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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 | |
dc.contributor.author | Pi-Hung Kao | en |
dc.contributor.author | 高碧鴻 | zh_TW |
dc.date.accessioned | 2021-06-13T00:30:21Z | - |
dc.date.available | 2017-07-25 | |
dc.date.copyright | 2007-08-08 | |
dc.date.issued | 2007 | |
dc.date.submitted | 2007-07-25 | |
dc.identifier.citation | 1. Cai, H.; Yin, D.; Zhang, L. & Wang, Y. The synthesis of a new probe for PET imaging reporter gene HSV1-tk : 2-amino-6-[18F]fluoro-9-(4-hydroxy-3- hydroxymethylbutyl) purine (6-[18F]fluoropenciclovir). J. Labelled Compd. Radiopharm. 2006, 49, 653-661.
2. Phelps, M. E. PET : Molecular Imaging and Its Biological Applications. New York, Springer, c2004. 3. Bailey, D. L.; Townsend, D. W.; Valk, P. E. & Maisey, M. N. Positron Emission Tomography : Basic Sciences. London, New York, Springer, c2005. 4. Valk, P. E.; Delbeke, D.; Bailey, D. L.; Townsend, D. W. & Maisey, M. N. Positron Emission Tomography : Clinical Practice. London, Springer, c2006. 5. Yuna, M.; Oha, S. J.; Hab, H. J.; Ryua, J. S. & Moona, D. H. High radiochemical yield synthesis of 3’-deoxy-3’-[18F]fluorothymidine using (5’-O-dimethoxytrityl-2’-deoxy-3’-O-nosyl-β-D-threopentofuranosyl)thymine and its 3-N-Boc-protected analogue as a labeling precursor. Nucl. Med. Biol. 2003, 30, 151-157. 6. Shields, A. F.; Grierson, J. R.; Dohmen, B. M.; Machulla, H. J.; Stayanoff, J. C.; Lawhorn-Crews, J. M.; Obradovich, J. E.; Muzik, O. & Manger, T. J. Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nature Medicine. 1998, 4, 1334-1336. 7. Gollnic, K. S. Merbromin(mercurochrome)- a phtosensitizer for inglet oxygen reaction. J. Phtochem. Phtobiol. B. Biol. 1990, 5, 85-93. 8. Morier-Teissier, E.; Boitte, N.; Helbecque, N.; Bernier, J. L.; Pommery, N.; Duvalet, J. L.; Fournier, C.; Hecquet, B.; Catteau, J. P. & Henichart, J. P. Synthesis and antitumor properties of an anthraquinone bisubstituted by the copper chelating peptide Gly-Gly-L-His. J. Med. Chem. 1993, 36, 2084-2090. 9. Gatto, B.; Zagotto, G.; Sissi, C.; Cera, C.; Uriarte, E.; Palu, G.; Capranico, G. & Palumbo, M. Peptidyl anthraquinones as potential antineoplastic drugs: synthesis, DNA binding, redox cycling, and biological activity. J Med Chem. 1996, 39, 3114-3122. 10. Routier, S.; Cotelle, N.; Catteau, J. P.; Bernier, J. L.; Waring, M. J.; Riou, J. F. & Bailly, C. Salen-anthraquinone conjugates. Synthesis, DNA-binding and cleaving properties, effects on topoisomerases and cytotoxicity. Bioorg. Med. Chem. 1996, 4, 1185-1196. 11. Fox, E. J. Mechanism of action of mitoxantrone. Neurology 2004, 63, S15-18. 12. Barasch, D.; Zipori, O.; Ringel, I.; Ginsburg, I.; Samuni, A. & Katzhendler, J. Novel anthraquinone derivatives with redox-active functional groups capable of producing free radicals by metabolism: are free radicals essential for cytotoxicity? Eur. J. Med. Chem. 1999, 34, 597-615. 13. Giles, G. I. & Sharma, R. Solid phase synthesis of anthraquinone peptides and their evaluation as topoisomerase I inhibitors. J. Pept. Sci. 2005, 11, 417-423. 14. Chen, W. R. Design and synthesis of amido- and carbamoyl-anthraquinones as potential antitumor agents. 國立台灣大學醫學院藥學研究所碩士論文, July 2005. 15. Chen, H. W. Design and synthesis of amido-, amino- and ureido- anthraquinones as potential antitumor agents. 國立台灣大學醫學院藥學研究所碩士論文, July 2005. 16. Zee-Cheng, R. K. & Cheng, C. C. Antineoplastic agents. Structure-activity relationship study of bis(substituted aminoalkylamino)anthraquinones. J. Med. Chem. 1978, 21, 291-294. 