石膽酸C4含氟唾液酸轉移酶抑制劑和苯並惡嗪酮相關的螢光探針之合成及生物研究

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姓名

劉明鑫(Ming-Xin Liu) 查詢紙本館藏

畢業系所

化學學系

論文名稱

石膽酸C4含氟唾液酸轉移酶抑制劑和苯並惡嗪酮相關的螢光探針之合成及生物研究
(Synthesis and biology of lithocholic acid C4 fluorine-containing sialyltransferase inhitors and benzoxazinone-related fluorescent probes.)

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摘要(中)

第一部份
根據研究指出唾液酸轉移酶的異常表現量與許多癌症有關聯。因此能發展出具良好活性的唾液酸轉移酶抑制劑，進而調控唾液酸的表現途徑，是我們實驗室努力的目標。本文所合成的化合物是以石膽酸為主結構，利用具有高效率與選擇性的Selectfluor試劑在C4位置引入一個氟原子做修飾，並進一步合成出Lith-O-Asp-NBD之氟取代衍生物做為有效的抗癌化合物。分別透過MTT assay及Wound healing assay實驗來探討氟取代石膽酸類似物對於生物活性的影響。透過生物實驗發現化合物JO-5b、JO-13a、JO-13b具有較好的抑制效果。
第二部分
螢光標記法具有高靈敏度、選擇性好等優點，目前應用相當廣泛。近年來新型的分子顯影劑之臨床轉譯與發展透過早期病變檢測、分子標靶治療、治療監測以及開發新的抗癌藥物能夠明顯改善乳癌患者的癌症轉移。本文所合成的化合物是以benzoxazinone為主體，藉由修飾其官能基來探討分子探針之結構與量子產率之間的關係。透過光學性質分析發現JO-35的量子產率最高 (Φ = 0.39)，其結構上的胺基會與環上的氧原子形成分子內氫鍵，若是替換成其他官能基會使分子探針失去螢光的特性。

摘要(英)

PartI.
According to many researches, abnormal expression of the sialyltransferase has been found to actually connect with many cancers. Therefore, purposes and objectives of this study are making effort to develop effective sialyltransferase inhibitors and regulate the level of sialyltransferase expression.In the thesis, the main structure of our compounds are lithocholic acid. We used high efficient and selective reagent─Selectfluor to add a fluorine atom at the C4 position as modification, and we synthesized fluorinated compound of Lith-O-Asp-NBD as effective anti-cancer compound further.Through MTT assay and Wound healing assay experiment to discuss fluorinated compound’s influence on biologically activity. Interestingly, We found that compounds JO-5b, JO-13a, JO-13b possess potent anti-metastasis ability.
PartII.
Fluorescent labeling has the advantage of high sensitivity and good selectivity for the use in a wide range of applications. In recent years, novel molecular imaging agents were developed for the use of clinical translation through early lesion detection, molecular targeted therapy, therapeutic monitoring, and the development of new anti-cancer drugs. This action significantly improves diagnosis and therapy in patients with breast cancer metastasis. In this thesis, the main structure of our compounds is benzoxazinone. We modified its functional group to explore the relationship between structure and fluorescent quantum yield of molecular probes. Through analysis of the optical property, we found that Jo-35 has the highest quantum yield (Φ = 0.39) compared to that of others. Intramolecular hydrogen bond was confirmed in the skeleton between oxygen atom and amino group of the benzene ring. Molecular probes drop the fluorescent property if the intramolecular hydrogen bond is absent due to replacement of the amino group by other atom and/or moiety.

