas. Semin. Nucl. Med. 2017, 47 (1), 5-17.
46. Kramer, S. D.; Mu, L. J.; Muller, A.; Keller, C.; Kuznetsova, O. F.; Schweinsberg, C.; Franck, D.; Muller, C.; Ross, T. L.; Schibli, R.; Ametamey, S. M., 5-(2-F-18-Fluoroethoxy)-L-Tryptophan as a Substrate of System L Transport for Tumor Imaging by PET. J. Nucl. Med. 2012, 53 (3), 434-442.
47. Li, L.; Hu, W. M.; Jia, Y. X., Synthetic studies of cyclic peptides stephanotic acid methyl ester, celogentin C, and moroidin. Tetrahedron 2014, 70 (42), 7753-7762.
48. Bartolucci, S.; Bartoccini, F.; Righi, M.; Piersanti, G., Direct, Regioselective, and Chemoselective Preparation of Novel Boronated Tryptophans by Friedel-Crafts Alkylation. Org. Lett. 2012, 14 (2), 600-603.
49. Ruiz-Castillo, P.; Buchwald, S. L., Applications of Palladium-Catalyzed C-N Cross-Coupling Reactions. Chem. Rev. 2016, 116 (19), 12564-12649.
50. Li, J. J.; Gribble, G. W., Palladium in heterocyclic chemistry: a guide for the synthetic chemist. 1st ed.; Elsevier: Amsterdam, 2000; Vol. 20, 3-6.
51. Jia, Y. X.; Bois-Choussy, M.; Zhu, J. P., Synthesis of DEFG ring of complestatin and chloropeptin I: Highly atropdiastereoselective macrocyclization by intramolecular Suzuki-Miyaura reaction. Org. Lett. 2007, 9 (12), 2401-2404.
52. Isidro-Llobet, A.; Alvarez, M.; Albericio, F., Amino Acid-Protecting Groups. Chem. Rev. 2009, 109 (6), 2455-2504.
53. Jarowicki, K.; Kocienski, P., Protecting groups. J. Chem. Soc. Perk. T. 1. 2001, (18), 2109-2135.
54. Han, G.; Tamaki, M.; Hruby, V., Fast, efficient and selective deprotection of the tert-butoxycarbonyl (Boc) group using HCl/dioxane (4 M). J. Pept. Res. 2001, 58 (4), 338-341.
55. Loach, R. P.; Fenton, O. S.; Amaike, K.; Siegel, D. S.; Ozkal, E.; Movassaghi, M., C7-Derivatization of C3-Alkylindoles Including Tryptophans and Tryptamines. J. Org. Chem. 2014, 79 (22), 11254-11263.
56. Shinohara, T.; Deng, H. B.; Snapper, M. L.; Hoveyda, A. H., Isocomplestatin: Total synthesis and stereochemical revision. J. Am. Chem. Soc. 2005, 127 (20), 7334-7336.
57. 謝宜庭, "6-硼色胺酸類似物與5-硼芬布芬之製備與生物分析以用於硼中子捕獲治療" (碩士論文), 國立清華大學生醫工程與環境科學研究所, 新竹市。2017.
58. Olah, G. A.; Narang, S. C., Iodotrimethylsilane - a Versatile Synthetic Reagent. Tetrahedron 1982, 38 (15), 2225-2277.
59. Li, B.; Berliner, M.; Buzon, R.; Chiu, C. K. F.; Colgan, S. T.; Kaneko, T.; Keene, N.; Kissel, W.; Le, T.; Leeman, K. R.; Marquez, B.; Morris, R.; Newell, L.; Wunderwald, S.; Witt, M.; Weaver, J.; Zhang, Z. J.; Zhang, Z. L., Aqueous phosphoric acid as a mild reagent for deprotection of tert-butyl carbamates, esters, and ethers. J. Org. Chem. 2006, 71 (24), 9045-9050.
60. Liu, Z. J.; Yasuda, N.; Simeone, M.; Reamer, R. A., N-Boc Deprotection and Isolation Method for Water-Soluble Zwitterionic Compounds. J. Org. Chem. 2014, 79 (23), 11792-11796.
61. Jung, M. E.; Lyster, M. A., Conversion of Alkyl Carbamates into Amines Via Treatment with Trimethylsilyl Iodide. J. Chem. Soc. Chem. Comm. 1978, (7), 315-316.
62. Shemin, D.; Herbst, R. M., The condensation of alpha-keto acids and acetamide. J. Am. Chem. Soc. 1938, 60, 1954-1957.
63. Carey, F. A.; Sundberg, R. J., Advanced organic chemistry: part A: structure and mechanisms. 5th ed.; Springer Science & Business Media: New York, 2007, 243.
64. Rothstein, E., Experiments in the Synthesis of Derivatives of Alpha-Aminoacrylic Acid from Serine and N-Substituted Serines. J. Chem. Soc. 1949, (Aug), 1968-1972.
65. Simons, C.; Hanefeld, U.; Arends, I. W. C. E.; Sheldon, R. A.; Maschmeyer, T., Noncovalent anchoring of asymmetric hydrogenation catalysts on a new mesoporous aluminosilicate: Application and solvent effects. Chem-Eur. J. 2004, 10 (22), 5829-5835.