17. Marmur, J. & Doty, P. Determination of the base composition of deoxyribonucleic acid from its thermal denaturation temperature. J. Mol. Biol. 1962, 5 109-118. 18. Bailly, C.; Routier, S.; Bernier, J. L. & Waring, M. J. DNA recognition by two mitoxantrone analogues: influence of the hydroxyl groups. FEBS Lett. 1996, 379, 269-272. 19. Routier, S.; Bernier, J. L.; Catteau, J. P.; Riou, J. F. & Bailly, C. Synthesis, DNA binding, topoisomerase II inhibition and cytotoxicity of two guanidine-containing anthracene-9,10-diones. Anticancer Drug Des. 1998, 13, 407-415. 20. Lin, C. C. Synthetic studies on the monomers for oligourea peptidomimetics. 國立台灣大學醫學院藥學研究所碩士論文, July 2003. 21. Leonard, G. A.; Brown, T. & Hunter, W. H. Anthracycline binding to DNA. Eur. J. Biochem. 1992, 204, 69-74. 22. Grierson, J. R. & Shields, A. F. Radiosynthesis of 3’-deoxy-3’- [18F]fluorothymidine : [18F]FLT for Imaging of Cellular Proliferation In Vivo. Nucl. Med. Biol. 2000, 27, 143-156. 23. Martin, S. J.; Eisenbarth, J. A.; Wagner-Utermann, U.; Mier, W.; Henze, M.; Pritzkow, H.; Haberkorn, U. & Eisenhut, M. A new precursor for the radiosynthesis of [18F]FLT. Nucl. Med. Biol. 2002, 29, 263-273. 24. Meikle, I.; Cummings, J.; Macpherson, J. S.; Hadfield, J. A. & Smyth, J. F. Biochemistry of topoisomerase I and II inhibition by anthracenyl-amino acid conjugates. Biochem. Pharma. 1995, 49, 1747-1757. 25. Cory, M.; McKee, D. D.; Kagan, J.; Henry, D. W. & Milled, J. A. Design, synthesis, and DNA binding properties of bifunctional intercalators. Comparison of polymethylene and diphenyl ether chains connecting phenanthridine. J. Am. Chem. Soc. 1985, 107, 2528-2536. 26. Collier, D. A. & Neidle, S. Synthesis, molecular modeling, DNA binding, and antitumor properties of some substituted amidoanthraquinones. J. Med. Chem. 1988, 31, 847-857. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/28934 | - |
dc.description.abstract | 正子斷層掃描是近年來在醫藥研究領域,發展出來的新興非侵入性造影技術,目前已被應用於癌症的診斷、基因治療情形的監控、心肌功能的評估以及生物體內酵素、接受器和轉運體的定位及造影等;而且正子斷層掃描在藥物的開發及研究方面,也扮演相當重要的角色。由於先前一系列比mitoxantrone(MX)和ametantrone(AT)有更高抗癌活性的蒽醌類抗癌藥物已被製備出來,因此,本研究的目的為結合製備這些蒽醌類抗癌藥物的觀念,以及正子斷層掃描的技術,設計與合成一系列新穎的氟化胺基蒽醌類抗腫瘤化合物,做為正子斷層掃描測量腫瘤細胞增生的腫瘤造影劑。
放射氟十八標記的去氧葡萄糖目前已被廣泛使用於正子斷層掃描的腫瘤造影,但因為正常細胞也會攝取利用葡萄糖,造成氟十八去氧葡萄糖的專一性不佳。因此,設計與合成放射性標記胸腺嘧啶類的衍生物,就能克服這個問題;且因為氟十八胸腺嘧啶在生物體內不會被分解,但會代謝滯留在增生的細胞內,所以此為目前最有潛力的放射造影試劑。並且,可供放射標記成氟十八胸腺嘧啶的前導物1也成功地被合成出來,且經過一次再結晶後,其純度和市面販售但價格昂貴的前趨產品不相上下。而藉由和台大醫院核醫部技術合作,氟十八胸腺嘧啶已成功地被製備,並且在狗及人的正子斷層掃描實驗中,都獲得相當良好的造影效果。 接著,將氟基接上MX和AT骨架而合成的無放射活性氟化胺基蒽醌類’’冷化合物’’被合成出來後(化合物2-1 ~ 5-3),再從中挑選出較具藥理活性者,將來改以放射標記製備成’’熱化合物’’ ,即可做為正子斷層掃描的腫瘤造影試劑。一邊保留MX和AT的-[(2-胺乙基)胺基]或-[(2-羥乙基)乙二胺基]支鏈、另一邊則為氟基接合不同碳數支鏈的氟化胺基蒽醌類化合物已被合成出來,並可藉此來評估氟基和胺基不同的位置和距離,對生物活性可能會造成的影響。最後,參考文獻利用測定DNA的熔化溫度,來探討這些合成的蒽醌類抗癌化合物之抗癌機轉,及其和DNA雙股螺旋間的作用關係,即可以此做為後續藥理活性篩選的初步評估。 | zh_TW |
dc.description.abstract | Positron emission tomography (PET) is a newly developed noninvasive imaging technique and is now regularly used in the diagnosis and staging of cancer, monitoring gene therapy, assessment of myocardium function and mapping for enzyme, receptor and transporter. Additionally, PET also plays an important role in the drug discovery and development. In our laboratory, previously, many anthraquinones that have better anti-tumor activity than mitoxantrone (MX) and ametantrone (AT) have been synthesized. The aim of this study is to combine the concept of anthraquinone synthesis and the PET technique to design and synthesize novel antitumor imaging agents that can be employed to measure tissue and tumor proliferation with PET.
