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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 忻凌偉(Ling-Wei Hsin) | |
dc.contributor.author | Kai-Ting Shih | en |
dc.contributor.author | 施凱庭 | zh_TW |
dc.date.accessioned | 2021-06-08T01:42:41Z | - |
dc.date.copyright | 2016-08-26 | |
dc.date.issued | 2016 | |
dc.date.submitted | 2016-08-18 | |
dc.identifier.citation | 1. Lo, M.; Wang, Y. Z.; Gout, P. W. The x-c Cystine/Glutamate Antiporter: A Potential Target for Therapy of Cancer and Other Diseases. J. Cell. Physiol. 2008, 215, 593–602.
2. Christensen, H. N. Role of Amino Acid Transport and Countertransport in Nutrition and Metabolism. Physiol. Rev. 1990, 70, 43-77. 3. Chillarόn, J.; Roca, R.; Valencia A.; Zorzano, A.; Palacín, M. Heteromeric amino acid transporters: biochemistry, genetics, and physiology. Am. J. Physiol. Renal Physiol. 2001, 281, 995–1018. 4. Patel, S. A.; Warren, B. A.; Rhoderick, J. F.; Bridges, R. J. Differentiation of substrate and non-substrate inhibitors of transport system x-c : an obligate exchanger of L-glutamate and L-cystine. Neuropharmacology. 2004, 46, 273–284. 5. Makowske, M.; Christensen, H. N. Contrasts in Transport Systems for Anionic Amino Acids in Hepatocytes and a Hepatoma Cell Line HTC. J. Biol. Chem. 1982, 257, 5563-5670. 6. Bannai, S. Transport of cystine and cysteine in mammalian cells. Biochim. Biophys. Acta. 1984, 779, 289-306. 7. Maechler, P.; Wollheim, C. B. Mitochondrial glutamate acts as a messenger in glucose-induced insulin exocytosis. Nature. 1999, 402, 685-689. 8. Gout, P. W.; Buckley, A. R.; Simms, C. R.; Bruchovsky, N. Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the x-c cystine transporter: a new action for an old drug. Leukemia. 2001, 15, 1633–1640. 9. Chung, W. J.; Lyons, S. A.; Nelson, G. M.; Hamza, H.; Gladson, C. L.; Gillespie, G. Y.; Sontheimer, H. Inhibition of Cystine Uptake Disrupts the Growth of Primary Brain Tumors. J. Neurosci. 2005, 25, 7101–7110. 10. Bassi, M. T.; Gasol, E.; Manzoni, M.; Pineda, M.; Riboni, M.; Martín, R.; Zorzano, A.; Borsani, G.; Palacín, Manuel. Identification and characterisation of human xCT that co-expresses, with 4F2 heavy chain, the amino acid transport activity system xc–. Pflügers Arch – Eur. J. Physiol. 2001, 442, 286–296. 11. Doxsee, D. W.; Gout, P. W.; Kurita, T.; Lo, M.; Buckley, A. R.; Wang, Y.; Xue, H.; Karp, C. M.; Cutz, J. C.; Cunha, G. R.; Wang, Y. Z. Sulfasalazine-Induced Cystine Starvation: Potential Use for Prostate Cancer Therapy. Prostate. 2007, 67, 162-171. 12. Koglin, N.; Mueller, A.; Berndt, M.; Schmitt-Willich, H.; Toschi, L; Stephens, A.W.; Gekeler V.; Friebe, M.; Dinkelborg, L.M. Specific PET Imaging of xC- Transporter Activity Using a 18F-Labeled Glutamate Derivative Reveals a Dominant Pathway in Tumor Metabolism. Clin. Cancer Res. 2011, 17, 6000-6011. 13. Baek, S.; Choi, C. M.; Ahn, S. H.; Lee, J. W.; Gong, G.; Ryu, J.S.; Oh, S. J.; Bacher-Stier, C.; Fels, L.; Koglin, N.; Hultsch, C.; Schatz, C. A.; Dinkelborg, L. M.; Mittra, E. S.; Gambhir, S. S.; Moon, D. H. Exploratory Clinical Trial of (4S)-4-(3-[18F]fluoropropyl)-Lglutamate for Imaging xC- Transporter Using Positron Emission Tomography in Patients with Non–Small Cell Lung or Breast Cancer. Clin. Cancer Res. 2012, 18, 5427-5437. 