含有香豆素的石膽酸類似物作為唾液酸轉移酶抑制劑的合成與初步活性測試

以作者查詢圖書館館藏

、以作者查詢臺灣博碩士

、以作者查詢全國書目

、勘誤回報

、線上人數：6

、訪客IP：18.221.235.209

姓名

呂柏葦(Po-wei Lu) 查詢紙本館藏

畢業系所

化學學系

論文名稱

含有香豆素的石膽酸類似物作為唾液酸轉移酶抑制劑的合成與初步活性測試
(A Series of Lithocholic Acid Analogs with Coumarin Moieties as Sialyltransferase Inhibitors: Synthesis and Preliminary Bioactivity Studies)

相關論文

★ 含胺基之二苯乙烯衍生物的分子內光誘導電子轉移之C-N斷鍵反應及激態錯合體之研究	★ 新型含1,2,3-三氮唑之雙光子吸收材料的合成及其光學性質探討
★ 紫質衍生物研究：間位苯卟啉分子的鋅離子感測及大環紫質的構型	★ Squamocin 之合成研究
★ 發展4,4’-亞甲基對苯胺或聯苯胺為骨架的四氯衍生物作為人類麩胺基硫轉移酶抑制劑的合成及構效關係的探討	★ 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
★ 合成和優化2-(1-乙基-3,5-二甲基-1H-吡唑-4-基)乙-1-胺衍生物和其抗三陰性乳腺癌細胞的體外活性研究	★ 以蛋白質體學探討在大腸桿菌中甲醇利用代謝途徑
★ LCA-Fentanyl Hybrid Molecules: Anaesthetic Implications of Antimetastasis Chemotherapy	★ Data-independent acquisition mass spectrometry analysis for identification of cerebrospinal fluid biomarker of reversible cerebral vasoconstriction syndrome
★ 從手性N-亞磺醯胺進行非對映選擇性磷酯基化反應建構高度選擇性的α-胺基磷酸酯	★ DNA型式碳水化合物抗原之生物偵測器的開發及應用
★ 設計合成新型的唾液酸轉移酶抑制劑	★ 合成具有分子腳架之多並苯化合物且用於自組裝分子薄膜之研究
★ 1,3-偶極環化加成反應在藥物合成與醣晶片上的應用	★ 平面化寡聚萘分子之合成及其光學、電學性質研究

檔案

[Endnote RIS 格式]

[Bibtex 格式]

[相關文章]

[文章引用]

[完整記錄]

[館藏目錄]

至系統瀏覽論文 ( 永不開放)

摘要(中)

近年來，癌症的轉移往往伴隨唾液酸轉移酶的異常表現，因此發展唾液酸轉
移酶的抑制劑，並測試其抑制活性，了解化合物結構與抑制能力的關係，期望能
以抑制唾液酸轉移酶為分子標靶來達到抗癌症轉移的效果。
以Lith-O-Asp 為主結構，並透過DMMTM BF4 耦合試劑和SOCl2 醯氯化合
成醯胺鍵連接一系列的香豆素衍生物，分別透過細胞傷口癒合分析及唾液酸轉移
酶抑制實驗來探討香豆素衍生物上的取代基對於生物活性的影響。透過生物實驗
可以發現KE-49、KE-50、KE-89 及KE-126 有較明顯的抑制能力，代表香豆素
上的羥基有助於增進抑制活性，其中又以C7 號位的羥基取代最為明顯，另外在
C8 號位增加一個甲基取代也有助於活性的提升。

摘要(英)

Recently, aberrant sialylation is found in cancer metastasis frequently.
Empolying the strategy of the relationships between structure and activity , we use
sialyltrasdferase as the molecular target to develop its inhibitors in order to attenuate
cancer metastasis.
Preparation of Lith-O-Asp-coumarin derivatives was successfully accomplished
through the coupling reaction between Lith-O-Asp and coumarin moieties using
DMMTM BF4 (4-(4,6-dimethoxy-(1,3,5)triazin-2-yl)-4-methyl-morpholinium tetrafluoroborate)
or SOCl2 as the reagents. Extensive SAR studies were performed using
different substituted-coumarin analogs under the wound healing and sialyltransferase
inhibitor assays. Among the Lith-O-Asp-coumarin derivatives, the
hydroxyl-substituent analogs at C-7 position were observed to have the hightest
biological activity. It is also noteworthy that the methyl-substituent analogs at C-8
position also display significantly increased biological activity toward both assays.

