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研究生：	謝逢軍 Hsieh, Feng-Chun
論文名稱：	石膽酸二聚體對於唾液酸轉移酶及癌細胞轉移之影響 Lithocholic Acid Dimer Applied for Human Sialyltransferase Inhibitor
指導教授：	李文山 Li, Wen-Shan 林文偉 Lin, Wen-Wei
學位類別：	碩士 Master
系所名稱：	化學系 Department of Chemistry
論文出版年：	2020
畢業學年度：	108
語文別：	英文
論文頁數：	115
中文關鍵詞：	唾液酸、唾液酸轉移酶抑制劑、癌症轉移、石膽酸
英文關鍵詞：	Sialic acid, Sialyltransferase inhibitor, Tumor metastasis, Lithocholic acid
DOI URL：	http://doi.org/10.6345/NTNU202000834
論文種類：	學術論文
相關次數：	點閱：143 下載：2
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本篇論文合成了具有不同的鏈及取代基的石膽酸二聚體類似物AK10165、AK10169、AK10172、AK10173、AK10181、AK10183、AK10184、AK10192、AK10194、AK10195、AK10196和AK10199，並且評估其細胞毒性、抑制唾液酸轉移酶能力，以及癌細胞轉移能力。綜上所述，石膽酸二聚體類似物幾乎沒有細胞毒性並顯示出對MDA-MB-231乳癌細胞的輕度抗轉移能力，其IC50為40 μM至80 μM。在這些石膽酸二聚體中，AK10165對ST6Gal I表現出最佳的抑制活性其IC50為18 μM。一系列的石膽酸二聚體也證明了輕微的唾液酸轉移酶抑制選擇性。更多的石膽酸二聚體臨床應用之近一步研究正在進行中。

In this work, the LCA dimer analogues AK10165, AK10169, AK10172, AK10173, AK10181, AK10183, AK10184, AK10192, AK10194, AK10195, AK10196 and AK10199 with different conjugate linkers and substituents were synthesized and evaluated their cytotox-icity, sialyltransferase isozyme inhibition, and anti-migration properties. To sum up, there is little cytotoxicity found in lithocholic acid dimer analogues, and mild anti-migratory capability were showed against MDA-MB-231 tumor cells, with IC50 ranging from 40 μM to 80 μM. Among these LCA dimers, AK10165 displayed the best inhibitory activity toward ST6Gal I with as IC50 value of 18 μM. A slight sialyltransferase isozyme selectivity is also demonstrated in their series of LCA dimers. Further study to pursue clinical application of LCA dimers is in progress.

謝辭  I
中文摘要  II
Abstract  III
Contents  IV
Scheme Contents  VII
Table Contents  VIII
Figure Contents  IX
List of Abbreviation  XI

I. Introduction  1
1  Cancer and death  1
2  Sialic acid and sialyltransferase  3
3  Mechanism of sialylation  7
4  Sialic acid and tumors ─ Metastasis  9
5  Sialyltransferase inhibitors  10
5  Previous works  12
6 Research motivation  14

II.  Results and Discussion  15
1  Synthesis strategy  15
1.1  Synthesis of lithocholic acid dimers  15
1.2  Synthesis of chiral lithocholic acid dimers  17
1.3  Synthesis of modified lithocholic acid dimers  19
1.4  Synthesis of substituent groups  21
2  Biological Experiments Section: in vitro studies  22
2.1  The cytotoxicity of lithocholic acid dimer analogues  22
2.2  Inhibition to ST3Gal I and ST6Gal I  24
2.3  The anti-migratory activity of lithocholic acid dimer analogues  25
3  Structure Activity Relation Analysis  27

III.  Conclusions  28

IV.  Experimental Section  29
1  General procedures  29
2  Synthetic Method  30
2.1  Preparation of lithocholic acid with protecting group and its intermediates  30
2.2  Preparation of AK10165  36
2.3  Preparation of AK10169  37
2.4  Preparation of AK10172  39
2.5  Preparation of AK10173  40
2.6  Preparation of AK10181  41
2.7  Preparation of AK10183  42
2.8  Preparation of AK10184  43
2.9  Preparation of AK10192  44
2.10  Preparation of AK10194  45
2.11  Preparation of AK10195  46
2.12  Preparation of AK10196  47
2.13  Preparation of AK10199  48
3  Biological Experimental Method  49
3.1  Cell line used in biological experiments  49
3.2  MTT assay  49
3.3  Sialyltransferase assay  49
3.4  Transwell migration assay  50

V.  Reference  51

VI.  Appendix I – Spectra  56

VII.  Appendix II – Molecular Modeling of docking  106
1  Introduction  106
2  Results and Discussion  108
3  Conclusion  111
4  Experimental Section  112
                                

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