關鍵字(中)

★ 唾液酸
★ 螢光標記

關鍵字(英)

論文目次

目錄
摘要 I
Abstract II
誌謝 IV
目錄 V
流程目錄 VIII
圖目錄 IX
表目錄 XI
Part I. 1
一、緒論 1
1.1 唾液酸的結構與功能 1
1.2 唾液酸轉移酶在生物上的功能 3
1.3 唾液酸轉移酶抑制劑 5
1.3.1 受體類似物抑制劑 5
1.3.2 過渡態類似物抑制劑 6
1.3.3 供體類似物抑制劑 7
1.4石膽酸衍生物作為抑制劑 8
1.4.1 石膽酸的結構與功能 9
1.4.2 已知的石膽酸衍生物抑制劑 10
1.5 以氟修飾石膽酸之藥物應用 12
二、實驗結果與討論 13
2.1 實驗動機 13
2.2合成Fluorine substitution的石膽酸衍生物 14
2.3 生物活性分析結果與討論 18
2.3.1 Cytotoxicity in MDA-MB-231 breast cancer cell 19
2.3.2 傷口癒合測試 (Wound healing assay) 20
2.4結論 23
三、實驗步驟與數據 23
3.1 實驗儀器 23
3.2 實驗藥品 26
3.3 實驗方法 28
3.3.1 JO-5a, JO-5b的合成方法： 28
3.3.2 JO-13a, JO-13b的合成方法： 32
四、參考文獻 37
五、圖譜附錄 40
Part II. 56
一、緒論 56
二、實驗結果與討論 58
2.1 實驗動機 58
2.2 形成六員環螢光探針之反應機構 62
2.3 六員環與八員環之1H NMR、13C NMR圖譜比較 63
2.4合成Benzoxazinone的衍生物 67
2.5 Ninhydrin test 77
2.6 光學性質分析 78
2.6.1 紫外光/可見光吸收及螢光特性 78
2.6.2 螢光量子產率 89
2.7 各化合物在日光、紫外光照射下所呈現之顏色 94
2.8 結論 96
三、實驗步驟與數據 98
3.1 實驗儀器 98
3.2 實驗藥品 99
3.3 實驗方法 102
3.3.1 化合物JO-20的合成： 102
3.3.2 化合物JO-35的合成： 105
3.3.3 化合物JO-42的合成： 109
3.3.4 化合物JO-54的合成： 112
3.3.5 化合物JO-65的合成： 115
3.3.6 化合物JO-84的合成： 117
3.3.7 化合物JO-90的合成： 119
3.3.8 化合物JO-92的合成 121
3.3.8 化合物JO-96的合成： 123
四、參考文獻 125
五、圖譜附錄 126