關鍵字(中)

★ 唾液酸
★ 唾液酸轉移酶
★ 香豆素

關鍵字(英)

★ sialic acid
★ Sialyltransferase
★ Coumarin

論文目次

中文摘要......... ......................................... I
Abstract ................................................ II
目錄.................................................... III
圖目錄.................................................... VI
表目錄................................................... VII
一、導論................................................... 1
1.1 唾液酸的結構與功能....................................... 1
1.2 生物上唾液酸轉移酶的功能.................................. 3
1.3 唾液酸轉移酶抑制劑....................................... 4
1.3.1 供體類似物抑制劑....................................... 4
1.3.2 過渡態類似物抑制劑..................................... 4
1.3.3 受體類似物抑制劑....................................... 5
1.4 石膽酸衍生物作為抑制劑.................................... 6
1.4.1 石膽酸的結構與功能..................................... 6
1.4.2 已知的石膽酸衍生物抑制劑................................ 7
1.5 香豆素(coumarin)的結構與應用 ............................ 8
二、結果與討論............................................. 10
2.1 實驗動機.............................................. 10
2.2 化學合成.............................................. 12
2.2.1 合成石膽酸-胺基酸衍生物 ............................... 12
2.2.2 合成香豆素衍生物...................................... 13
2.2.3 合成三嗪類(Triazines)的耦合試劑 ...................... 17
2.2.4 以耦合試劑合成含有香豆素的石膽酸-胺基酸衍生物 ............. 19
2.2.5 以SOCl2 合成含有香豆素的石膽酸-胺基酸衍生物 ............. 20
2.3 生物活性測試........................................... 22
2.3.1 細胞傷口癒合分析 (Wound healing assay) ............... 22
2.3.2 唾液酸轉移酶活性測試.................................. 27
2.4 結論................................................. 29
三、實驗步驟和數據.......................................... 30
3.1 實驗儀器.............................................. 30
3.2 實驗藥品.............................................. 32
3.3 一般實驗方法........................................... 35
3.3.1 化合物3 的合成：..................................... 35
3.3.2 化合物5 的合成：..................................... 36
3.3.3 化合物KE-46 的合成： ................................ 36
3.3.4 化合物KE-49 的合成： ................................ 38
3.3.5 化合物KE-50 的合成： ................................ 40
3.3.6 化合物KE-89 的合成： ................................ 42
3.3.7 化合物KE-90 的合成： ................................ 44
3.3.8 化合物KE-94 的合成： ................................ 46
3.3.9 化合物KE-106 的合成： ............................... 48
3.3.10 化合物KE-119 的合成： .............................. 50
3.3.11 化合物KE-123 的合成： .............................. 52
3.3.12 化合物KE-125 的合成： .............................. 53
3.3.13 化合物KE-126 的合成： .............................. 55
四、參考文獻............................................... 57
五、光譜附錄............................................... 60