[18F]Fluorodeoxyglucose ([18F]FDG) is widely used for tumor imaging with PET, but it is not specific because other normal cells can also utilize glucose. Thus, radiolabeled thymidine derivatives have been developed to overcome the limitations of [18F]FDG. One of their analogs, [18F]fluorine-labeled thymidine (3’-deoxy-3’- fluorothymidine, [18F]FLT) appears to be the most promising radiopharmaceutical because of the lack of in vivo degradation and metabolic trapping in proliferating cells. Precursor 1 for synthesizing [18F]FLT had been synthesied in our lab. After purified by recrystallization, the purity of the precursor 1 was comparable with that of the commercial product. Through the cooperation with the department of Nuclear Medicine of National Taiwan University Hospital, we have prepared [18F]FLT successfully with our precursor 1 and the image quality for PET in humans and dogs was good. Fluoroaminoanthraquinones with fluorine attached to MX and AT backbones have been synthesized as “cold compounds” (compounds 2-1 ~ 5-3). Among them, more potent compounds will be choosed for radiolabeling as “hot compounds” for PET tumor imaging. First, the compounds with one -[(aminoethyl)amino] or -[(2-hydroxyethyl)ethylenediamino] side chain of MX and AT and the other one side chain of fluorine-substituted alkyl groups with different carbon numbers have been synthesized. Then the different positions and chain lengths between fluorine and the amine group may influence the pharmacological activities of these fluoroaminoanthraquinones. And these can be used as the authentic samples for identifying the 18F-labeled compounds in the future. Finally, we utilized the DNA melting temperature (△Tm) measurement technique to provide information about the interaction of the synthetic anthraquinones with the DNA double helix; these can be the initial pharmacological evaluation for our synthetic compounds in the future. | en |
dc.description.provenance | Made available in DSpace on 2021-06-13T00:30:21Z (GMT). No. of bitstreams: 1 ntu-96-R94423019-1.pdf: 3882796 bytes, checksum: 26aaed93044dd59ae56626ffc287a26b (MD5) Previous issue date: 2007 | en |
dc.description.tableofcontents | 目 錄
口試委員會審定書 ……………………………………………….……………. i 誌謝 …………………………………………………………..…………………. ii 中文摘要 ………………………………………………………………………… iii 英文摘要 …………………………………………………………………………. v 目錄 ……………………………………………………………………………... vii 圖目錄 …………………………………………………………………………… ix 表目錄 ……………………………………………………………………………… x 路徑目錄 ………………………………………………………………………….. xi 背景 …………………………………………………………….…………….….. 1 研究目的 ……………………………………………………… 7 結果與討論 一、 氟十八胸腺嘧啶的前導物1之合成 …………..…….………… 8 二、 合成的前導物1之純度分析 …………………………………… 13 三、 氟化胺基蒽醌類化合物之合成 ………………………….