14. Mittra1, E. S.; Koglin, N.; Mosci, C.; Kumar, M.; Hoehne, A.; Keu, K. V.; Iagaru, A. H.; Mueller, A.; Berndt, M.; Bullich, S.; Friebe, M.; Schmitt-Willich, H.; Gekeler, V.; Fels, L. M.; Bacher-Stier, C.; Moon, D. H.; Chin, F. T.; Stephens, A. W.: Dinkelborg, L. M.; Gambhir, S. S. Pilot Preclinical and Clinical Evaluation of (4S)-4-(3-[18F]Fluoropropyl)-L-Glutamate (18F-FSPG) for PET/CT Imaging of Intracranial Malignancies. PLoS One. 2016, 11, doi: 10.1371/journal.pone.0148628. 15. Sheikh, M. C.; Takagi, S.; Yoshimura, T.; Morita, H. Mechanistic studies of DCC/HOBt-mediated reaction of 3-phenylpropionic acid with benzyl alcohol and studies on the reactivities of ‘active ester’ and the related derivatives with nucleophiles. Tetrahedron. 2010, 66, 7272-7278. 16. Konda, Y.; Takahashi, Y.; Arima, S.; Sato, N.; Takeda, K.; Dobashi, K.; Baba, M.; Harigaya, Y. First total synthesis of Mer-N5075A and a diastereomeric mixture of and -MAPI, new HIV-I protease inhibitors from a species of Streptomyces. Tetrahedron. 2001, 57, 4311-4321. 17. Pedregal, C.; Collado, I.; Escribano, A.; Ezquerra, J.; Domínguez, C.; Mateo, A. I.; Rubio, A.; Baker, S. R.; Goldsworthy, J.; Kamboj, R. K.; Ballyk, B. A.; Hoo, K.; Bleakman, D. 4-Alkyl- and 4-Cinnamylglutamic Acid Analogues Are Potent GluR5 Kainate Receptor Agonists. J. Med. Chem. 2000, 43, 1958-1968. 18. Zhao, Y.; Gavai, A. V.; Gill, P; Kim, S. H.; Fink, B. E.; Chen, L.; Saulnier, M. G.; Han, W. C. WO2104/047397 A1, 2014. 19. Pimlott, S. L.; Sutherland, A. Molecular tracers for the PET and SPECT imaging of disease. Chem. Soc. Rev. 2011, 40, 149–162. 20. Ametamey, S. M.; Honer, M.; Schubiger, P. A. Molecular Imaging with PET. Chem. Rev. 2008, 108, 1501–1516. 21. Tredwell, M.; Gouverneur V. 18F Labeling of Arenes. Angew. Chem. Int. Ed. 2012, 51, 11426 – 11437. 22. Pike, V. W.; Aigbirhio, F. I. Reactions of Cyclotron-produced [18F]Fluoride with Diaryliodonium Salts-a Novel Single-step Route to No-carrier-added [18F]Fluoroarenes. J. Chem. Soc., Chem. Commun. 1995, 21, 2215-2216. 23. Merritt, E. A.; Olofsson, B. Diaryliodonium Salts: A Journey from Obscurity to Fame. Angew. Chem. Int. Ed. 2009, 48, 9052 – 9070. 24. Pike, V. W.; Butt, F.; Shah, A.; Widdowsonb, D. A. Facile synthesis of substituted diaryliodonium tosylates by treatment of aryltributylstannanes with Koser’s reagent. J. Chem. Soc., Perkin Trans. 1999, 1, 245–248. 25. Landge, K. P.; Jang, K. S.; Lee, S. Y.; Chi, D. Y. Approach to the Synthesis of Indoline Derivatives from Diaryliodonium Salts. J. Org. Chem. 2012, 77, 5705−5713. 26. Bielawski, M.; Aili, D.; Olofsson, B. Regiospecific One-Pot Synthesis of Diaryliodonium Tetrafluoroborates from Arylboronic Acids and Aryl Iodides. J. Org. Chem. 2008, 73, 4602–4607. 27. Chen, W. H. Synthesis of Novel 5-HT7 Receptor Ligands as Potential Positron Emission Tomography Imaging Agents. 國立台灣大學醫學院藥學研究所碩士班論文, July, 2012. 