參考文獻

1. Li, Y.; Chen, X., Sialic acid metabolism and sialyltransferases: natural functions and
applications. Appl Microbiol Biotechnol 2012, 94 (4), 887-905.
2. Weijers, C. A.; Franssen, M. C.; Visser, G. M., Glycosyltransferase-catalyzed synthesis of
bioactive oligosaccharides. Biotechnology advances 2008, 26 (5), 436-456.
3. Boons, G. J.; Demchenko, A. V., Recent advances in o-sialylation. Chemical reviews
2000,100 (12), 4539-4566.
4. Varki, A., Glycan-based interactions involving vertebrate sialic-acid-recognizing proteins.
Nature 2007,446 (7139), 1023-1029.
5. Cabral, M. G.; Piteira, A. R.; Silva, Z.; Ligeiro, D.; Brossmer, R.; Videira, P. A., Human
dendritic cells contain cell surface sialyltransferase activity. Immunology letters 2010,131 (1),
89-96.
6. De Clercq, E., Antiviral agents active against influenza A viruses. Nature reviews. Drug
discovery 2006,5 (12), 1015-1025.
7. Lee, M.; Park, J. J.; Ko, Y. G.; Lee, Y. S., Cleavage of ST6Gal I by radiation-induced BACE1
inhibits golgi-anchored ST6Gal I-mediated sialylation of integrin beta1 and migration in colon
cancer cells. Radiation oncology 2012,7, 47.
8. Harduin-Lepers, A.; Vallejo-Ruiz, V.; Krzewinski-Recchi, M.-A.; Samyn-Petit, B.; Julien, S.;
Delannoy, P., The human sialyltransferase family. Biochimie 2001,83 (8), 727-737.
9. Olio, F. D.; Malagolini, N.; di Stefano, G.; Minni, F.; Marrano, D.; Serafini-Cessi, F.,
Increased CMP-NeuAc:Galβ1,4GlcNAc-R α2,6 sialyltransferase activity in human colorectal
cancer tissues. International Journal of Cancer 1989,44 (3), 434-439.
10. 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 letters 1993,75 (3), 143-149.
11. Burchell, J.; Poulsom, R.; Hanby, A.; Whitehouse, C.; Cooper, L.; Clausen, H.; Miles, D.;
Taylor-Papadimitriou, J., An alpha2,3 sialyltransferase (ST3Gal I) is elevated in primary breast
carcinomas. Glycobiology 1999,9 (12), 1307-11.
12. Wang, X.; Zhang, L.-H.; Ye, X.-S., Recent development in the design of sialyltransferase
inhibitors. Medicinal Research Reviews 2003,23 (1), 32-47.
13. Schaub, C.; Muller, B.; Schmidt, R., New sialyltransferase inhibitors based on CMP-quinic
acid: development of a new sialyltransferase assay. Glycoconjugate journal 1998,15 (4),
345-354.
14. 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 Letters
1998,39 (7), 509-512.
15. Whalen, L. J.; McEvoy, K. A.; Halcomb, R. L., Synthesis and evaluation of
58
phosphoramidate amino acid-based inhibitors of sialyltransferases. Bioorganic & medicinal
chemistry letters 2003,13 (2), 301-4.
16. Schaub, C.; Müller, B.; Schmidt, Richard R., Sialyltransferase Inhibitors Based on
CMP-Quinic Acid. European Journal of Organic Chemistry 2000,2000 (9), 1745-1758.
17. Danielle, S.; Ralf, S.; ouml; rer; Tobias, H.; Richard, R. S., Asymmetric synthesis and
affinity of potent sialyltransferase inhibitors based on transition-state analogues: SPECIAL
SECTION: SYNTHESIS OF BIOACTIVE COMPOUNDS. Glycoconjugate journal 2004,21 (5),
205-219.
18. Kajihara, Y.; Kamitani, T.; Sato, R.; Kamei, N.; Miyazaki, T.; Okamoto, R.; Sakakibara, T.;
Tsuji, T.; Yamamoto, T., Synthesis of CMP-9″-modified-sialic acids as donor substrate
analogues for mammalian and bacterial sialyltransferases. Carbohydrate Research 2007,342
(12–13), 1680-1688.
19. Wu, C. Y.; Hsu, C. C.; Chen, S. T.; Tsai, Y. C., Soyasaponin I, a potent and specific
sialyltransferase inhibitor. Biochemical and biophysical research communications 2001,284
(2), 466-9.
20. Chang, W.-W.; Yu, C.-Y.; Lin, T.-W.; Wang, P.-H.; Tsai, Y.-C., Soyasaponin I decreases the
expression of α2,3-linked sialic acid on the cell surface and suppresses the metastatic
potential of B16F10 melanoma cells. Biochemical and biophysical research communications
2006,341 (2), 614-619.
21. Chang, K. H.; Lee, L.; Chen, J.; Li, W. S., Lithocholic acid analogues, new and potent
alpha-2,3-sialyltransferase inhibitors. Chemical communications 2006, (6), 629-31.
22. 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 research 2011,71 (2), 473-83.
23. 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. Journal of cellular physiology 2010,223 (2), 492-9.
24. Kumar, A.; Maurya, R. A.; Sharma, S.; Ahmad, P.; Singh, A. B.; Bhatia, G.; Srivastava, A. K.,
Pyranocoumarins: A new class of anti-hyperglycemic and anti-dyslipidemic agents.
Bioorganic & medicinal chemistry letters 2009,19 (22), 6447-6451.
25. Bhavsar, D.; Trivedi, J.; Parekh, S.; Savant, M.; Thakrar, S.; Bavishi, A.; Radadiya, A.; Vala,
H.; Lunagariya, J.; Parmar, M.; Paresh, L.; Loddo, R.; Shah, A., Synthesis and in vitro anti-HIV
activity of N-1,3-benzo[d]thiazol-2-yl-2-(2-oxo-2H-chromen-4-yl)acetamide derivatives using
MTT method. Bioorganic & medicinal chemistry letters 2011,21 (11), 3443-6.
26. Kosiova, I.; Janicova, A.; Kois, P., Synthesis of coumarin or ferrocene labeled nucleosides
via Staudinger ligation. Beilstein journal of organic chemistry 2006,2, 23.
27. Dighe, N. S.; Pattan, S. R.; Dengale, S. S.; Musmade, D. S.; Shelar, M.; Tambe, V.; Hole, M.
59
B., Synthetic and pharmacological profiles of coumarins: A review. Archives of Applied
Science Research 2010,2 (2), 65-71.
28. K, M. P.; Dipak, S.; Arti, D., OVERVIEW OF SYNTHESIS AND ACTIVITY OF
COUMARINS. E-International Scientific Research Journal 2012,4 (1), 16-37.
29. Gikas, E.; Parissi-Poulou, M.; Kazanis, M.; Vavagianis, A., New Facile Synthesis of
7-Hydroxy-6-amino-4-substituted Benzopyran-2-ones. ChemInform 2005,36 (14), no-no.
30. Potdar, M. K.; Mohile, S. S.; Salunkhe, M. M., Coumarin syntheses via Pechmann
condensation in Lewis acidic chloroaluminate ionic liquid. Tetrahedron Letters 2001,42 (52),
9285-9287.
31. Brubaker, A. N.; DeRuiter, J.; Whitmer, W. L., Synthesis and rat lens aldose reductase
inhibitory activity of some benzopyran-2-ones. Journal of medicinal chemistry 1986,29 (6),
1094-1099.
32. Montalbetti, C. A. G. N.; Falque, V., Amide bond formation and peptide coupling.
Tetrahedron 2005,61 (46), 10827-10852.
33. Raw, S. A., An improved process for the synthesis of DMTMM-based coupling reagents.
Tetrahedron Letters 2009,50 (8), 946-948.

指導教授

李文山、侯敦仁
(Wen-shan Li、Duen-ren Hou)

審核日期

2013-8-26

推文