參考文獻

1. Traving, C.; Schauer, R., Structure, function and metabolism of sialic acids. Cell. Mol. Life Sci. 1998, 54, 1330-1349.
2. Harduin-Lepers, A.; Vallejo-Ruiz, V.; Krzewinski-Recchi, M. A.; Samyn-Petit, B.; Julien, S.; Delannoy, P., The human sialyltransferase family. Biochimie 2001, 83, 727-737.
3. Fuster, M. M.; Esko, J. D., The sweet and sour of cancer: glycans as novel therapeutic targets. Nat. Rev. Cancer 2005, 5, 526-542.
4. De Clercq, E., Antiviral agents active against influenza A viruses. Nat. Rev. Drug Discov. 2006, 5, 1015-1025.
5. Harduin-Lepers, A.; Vallejo-Ruiz, V.; Krzewinski-Recchi, M. A.; Samyn-Petit, B.; Julien, S.; Delannoy, P., The human sialyltransferase family. Biochimie 2001, 83, 727-737.
6. Schaub, C.; Müller, B.; Schmidt, Richard R., Sialyltransferase Inhibitors Based on CMP-Quinic Acid. Eur. J. Org. Chem. 2000, 9, 1745-1758.
7. Hildebrandt, H.; Becker, C.; Gluer, S.; Rosner, H.; Gerardy-Schahn, R.; Rahmann, H., Polysialic acid on the neural cell adhesion melocule correlates with expression of polysialytransferases and promotes neuroblastoma cell growth. Cancer Res. 1998, 58, 779-784.
8. Gessner, P.; Riedl, S.; quentmaier, A; Kemmner, W., Enhanced activity of CMP- NeuAc: Galβ1-4GlcNAc: α2,6-sialyltransferase in metastasizing human colorectal tumor tissue and serum of tumor patients. Cancer Lett. 1993, 75, 143-149.
9. Dall′Olio, F.; Chiricolo, M.; D′Errico, A.; Gruppioni, E.; Altimari, A.; Fiorentino, M.; Grigioni, W. F., Expression of beta-galactoside alpha2,6 sialyltransferase and of alpha2,6-sialylated glycoconjugates in normal human liver, hepatocarcinoma, and cirrhosis. Glycobiology 2004, 14, 39-49.
10. Naito, H.; Ma, Y.; Uemura, K.; Arano, Y.; Kawasaki, T., Metabolic properties of normal and mutant mannan-binding proteins in mouse plasma. BBRC 1999, 256 (1), 231-234
11. Burchell, J.; Poulsom, R.; Hanby, A.; Whitehouse, C.; Cooper, L.; Clausen, H.; Miles, D.; Taylor-Papadimitriou, J., An α2,3 sialyltransferase (ST3Gal I) is elevated in primary breast carcinomas. Glycobiology 1999, 9, 1307-1311.
12 . Picco, G.; Julien, S.; Brockhausen, I.; Beatson, R.; Antonopoulos, A.; Haslam, S.; Mandel, U.; Dell, A.; Pinder, S.; Taylor-Papadimitriou, J.; Burchell, J., Over-expression of ST3Gal-I promotes mammary tumorigenesis. Glycobiology 2010, 20, 1241-1250.
13. Kajihara, Y.; Kodama, H.; Wakabayashi, T.; Sato, K.; Hashimoto, H., Characterization of inhibitory activities and binding mode of synthetic 6′-modified methyl N-acetyl-beta-lactosaminide toward rat liver CMP-D-Neu5Ac: D-galactoside-(2-->6)-alpha-D-sialyltransferase. Carbohydr. Res. 1993, 247, 179-193.
14. Müller, B.; Schaub, C.; Schmidt, R. R., Efficient sialytransferase inhibitors based on transition-state analogues of the sialyl donor. Angew. Chem. Int. Ed. 1998, 37, 2893-2897.
15. Amann, F.; Schaub, C.; Müller, B.; Schmidt R. R., New potent sialytrasnsferase inhibitors-synthesis of donor and of transition-state nalogues of sialyl donor CMP-Neu5Ac. Chem. Eur. J. 1998, 4, 1106-115.
16. Schworer, R.; Schmidt, R. R., Efficient sialyltransferase inhibitors base on glycosides of N-acetylglucosamine. J. Am. Chem. Soc. 2002, 124, 1632-1637.
17. Sun, H. B.; Yang, J. S.; Amaral, K. E.; Horenstein, B. A., Synthesis of a new transition-state analog of the sialy donor. Inhibition of sialyltransferases. Tetrahedron Lett. 2001, 42, 2451-2453.
18. Müller, B.; Martin, T. J.; Schaub, C.; Schmidt, R. R., Synthesis of phosphonate analogues of CMP-Neu5Ac determination of α(2–6)-sialyltransferase inhibition. Tetrahedron Lett. 1998, 39, 509-512.
19. Hatanaka,Y.; Kaneoka, Y., Preparation of cytidine analogs and CMP-sialic acid analogs. Chem. Abstr. 1993, 119, 49839v.
20. Schaub, C.; Muller, B.; Schmidt, R., New sialyltransferase inhibitors based on CMP-quinic acid: development of a new sialyltransferase assay. Glycoconjugate J. 1998, 15, 345-354.
21. Whalen, L. J.; McEvoy, K. A.; Halcomb, R. L., Synthesis and evaluation of phosphoramidate amino acid-based inhibitors of sialyltransferases. Bioorg. Med. Chem. Lett. 2003, 13, 301-304.
22. Wu, C. Y.; Hsu, C. C.; Chen, S. T.; Tsai, Y. C., Soyasaponin I, a potent and specific sialyltransferase inhibitor. Biochem. Biophys. Res. Commun. 2001, 284, 466-469.
23. Chang, K.-H.; Lee, L.; Chen, J.; Li, W.-S., Lithocholic acid analogues, new and potent α-2,3-sialyltransferase inhibitors. Chem. Comm. 2006, 10, 629-631.
24. Mizushina, Y.; Kasai, N.; Sugawara, F.; Yoshida, H.; Sakaguchi, K., Three-dimensional structural model analysis of the binding site of lithocholic acid, an inhibitor of DNA polymerase β and DNA topoisomerase II. J. Biochem. 2001, 130, 657-664.
25. Chen, J. Y.; Tang, Y. A.; Huang, S. M.; Juan, H. F.; Wu, L. W.; Sun, Y. C.; Wang, S. C.; Wu, K. W.; Balraj, G.; Chang, T. T.; Li, W. S.; Cheng, H. C.; Wang, Y. C., A novel sialyltransferase inhibitor suppresses FAK/paxillin signaling and cancer angiogenesis and metastasis pathways. Cancer Res. 2011, 71, 473-483.
26. Chiang, C. H.; Wang, C. H.; Chang, H. C.; More, S. V.; Li, W. S.; Hung, W. C., A novel sialyltransferase inhibitor AL10 suppresses invasion and metastasis of lung cancer cells by inhibiting integrin-mediated signaling. J. Cell. Physiol. 2010, 223, 492-499.
27. Cerri, A.; Blanchi, G.; Fedrizzi, G.; Ferrari, P.; Gobbini, M.; Marazzi, G.; Torri, M. Aminooxime derivatives of 2- and/or 4-substituted androstanes and androstenes as medicaments for cardiovascular disorders WO 2009/047101 A1

