Synthesis and biological evaluation of pyrazole derivatives as antitumor agents

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游懷真(Huai-Chen Yu) 查詢紙本館藏

畢業系所

化學學系

論文名稱

(Synthesis and biological evaluation of pyrazole derivatives as antitumor agents)

★ Natural amino acid conjugates of lithocholic acid as α-2,6-sialyltransferase inhibitors with antimigratory and antiangiogenic activity

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至系統瀏覽論文 (2027-7-1以後開放)

摘要(中)

吡唑是一個重要的藥理特徵結構和極具意義的特殊骨架，它是一種
由五個成員的異環組成的結構，具有強大的藥理特徵，廣泛的治療包括
抗炎、抗微生物、抗焦慮、抗癌等。
石膽酸本身針對唾液酸轉移酶也有抑制效果，故設計藥物分子的想
法是將吡唑合成到石膽酸的結構中，並研究能否達成更佳的抗癌效果。
我們合成出了 YHC001-YHC010 的化合物進行藥物毒性的相關生物學
評估。
其中，YHC001 對於 MDA-MB-231 細胞具有毒性，且針對唾液酸
轉移酶亦有抑制效果。未來希望能夠以此結構為基礎更進一步合成出
相關的衍生物去測試對於癌細胞的相關治療效果。

摘要(英)

Pyrazole serves as a crucial pharmacological feature structure and a
remarkably meaningful unique scaffold. It is a structure composed of a five membered heterocycle, possessing potent pharmacological characteristics
and a wide range of therapeutic applications, including anti-inflammatory,
antimicrobial, anxiolytic and anticancer activities.
Lithocholic acid itself exhibits inhibitory effects on sialyltransferase.
Therefore, the idea behind designing drug molecules is to incorporate
pyrazole into the structure of lithocholic acid to explore the potential for
enhanced anticancer effects. We synthesized compounds YHC001 to
YHC010 and conducted relevant biological evaluations.
Among them, YHC001 demonstrated cytotoxicity against MDA-MB231 cells and exhibited inhibitory effects on sialyltransferase. In the future,
it is hoped that this structure can serve as a basis for further synthesis of
related derivatives to evaluate their therapeutic effects on other cancer cells.

關鍵字(中)

★ 吡唑
★ 石膽酸

關鍵字(英)

★ Pyrazole
★ Lithocholic acid

論文目次

中文摘要........................................................................................................i
Abstract........................................................................................................ii
Table of Contents .......................................................................................iii
List of Figures.............................................................................................vi
List of Tables .............................................................................................vii
List of Schemes.........................................................................................viii
List of Abbreviation...................................................................................ix
Chapter I Introduction ............................................................................... 1
1-1 Background.......................................................................................... 1
1-2 Metastasis process ............................................................................... 2
1-3 Glycoconjugates .................................................................................. 3
1-4 Glycosylation facilitates the acquisition of all cancer hallmark
capabilities. ................................................................................................ 5
1-5 Sialic acid............................................................................................. 7
1-6 Sialyltransferase................................................................................... 9
1-7 Sialyltransferase inhibitors................................................................ 12
1-7-1 Inhibitor of acceptor analogs....................................................... 12
1-7-2 Inhibitor of donor analogs........................................................... 14
1-7-3 Inhibitor of transition-state analogs............................................ 16
1-7-4 Other sialytransferase inhibitors ................................................. 17
1-8 Triple-negative breast cancer (TNBC).............................................. 18
1-9 Research motivation .......................................................................... 19
Chapter II Result and discussion............................................................. 20
2-1 Retrosynthetic analysis of pyrazole derivatives................................ 20
2-2 Synthesis strategy .............................................................................. 22
2-2-1 Synthesis of YHC001 and YHC002 .......................................... 22
2-2-2 Synthesis of YHC003 - YHC010............................................... 23
2-2-3 Synthesis of intermediate of YHC003........................................ 24
2-2-4 Synthesis of intermediate of YHC010........................................ 25
2-3 The isomers produced during the chemical synthesis process.......... 26
2-4 Biological experiments in vitro studies............................................. 31
2-4-1 Cytotoxicity of YHC001-YHC010 in MDA-MB-231 cell........ 31
2-4-2 Bioactivity on ST3Gal I and ST6Gal I ....................................... 33
2-4-3 Anti-migration effect of YHC001-YHC010.............................. 35
Chapter Ⅲ Conclusion............................................................................. 38
Chapter IV Material and Methods.......................................................... 39
4-1 General procedure.............................................................................. 39
4-2 Synthetic method ............................................................................... 40
4-2-1 Synthesis of intermediate of YHC001........................................ 40
4-2-2 Synthesis of YHC001 ................................................................. 43
4-2-3 Synthesis of YHC002 ................................................................. 44
4-2-4 Synthesis of intermediates of YHC003-YHC010...................... 45
4-2-5 Synthesis of intermediate of YHC003........................................ 46
4-2-6 Synthesis of YHC003 ................................................................. 47
4-2-7 Synthesis of YHC004 ................................................................. 48
4-2-8 Synthesis of YHC005 ................................................................. 50
4-2-9 Synthesis of YHC006 ................................................................. 51
4-2-10 Synthesis of YHC007 ............................................................... 53
4-2-11 Synthesis of YHC008 ............................................................... 54
4-2-12 Synthesis of YHC009 ............................................................... 56
4-2-13 Synthesis of intermediate of YHC010...................................... 57
v
4-2-14 Synthesis of YHC010 ............................................................... 58
4-3 Bioassay methods.............................................................................. 59
4-3-1 Cell line used in bioassay............................................................ 59
4-3-2 MTT cytotoxicity assay .............................................................. 60
4-3-3 Sialyltransferase activity assay ................................................... 60
4-3-4 Transwell migration assay .......................................................... 61
Chapter V Reference................................................................................. 63
Chapter VI Spectra Appendix ................................................................. 68

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指導教授

李文山侯敦仁(Wen-Shan Li Duen-Ren Hou)

審核日期

2023-7-27

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