28. Chandrasekhar, J.; Kozikowski, A. P.; Liu, J.; Tueckmantel, W.; Walker, J. R.; Yuen, P.W. US20100152450 (A1), 2010. 29. Berthel, S. J.; Cheung, A.W; Kim, K; Thakkar, K. C.; Yun, W. US2004/0235872 A1, 2004. 30. Kielar, F.; Wang, Q.; Boyle, P. D.; Franz, K. J. A boronate prochelator built on a triazole framework for peroxide-triggered tridentate metal binding. Inorganica Chimica Acta. 2012, 393, 294–303. 31. Martinez, E.; Talley, J. J.; Antonelli, S.; Barden, T. C.; Lundrigan-Soucy, R.; Schairer, W. C.; Yang, J. J. WO2005/047248 A1, 2005. 32. Liu, S.; Bai, H.; Sun, Q.; Zhang, W.; Qian, J. Naphthalimide-based fluorescent photoinduced electron transfer sensors for saccharides. RSC Adv. 2015, 5, 2837–2843. 33. Ni, W.; Fang, H.; Springsteen, G.; Wang, B. The Design of Boronic Acid Spectroscopic Reporter Compounds by Taking Advantage of the pKa-Lowering Effect of Diol Binding: Nitrophenol-Based Color Reporters for Diols. J. Org. Chem. 2004, 69, 1999-2007. 34. Ahn, S. J.; Lee, C. Y.; Kim, N. K.; Cheon, C. H. Metal-Free Protodeboronation of Electron-Rich Arene Boronic Acids and Its Application to ortho-Functionalization of Electron-Rich Arenes Using a Boronic Acid as a Blocking Group. J. Org. Chem. 2014, 79, 7277−7285. 35. Beenen, M. A.; An, C.; Ellman, J. A. Asymmetric Copper-Catalyzed Synthesis of -Amino Boronate Esters from N-tert-Butanesulfinyl Aldimines. J. Am. Chem. Soc. 2008, 130, 6910–6911. 36. Ranta, J.; Kumpulainen, T.; Lemmetyinen, H.; Efimov, A. Synthesis and Characterization of Monoisomeric 1,8,15,22-Substituted (A3B and A2B2) Phthalocyanines and Phthalocyanine-Fullerene Dyads. J. Org. Chem. 2010, 75, 5178–5194. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/19025 | - |
dc.description.abstract | 為了能夠有選擇性的將18F導入4-硝基苯丙基,本研究以利用新型離去基的親核性氟取代反應為策略,進行氟取代4-硝基苯丙基合成子的開發。2-溴基-4-(3-溴丙基)-1-硝基苯化合物22以及3-(4-硝基-2-(4,4,5,5-四甲基-1,3,2-二氧硼雜環戊烷-2-基)苯基)丙酸化合物24皆成功的被製備作為未來合成2-以及3-[18F]氟基4-硝基苯取代衍生物之合成子。
(4S)-4-(3-[18F]氟丙基)麩胺酸 ((4S)-4-(3-[18F]Fluoropropyl)- L-glutamate, [18F]FSPG) 是一個具有潛力可評估xc-胱胺酸/麩胺酸反向轉運體的腫瘤正子斷層掃描診斷探針。為了提供高光學純度的[18F]FSPG以及前驅物供臨床試驗使用,本研究對造成外消旋現象的關鍵反應參數進行研究,並且開發再結晶的方法純化關鍵中間體藉以提高光學純度 (ee : 42% → 99%) 。透過最佳化的反應條件或是再結晶的方法可以合成出高光學純度的(2S,4S)-FSPG。除此之外,為了能夠提供FSPG非鏡像異構物作為人體臨床試驗時的品質管制參考,本研究也成功建立(2S,4R)-FSPG的合成方法。 | zh_TW |
dc.description.abstract | Nucleophilic aromatic substitution (SNAr) is a common approach to synthesize radiolabeled aryl fluorides. In these reactions, the most widely used leaving groups include trimethylammonium and nitro groups. However, it is a challenge to introduce a fluoride atom into 4-nitrophenylalkane. According to our previous research, it is found that fluorination of 2,4-dinitrophenyl-substituted compound showed low selectivity to yield 2-fluoro-4-nitrophenyl-substituted compound. In this study, novel substituents were used as leaving groups for the selective nucleophilic fluorination. The 2-bromo-4-(3-bromopropyl)-1-nitrobenzene compound 22 and 3-(4-nitro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoic acid compound 24 were successfully prepared as the synthons for the future synthesis of 2-and 3-[18F]fluoro-substituted 4-nitrophenyl-substituted compounds.