1. Weigelt, B.; Peterse, J. L.; van′t Veer, L. J. Breast cancer metastasis: markers and models. Nature Review Cancer, 2005, 5, 591−602.
2. Mehlen, P.; Puisieux, A. Metastasis: a question of life or death.
Nature Review Cancer, 2006, 6, 449−58.
3. Alexei Bogdanov, Jr and Ralph Weissleder In vivo imaging of gene delivery and expression. Trends in Biotechnology, 2002, 20, S11-S18.
4. Schellingerhout, D., et al. Mapping the in vivo distribution of herpes simplex virions. Human Gene Therapy, 1998, 9, 1543-1549.
5. Schellingerhout, D., et al. Quantitation of HSV mass distribution in a rodent brain tumor model. Gene Therapy, 2000, 7, 1648-1655.
6. Thomas Potrawa; Joachim Schulz. Organic fluorescent sulfonyl ureido benzoxazinone pigments. US 2009/0085344 A1
7. Thomas Potrawa, Joachim Schulz. Aryl-ureido benzoxazinone compounds. US 7192471 B2.
8. Sachin B. Baravkar; Arup Roy; Rupesh L. Gawade; Vedavati G.
Puranik; Gangadhar J. Sanjayan. Nucleophilic Ring-Opening of
Benzoxazinones by DBU: Some Observations. Synthetic Communications, 2014, 44, 2955-2960.
9. Li Qiu; Xiao Wang; Na Zhao; Shiliang Xu; Zengjian An; Xuhui Zhuang; Zhenggang Lan; Lirong Wen; Xiaobo Wan. Reductive Ring Closure Methodology toward Heteroacenes Bearing a Dihydropyrrolo[3,2‑b]pyrrole Core: Scope and Limitation. Journal of Organic Chemistry, 2014, 79, 11339−11348.
10. S. Dhami, A. J. de Mello, G. Rumbles, S. M. Bishop, D. Phillips and A. Beeby, Phthalocyanine fluorescence at high concentration: dimers or reabsorption effect? Photochemistry and Photobiology, 1995, 61, 341.
11. Tao Xing; Chengqiong Mao; Bin Lai; Lifeng Yan, Synthesis of Disulfide-Cross-Linked Polypeptide Nanogel Conjugated with a Near-Infrared Fluorescence Probe for Direct Imaging of Reduction-Induced Drug Release. Applied Materials & Interfaces, 2012, 4, 5662−5672.

指導教授

李文山、侯敦仁(Wen-Shan Li Dui-Ren Hou)

審核日期

2015-7-28

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