66. Angelini, E.; Balsamini, C.; Bartoccini, F.; Lucarini, S.; Piersanti, G., Switchable reactivity of acylated alpha,beta-dehydroamino ester in the Friedel-Crafts alkylation of indoles by changing the Lewis acid. J. Org. Chem. 2008, 73 (14), 5654-5657.
67. De Simone, U.; Manzo, L.; Ferrari, C.; Bakeine, J.; Locatelli, C.; Coccini, T., Short and long-term exposure of CNS cell lines to BPA-f a radiosensitizer for Boron Neutron Capture Therapy: safety dose evaluation by a battery of cytotoxicity tests. Neurotoxicology 2013, 35, 84-90.
68. Imperio, D.; Del Grosso, E.; Fallarini, S.; Lombardi, G.; Panza, L., Anomeric sugar boronic acid analogues as potential agents for boron neutron capture therapy. Beilstein J. Org. Chem. 2019, 15, 1355-1359.
69. Imperio, D.; Del Grosso, E.; Fallarini, S.; Lombardi, G.; Panza, L., Synthesis of Sugar-Boronic Acid Derivatives: A Class of Potential Agents for Boron Neutron Capture Therapy. Org. Lett. 2017, 19 (7), 1678-1681.
70. Luderer, M. J.; Muz, B.; de la Puente, P.; Chavalmane, S.; Kapoor, V.; Marcelo, R.; Biswas, P.; Thotala, D.; Rogers, B.; Azab, A. K., A Hypoxia-Targeted Boron Neutron Capture Therapy Agent for the Treatment of Glioma. Pharm. Res-Dordr. 2016, 33 (10), 2530-2539.
71. Hattori, Y.; Kurihara, K.; Kondoh, H.; Asano, T.; Kirihata, M.; Yamaguchi, Y.; Wakamiya, T., Biological evaluation of fluorinated p-boronophenylalanine derivatives as a boron carrier. Protein Peptide Lett. 2007, 14 (3), 269-272.
72. Hattori, Y.; Asano, T.; Niki, Y.; Kondoh, H.; Kirihata, M.; Yamaguchi, Y.; Wakamiya, T., Study on the compounds containing F-19 and B-10 atoms in a single molecule for the application to MRI and BNCT. Bioorgan. Med. Chem. 2006, 14 (10), 3258-3262.
73. Kobayashi, K.; Ohnishi, A.; Promsuk, J.; Shimizu, S.; Kanai, Y.; Shiokawa, Y.; Nagane, M., Enhanced tumor growth elicited by L-type amino acid transporter 1 in human malignant glioma cells. Neurosurgery 2008, 62 (2), 493-503.
74. Di, L.; Artursson, P.; Avdeef, A.; Ecker, G. F.; Faller, B.; Fischer, H.; Houston, J. B.; Kansy, M.; Kerns, E. H.; Kramer, S. D.; Lennernas, H.; Sugano, K., Evidence-based approach to assess passive diffusion and carrier-mediated drug transport. Drug Discov. Today 2012, 17 (15-16), 905-912.
75. Scott, D. O.; Ghosh, A.; Di, L.; Maurer, T. S., Passive drug permeation through membranes and cellular distribution. Pharmacol. Res. 2017, 117, 94-102.
76. Menichetti, L.; Gaetano, L.; Zampolli, A.; Del Turco, S.; Ferrari, C.; Bortolussi, S.; Stella, S.; Altieri, S.; Salvadori, P. A.; Cionini, L., In vitro neutron irradiation of glioma and endothelial cultured cells. Appl. Radiat. Isotopes 2009, 67 (7-8), S336-S340.
77. Adamczyk, M.; Johnson, D. D.; Reddy, R. E., Collagen cross-links: a convenient synthesis of tert-butyl-(2S)-2-[(tert-butoxycarbonyl)amino]-4-(2-oxiranyl)butanoate. Tetrahedron-Asymmetr 1999, 10 (4), 775-781.
78. 周佑晟, "合成與評估硼色胺酸類似物於硼中子捕獲治療之應用" (碩士論文)，國立清華大學生醫工程與環境科學研究所，新竹市。2017.
79. Kadayifcioglu, N.; Acar, H. Y., Synthesis of poly(2-acetamidoacrylic acid) and its PEGMA block copolymer via ATRP in water. Eur. Polym. J. 2013, 49 (10), 3366-3376.
80. Dedeoglu, B.; Ugur, I.; Degirmenci, I.; Aviyente, V.; Barcin, B.; Cayli, G.; Acar, H. Y., First RAFT polymerization of captodative 2-acetamidoacrylic acid (AAA) monomer: An experimental and theoretical study. Polymer 2013, 54 (19), 5122-5132.
81. Ha, E. J.; Kim, B. S.; Park, C. H.; Lee, J. O.; Paik, H. J., Electroactive hydrogel comprising poly(methyl 2-acetamido acrylate) for an artificial actuator. J. Appl. Phys. 2013, 114 (5), 054701.
82. Gladiali, S.; Pinna, L., Asymmetric Hydroformylation of N-Acyl 1-Aminoacrylic Acid-Derivatives by Rhodium/Chiral Diphosphine Catalysts. Tetrahedron-Asymmetr 1991, 2 (7), 623-632.
83. Billingsley, K. L.; Barder, T. E.; Buchwald, S. L., Palladium-catalyzed borylation of aryl chlorides: Scope, applications, and computational studies. Angew. Chem. Int. Edit. 2007, 46 (28), 5359-5363.