….… 19 四、 合成天門冬醯胺酸尿素單體過程之研究 …………………….. 28 五、 DNA結合能力實驗及分析結果 ………………………………. 39 六、 人類前列腺癌細胞株抑制活性結果及分析 ……….…………… 45 結論 …………………………………………………………………………….. 50 實驗部分 一、 試劑、溶劑及材料來源 ………………………...………………… 51 二、 一般儀器與方法 ……………………………..………………….. 54 三、 實驗步驟與分析數據 …………………………………………… 59 DNA結合能力實驗步驟 ……………………………………….. 99 參考文獻 ……………………………………………………………………...… 100 附表目錄 ………………………………………………………………………… 103 附表 ……………………………………………………………………………... 104 附圖目錄 ………………………………………………………………………… 110 附圖 ……………………………………………………………………………… 112 圖 目 錄 圖一、Glucose、[18F]FDG、Thymidine、[3H]Thymidine、[11C]Thymidine和 [18F]FLT之化學結構 …………………………………………………..… 2 圖二、蒽醌類抗腫瘤藥物之化學結構 …………………………………………. 3 圖三、醯胺基(amido-)、胺基(amino-)、脲基(ureido-)、胺基甲醯基(carbamoyl-) 與氟化胺基(fluoroamino-)蒽醌類抗腫瘤化合物之化學結構通式 …. 5 圖四、市面上購買得到的前導物之HPLC層析圖譜及統計數據 ………..……. 13 圖五、合成的前導物1(只經過一次快速柱層析、未經過再結晶純化)之HPLC層析圖譜及統計數據 ……………………………………….…………… 14 圖六、合成的前導物1(經過一次快速柱層析及一次再結晶純化)之HPLC層析圖譜及統計數據 …………………………………………………………. 15 圖七、合成的前導物1(經過一次快速柱層析及一次再結晶純化,但和C.為不同批次的純化產物)之HPLC層析圖譜及統計數據 ……………..………. 16 圖八、合成的前導物1(C.配製好HPLC樣品溶液後,室溫下放置一天)之HPLC層析圖譜及統計數據 …………………….…………………...…………. 17 圖九、目標氟化胺基蒽醌類化合物2-1 ~ 5-3之化學結構 ……..……………… 19 圖十、合成的蒽醌類抗腫瘤化合物結構圖 ………………………………………. 40 表 目 錄 表一、起始物17A(含少量環化化合物17A-c)進行微波反應之結果整理 …. 32 表二、起始物17A(含少量環化化合物17A-c)進行油鍋加熱反應之結果整理.. 38 表三、蒽醌類化合物的△Tm值及對PC-3癌細胞株抑制活性結果整理 …..… 41 表四、蒽醌類化合物對人類癌細胞株的抑制活性結果整理 ..…………..…….. 46 表五、蒽醌類化合物對人類前列腺癌細胞株的抑制活性結果整理 ……..……. 47 路 徑 目 錄 路徑一、Yuna, M. et al.對[18F]FLT之逆合成分析……………………………… 8 路徑二、前導物1之逆合成分析 ……………………………...…………………. 9 路徑三、化合物1-3之合成途徑 ………………………………………………… 10 路徑四、目標前導物1之合成途徑 …………………………...…………………. 11 路徑五、化合物2和3之逆合成分析 …………………………….…………….. 20 路徑六、化合物2b、3b、4b、5b之合成途徑 ………………………..………….. 21 路徑七、化合物2d、3d、4d、5d之合成途徑 …………………………………… 23 路徑八、目標化合物2-1、2-2、2-3、3-1、3-2、3-3之合成路徑 ….…………… 24 路徑九、目標化合物4-1、4-2、4-3、5-1、5-2、5-3之合成路徑 …….………… 25 路徑十、目標化合物2-3及副產物2-3-c之合成路徑 ……..…………………… 26 路徑十一、化合物12和13之合成路徑 ………………………………………… 27 路徑十二、尿素單體之逆合成分析 ………………………………...…………… 29 路徑十三、化合物16A之合成途徑 ……………………………….…………… 29 路徑十四、化合物17A之合成途徑 ……………………………….…………… 30 路徑十五、化合物18A之合成途徑 ……………………………….…………… 31 路徑十六、目標化合物18A、副產物18A-c之合成途徑 ……………………… 32 | |
dc.language.iso | zh-TW | |
dc.title | 設計與合成具潛力用於正子斷層掃描的腫瘤造影劑 | zh_TW |
dc.title | Design and Synthesis of Potential Tumor Imaging Agents for Positron Emission Tomography | en |
dc.type | Thesis | |
dc.date.schoolyear | 95-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 王光昭,林淑萍,薛晴彥 | |
dc.subject.keyword | 正子斷層掃描,氟化胺基蒽,醌,類抗腫瘤化合物, | zh_TW |
dc.subject.keyword | Positron emission tomography,Fluoroaminoanthraquinone, | en |
dc.relation.page | 146 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2007-07-26 | |
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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