(4S)-4-(3-[18F]Fluoropropyl)-L-glutamate (BAY 94-9392, or [18F]FSPG) is a potential tumor-imaging molecular probe to assess system xC- transporter activity using positron emission tomography (PET). Optically pure precursor for the radiosynthesis of [18F]FSPG is crucial to provide high-quality [18F]FSPG for clinical use. To improve the enantiomeric purity of the precursor and reference standard of [18F]FSPG, the key reaction parameters causing the racemization of the intermediates and products were studied. In addition, to recover the desired enantiomer from the intermediates with lower ee, a recrystallization method has been developed to effectively recover the desired enantiomer with high ee (42% → 99%). In conclusion, optically pure precursor and standard of (2S,4S)-FSPG can be obtained either by the optimized reaction conditions, or by recrystallization method. Moreover, to provide the diastereomers of FSPG as references for quality control in human clinical study, the synthesis method for (2S,4R)-FSPG was developed. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T01:42:41Z (GMT). No. of bitstreams: 1 ntu-105-R03423023-1.pdf: 14116144 bytes, checksum: 52c8b738b0e1de808b6ad486d180d89b (MD5) Previous issue date: 2016 | en |
dc.description.tableofcontents | 口試委員審定書
誌謝 II 中文摘要 III Abstract IV 總目錄 VI 圖目錄 VIII 表目錄 IX 路徑目錄 X 英文縮寫表 XI 第一部分:3-氟丙基-麩胺酸立體異構物的合成研究 1 第一章、緒論 2 1.1 xc-胱胺酸/麩胺酸反向轉運體 2 1.2 (4S)-4-(3-氟丙基)-L-麩胺酸 ((4S)-4-(3-Fluoropropyl)-L-glutamic acid, FSPG) 3 1.3研究動機與目的 4 2.1 FSPG中間體之關鍵反應參數研究 5 2.2 中間體化合物7再結晶方法之開發 7 2.3 3-氟丙基-麩胺酸立體異構之合成 9 2.4 化合物16之合成分析 10 2.5 化合物17之合成 12 2.6利用化合物17進行化合物16之合成 13 2.7 化合物2之合成分析 13 2.8 FSPG異構物之HPLC分析 14 2.8 化合物9之合成改善 17 第三章、結論 18 第二部分:4-硝基-氟苯丙基合成子的合成研究 19 第一章、緒論 20 1.1 正子斷層掃描之原理 20 1.2 18F的放射性標記 21 1.3 研究動機與目的 22 第二章、結果與討論 24 2.1.1 4-硝基氟苯丙基化合物合成子之逆合成分析 24 2.1.2 化合物40之模型研究 24 2.2 化合物41之模型研究 28 第三章、結論 32 實驗部分 33 一、 實驗藥品及溶劑來源 33 二、 一般儀器與方法 35 三、 合成步驟與數據分析 36 參考文獻 68 附件目錄 73 附件 77 | |
dc.language.iso | zh-TW | |
dc.title | 開發新穎正子影像藥物:3-氟丙基-麩胺酸立體異構物與4-硝基-氟苯丙基合成子的合成研究 | zh_TW |
dc.title | Synthesis of Stereoisomers of 4-(3-Fluoropropyl)-L-glutamic acid and 3-[4-nitro-fluorophenyl]propyl Synthon for the Development of Novel PET Imaging Agents | en |
dc.type | Thesis | |
dc.date.schoolyear | 104-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 陳基旺(Ji-Wang Chern),王光昭(Guang-Zhao Wang),梁碧惠(Pi-Hui Liang) | |
dc.subject.keyword | 3-氟丙基-麩胺酸,腫瘤正子斷層掃描診斷探針,親核性取代反應,合成子, | zh_TW |
dc.subject.keyword | (3-Fluoropropyl)-glutamate,tumor-imaging molecular probe,nucleophilic aromatic substitution,synthons, | en |
dc.relation.page | 183 | |
dc.identifier.doi | 10.6342/NTU201603222 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2016-08-18 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥學研究所 | zh_TW |
顯示於系所單位: | 藥學系 |
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